A Phase II Trial of MK-3475 (Pembrolizumab) and Interferon Gamma 1-b Combination Immunotherapy in Patients With Previously Treated Mycosis Fungoides and Sezary Syndrome (Treatment Group 1) and in Patients With Advanced Synovial Sarcoma (Treatment Group 2)
Phase: PHASE2
Conditions: Metastatic Myxoid Liposarcoma, Metastatic Round Cell Liposarcoma, Metastatic Synovial Sarcoma, Recurrent Mycosis Fungoides and Sezary Syndrome, Refractory Mycosis Fungoides and Sezary Syndrome, Stage IB Mycosis Fungoides and Sezary Syndrome AJCC v7, Stage II 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 III 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 IV 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, Unresectable Synovial Sarcoma
Sponsor: National Cancer Institute (NCI)

NCI Protocol #: CITN-13 
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SUMMARY OF CHANGES 
 
For Protocol Amendment #6, v1.0 
 
NCI Protocol #: CITN-13, A6_v1.0 
Local Protocol #: CITN-13, A6_v1.0 
 
Protocol Date: March 3, 2020 
 
I. CTEP Request for Rapid Amendment: 
# 
Section 
Pages 
Comments 
1. 
7.1.1 
73-81 
Insertion of Revised CAEPR (Version 2.5, December 27, 2019) per CTEP 
Request for Rapid Amendment dated February 14, 2020. The following 
changes are incorporated: 
• Added New Risk:  
Rare but Serious: Eye disorders - Other (Vogt-Koyanagi-Harada 
syndrome); Nervous system disorders - Other (non-infectious myelitis) 
 
2. 
8.1.1 
91 
Removed “Allow the required number of vials to equilibrate to room 
temperature” since it is no longer required by the pharmaceutical collaborator.  
3. 
8.1.1 
92 
Revised stability information to read: “Administer prepared solutions 
immediately after preparation.  If not administered immediately, prepared 
solutions may be stored refrigerated for up to 24 hours.  MK-3475 solutions may 
be stored at room temperature for a cumulative time of up to 6 hours.” 
 
II. 
Administrative Changes 
# 
Section 
Pages 
Comments 
4. 
All 
sections 
All 
pages 
Revised protocol version and date throughout the protocol 
 
 
 
 
 

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NCI Protocol #: CITN-13 
Local Protocol #: CITN-13 
ClinicalTrials.gov Identifier: 
NCT03063632 
TITLE: A Phase II Trial of MK-3475 (pembrolizumab) and Interferon Gamma 1-b Combination 
Immunotherapy in Patients with Previously Treated Mycosis Fungoides and Sézary Syndrome 
(Treatment Group 1) and in Patients with Advanced Synovial Sarcoma (Treatment Group 2) 
Coordinating Center: 
Cancer Immunotherapy Trials Network (CITN), Fred 
Hutchinson Cancer Research Center 
Principal Investigator: 
Michael S Khodadoust, M.D. 
Stanford University School of Medicine 
300 Pasteur Drive 
S140A Grant Building 
Stanford, CA 94305 
Tel: (650) 725-6451 
Email: mkhodado@stanford.edu 
 
Co-Principal Investigator  
for Synovial Sarcoma:                            Seth Pollack, M.D. 
Clinical Research Division  
Fred Hutchinson Cancer Research Center 
1100 Fairview Ave N 
Seattle, WA 98109 
Tel: (206) 667-6629 
Email: spollack@fredhutch.org 
                                                                   
 
Participating organizations: 
CITN – Cancer Immunotherapy Trials Network  
 
 

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Statisticians: 
 
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 
Bob Salim 
Axio Research 
2601 4th Ave., #200 
Seattle, WA 98121 
206.547.2829   
bobs@axioresearch.com 
 
Responsible Research Nurse: N/A 
Responsible Data Manager: N/A 
NCI-Supplied Agent:  
MK-3475 (pembrolizumab) (NSC 776864) 
NCI-Supplied Agent:  
Interferon Gamma-1b, Horizon Pharmaceuticals 
(NSC 600662)  
Protocol Type/Version #/Version Date: Amendment 6/Version 1.0/ March 3, 2020 
 
IND #:  
IND Sponsor: DCTD, NCI 
 
 

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CONTACT INFORMATION 
For regulatory 
requirements: 
For patient enrollments: 
For study data 
submission: 
Regulatory documentation 
must be submitted to the 
CTSU via the Regulatory 
Submission Portal. 
 (Sign in at www.ctsu.org, and 
select the Regulatory > 
Regulatory Submission..)  
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately at 1-866-651-
2878 to receive further 
instruction and support. 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 
for regulatory assistance. 
Refer to the patient enrollment section 
of the protocol for instructions on using 
the Oncology Patient Enrollment 
Network (OPEN). OPEN can be 
accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ 
or https://OPEN.ctsu.org. 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com. 
Data collection for this 
study will be done 
exclusively through 
Medidata Rave. Refer to 
the data submission section 
of the protocol for further 
instructions. 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific page located on the CTSU members’ website (https://www.ctsu.org). Access 
to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program - 
Identity and Access Management (CTEP-IAM) registration system and requires log 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 
Regulatory Support System (RSS).  
For clinical questions (i.e., patient eligibility or treatment-related) 
Contact the CITN Central Operations and Statistical Center at citn@fhcrc.org or 206-667-7607  
For nonclinical questions (i.e., unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or 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 Website is located at https://www.ctsu.org. 
 
 

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SCHEMA 
Title 
A Phase II Trial of MK-3475 (pembrolizumab) and Interferon Gamma 1-b 
Combination Immunotherapy in Patients with Previously Treated Mycosis 
Fungoides and Sézary Syndrome (Treatment Group 1) and in patients with 
Advanced Synovial Sarcoma (Treatment Group 2) 
Trial Phase 
Phase II 
Clinical Indication Treatment Group 1: Stage IB-IVB Mycosis Fungoides/Sézary Syndrome, and 
who have relapsed, are refractory, or progressed after at least one standard 
systemic therapy 
Treatment Group 2: Translocation associated sarcoma that generally 
expresses NY-ESO-1 (e.g. Synovial Sarcoma or Myxoid/Round Cell 
Liposarcoma). Patient must have metastatic or unresectable disease. 
 
Trial Type 
Nonrandomized, open-label, phase II, interventional study 
Type of control 
None 
Route of 
administration 
Intravenous (IV) for MK-3475 (pembrolizumab), Subcutaneous for Interferon-
Gamma 
Trial Blinding 
None 
Treatment 
Groups 
Treatment Group 1: 
Patients with Mycosis Fungoides and Sézary Syndrome: MK-3475 
(pembrolizumab), 200 mg every 3 weeks in combination with Interferon 
Gamma-1b (ACTIMMUNE®), 50 mcg/m2 three times per week. 
 
Treatment Group 2: 
Patients with advanced synovial sarcoma: MK-3475 (pembrolizumab), 200 
mg every 3 weeks [2 mg/kg (max= 200 mg) in patients under 18 years of age] 
in combination with Interferon Gamma-1b (ACTIMMUNE®), 100 mcg/m2 once 
per week. 
 
Number of trial 
subjects 
Treatment Group 1: Mycosis Fungoides and Sézary Syndrome (n=30) 
Treatment Group 2: Synovial Sarcoma (n=16) 
Estimated 
duration of trial 
3 years 
Duration of 
Participation 
Patients may receive study directed therapy for up to 2 years if they continue to 
respond.  
 
 

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TABLE OF CONTENTS 
SCHEMA ...................................................................................................................................................... 5 
TABLE OF CONTENTS .............................................................................................................................. 6 
1. 
OBJECTIVES ....................................................................................................................................... 8 
1.1 
Primary Objectives ........................................................................................................................ 8 
1.2 
Secondary Objectives .................................................................................................................... 8 
1.3 
Exploratory Objectives ............................................................................................................... 10 
2. 
BACKGROUND ................................................................................................................................ 11 
2.1 
Relapsed/Refractory Mycosis Fungoides/Sézary Syndrome (Treatment Group 1) .................... 11 
2.2 
Synovial Sarcoma (Treatment Group 2) ..................................................................................... 13 
2.3 
CTEP IND Agent(s) .................................................................................................................... 15 
2.4 
Rationale ..................................................................................................................................... 17 
2.5 
Correlative Studies Background (Treatment Group 1) ............................................................... 30 
2.6 
Correlative Studies Background (Treatment Group 2) ............................................................... 33 
3. 
PATIENT SELECTION ..................................................................................................................... 37 
3.1 
Eligibility Criteria ....................................................................................................................... 37 
3.2 
Exclusion Criteria ....................................................................................................................... 41 
3.3 
Inclusion of Women and Minorities ........................................................................................... 45 
4. 
REGISTRATION PROCEDURES (Treatment Group 1 and 2) ......................................................... 45 
4.1 
Investigator and Research Associate Registration with CTEP ................................................... 45 
4.2 
CTSU Registration Procedures ................................................................................................... 46 
4.3 
Patient Enrollment ...................................................................................................................... 48 
4.4 
General Guidelines ...................................................................................................................... 49 
5. 
TREATMENT PLAN ......................................................................................................................... 50 
5.1 
Agent Administration .................................................................................................................. 50 
5.2 
Study Design, Interim Futility, and Safety Evaluation ............................................................... 54 
5.3 
General Concomitant Medication and Supportive Care Guidelines (Treatment Group 1 and 2) 56 
5.4 
Duration of Therapy (Treatment Group 1 and 2) ........................................................................ 57 
5.5 
Duration of Follow-Up (Treatment Group 1 and 2) .................................................................... 58 
5.6 
Criteria to Resume Treatment (Treatment Group 1 and 2) ......................................................... 59 
5.7 
Contraception and Pregnancy (Treatment Group 1 and 2) ......................................................... 59 
5.8 
Treatment Beyond Progression ................................................................................................... 61 
5.9 
Guidelines for Management of Skin Flare Reaction in Patients with Mycosis Fungoides and 
Sézary Syndrome (Treatment Group 1) ............................................................................................... 64 
5.10 
Discontinuation of Treatment Following Complete Response (Treatment Group 1 and 2) ... 64 
5.11 
Treatment Up to 2 Years (Treatment Group 1 and 2) ............................................................. 64 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ................................................................................. 65 
6.1 
Dose Modifications and Supportive Care Guidelines for Drug-Related Adverse Events 
(Treatment Group 1 and 2) ................................................................................................................... 65 
7. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS (Treatment Group 1 and 2) ... 73 
7.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) .................................... 73 
7.2 
Adverse Event Characteristics .................................................................................................... 83 

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7.3 
Expedited Adverse Event Reporting ........................................................................................... 83 
7.4 
Routine Adverse Event Reporting .............................................................................................. 85 
7.5 
Secondary Malignancy ................................................................................................................ 85 
7.6 
Second Malignancy ..................................................................................................................... 86 
8. 
PHARMACEUTICAL INFORMATION (Treatment Group 1 and 2) ............................................... 86 
8.1 
CTEP IND Agent(s) .................................................................................................................... 86 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES .......................................................... 90 
9.1 
Mycosis Fungoides and Sézary Syndrome (Treatment Group 1) ............................................... 90 
9.2 
Synovial Sarcoma (Treatment Group 2) ..................................................................................... 99 
10. 
STUDY CALENDAR .................................................................................................................. 105 
10.1 
Mycosis Fungoides and Sézary Syndrome (Treatment Group 1) ......................................... 105 
10.2 
Synovial Sarcoma (Treatment Group 2) ............................................................................... 110 
11. 
MEASUREMENT OF EFFECT ................................................................................................... 113 
11.1 
Mycosis Fungoides/Sézary Syndrome (Treatment Group 1) ................................................ 113 
11.2 
Synovial Sarcoma (Treatment Group 2) ............................................................................... 119 
12. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY REQUIREMENTS 
(Treatment Group 1 and 2) ....................................................................................................................... 120 
12.1 
Study Oversight .................................................................................................................... 120 
12.2 
Data Reporting ...................................................................................................................... 120 
12.3 
CTEP Multicenter Guidelines ............................................................................................... 122 
12.4 
Collaborative Agreements Language .................................................................................... 123 
13. 
STATISTICAL CONSIDERATIONS .......................................................................................... 124 
13.1 
Mycosis Fungoides/Sézary Syndrome (Treatment group 1) ................................................. 124 
13.2 
Synovial Sarcoma (Treatment Group 2) ............................................................................... 130 
14. 
REFERENCES ............................................................................................................................. 135 
APPENDIX A PERFORMANCE STATUS CRITERIA .......................................................................... 139 
APPENDIX B CTEP MULTICENTER GUIDELINES ........................................................................... 140 
APPENDIX C BIOASSAY TEMPLATES ............................................................................................... 142 
APPENDIX D STANDARDIZED MEDICAL PHOTOGRAPHY .......................................................... 147 
APPENDIX E MODIFIED SEVERITY-WEIGHTED ASSESSMENT TOOL (MSWAT) .................... 148 
 
 
 

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1. 
OBJECTIVES 
1.1 
Primary Objectives 
Treatment Group 1 
1.1.1 To assess the overall response rate (ORR) of MK-3475 (pembrolizumab) and IFN-
gamma (Actimmune®) combination immunotherapy in subjects with previously treated 
Mycosis Fungoides or Sézary Syndrome. 
In this single stage phase II open label trial, we will have an interim futility analysis. 
When 12 patients have been followed for 6 months, we will perform the interim futility 
analysis. If ORR is less than 33% (4 or less CR+PR), the trial will stop and we will 
accept the null that combination therapy is no better than monotherapy. Otherwise, trial 
will continue until 30 patients accrue. If ORR is at least 57% (17 or more CR+PR) at the 
final analysis, we will accept the alternative that combination therapy is significantly 
better than monotherapy. 
 
Hypothesis: Administration of MK-3475 (pembrolizumab) and IFN-gamma 
(Actimmune®) as a combination immunotherapy regimen to subjects with previously 
treated Mycosis Fungoides or Sézary Syndrome will result in a clinically meaningful 
ORR that is an improvement over the ORR of MK-3475 (pembrolizumab) or IFN-gamma 
as monotherapy. 
Treatment Group 2  
1.1.2 To determine whether the combination of interferon gamma-1b (ACTIMMUNE®) and 
MK-3475 (pembrolizumab) improves the ORR of pembrolizumab in patients with 
unresectable or metastatic synovial sarcoma. 
The ORR of single agent pembrolizumab is ≤ 5%. Accordingly, a Simon 2-stage design 
will be used:  Twelve patients will be enrolled initially. If 0 respond the study will be 
stopped for futility.  Otherwise, an additional four patients will be enrolled.  If three or 
more out of 16 patients respond, the treatment will be considered promising and would 
likely lead to widespread use of this regimen in the clinic. 
 
Hypothesis: The combination of interferon gamma-1b and MK-3475 (pembrolizumab) 
will lead to an ORR of ≥25% in patients with metastatic or unresectable synovial 
sarcoma. The ORR is defined by the complete response rate (CR) plus the partial 
response rate (PR) by RECIST 1.1. 
 
1.2 
Secondary Objectives 
Treatment Group 1 

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1.2.1 To explore the safety/tolerability and clinical activity of MK-3475 (pembrolizumab) and 
IFN-G (Actimmune®) in subjects with previously treated Mycosis Fungoides or Sézary 
Syndrome with respect to the following secondary endpoints:  
1.2.1.1 
Safety and tolerability (interim safety review based on distinct patient SAE’s 
following the first 3 doses of pembrolizumab (10 weeks of therapy) that are 
attributable to study drugs; We will allow 10% or less of patients to develop study 
drug related SAEs. If 4 or more patients amongst the first 12 evaluable patients for 
toxicity at pre-C4 (week 10) have experienced study drug related serious adverse 
events (SAEs), we will conclude that the combination immunotherapy regimen is too 
toxic and accrual will stop. If accrual is not stopped for either interim futility or safety 
reasons, a final safety evaluation will be conducted based on the percentage of the 30 
patients who have experienced SAEs. We will consider the safety profile being 
acceptable if less than 6 patients have experienced study drug related SAEs. 
Otherwise, we will evaluate the tradeoff between safety and efficacy benefits based 
on the magnitude of ORR improvements.  
1.2.1.2 
Time to response (TTR) 
1.2.1.3 
Duration of response (DOR): Defined as the time interval between the date of first 
response (CR/PR) and the date of progression 
1.2.1.4 
Progression-free survival (PFS): Defined as the time from enrollment to PD or death, 
whichever occurs earlier, based upon investigator assessment. Patients without 
documented PD/death will be censored at the last disease assessment date.  
1.2.1.5 
Event-free survival (EFS events defined as termination due to toxicity, initiation of 
next significant treatment, progressive disease, or death of any cause). 
1.2.1.6 
Percentage of all patients who have a response duration of at least 12 months 
(ORR12) 
 
Hypothesis: Combination immunotherapy of MK-3475 (pembrolizumab) and IFN-
gamma (Actimmune®) will have acceptable safety/tolerability profile in previously 
treated Mycosis Fungoides/Sézary Syndrome population and meaningful clinical activity 
will be reflected in other clinical outcome parameters including DOR, PFS, EFS and 
ORR12. 
 
 
 
 
 
 
 

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Treatment Group 2 
1.2.2 To determine the progression-free survival (PFS) and overall survival (OS) for patients 
with advanced synovial sarcoma receiving interferon gamma-1b and MK-3475 
(pembrolizumab). 
1.2.3 To determine the tolerability of the combination of interferon gamma-1b and MK-3475 
(pembrolizumab) based on CTCAE version 5.0 
Hypotheses: The combination of interferon gamma-1b and pembrolizumab will lead to 
superior PFS and OS. Both RECIST v. 1.1 and the immune related response criterion will 
be used for this endpoint.  
The combination of interferon gamma-1b and MK-3475 (pembrolizumab) will be well 
tolerated in patients with advanced synovial sarcoma. 
 
1.3 
Exploratory Objectives 
Treatment Group 1 
1.3.1 To investigate the relationship between the following putative biomarkers for 
combination immunotherapy of MK-3475 (pembrolizumab) and IFN-gamma 
(Actimmune®) and clinical outcomes (as measured by safety/tolerability and ORR, DOR, 
PFS, EFS) in subjects with previously treated Mycosis Fungoides/Sézary Syndrome, 
including tumor/microenvironment (PD-1/PD-L1/PD-L2 expression, CTLs, Tregs, 
macrophages, DCs; nanostring gene expression profile), systemic immune response (flow 
cytometry, CyTOF, Luminex multiplexed cytokine profile), and molecular/genomic 
immune correlates (exome sequencing, high throughput sequencing (HTS) for TCR) 
Hypothesis: The putative biomarkers and immune regulators tested will be related to 
clinical response induced by combination immunotherapy of MK-3475 (pembrolizumab) 
and IFN-gamma (Actimmune®) and will help define actionable causes of not achieving 
CR. 
 
Treatment Group 2 
 
1.3.2 To investigate paired, serial biopsy specimens from pre-treatment and 8-12 weeks after 
starting treatment for the following: 
• MHC class I expression (scored by pathologist)  
• Number of infiltrating T cells per mm2 
• Tumor associated macrophage number and phenotype using multiplex 
immunohistochemistry 
• T cell clonality 
• Gene expression profiling 
 

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To investigate peripheral blood samples from patients to determine: 
• The number and phenotype of T cells specific for CT antigens and potential neo-antigens 
• The phenotype and activation state of circulating monocytes and PBMC 
• Cytokines associated with response 
 
Hypotheses:  
The combination of interferon gamma-1b and MK-3475 (pembrolizumab) will lead to 
increased MHC expression and T cell infiltration on paired, serial tumor biopsies. 
 
The combination of interferon gamma-1b and MK-3475 (pembrolizumab) will lead to 
increased antigen-specific T cells and T cell responses targeting NY-ESO-1, PRAME and 
MAGE-A4 and a potential neo-antigen, the SSX-SYT fusion protein, in the peripheral 
blood of synovial sarcoma patients. 
 
The combination of interferon gamma-1b and MK-3475 (pembrolizumab) will lead to 
increased MHC expression on peripheral monocytes and increased activation of effector 
T cells. 
2. 
BACKGROUND 
2.1 
Relapsed/Refractory Mycosis Fungoides/Sézary Syndrome (Treatment Group 1) 
Mycosis fungoides/Sézary syndrome is the most common type of cutaneous T-cell lymphoma 
(CTCL), a subset of mature non-Hodgkin lymphoma. Mycosis Fungoides exhibits an 
epidermotropic clonal expansion of CD4+ T helper cells that induces pleomorphic skin lesions. 
Mycosis Fungoides 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. Sézary syndrome  is a leukemic 
variant of CTCL in which subjects have generalized erythroderma and are at risk for lymph node 
and visceral disease. Mycosis Fungoides /Sézary Syndrome comprise the most common 
cutaneous T-cell lymphomas, with continued increase in overall annual incidence (currently 
approximately 0.9 per 100,000 persons in the United States). 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) [Horwitz 2008].  
Therapeutic options for Mycosis Fungoides and Sézary Syndrome are primarily determined by 
the patient’s clinical stage. The National Comprehensive Cancer Network [NCCN 2016] has 
recently published consensus guidelines for stage-based treatment of Mycosis Fungoides /Sézary 
Syndrome. The first line treatment of early stage Mycosis Fungoides (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, low-dose methotrexate, interferons (alpha and gamma), extracorporeal 

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photopheresis, total skin electron beam therapy, HDAC inhibitors (vorinostat, romidepsin), 
brentuximab vedotin, cytotoxic chemotherapeutic agents (pralatrexate, liposomal doxorubicin, 
gemcitabine), and investigational agents. Only 4 systemic agents (bexarotene, denileukin 
diftitox, vorinostat, romidepsin) are FDA approved, thus most are used off-label without 
prospective trial data. Despite a wide array of available therapeutic options, subjects with 
Mycosis Fungoides and Sézary Syndrome remain incurable other than a subset of patients who 
receive allogeneic HSC transplantation. Response rates for FDA-approved systemic agents are 
30-35% with infrequent complete responses; these clinical responses are often short-lived with 
most approved agents yielding median duration of responses in the range of 6 months [Duvic 
2001];[Olsen 2001];[Olsen 2007] with the exception of romidepsin with a median near 12 
months [Whittaker 2010].  
It has been understood that immune impairment or dysregulation is a key contributor towards the 
clinical and pathologic characteristics in patients with Mycosis Fungoides or Sézary Syndrome 
[Kim 2005]; [Spaccarelli 2015]. The malignant T cells in Mycosis Fungoides/Sézary 
Syndromeare typically mature homing or resident memory CD4+ T cells which mostly exhibit a 
Th2 phenotype with secretion of IL-4, IL-5, and IL-10 cytokines. This increased Th2 activity is 
thought to provide/induce suppression of Th1-mediated immune activity. There is evidence of 
decreased production of IFN-G, IL-12, and IFN-Alpha in patients with Mycosis 
Fungoides/Sézary Syndrome and attempts to correct this suppressed state with cytokine or other 
immune therapies have resulted in meaningful clinical responses. The decreased Th1 activity 
may also partly account for the underlying impaired function and decreased numbers of dendritic 
cells observed in Mycosis Fungoides/Sézary Syndrome. There are also reports of decreased 
number and/or function of NK cells and possible immune suppressive roles of regulatory T cells 
in the tissue microenvironment. 
Furthermore, there has been mounting evidence that T cell immunity may be pertinent for 
clinical anti-tumor activity in Mycosis Fungoides/Sézary Syndrome: 
2.1.1 Tumor-infiltrating T cells are prognostic of survival. 
CD8+ Cytotoxic T Lymphocytes (CTLs) are present in Mycosis Fungoides lesions and 
high proportion of these cells correlated with an improved prognosis [Hoppe 1995]; 
[Vermeer 2001].  
2.1.2 Therapies which augment T cell function are effective in Mycosis Fungoides/Sézary 
Syndrome. 
Interferon alpha has been shown in a number of studies to be a highly active agent in 
CTCL with overall response rate (ORR) ranging from 40% to 50% with concurrent 
improvement in T cell cytotoxicity.  
Interferon gamma has been used as a monotherapy in 16 patients with refractory disease, 
with an ORR of 30% and duration of response (DOR) of 10 months and concurrent 
augmented T cell activity [Kaplan 1990].  

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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 [Rook 1999]; [Duvic 2006]. 
In a phase 1 study of 28 patients with recurrent or advanced CTCL who received 
CPG7909 (TLR9 agonist), in weekly subcutaneous doses for 24 weeks, the ORR was 
25% [Kim 2004]. Five patients (18%) achieved PRs and 2 (7%) achieved CRs. Moreover, 
Kim utilized an in-situ vaccination method in which this CPG7909 was combined with 
local radiation therapy, which demonstrated meaningful clinical responses in distant 
lesions [Kim 2012] validating the potential of anti-tumor T cell responses.  
Allogeneic HSC transplantation is superior to autologous transplantation with superior 
progression-free survival [Wu 2009]. Long-term, if not curative, clinical responses are 
demonstrated in patients with advanced, high-risk Mycosis Fungoides/Sézary Syndrome, 
in support of effective graft versus lymphoma T cell response. 
2.1.3 PD-1 and PD-L1 expression in lesional tissue and peripheral blood tumor cells in 
Mycosis Fungoides/Sézary Syndrome, which may serve to create an immune-suppressive 
microenvironment, evade immune surveillance, and inhibit anti-tumor T cell activity 
[Samimi 2010]; [Kantekure 2012]. 
2.1.4 Genomic evidence of immune escape in Mycosis Fungoides/Sézary Syndrome. Reports 
of 9p24.1/PD-L2 translocation, breakpoints in PD-L1 (CD274), recurrent Single 
Nucleotide Variant (SNV) in CD28, or CTLA4-CD28 fusion in Mycosis 
Fungoides/Sézary Syndrome support a potential genomic basis for immune evasion 
[Lesokhin 2014]; [Ungewickell 2015]; [Choi 2015]. 
2.2 
Synovial Sarcoma (Treatment Group 2) 
Synovial sarcoma is a rare, translocation-driven, soft-tissue sarcoma (STS) subtype affecting 
approximately 800 Americans annually, most commonly young adults (typically about 20-30 
years of age), but also children and adolescents. These cancers often initially present with 
localized, curable disease but for about 50% of patients, the median survival is approximately 16 
months [Constantinidou 2013]; [Ladanyi 2002]; [Sultan 2009]; [Kampe 1993]. Synovial sarcoma 
should be an ideal target disease for immunotherapy as these tumors typically have high 
expression level of a number of highly-immunogenic, cancer-testis (CT) antigens including NY-
ESO-1, MAGE-A4 and PRAME (Fig. 1) [Sultan 2009]. Unlike other cancers that most often 
have sporadic heterogeneous expression of CT antigens, in synovial sarcoma tumors NY-ESO-1 
is expressed in >80% of patients and generally with very strong, homogenous expression 
throughout the tumor (Fig. 2). Despite strong expression of these highly immunogenic proteins, 
synovial sarcoma has not responded well to anti-programmed death-1 (anti-PD-1)/ anti-
programmed death-ligand 1 (anti-PD-L1) targeted therapies. In the SARC28 study, only one of 
10 synovial sarcoma patients had a partial response, and no PRs were seen on the Alliance trial 
using nivolumab [Tawbi 2016]; [D’Angelo 2015]. A randomized vaccine trial recently presented 
at the 2017 ESMO treated 43 patients with single agent atezolizumab and none had a PR 
[Chawla 2017].  
 

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Fig. 1: Heat map illustrating results 
from a custom made qPCR array testing for levels of gene expression of 19 Cancer-Testis 
Antigens. RNA was extracted from frozen, banked well/de-differentiated liposarcomas (MRCL 
not shown), leiomyosarcomas, undifferentiated pleomorphic sarcomas and synovial sarcoma 
tumors. Synovial sarcoma tumors had strong expression of NY-ESO-1, MAGE-A4 and PRAME. 
 
 
 
Fig. 2: Immunohistochemistry testing for NY-ESO-1 expression in a synovial sarcoma patient 
treated at the Seattle Cancer Care Alliance. This staining illustrates the classic homogenous 
staining pattern 
 

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2.3 
CTEP IND Agent(s) 
2.3.1 MK-3475 (pembrolizumab) 
MK-3475 (pembrolizumab) has high affinity and potent receptor-blocking activity for the 
programmed cell death 1 (PD-1) receptor, based on preclinical in vitro data 
(Investigator’s Brochure, 2016). MK-3475 (pembrolizumab) has an acceptable preclinical 
safety profile and is being advanced for clinical development as an intravenous (IV) 
immunotherapy for advanced malignancies. 
The importance of intact immune surveillance function in controlling outgrowth of 
neoplastic transformations has been known for decades [Disis 2010]. Accumulating 
evidence shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and 
favorable prognosis in various malignancies. In particular, the presence of CD8+ T-cells 
and the ratio of CD8+ effector T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with 
improved prognosis and long-term survival in solid malignancies, such as ovarian, 
colorectal, and pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and 
renal cell carcinoma. Tumor-infiltrating lymphocytes can be expanded ex vivo and re-
infused, inducing durable objective tumor responses in cancers such as melanoma 
[Dudley 2005]; [Hunder 2008].  
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated 
T-cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to cluster of differentiation 28 (CD28) and cytotoxic T 
lymphocyte-associated protein 4 (CTLA-4) that has been shown to negatively regulate 
antigen receptor signaling upon engagement of its ligands (programmed cell death ligand 
1 [PD-L1] and/or programmed cell death ligand 2 [PD-L2]) [Greenwald 2005]; [Okazaki 
2001].  
The structure of murine PD-1 has been resolved [Zhang 2004]. PD-1 and family members 
are type I transmembrane glycoproteins containing an Ig Variable–type (IgV type) 
domain responsible for ligand binding and a cytoplasmic tail responsible for the binding 
of signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling 
motifs, an immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor 
tyrosine-based switch motif. Following T-cell stimulation, PD-1 recruits the tyrosine 
phosphatases, SHP 1 and SHP-2, to the immunoreceptor tyrosine-based switch motif 
within its cytoplasmic tail, leading to the dephosphorylation of effector molecules such as 
CD3 zeta (CD3ζ), protein kinase C-theta (PKCθ), and zeta-chain-associated protein 
kinase (ZAP70), which are involved in the CD3 T-cell signaling cascade [Chemnitz 
2004]; [Sheppard 2004]; [Riley 2009]. The mechanism by which PD-1 down modulates 
T-cell responses is similar to, but distinct from, that of CTLA-4, because both molecules 
regulate an overlapping set of signaling proteins [Parry 2005]; [Francisco 2010]. As a 
consequence, the PD-1/PD-L1 pathway is an attractive target for therapeutic intervention 
in Mycosis Fungoides/Sézary Syndrome. 

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2.3.2 MK-3475 (pembrolizumab) Background and Clinical Trials 
MK-3475 (pembrolizumab, Keytruda®), a humanized monoclonal antibody against the 
PD-1 protein, has been developed by Merck & Co. for the treatment of cancer. MK-3475 
(pembrolizumab) is approved for treatment of melanoma in several countries; in the 
United States (US) and European Union it is approved for the treatment of advanced 
(unresectable or metastatic) melanoma in adults. MK-3475 (pembrolizumab) has also 
been approved for treatment of NSCLC in several countries; in the US it is indicated for 
the treatment of patients with metastatic NSCLC whose tumors express PD-L1 as 
determined by a Food and Drug Administration (FDA)-approved test and who have 
disease progression on or after platinum-containing chemotherapy. Patients with NSCLC 
and epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) 
genomic tumor aberrations should also have disease progression on FDA-approved 
therapy for these aberrations before receiving MK-3475 (pembrolizumab). MK-3475 
(pembrolizumab) is approved in the US for the treatment of patients with recurrent or 
metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on 
or after platinum-containing chemotherapy. 
MK-3475 (pembrolizumab) has demonstrated initial clinical efficacy in single-arm 
monotherapy trials in patients with NSCLC, HNSCC, urothelial cancer, gastric cancer, 
triple negative breast cancer, and Hodgkin’s Lymphoma as determined by response rate. 
Ongoing clinical trials are being conducted in these tumor types as well as a number of 
other advanced solid tumor indications and hematologic malignancies. For study details 
please refer to the [Investigator’s Brochure 2016].  
2.3.3 Interferon-Gamma-1b (Actimmune) 
In order to address the putative Th1 vs Th2 imbalance in Mycosis Fungoides/Sézary 
Syndrome, various cytokines have been used to reverse the host’s immune profile 
including the interferons and interleukins. Treatment with interferons has long been part 
of standard of care in patients with Mycosis Fungoides or Sézary Syndrome and is listed 
as an off-label treatment option in the NCCN Practice Guidelines [NCCN 2016]. 
Subcutaneously administered IFN-alpha or IFN-gamma can be used alone or in 
combination with skin-directed or systemic therapies to augment anti-tumor clinical 
response and to improve overall clinical outcome [Bunn 1986] [Kaplan 1990]; [Raphael 
2011]; [Spaccarelli 2015].  
However, interferon type cytokine therapy has been limited by short-lived responses or 
undesirable toxicities when doses are increased to improve clinical responses. Thus the 
key role for interferons in the treatment landscape in Mycosis Fungoides/Sézary 
Syndrome (CTCL) has been to find rational partnering agents for potential synergistic 
activity to yield a more meaningful clinical outcome and address the unmet need of 
therapies with more reliable and durable responses in Mycosis Fungoides/Sézary 
Syndrome.  
Of the two interferons used in treatment of patients with Mycosis Fungoides/Sézary 
Syndrome, IFN-gamma has been less commonly used than IFN-alpha. The initial greater 

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availability of IFN-alpha led to greater use followed by more experience and publications 
with IFN-alpha. Although there were no rigorously planned/conducted prospective trials 
with IFN-alpha monotherapy, given reports of efficacy in patient series, IFN-alpha has 
been widely accepted as useful in all clinical stages of Mycosis Fungiodes and Sézary 
Syndrome. IFN-alpha has been shown to activate CD8+ T cells and NK cells and to 
reduce the production of suppressive cytokines, IL-4 and IL-5. However, its common 
toxicities including fatigue, asthenia, flu-like symptoms, and mood changes/depression 
can be a deterrent for chronic use. 
The only commercially available source of IFN-gamma is IFN-gamma-1b 
(Actimmune®), a recombinant form of IFN-gamma approved by the FDA for the 
treatment of chronic granulomatous disease and osteopetrosis. Although there has been 
less clinical use of IFN-gamma, it has a potential for much broader and potent immune 
activation than IFN-alpha, with influence in both the innate and adaptive immunity. 
Endogenous IFN-gamma secreted during immune responses is central to effective T cell 
responses and is used as a surrogate or pharmacodynamic marker of successful immune 
activation in pre-clinical and clinical studies of cancer immune therapies. More 
specifically, IFN-gamma can stimulate dendritic cells (DCs) and macrophages to 
upregulate their MHC molecules leading to enhanced antigen presentation, activation of 
cytotoxic T cells (CTLs)/NK cells, and increasing expression of costimulatory molecules 
[McGinnis 2005]; [Spaccarelli 2015]. These features highlight advantages of using IFN-
gamma over IFN-alpha. IFN-gamma is considered essential for the Th1 immune 
response, and IFN-gamma treatment in patients with Mycosis Fungoides/Sézary 
Syndrome has shown normalization of the Th2 skewing and activation of CTLs [Seo 
1998]; [Hino 2005]. The adverse effects of IFN-gamma are similar to those of IFN-alpha, 
including the flu-like symptoms, fatigue, dose-dependent cytopenias, and potential for 
aggravating autoimmune phenomena. However, the severity of these adverse effects 
appear to be less with IFN-gamma and with less concern for impairment of the cognitive 
function or mood changes than with IFN-alpha.  
In summary, IFN-gamma is likely better tolerated at the active dose ranges than IFN-
alpha, and capable of broader range of immune activity spanning from priming of DCs, 
augment APC function, enhancement of cytotoxicity mediated by CD8+ T cells and NK 
cells, reduced Th2 immune activity, increased Th1 immune activity, inhibition of 
regulatory T cells, and inhibition of tumor cell proliferation, which collectively constitute 
a great profile as cancer immunotherapy. Central to the current proposed protocol, the 
efficacy of IFN-gamma in driving T cell responses is limited by downstream IFN-gamma 
induction of PD-L1. 
2.4 
Rationale 
2.4.1 Rationale for MK-3475 (pembrolizumab) Dose Selection 
The dose of MK-3475 (pembrolizumab) planned to be studied in this trial is 200 mg 
administered every 3 weeks (Q3W). The dose recently approved in the US and several 
other countries for treatment of melanoma patients is 2 mg/kg Q3W. Information on the 
rationale for selecting 200 mg Q3W is summarized below. 

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The initial phase 1 study of MK-3475 (pembrolizumab) (KN001) evaluated 5 dose levels 
(1 mg/kg every 2 weeks [Q2W], 3 mg/kg Q2W, 10 mg/kg Q2W, 2 mg/kg Q3W, and 10 
mg/kg Q3W) in patients with advanced solid tumors. All 5 dose levels were well 
tolerated and no dose-limiting toxicities (DLTs) were observed. MK-3475 
(pembrolizumab) showed evidence of target engagement and objective evidence of tumor 
size reduction at all dose levels (1 mg/kg, 3 mg/kg, and 10 mg/kg Q2W). No maximum 
tolerated dose (MTD) has been identified to date. In addition, 2 randomized cohort 
evaluations of melanoma patients receiving MK-3475 (pembrolizumab) 2 mg/kg or 10 
mg/kg Q3W have been completed, and 1 randomized cohort evaluating 10 mg/kg Q3W 
or 10 mg/kg Q2W has also been completed. The clinical efficacy and safety data 
demonstrate a lack of any important differences in efficacy or safety profile across doses. 
An integrated body of evidence suggests that 200 mg Q3W is expected to provide similar 
response to 2 mg/kg Q3W, 10 mg/kg Q3W, and 10 mg/kg Q2W. Previously, a flat MK-
3475 (pembrolizumab) exposure-response relationship for efficacy and safety has been 
found in patients with melanoma in the range of doses between 2 mg/kg and 10 mg/kg. 
Exposures for 200 mg Q3W are expected to lie within this range and will be close to 
those obtained with 2 mg/kg Q3W dose. 
The PK profile of MK-3475 (pembrolizumab) is consistent with that of other humanized 
monoclonal antibodies, which typically have a low clearance and a limited volume of 
distribution. A population PK model, which characterized the influence of body weight 
and other patient covariates on exposure, has been developed. The distribution of 
exposures from the 200 mg fixed dose are predicted to considerably overlap those 
obtained with the 2 mg/kg dose and importantly will maintain individual patient 
exposures within the exposure range established in melanoma as associated with maximal 
clinical response. The PK properties of MK-3475 (pembrolizumab), specifically the 
weight-dependency in clearance and volume of distribution, are consistent with no 
meaningful advantage to weight-based dosing relative to fixed dosing. 
In translating to other tumor indications, similarly flat exposure-response relationships 
for efficacy and safety as observed in patients with melanoma can be expected. As the 
antitumor effect of MK-3475 (pembrolizumab) is driven through immune system 
activation rather than through a direct interaction with tumor cells, it is rendered 
independent of the specific tumor type. In addition, available PK results in patients with 
melanoma, NSCLC, and other tumor types support a lack of meaningful difference in PK 
exposures obtained at tested doses across tumor types. Thus, the 200 mg Q3W fixed-dose 
regimen is considered an appropriate fixed dose for other tumor indications as well. 
A fixed-dose regimen will simplify the dosing regimen to be more convenient for 
physicians and to reduce potential for dosing errors. A fixed-dosing scheme will also 
reduce complexity in the logistical chain at treatment facilities and reduce wastage. The 
existing data suggest 200 mg Q3W as the appropriate dose for MK-3475 
(pembrolizumab). 

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2.4.2 Immune checkpoint blockade in Mycosis Fungoides/Sézary Syndrome to augment anti-
tumor T cell response 
With the goal of unleashing the desired anti-tumor T cell response in Mycosis Fungoides 
and Sézary Syndrome, we conducted a clinical trial with anti-PD-1 monoclonal antibody, 
MK-3475 (pembrolizumab), initiated and coordinated by CITN and jointly funded by 
Merck. MK-3475 (pembrolizumab) is a potent and highly selective humanized mAb of 
the immunoglobulin G4 (IgG4)/kappa isotype designed to directly block the interaction 
between PD-1 and its ligands, PD-L1 and PD-L2. PD-1 is an immune-checkpoint 
receptor expressed on T cells that can suppress antitumor immunity when bound to either 
of its ligands, PD-L1 or PD-L2. Some tumor cells up-regulate the PD-1 or PD-1 ligands 
to evade active T-cell immune surveillance. MK-3475 (pembrolizumab) or nivolumab 
has been shown to effectively block the interaction between PD-1 and its ligands, thereby 
enhancing tumor regression in melanoma, other solid tumors, or Hodgkin lymphoma 
[Topalian 2012]; [Robert 2015] [Ansell 2015]. 
2.4.3 Anti-PD-1 monoclonal antibody MK-3475 (pembrolizumab) monotherapy in Mycosis 
Fungoides/Sézary Syndrome: CITN-10 clinical trial 
We explored the clinical activity of MK-3475 (pembrolizumab) as an immune checkpoint 
blockade targeting PD-1 to restore and augment the effector T cell activity. 
Approximately one third of patients responded and many of the responses appear to be 
durable and increasing over time with continued therapy.  
Patients (pts) with Mycosis Fungoides/Sézary Syndrome stages IB-IV with at least 1 
prior systemic therapy were enrolled in this phase 2, single-arm study. A Simon two-
stage design was applied where stage 2 was initiated with 1 of 9 pts achieving an 
objective response. MK-3475 (pembrolizumab) was administered at 2 mg/kg every 3 
weeks with treatment allowed up to 2 years. Primary endpoint was overall response rate 
as determined by the consensus global response criteria (GRS). Secondary endpoints 
include safety/tolerability, TTR, and DOR/PFS. Expansive correlative science was 
planned and is ongoing to evaluate biomarkers of clinical response and to elucidate the 
mechanisms of immune escape in those who fail to respond or develop new tumors on 
therapy. 
Enrollment of the planned 24 pts is completed and all received at least one dose of MK-
3475 (pembrolizumab). Median age is 67 (44-85); 18 are male. All but 1 patient (stage 
IB) had advanced disease (stages IIB-IV); 2 IIB, 3 IIIA, 3 IIIB, 15 with IVA. 15 of 24 
were SS. Most pts were heavily treated with median of 4 prior systemic therapies (range 
1-10). Nine pts have confirmed clinical response (38% ORR; 8 PR, 1 CR) and 5 of these 
responders are continuing on therapy with median follow-up of 49 weeks. Of the 9 
current responders, 5 are Mycosis Fungoides (2 IIB, 2 IIIA, 1 IIIB; 4, 6, 3 and 7 prior 
systemic therapies) and 4 SS (4 IVA; 1, 3, 4, and 6 prior systemic therapies). Two of the 
PRs are in near global CR; both are SS with complete clearing of circulating Sézary cells. 
Four pts had deep skin response with >90% mSWAT reduction (3 SS, all IVA; 1 
Mycosis Fungoides, IIIA). Median time to response is 11 weeks (range 8-22 weeks). 
Median PFS is 44 weeks and 75% were progression-free at 6 months by KM estimate. To 

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date, related AEs reported in greater than 5% of patients are dermatitis (n=6), anemia 
(n=3), leukopenia (n=3), elevated liver enzymes (n=2), diarrhea (n=2), and pneumonitis 
(n=2). Most AEs were grade 1-2 and limited to AEs previously reported with MK-3475 
(pembrolizumab) in other malignancies. Grade 3/4 AEs were immune mediated 
exfoliative dermatitis (n=2), anemia (n=2), elevated liver enzymes (n=1), pneumonitis 
(n=1), and hyperuricemia (n=1). Only two MK-3475 (pembrolizumab) related SAE’s 
were reported including one grade 3 pneumonitis and one grade 3 diarrhea secondary to 
steroid refractory duodenitis. In one patient with moderate immune-mediated skin disease 
flare, we observed significant tumor-infiltrating CD8+ T cells, followed by clinical 
response. 
Planned and ongoing correlative studies include those to characterize the tumor 
microenvironment (IHC/multiparametric, nanostring gene expression profiling, 
multiplexed ion beam imaging), systemic immune response (flow cytometry, CyTOF, 
Luminex cytokine profiling), and the molecular/genomic immune profile (exome 
sequencing, neoantigen discovery, high throughput sequencing of TCR). 
In summary, we observed meaningful clinical responses in previously treated Mycosis 
Fungoides /Sézary Syndrome with MK-3475 (pembrolizumab) including deep PRs and a 
global CR with 38% ORR. In the blood compartment of SS pts, MK-3475 
(pembrolizumab) is capable of clearing the malignant T cells. The PFS data is continuing 
to mature and the ongoing responses in several responders is very encouraging and may 
be reflective of a potential sustained antitumor immune response. Overall toxicity profile 
is acceptable in this population and limited to those expected with checkpoint blockade. 
Very comprehensive correlative studies are planned, that will help design immune 
strategies to improve the clinical outcome beyond that observed with MK-3475 
(pembrolizumab) monotherapy and the planned trial of MK-3475 (pembrolizumab) plus 
IFN-gamma. 
The CITN-10 trial was designed and implemented when the commonly accepted dose of 
MK-3475 (pembrolizumab) was 2mg/kg administered every 3 weeks. Since then the flat 
dose of 200mg IV every 3 weeks has become well accepted based upon the extensive 
rationale outlined in section 2.3.1. In this trial we will utilize the flat dose of 200mg IV 
every 3 weeks with the understanding that it will be comparable to the 2mg/kg IV every 3 
weeks utilized in the CITN-10 trial.  

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2.4.4 Clinical activity and tolerability of interferon gamma (IFN-gamma) therapy in Mycosis 
Fungoides/Sézary Syndrome 
Although IFN-gamma has not been widely used in Mycosis Fungoides/Sézary Syndrome 
(CTCL), earlier reports and sizable cohort experience at U Penn (personal 

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communications by A Rook) have shown promising activity either as monotherapy or as 
part of combination strategy [Kaplan 1990]; [Sugaya 2014]; [Raphael 2011].  
As early as 1990, Kaplan et al reported in their phase 2 study of IFN-gamma in Mycosis 
Fungoides/Sézary Syndrome, 31% ORR (all PRs) among 16 patients with clinical stage 
ranging from IB to IVB [Kaplan 1990]. One of 5 responders previously progressed on 
IFN-alpha. IFN-gamma was administered IM x 8 weeks, initial dose of 0.25 mg/m2 per 
day, and escalated to 0.5 mg/m2 per day after 1 week if tolerated. 
Later, Dummer et al reported 5 Mycosis Fungoides/Sézary Syndrome patients treated 
with intralesional administration of IFN-g expressing plasmid constructed with an 
adenoviral vector [Dummer 2004]. The intralesional injections were followed by not only 
impressive improvement of treated lesions but regression of distant/untreated lesions 
associated with increased serum levels of IFN-gamma. 
More recently, Sugaya and colleagues conducted a phase 2 study of IFN-gamma 
monotherapy in 15 pts with stage IA – IIIA Mycosis Fungoides/CTCL [Sugaya 2014]. 
Eleven of 15 pts had PRs including 9 of 10 with early stage (IA-IIA) and 2 of 5 with 
more advanced stage (IIB/IIIA) Mycosis Fungoides. IFN-gamma was administered IV at 
2 MU daily x 5 days for 4 weeks, followed by intermittent SC injections. It is important 
to note that this trial excluded any patient with clinically significant blood disease or 
anyone with LN or visceral involvement. 
Shimauchi et al treated 12 pts with Mycosis Fungoides with a 4-week course of 
combination therapy of IFN-g daily x 5 days and nbUVB phototherapy given 3 times per 
week [Shimauchi 2008]. Of 12pts, 6 had PR and 4 CR. Th1 cytokine levels were 
increased and Th2 cytokines decreased in the combination group whereas control pts with 
nbUVB treatment alone did not show he favorable cytokine profile changes. 
In a retrospective cohort study of 98 Sezary syndrome pts managed with multimodality 
immunomodulatory therapy by U Penn investigators, 75% ORR was reported with 30% 
CR rate [Raphael 2011]. All 73 pts with objective response were treated with 
photopheresis. Of these, IFN-gamma was added in 23 patients who were either intolerant 
or refractory to IFN-alpha and/or bexarotene to achieve PR or CR. The authors 
recommend a starting dose of 25-50 mcg/m2 (0.5-1 MU/m2), given SC thrice-weekly to 
daily, as tolerated. The high ORR observed in this multimodality immunotherapy study 
supports potential utility of IFN-g as part of a combination strategy to target synergistic 
immune activity. 
In all of these studies in Mycosis Fungoides/Sézary Syndrome, IFN-gamma was observed 
as well-tolerated with mostly grade 1-2 AEs including local injection site reaction, flu-
like symptoms, asthenia, neutropenia, mood affect, and elevated liver function tests. 
2.4.5 Rationale for a combination approach of anti-PD-1 antibody and IFN-gamma 
The clinical ORR with MK-3475 (pembrolizumab) monotherapy is ~33% and that for the 
comparable clinical stage patients treated with IFN-gamma as monotherapy is also ~33%. 

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IFN-gamma activated immune CD8+ T cells but is limited by induction of PD-L1. Anti-
PD1 unleashes activated CD8+ T cells. Both are effective as single agents. In all 
likelihood, or at least theoretically, the combination will be synergistic. The combination 
of agents could provide substantial and sustained responses.  
IFN-gamma is thought to be a critical antitumor cytokine and serves as a key biomarker 
of antitumor immune response in cancer immunotherapy. And as described, IFN-gamma 
has objective clinical activity in patients with Mycosis Fungoides/Sézary Syndrome and 
correlative studies in the clinical responders have shown evidence towards normalization 
of disease related immune dysregulation. However, there is also a concern that IFN-
gamma, secreted by CTLs, can act as an inducer of immune escape activity through 
mechanisms such as increasing PD-1 or PD-L1 expression when tumor cells encounter 
CTLs in the local environment [Mandai 2016]. This potential dual opposing role of IFN-
gamma may be a key mechanism for immune escape in various immunotherapies. Thus, 
combining an anti-PD-1 agent, such as MK-3475 (pembrolizumab) will address this 
potential escape path created by IFN-gamma in the local tissue while harnessing the 
broad and potent immune activating role of IFN-gamma. Furthermore, we have 
scheduled a week of a lead-in block where IFN-gamma is given as monotherapy with an 
intent to optimize priming of DCs and activated immune milieu, and up-regulate PD-1 
and/or PD-L1 expression immediately before targeting PD-1 followed by countering any 
blockade in immune activation with MK-3475 (pembrolizumab). Moreover, we will have 
an opportunity to generate immune correlative studies with IFN-gamma alone before 
evaluating biologic effects of the combination immune strategy. 
We hypothesize that combining an anti-PD-1 agent, MK-3475 (pembrolizumab), with 
IFN-gamma, an immune-augmenting agent with a wide range of immune activity, would 
result in a synergistic or complementary immune activity and yield superior clinical 
outcome with improved ORR and PFS in similar cohort of Mycosis Fungoides/Sézary 
Syndrome patients studied with MK-3475 (pembrolizumab) monotherapy. We would 
deem the combination successful if the ORR is 58% or greater, our primary efficacy 
endpoint. We also hope to improve the PFS with favorable DOR, our secondary 
endpoints.  
With combination immune strategies, we are always mindful of possible additive 
toxicities, thus safety/tolerability is an important endpoint especially in our CTCL 
population where the disease course is often chronic and a curative outcome is not 
anticipated other than with an allogeneic HSC transplantation. Immune checkpoint 
blockade has been known to induce immune-mediated adverse events, although, anti-PD-
1 agents have demonstrated a better safety profile than PD-L1 or CTLA-4 blockade 
[Weber 2015]; [Larkin 2015]. Our monotherapy with MK-3475 (pembrolizumab) has 
demonstrated an acceptable toxicity profile; however, we have observed a subset of 
patients experiencing grade 3 skin reactions and one patient with possible MK-3475 
(pembrolizumab) related grade 3 pneumonitis which was reported as a serious adverse 
event (SAE). Interferons have been associated with anticipated immune activating 
cytokine related adverse events. Patients who receive continuous dosing of interferons 
suffer from constant symptoms that can lead to decreased quality of life and early 
termination of treatment. Thus, we plan to use an interrupted dosing strategy of IFN-

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gamma where after the first 12 weeks of the combination course, patients will have 
interval courses off and on IFN-gamma, which we hope will result in acceptable 
tolerability while improving the efficacy profile beyond what we observed with anti-PD-
1 monotherapy. We plan to keep the MK-3475 (pembrolizumab) dose schedule the same 
as the monotherapy trial, administered uninterrupted throughout the combination trial, 
thus keeping IFN-gamma as the only agent that will be given as immune boost blocks. 
We plan to allow dose increase of IFN-gamma to optimize best responses if patients 
demonstrate acceptable tolerability profile. To ensure overall safety of our patients, we 
have scheduled an interim planned safety based evaluation at week 10, C4D1 of MK-
3475 (pembrolizumab) dosing in the first 12 patients enrolled in the study. If 4 or more 
out of 12 patients experience a study drug related SAE within the first 10 weeks of 
therapy, the trial will not be allowed to continue further enrollment and treatment unless 
or until reviewed and approved by the CITN and NCI CTEP.  
Essential to this trial is to incorporate correlative studies that are critical for maximal 
learning of the mechanism of improved efficacy and/or immune escape in those who do 
not benefit or experience disease progression on therapy. The planned correlatives will be 
exploratory in nature and not considered endpoints. We aim to be robust and 
comprehensive with our correlative science and plan to evaluate the local and systemic 
immune activity/mechanisms and characterize gene expression profiles and mutational 
landscape to further understand the mechanism(s) and biomarkers of successful or failed 
anti-tumor immune response. We will apply state-of-the-art and/or novel tools to achieve 
this goal.  
2.4.6 Previous Clinical Experience in Synovial Sarcoma (Treatment Group 2) and Rationale 
To better understand the reasons why these tumors do not respond to anti-PD-1/PD-L1 targeted 
therapies, the tumor microenvironment (TME) and potential mechanisms of immune evasion in 
these tumors were analyzed. A retrospective analysis of immune-related gene expression in 
synovial sarcoma and several other STS subtypes was performed, using the NanoString platform 
(Fig. 3). It was observed that synovial sarcoma tumors had significantly lower expression of 
genes associated with inflammation, T cell activity, and antigen presentation (p<0.05, t-test, for 
HLA-A, B and C), compared with certain other common sarcoma subtypes including 
undifferentiated pleomorphic sarcoma (UPS) and leiomyosarcoma (LMS) (Fig. 4). Genes 
associated with T cell infiltration (e.g. IL-7R) were also less expressed in synovial sarcoma 
tumors (Fig. 5). Low MHC class I and class II expression in 18 synovial sarcoma cases by 
immunohistochemistry (IHC) was confirmed (Fig. 6). Almost all cases had either absent (0+) or 
low (1+) levels of class I MHC staining and no cases had high or very high (3-5+) staining. Low 
levels of T cell infiltration using deep sequencing of the TCR Vβ region was confirmed, in 
collaboration with Adaptive Biotechnologies. It was found that synovial sarcoma tumors had few 
tumor-infiltrating T cells based on the T cell fraction (not shown) and lower clonality (Fig. 7), 
suggesting a less “focused” oligoclonal response. Low levels of PD-L1 and PD-1 in these tumors 
by IHC were also observed, as would be expected in a “cold” tumor where immune evasion is 
achieved through avoidance rather than inhibition of infiltrating T cells (Fig. 8) [Pollack 2017]. 
In summary, these synovial sarcoma TME lacked all of the features that would be expected in a 
tumor type responsive to checkpoint blockade. 
 

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Fig. 3: Heat map illustrating gene expression data from the nanostring platform including 780 
genes, a majority of which were related to immunity. A cluster analysis of genes significantly 
different between sarcoma subtype found 7 gene groups. Synovial sarcoma had lower levels of 
genes related to antigen presentation and T cell infiltration. 
 
 
 
 
 
Fig. 4: Nanostring data illustrating expression of class I MHC genes in soft tissue sarcoma 
subtypes.* p< 0.05, ** p<0.005 
 
 

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Fig. 5: Nanostring gene expression of CD3D and IL7R, two genes associated with T cell 
infiltration. * p< 0.05, ** p<0.005 
 
 
 
Fig. 6: Immunohistochemistry of a synovial sarcoma lung metastasis. This tumor stains strongly 
with NY-ESO-1 (left) but class I MHC staining is absent on the tumor cells (right). 
 
 
 

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Fig. 7: Results of deep sequencing of the TCR Vβ region on FFPE preserved tumor samples. 
Leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma (UPS) and synovial sarcoma 
results are shown. T cell fraction (left) and clonality (right) are shown. Liposarcoma tumors also 
had low T cell fraction and clonality (not shown). * p< 0.05, ** p<0.005
Fig. 8: Immunohistochemistry for PD-L1 on SS tumors. Staining was scored on a scale from 0 
(absent staining) to 5 (homogenous staining) by a pathologist blinded to the tumor type.

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2.4.7 A Trial of Interferon-gamma (IFN-γ) to inflame the synovial sarcoma and myeloid/round 
cell liposarcoma (MRCL) Microenvironment 
Interferon-gamma (IFN-γ) is one of the most highly inflammatory cytokines and is capable of 
activating diverse immune cell repertoires and increases antigen presentation in a wide variety of 
tissues and tumor types [Propper 2003]. As had been seen in other tumor models, it was shown 
in vitro that class I MHC could be increased on synovial sarcoma tumor cells resulting in 
improved T cell mediated tumor killing. However, IFN-γ had never been studied in the context 
of an immunologically "cold" tumor in humans. Based on this data, an IRB-approved protocol to 
determine the impact of weekly IFN-γ (100 mcg/m2 subcutaneously) on the sarcoma immune 
microenvironment was started (NCT01957709; PI: Pollack). On this protocol five patients who 
had undergone pre- and post-treatment biopsies were treated. IFN-γ was well tolerated on the 
weekly schedule; although patients had flu-like symptoms on the day of the injection, most felt 
better by the following day. No patients had any grade 3 or higher toxicity related to the IFN-γ. 
MHC expression was significantly increased post-treatment (p<0.05; Fig. 9). By flow cytometry, 
HLA-ABC expression on tumor cells rose from a mean of 3.3% to 17.0%. A substantial 
infiltration with class II expression on infiltrating cells was also noted. Markedly increased 
CD3+ T cell infiltration was also observed in each patient (Fig. 10). In order to interrogate the 
specificity of these T cells, TIL were expanded from each 1-2 mm core sample. Using an 
ELISPOT assay consisting of overlapping 15 amino acid peptides from the most immunogenic 
regions of cancer testis antigens (including NY-ESO-1) it was found that post-treatment T cells 
had improved recognition of these antigens (Fig. 11). Importantly however, increased PD-L1 
both on tumor cells and tumor-infiltrating macrophages in patients on the trial was observed 
suggesting that this checkpoint may be an important blockade preventing T cell mediated tumor 
elimination. 
 
In conclusion it has been shown that IFN-γ can consistently transform this cold TME into a hot 
TME.  Accordingly, it is likely that synovial sarcoma patients treated with IFN-γ will respond to 
checkpoint inhibition. The proposed study will test the concept that concurrent IFN-γ and anti-
PD-1 will induce remissions and benefit patients. 
 
 
 

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Fig. 9: Flow cytometry for class I MHC molecules on freshly procured tumor samples from 
synovial sarcoma and MRCL patients treated with weekly IFNγ. In order to focus on tumor cells 
and not immune cells, data was gated on CD45- cells. Histogram from a synovial sarcoma 
patient is shown (left). Percentage class I MHC+ cells before and after IFNγ treatment in the first 
4 patients on the trial is shown (right). 
 
 
Fig. 10: Flow cytometry staining for CD3+ cells on freshly procured tumor samples from 
synovial sarcoma and MRCL patients treated with weekly IFNγ. 
 
 
 
Fig. 11: Tumor infiltrating lymphocytes were expanded and tested for antigen recognition by 
ELIspot using a panel of overlapping 15mer peptides from the most immunogenic regions NY-
ESO-1, MAGE-A3, MAGE-A4, MAGE-A9 and PRAME.  
 
NY-ESO-1
Mage-A3
MAGE-A4
MAGE-A9
PRAME
0
20
40
spots/well
Patient 1
NY-ESO-1
Mage-A3
MAGE-A4
MAGE-A9
PRAME
0
10
20
30
40
spots/well
Patient 2
Pre-IFNγ
Post-IFNγ

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2.5 
Correlative Studies Background (Treatment Group 1) 
The proposed trial provides a rich context for the investigation of biomarkers for anti-PD1 
therapy. Treatment of cutaneous T cell lymphomas with MK-3475 (pembrolizumab) 
monotherapy produced a response rate of ~33%, and we expect that the addition of interferon 
gamma will result in an even higher rate of clinical response. This high rate of response will 
improve our statistical power in discovering novel biomarkers. Additionally, as a cutaneous 
malignancy with frequent leukemia, CTCL affords the opportunity for serial collection of high 
quality biopsies of skin and blood. Thus, from an exploratory biomarker perspective, this disease 
offers an opportunity to investigate the determinants of response and resistance to anti-PD-1 and 
immune therapies, as well as to discover additional molecular targets governing immune 
dysregulation in cancer.  
Correlates will focus on potential predictive biomarkers for PD-1 therapy (e.g., as expression of 
PD-L1 and mutational/neoantigen burden) and assessment of the effects of IFN-gamma (e.g.,Th1 
vs Th2 skewing). The addition of interferon gamma is hypothesized to affect the tumor 
microenvironment in two ways: 1) IFN-gamma will upregulate PD-L1 expression on suppressive 
cell populations. 2) IFN-gamma will skew CD4 T cells towards a Th1 phenotype. Sampling time 
points have been selected to explore these effects. 
The majority of proposed biomarkers are designed to be hypothesis-generating by applying novel 
technologies such as multiple ion beam imaging and CyTOF to provide means to analyze the 
effects of checkpoint blockade both systemically and in the tumor microenvironment in an 
unprecedented manner. We anticipate that these studies will yield candidate biomarkers that 
correlate with prognosis, have predictive value in the selection of which subjects benefit from 
anti-PD1/IFN-gamma immunotherapy, and will investigate the hypothesis that Th1 skewing of 
the T cell repertoire can potentiate immune checkpoint blockade therapy. 
Assays may include but are not be limited to: 
2.5.1 Chromagenic (Single-Color) immunohistochemistry for PD-L1  
PD-L1 expression has emerged as the leading biomarker for response to anti-PD1 
therapy, but studies thus far have found this to be far from a perfect biomarker. This may 
be due at least in part to the dynamic nature of PD-L1 expression. Interferon gamma is 
known to upregulate PD-L1 expression in some tumor cells and frequently on tumor 
infiltrating leukocytes. With this biomarker we will explore the predictive value of PD-
L1 expression before treatment as well as the inducible expression after interferon 
gamma treatment. FFPE skin biopsies will be stained with the FDA approved 22C3 
assay. Staining will be assess both pre-treatment and after interferon gamma treatment. 
We will test whether PD-L1 expression (baseline and/or inducible) correlates with MK-
3475 (pembrolizumab) response in the Mycosis Fungoides/Sézary Syndrome population. 
2.5.2 Multiparametric immunohistochemistry 
The skin microenvironment plays a critical role in the development and progression of 
cutaneous T cell lymphomas (CTCL). There are a number of potentially suppressive 
immune populations, such as regulatory T cells and M2 macrophages, present within 

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CTCL involved skin that may blunt response to immunotherapy. Conversely, the 
presence of a tumor infiltrating lymphocyte population has been correlated with response 
to immune checkpoint blockade in other malignancies. To better define the spatial 
relationship between CTCL cells and the other key microenvironment residents, we will 
employ multiparametric immunohistochemistry for CD3, CD4, CD8, Foxp3, and CD163. 
In addition, we will co-stain for PD1, PD-L1, PD-L2, to define expression of these key 
markers on the relevant immune subsets. 
2.5.3 Multiplexed Ion Beam Imaging 
The skin microenvironment of CTCL includes CD8+ tumor infiltrating T cells, dendritic 
cells, macrophages, mast cells, and non-malignant CD4+ T cells including regulatory T 
cells. While the above studies will provide essential data with standard methodologies, 
they are unable to discriminate many critical cell populations due to the limitation of 
simultaneously detectable parameters. As a relevant example, in CTCL, the malignant T 
cells themselves can only be reliably identified by the expression pattern of a minimum 
of two parameters, typically CD4 and either CD7 or CD26. Until recently, there has been 
no imaging technology available capable of providing sufficient dimensionality to both 
discriminate relevant immune populations and simultaneously detect expression of other 
key markers.  
A mass spectrometry-based approach dubbed multiplexed ion beam imaging (MIBI) is a 
novel approach to antibody-mediated labeling and imaging of tissue. The use of heavy 
metal isotope labels enables high dimensional multiplexing with minimal overlap 
between metals from formalin-fixed paraffin embedded tissue samples resulting in a 
theoretical limit of over 100 parameters collected per image. Currently, access to MIBI 
technology is very limited, with only two systems available worldwide. In collaboration 
with researchers at Stanford University, we have the opportunity to apply MIBI 
technology to study the CTCL skin microenvironment in unprecedented detail from 
primary patient samples collected before and during therapy. Through high dimensional 
analysis, we will decipher the complex interactions between tumor cells and the diverse 
immune residents within their local microenvironment. MIBI is uniquely capable of 
simultaneously discerning both the spatial relationship between CTCL cells and 
interacting immune cells and their relative expression of relevant immunomodulatory 
molecules such as PD-1 and PD-L1. Applying MIBI to paired samples will provide an 
unparalleled glimpse into the perturbation of the immune microenvironment induced by 
immune checkpoint blockade. 
2.5.4 Transcriptional Analyses 
The Nanostring platform will be used to profile mRNA expression of approximately 730 
genes in an attempt to define a gene set predictive for clinical response to MK-3475 
(pembrolizumab). The utility of this assay is two-fold. First, it will test the hypothesis 
that there is an immune related gene expression signature that predicts response to MK-
3475 (pembrolizumab) and interferon gamma. Second, it will assess for Th1 polarization 
by interferon gamma of helper T cells in the tumor site. Profiling will be performed on 

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RNA extracted from FFPE skin biopsies and may also be performed on peripheral blood 
mononuclear cells. 
2.5.5 Whole exome sequencing and Neoantigen prediction 
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. Neoantigen specific T cells will be detected by a combination of peptide-
MHC tetramer staining and functional assays such as upregulation of CD137, OX-40, and 
interferon-gamma production after stimulation with candidate neoantigen peptides.  
2.5.6 Immunophenotyping 
CyTOF is a mass spectrometry-based method of single cell analysis analogous to flow 
cytometry that is capable of collecting >30 parameters for each cell. CyTOF and 
multiparametric flow cytometry will be employed to extensively immunophenotype 
circulating peripheral lymphocytes before treatment, after 1 week of interferon gamma 
treatment and after the treatment with a combination of MK-3475 (pembrolizumab) and 
interferon gamma. In addition to standard immunophenotyping, cells will be analyzed 
with and without TCR stimulation (either by PMA/ionomycin or anti-CD3) to assess for 
function defects in T cells. 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 Mycosis 
Fungoides/Sézary Syndrome. Flow cytometry will also be used to evaluate peripheral 
blood mononuclear cells. 
2.5.7 Cytokine/Chemokine Analysis (serum ELISA) 
Perturbations in cytokines, chemokines, and growth factors have been associated with 
cancers and changes in plasma cytokine concentrations of proinflammatory and 
immunosuppressive cytokines may correlate with clinical responses to therapy. 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 
(before treatment) and on treatment. Exploratory analysis will be performed to determine 
whether any cytokines/chemokines correlate with response to therapy. These assays will 
also provide a glimpse into the systemic immune perturbations caused by systemic 
interferon gamma therapy. 
2.5.8 T cell receptor high throughput sequencing 
High throughput sequencing of TCR genes is emerging as a valuable disease marker and 
measure of minimal residual disease in cutaneous T cell lymphomas. In addition to 
providing a measurement of the burden of the malignant clone, high throughput 

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sequencing allows interrogation of the entire T cell repertoire. This correlate will enable 
an exploratory analysis of the TCR repertoire as a potential biomarker for response to 
therapy. Characteristics such as repertoire diversity and clonal dynamics will be 
correlated to clinical responses. We will also compare TCR to flow cytometry in the 
identification and quantification of Circulating Sézary Cells.  
2.5.9 Kyn/Trp Ratio 
IDO catabolizes the conversion of Tryptophan to Kynurenine, which has potent 
immunosuppressant properties. An increase in Kynurenine levels over time, relative to 
Tryptophan levels, is known to be inhibitory to T cell function. For patients who are 
failing anti-PD-1 therapy increased Kyn/Trp ratios could indicate that IDO expression 
may be leading to treatment failure. Kyn/Trp ratios will be assayed in patients receiving a 
regimen of MK-3475 (pembrolizumab) 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. 
This mechanism of resistance could potentially be overcome with an IDO inhibitor. 
2.5.10 Microbiome Analyses 
Recent evidence suggests that the microbiome has an effect on response to checkpoint 
blockade immunotherapy, and there is growing evidence that the intestinal microbiome in 
particular may have major influences on anti-tumor immune responses. The microbiota 
has long been known to have profound effects on innate and adaptive immunity. 
However, the impact and importance of the gut microbiome in human cancer patients’ 
responses to immunotherapy has not yet been well-characterized and will be important to 
determine. To begin to understand the role of the microbiome in responses to 
immunotherapy in this protocol, we will collect microbiome samples from patients and 
perform taxonomic profiling via 16S rRNA gene sequencing and metagenomic whole 
genome shotgun (WGS) sequencing. Fecal samples will be collected and stored using 
standard, at home stool-collection procedures and we will assess the landscape of the gut 
microbiome. Sequencing data will be analyzed and compared to clinical responses to 
determine whether response or non-response to treatment can be correlated with specific 
microbiota.  
2.6 
Correlative Studies Background (Treatment Group 2) 
2.6.1 Flow Cytometry for Selected Class I HLA Alleles and Tetramer Analyses for Antigen-
Specific T Cell Phenotyping on PBMC (Flow Cytometry) 
Antibodies for HLA-A02 and A-24 will be used to select patients for further analysis 
using MHC tetramers. Cryopreserved PBMC from those subjects expressing these alleles 
will be analyzed using flow panels that include MHC tetramers for known epitopes to 
NY-ESO-1, PRAME, MAGE-4, MAGE-A3, and MAGE-A9 along with other markers to 
look for changes in the number and phenotype of antigen specific T cells. Markers may 
include, but are not limited to: CD45, CD3, CD4, CD8, CD45RA, CD197 (CCR7), 
CD28, CD127, CD25, HLA-DR, CD279 (PD-1), CD278, CD45RO, CD62L, CD28 and 

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FoxP3. Additional MHC tetramers directed to MHC/peptide combinations may be used 
depending on availability and identifying potential appropriate MHC alleles from HLA-
typing. 
 
2.6.2 Immune Phenotype Panel (Multispectral Immunohistochemistry) 
Paired baseline and post-baseline tumor biopsies will be evaluated using quantitative 
multicolor immunohistochemistry (IHC) with Perkin-Elmer’s Vectra IHC platform. This 
platform employs spectral deconvolution imaging to separate optical signals from each 
antibody together with state-of–the-art image analysis capabilities to facilitate robust 
quantitative slide-based immunophenotyping. Multicolor tyramide-based IHC was 
previously employed to analyze PD-L1, PD-1 and their close spatial proximity, which 
was associated with response to anti-PD1 blockade. Using the Vectra multi-spectral 
imaging platform (PerkinElmer), adjacent tumor sections will be stained and imaged with 
a series of 5-6 antibodies per section simultaneously to investigate the spatial relationship 
between key immunomodulatory cell types and molecules.  The antibodies will include, 
but are not limited to, the following: CD8, CD4, PD-1, PD-L1, CD68, CD163, FOXP3, 
arginase, pan-MHC class I and class II. Data will be generated in the form of total 
positive cells, positive cells/mm2, percentage positive cells in a population, ratios of cells 
and molecules of interest (e.g. PD-L1:CD8 or FOXP3+CD4+:CD8).  Furthermore, 
quantitative analysis of tumor-infiltrating lymphocyte (TIL) distribution (i.e., stromal, 
and interface/invasive margin) will be performed. These analyses will be performed using 
qualified analytes and analytic tools at the immunopathology lab of the FHCRC in a non-
CLIA approved environment.  Chromogenic anti-PD-L1 immunohistochemical staining 
with the 22C3 antibody (Dako) kit (which has been approved as a companion diagnostic 
assay for the selection of NSCLC patients) will be performed in addition to the 
multispectral IHC (msIHC) to serve as both an independent test and control for the 
reproducibility of the msIHC assay. 
 
2.6.3 Immune Gene Expression Signature (NanoString®Gene Expression using the nCounter® 
Human Immunology V2 Panel and the nCounter®PanCancer Immune Profiling Panel) 
NanoString®-based gene expression analysis, specifically for the “IFN γ Signature”, will 
be used to test the hypothesis that the investigational study treatment regimen, IFNγ and 
pembrolizumab, will promote a pro-inflammatory anti-tumor immune response. We 
hypothesize that induction of such a response will correlate with clinical outcomes. RNA 
will be extracted from all paraffin-embedded tumor samples and analyzed using the 
NanoString® nCounter Immunology V2 Profiling Pane, which includes over 700 other 
genes associated with inflammation. The samples used for the planned gene expression 
analyses will be taken from tissue sections adjacent to those stained for multi-spectral 
IHC to facilitate comparison between these analysis sets. Samples will consist of matched 
pre- and post-treatment FFPE biopsies. 

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2.6.4 T Cell Receptor (TCR) Clonality (TCR ImmunoSeq) 
High throughput sequencing of TCR genes is emerging as a potentially valuable disease 
marker and allows interrogation of the entire T cell repertoire. This correlate enables an 
exploratory analysis of the TCR repertoire as a potential biomarker for response to 
therapy. Characteristics such as repertoire diversity and clonal dynamics, as surrogates of 
expanded responses against tumor antigens will be correlated to clinical responses. TCR 
sequencing will be performed when pretreatment and post-treatment biopsies are 
available. TCR repertoire analysis will be performed on RNA extracted from FFPE 
biopsies. TCR repertoire analysis has been standardized and commercialized by Adaptive 
Biosciences. The TCR sequences will also specifically be queried for sequences already 
known to encode for TCRs reactive to shared antigens often expressed in synovial 
sarcoma (e.g., MAGE-A3, NY-ESO-1, LAGE-1, and PRAME). 
 
2.6.5 PD-L1 Baseline and Post-Treatment (Immunohistochemistry)  
PD-L1 has been identified as an important correlative biomarker for clinical response to 
anti-PD-L1 and anti-PD-1 therapies. In particular, given that the function of MK-3475 
(pembrolizumab) is to block binding of PD-1 to PD-L1, expression of PD-L1 will be 
quantitated by IHC in baseline formalin-fixed paraffin-embedded tumor specimens, and 
from biopsies obtained after treatment. This is an important part of the correlative studies 
to explore whether this marker which correlates with response in other circumstances also 
correlates with response in this protocol population. For baseline samples, formalin-fixed, 
paraffin-embedded tissue block(s) from tumor obtained before treatment will be obtained 
by the clinical site either from archival samples obtained from the relevant pathology 
laboratories where they were processed and stored, or from baseline biopsy as part of this 
protocol (core, punch, or excisional). Post-treatment, formalin-fixed paraffin-embedded 
tumor specimens will be obtained from biopsy at week 8-12 as part of this protocol. 
 
2.6.6 Whole Blood Lymphocyte and Monocyte Immunophenotyping (Whole Blood 
Multiparametric Flow Cytometry) 
Multiparametric flow cytometry will be used to assess the effect of interferon gamma-1b 
and MK-3475 (pembrolizumab) on circulating lymphocyte and monocyte numbers and 
phenotype. 
We will assess the effects of treatment on the frequency and phenotypic character of 
PBMC subsets including dendritic cells (DCs), monocyte populations, T cells, NK cells, 
and B cells. The effect on these immune cell subtypes of checkpoint inhibitors, and other 
immune modulators is being investigated in other CITN trials and may provide important 
correlative information on the success or failure of combination immunotherapy. 

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A 14-color whole blood immunophenotyping assay will quantify in one panel the 
absolute number and proportion of T cells (both CD8+ and CD4+), NK cells 
(CD56+CD3-), NKT cells (CD56+CD3+), B cells (CD19+/CD20+), monocytes 
(CD16+), neutrophils (CD15+), as well as both myeloid DCs (CD45+HLA-
DR+CD11c+CD123-) and plasmacytoid DCs (CD45+HLA-DR+CD11c-CD123+). In 
addition, myeloid-derived suppressor cells (MDSC) will be measured using antibodies to 
HLA-DR, CD11b, and CD33 in this same multiparameter flow cytometric assay. 
Multiparameter flow cytometry on whole blood with a 12-color panel may also be used in 
parallel to further define the phenotype of T cells and to identify activated T cells, T-cell 
subsets (including regulatory T cells). This validated panel includes the markers CD45, 
CD3, CD4, CD8, CD45RA, CD197 (CCR7), CD28, CD127, CD25, HLA-DR, CD279 
(PD-1), CD278.  Assays will be performed under the direction of Dr. Steven Fling in the 
CIML at the Fred Hutch. 
 
2.6.7 Anti-Tumor Immune T cell Responses (ELISPOT) 
The ability of the investigational treatment to induce a tumor antigen-specific immune 
response will be assessed using ex vivo incubation of PBMC-derived T cells with 
autologous PBMC-derived antigen presenting cells (APCs), pulsed with peptide antigens 
from proteins that these tumors are known to express. Quantitation of the strength of the 
antigen-specific T cell responses using ELISPOT assays will be done and compared to 
each patient’s baseline and post-baseline T cell (IFN-γ secretion) for each of these known 
immunogenic antigens. The hypothesis predicts that treatment will lead to an increase in 
the strength and number of antigen-specific IFN-γ secreting T cells in responding 
patients. 
 
2.6.8 Multiplex Cytokines (Affymatrix or Luminex) 
We will perform a longitudinal analysis of cytokines, chemokines and other serum 
tumor/oncogene-associated proteins at baseline (before treatment) and on treatment. 
Exploratory analysis will be performed to determine whether any cytokines/chemokines 
correlate with response to therapy.  Serum cytokine analysis will be used to explore 
whether reactive changes in cytokine levels correlates with toxicity and efficacy of 
interferon gamma-1b and MK-3475 (pembrolizumab). 
 
2.6.9 Microbiome Analyses 
Recent evidence suggests that the microbiome has an effect on response to checkpoint 
blockade immunotherapy, and there is growing evidence that the intestinal microbiome in 
particular may have major influences on anti-tumor immune responses. The microbiota 
has long been known to have profound effects on innate and adaptive immunity. 

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However, the impact and importance of the gut microbiome in human cancer patients’ 
responses to immunotherapy has not yet been fully characterized. To begin to understand 
the role of the microbiome in responses to immunotherapy in this protocol, we will 
collect microbiome samples from patients and perform taxonomic profiling via 16S 
rRNA gene sequencing and metagenomic whole genome shotgun (WGS) sequencing. 
Fecal samples will be collected and stored using standard, at home stool-collection 
procedures and we will assess the landscape of the gut microbiome. Sequencing data will 
be analyzed and compared to clinical responses to determine whether response or non-
response to treatment can be correlated with specific microbiota.  
 
2.6.10 HLA Class I and Class II Typing 
To further select samples for analysis using additional, potential MHC/peptide tetramers, MHC 
typing will be performed. DNA will be extracted from residual blood collected at baseline and 
processed and sequenced in the laboratory of Dr. Dan Geraghty (FHCRC). 
 
3. 
PATIENT SELECTION 
3.1 
Eligibility Criteria  
3.1.1 Mycosis Fungoides/Sézary Syndrome (Treatment Group 1)  
3.1.1.1 
Stage IB-IVB Mycosis Fungoides/Sézary Syndrome, and who have relapsed, are 
refractory, or progressed after at least one standard systemic therapy. Maximal stage 
since diagnosis will determine eligibility. Current disease stage at time of entry will 
also be documented but will not be used for eligibility.  
3.1.1.2 
Subjects must have the following minimum wash-out from previous treatments and 
without treatment between documentation of relapse/progression and enrollment: 
• ≥2 weeks for local radiation therapy. 
• ≥8 weeks for low dose (12 Gy or less) Total Skin Electron Beam Therapy 
(TSEBT) 
• ≥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 alemtuzumab for which the washout is at 
least 16 weeks. 
• ≥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). 
• ≥2 weeks from resolution (i.e., < Grade 1 or at baseline) from AEs due to 
procedures performed or therapeutic agents administered. 
• ≥2 weeks for retinoids, interferons, vorinostat, romidepsin and denileukin diftitox. 

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• ≥4 weeks for doses of systemic corticosteroids greater than 10mg/day of 
Prednisone or equivalent. Patients who are on physiologic doses of corticosteroids 
(prednisone equivalent 10mg/day or less) may participate, however, they must be 
on a stable dose for at least 4 weeks before enrollment. Patients who are on low or 
moderate potency topical corticosteroids may participate if they are on a stable 
dose for at least 4 weeks before enrollment. Inhaled corticosteroids are 
acceptable. Local injections of corticosteroids are acceptable. All corticosteroids 
will be reported as concomitant medications. 
• ≥2 weeks for phototherapy. 
• ≥1 week for topical therapy (including retinoid, nitrogen mustard, or imiquimod). 
3.1.1.3 
Patients with prior treatment with IFN-gamma will be eligible, if they previously 
tolerated IFN-gamma, however patients must be off of IFN-gamma for at least three 
weeks before initiation of therapy on this trial.  
3.1.1.4 
Age ≥18 years.  
3.1.1.5 
Have measurable disease based on mSWAT (definition provided in Appendix). 
Tumor lesions situated in a previously irradiated area are considered measurable if 
progression has been demonstrated in such lesions. 
3.1.1.6 
Have a performance status of 0 or 1 on the ECOG Performance Scale. 
3.1.1.7 
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 
Hematological 
 
 
Absolute neutrophil count (ANC) 
≥1500/mcL 
 
Platelets 
≥100 000/mcL 
 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L  
Renal 
 
 
Creatinine OR  
 measured or calculated creatinine clearance 
(CrCl) a,b 
≤1.5 × ULN OR 
≥60 mL/min for patient with creatinine 
levels >1.5 × institutional ULN 
Hepatic 
 
 
Total bilirubin 
≤1.5 × ULN OR  
Direct bilirubin ≤ULN for patients with 
total bilirubin levels >1.5 × ULN 
 
AST (SGOT) and ALT (SGPT) 
≤2.5 × ULN OR  
≤5 × ULN for patients with liver metastases 
a Creatinine clearance (CrCl) should be calculated per institutional standard. 
b Glomerular filtration rate (GFR) can also be used in place of creatinine or CrCl. 

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3.1.1.8 
The effects of MK-3475 (pembrolizumab) and Interferon-gamma on the developing 
human fetus are unknown. For this reason and because anti-PD-1agents and 
Interferons may be teratogenic, women of child-bearing potential and men must agree 
to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) before study entry and for the duration of study participation.  
3.1.1.9 
Female patients of childbearing potential must have a negative urine or serum 
pregnancy test within 72 hours before receiving the first dose of study medication. If 
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required.  
3.1.1.10 
Female patients of childbearing potential (Section 5.7) must be willing to use an 
adequate method of contraception as outlined in Section 5.7 Contraception and 
Pregnancy, for the course of the study through 120 days after the last dose of study 
medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the patient. 
3.1.1.11 
Male patients of reproductive potential must agree to use an adequate method of 
contraception as outlined in Section 5.7 Contraception and Pregnancy, starting with 
the first dose of study therapy through 120 days after the last dose of study therapy. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the patient. 
3.1.1.12 
Should a woman become pregnant or suspect she is pregnant while she or her partner 
is participating in this study, she should inform her treating physician immediately. 
Men treated or enrolled on this protocol must also agree to use adequate 
contraception before the study, for the duration of study participation, and 4 months 
after completion of MK-3475 (pembrolizumab) and Interferon-gamma 
administration. 
3.1.1.13 
Ability to understand and the willingness to sign a written informed consent 
document. 
 

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3.1.2 Synovial Sarcoma (Treatment Group 2) 
3.1.2.1 
Diagnosis of translocation associated sarcoma that generally expresses NY-ESO-1 
(e.g., Synovial Sarcoma or Myxoid/Round Cell Liposarcoma). Tumor must have been 
reviewed by a bone and soft tissue pathologist. Patient must have metastatic or 
unresectable disease. 
3.1.2.2 
At least one prior line of chemotherapy 
3.1.2.3 
Age ≥12 years. Patients ≥18 years of age must be able and willing to provide 
informed consent. Patients under 18 years of age must have a parent or guardian 
willing and able to provide consent. 
3.1.2.4 
Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 
3.1.2.5 
Life expectancy greater than or equal to (>/=) 12 weeks 
3.1.2.6 
Measurable disease, as defined by RECIST v1.1 
3.1.2.7 
Tumor safely accessible for biopsy 
3.1.2.8 
Adequate hematologic and end organ function 
3.1.2.9 
For female participants of childbearing potential and male participants with partners 
of childbearing potential, agreement (by participant and/or partner) to use highly 
effective form(s) of contraception as outlined in Section 5.7  
 
 

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3.2 
Exclusion Criteria 
3.2.1 Mycosis Fungoides/Sézary Syndrome (Treatment Group 1) 
3.2.1.1 
Has disease that is suitable for local therapy administered with curative intent. 
3.2.1.2 
Patients who have had chemotherapy or targeted small molecule therapy within 4 
weeks (6 weeks for nitrosoureas or mitomycin C) before entering the study. 
3.2.1.3 
Patients who have had an allogeneic stem cell transplant are excluded because such 
transplants disrupt the normal immune response to a very substantial degree. In 
addition, emerging data suggests exacerbation of lethal GVHD may occur in such 
patients when treated post allotransplant with PD-1 blockade.  
3.2.1.4 
Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2. 
3.2.1.5 
Patients who have received an investigational agent or have used an investigational 
device within 4 weeks of the first dose of study drug. 
3.2.1.6 
Has a history of a well-characterized and defined immune deficiency before the 
diagnosis of Mycosis Fungoides/Sézary Syndrome or is receiving systemic steroid 
therapy greater than 10mg/day of Prednisone or equivalent within 4 weeks or any 
other form of immunosuppressive therapy within 7 days before the first dose of trial 
treatment. The use of physiologic replacement doses of corticosteroids, along with 
topical, inhaled and local injection is discussed in section 3.1.2.  
3.2.1.7 
Has had a prior monoclonal antibody within 4 weeks before 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. 
Note: The following will not be exclusionary: 
• Patients may have any grade alopecia or lymphopenia and still participate if other 
inclusion/exclusion criteria are met. Patients may have grade 1 or 2 neuropathy at 
baseline and still participate if other inclusion/exclusion criteria are met.  
3.2.1.8 
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 that has undergone potentially curative therapy, or in situ cervical cancer. 
3.2.1.9 
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 using the identical imaging 
modality for each assessment, either magnetic resonance imaging (MRI) or computed 
tomography (CT) scan, for at least 4 weeks before the first dose of trial treatment and 
any neurologic symptoms have returned to baseline), have no evidence of new or 

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enlarging brain metastases, and are not using steroids for at least 7 days before trial 
treatment.  
3.2.1.10 
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to MK-3475 (pembrolizumab) and Interferon-gamma. Patients who are 
hypersensitive to E. Coli are also excluded.  
3.2.1.11 
Has an active autoimmune disease that has required systemic treatment in the past 2 
years (i.e., with use of disease modifying agents, corticosteroids, or 
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, 
etc.) is not considered a form of systemic treatment. 
3.2.1.12 
Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis.  
3.2.1.13 
Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the patient’s participation 
for the full duration of the trial, or is not in the best interest of the patient to 
participate, in the opinion of the treating investigator. 
3.2.1.14 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, interstitial lung disease or active, non-infectious pneumonitis, congestive 
heart failure NYHA grade ≥3, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study 
requirements. 
3.2.1.15 
Pregnant women are excluded from this study because MK-3475 (pembrolizumab) 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 (pembrolizumab), breastfeeding should be 
discontinued if the mother is treated with MK-3475 (pembrolizumab). These potential 
risks may also apply to Interferon-gamma.  
MK-3475 (pembrolizumab) and Interferon-gamma may have adverse effects on a 
fetus in utero. Furthermore, it is not known if MK-3475 (pembrolizumab) or 
Interferon-gamma have 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 
screening visit through 120 days after the last dose of trial treatment.  
See Section 5.7 for information on contraception and pregnancy. 
3.2.1.16 
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. 
4. Must be on antiretroviral therapy and there must be minimal interactions or 

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overlapping toxicity of the antiretroviral therapy with the experimental cancer 
treatment.  
5. HIV viral load must be <200 copies/ mm3 by standard clinical assays.  
3.2.1.17 
Has known active hepatitis B (e.g., HBsAg reactive) or hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
Note: The following will not be exclusionary: 
1. A positive hepatitis B serology indicative of previous immunization (i.e., 
HBsAb positive and HBcAb negative), or a fully resolved acute HBV 
infection  
2. Patients with chronic HBV suppressed by appropriate antiretroviral therapy 
with activity against HBV, as outlined in DHHS guidelines 
3. Positive HCV serology but no detectable HCV RNA, indicative of 
spontaneously cleared HCV infection 
4. Patients who have been successfully treated for HCV as long as therapy for 
HCV has been completed 
3.2.1.18 
Has received a live vaccine within 30 days before the first dose of trial treatment. 
Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, chicken pox, yellow fever, seasonal flu (some), H1N1 flu, rabies, 
BCG, and typhoid vaccine. Seasonal flu vaccines that do not contain live virus are 
permitted.  
3.2.1.19 
Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
 

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3.2.2 Synovial Sarcoma (Treatment Group 2) 
3.2.2.1 
Any approved or investigational anti-cancer therapy within 14 days prior to initiation 
of study treatment.   
Note: Prior treatment with anti-programmed death-1 (anti-PD-1) or anti-programmed 
death-ligand 1 (anti-PD-L1) therapeutic antibodies is allowed as is prior therapy with 
other immunotherapies. 
3.2.2.2 
Active or untreated central nervous system (CNS) metastases as determined by 
computed tomography (CT) or magnetic resonance imaging (MRI) evaluation during 
screening and prior radiographic assessments. Patients with prior brain metastases or 
CNS disease are permitted, but must have completed treatment and either (1) have no 
evidence of active CNS disease for at least 4 weeks prior to the first dose OR (2) have 
stable CNS lesions, or be at least 2 weeks past radiation or gamma-knife therapy.  
Patients with past CNS disease must also have a Screening head CT or MRI 
demonstrating stable disease compared to their most recent CNS evaluation.  
3.2.2.3 
Active therapy for malignancies other than sarcoma.   
3.2.2.4 
Pregnant and lactating women 
3.2.2.5 
New York Heart Association (NYHA) class 3 or 4 or clinically symptomatic 
cardiovascular disease  
3.2.2.6 
Severe infections requiring intravenous antibiotic treatment within 2 weeks prior to 
initiation of treatment 
3.2.2.7 
Major surgical procedure other than for diagnosis within 4 weeks prior to initiation of 
treatment 
3.2.2.8 
Active autoimmune disease requiring systemic treatment with steroids greater than 10 
mg/day of prednisone or who have required steroids with a dose of 40 mg/day for the 
treatment of their autoimmune disease more than twice over the past year. Patients 
with an autoimmune disease who are on active therapy with a drug targeting TNF 
alpha.  
3.2.2.9 
Prior allogeneic stem cell or solid organ transplant 
3.2.2.10 
History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced 
pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening 
chest CT scan  
3.2.2.11 
Active tuberculosis  
3.2.2.12 
HIV on effective antiretroviral therapy will not be excluded.  
3.2.2.13 
Uncontrolled HBV infection, defined as plasma HBV DNA detectable by PCR  
o Note: the following will NOT be exclusionary:  
▪ 
A positive hepatitis B serology indicative of previous immunization (i.e., HBsAb 
positive and HBcAb negative), or a fully resolved acute HBV infection   
▪ 
Patients with chronic HBV suppressed by appropriate antiretroviral therapy with 
activity against HBV, as outlined in DHHS guidelines  
3.2.2.14 
Uncontrolled HCV infection, defined as plasma HCV RNA detectable by PCR.  
o Note:  the following will NOT be exclusionary:  

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▪ 
Positive HCV serology but no detectable HCV RNA, indicative of spontaneously 
cleared HCV infection  
▪ 
Patients who have been successfully treated for HCV as long as therapy for HCV 
has been completed 
 
3.3 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial. 
4. 
REGISTRATION PROCEDURES (TREATMENT GROUP 1 AND 2) 
4.1 
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 individuals contributing to NCI-sponsored trials to register and to renew 
their registration annually. To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (CTEP) Identity and Access Management (IAM) account at 
https://ctepcore.nci.nih.gov/iam. In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., 
clinical site staff requiring write access to OPEN, Rave, or acting as a primary site 
contact) must complete their annual registration using CTEP’s web-based Registration 
and Credential Repository (RCR) at https://ctepcore.nci.nih.gov/rcr.  
RCR utilizes five person registration types. 
• IVR – MD, DO, or international equivalent; 
• NPIVR – advanced practice providers (e.g., NP or PA) or graduate level 
researchers (e.g., PhD); 
• AP – clinical site staff (e.g., RN or CRA) with data entry access to CTSU 
applications (e.g., Roster Update Management System (RUMS), OPEN, Rave); 
• Associate (A) – other clinical site staff involved in the conduct of NCI-sponsored 
trials; and 
• Associate basic (AB) – individuals (e.g., pharmaceutical company employees) 
with limited access to NCI-supported systems. 
 
RCR requires the following registration documents: 

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Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
FDA Form 1572 
✓ 
✓ 
 
 
 
Financial Disclosure Form 
✓ 
✓ 
✓ 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
✓ 
✓ 
✓ 
 
 
GCP training 
✓ 
✓ 
✓ 
 
 
Agent Shipment Form (if applicable) 
✓ 
 
 
 
 
CV (optional) 
✓ 
✓ 
✓ 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access 
all CTEP and Cancer Trials Support Unit (CTSU) websites and applications. In addition, 
IVRs and NPIVRs must list all clinical practice sites and Institutional Review Boards 
(IRBs) covering their practice sites on the FDA Form 1572 in RCR to allow the 
following: 
• Addition to a site roster; 
• Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
• Act as the site-protocol Principal Investigator (PI) on the IRB approval; and 
• Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DLT). 
In addition, all investigators act as the Site-Protocol PI, consenting/treating/drug 
shipment, or as the CI on the DTL must be rostered at the enrolling site with a 
participating organization (i.e., Alliance). 
Additional information is located on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact 
the RCR Help Desk by email at RCRHelpDesk@nih.gov.  
4.2 
CTSU Registration Procedures 
This study is supported by the NCI CTSU. 
4.2.1 IRB Approval 
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical Trials 
Network (NCTN) and NCI Community Oncology Research Program (NCORP) Research Bases 
after March 1, 2019, all U.S.-based sites must be members of the NCI Central Institutional 
Review Board (NCI CIRB). In addition, U.S.-based sites must accept the NCI CIRB review to 
activate new studies at the site after March 1, 2019. Local IRB review will continue to be 
accepted for studies that are not reviewed by the CIRB, or if the study was previously open at the 
site under the local IRB. International sites should continue to submit Research Ethics Board 
(REB) approval to the CTSU Regulatory Office following country-specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for Local 
Context (SSW) to the CIRB using IRB Manager to indicate their intent to open the study locally. 

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The NCI CIRB’s approval of the SSW is automatically communicated to the CTSU Regulatory 
Office, but sites are required to contact the CTSU Regulatory Office at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB approvals 
across their Signatory Network. Site preferences can be set at the network or protocol level. 
Questions about establishing site preferences can be addressed to the CTSU Regulatory Office by 
emailing the email address above or calling 1-888-651-CTSU (2878). 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory Office 
using the Regulatory Submission Portal located in the Regulatory section of the CTSU website. 
Acceptable documentation of local IRB/REB approval includes: 
• Local IRB documentation; 
• IRB-signed CTSU IRB Certification Form; and/or 
• Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of 
Exemption Form. 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the IRB/REB 
approval) must meet the following criteria to complete processing of the IRB/REB approval 
record: 
• Holds an Active CTEP status; 
• Rostered at the site on the IRB/REB approval and on at least one participating roster; 
• If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile; and 
• Holds the appropriate CTEP registration type for the protocol. 
 
4.2.2 Additional Requirements 
Additional requirements to obtain an approved site registration status include: 
• An active Federal Wide Assurance (FWA) number; 
• An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization (PO); and 
• Compliance with all protocol-specific requirements (PSRs). 
 
4.2.3 Downloading Site Registration Documents 
Download the site registration forms from the protocol-specific page located on the 
CTSU members’ website. Permission to view and download this protocol and its 
supporting documents is restricted based on person and site roster assignment. To 
participate, the institution and its associated investigators and staff must be associated 
with the LPO or a PO on the protocol.  

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48 
 
• Log on to the CTSU members’ website (https://www.ctsu.org) using your CTEP-IAM 
username and password; 
• Click on Protocols in the upper left of your screen  
o Enter the protocol number in the search field at the top of the protocol tree, or 
o Click on the By Lead Organization folder to expand, then select CITN, and 
protocol number CITN-13; 
• Click on Documents, select Site Registration, and download and complete the forms 
provided. 
(Note: For sites under the CIRB initiative, IRB data will load automatically to the 
CTSU as described above.)   
4.2.4 Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal on the CTSU website.  
To access the Regulatory Submission Portal log on to the CTSU members’ website → 
Regulatory → Regulatory Submission. 
 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to 
receive further instruction and support. 
4.2.5 Checking Your Site’s Registration Status 
You can verify your site’s registration status on the members’ side of the CTSU website.  
• Log on to the CTSU members’ website; 
• Click on Regulatory at the top of your screen; 
• Click on Site Registration; 
• Enter your 5-character CTEP Institution Code and click on Go 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined above.. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling investigator’s 
status with the NCI or their affiliated networks. 
4.3 
Patient Enrollment 
4.3.1 OPEN 
The Oncology Patient Enrollment Network (OPEN)is a web-based registration system available 
on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and with the Lead 
Protocol Organization (LPO) registration/randomization systems or Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/randomization assignment. OPEN 

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49 
 
will populate the patient enrollment data in NCI’s clinical data management system, Medidata 
Rave. 
Requirements for OPEN access:   
• A valid CTEP-IAM account; 
• To perform enrollments or request slot reservations:  Be on a LPO roster, ETCTN 
Corresponding roster, or PO roster with the role of Registrar. Registrars must hold a 
minimum of an AP registration type; 
• If a Delegation of Tasks Log (DTL) is required for the study, the registrar(s) must hold 
the OPEN Registrar task on the DTL for the site; and 
• Have an approved site registration for a protocol prior to patient enrollment. 
.  
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient transfer in 
OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB approval on their 
Form FDA 1572 in RCR. If a DTL is required for the study, the IVR or NPIVR must be assigned 
the appropriate OPEN-related tasks on the DTL. 
 Prior to accessing OPEN, site staff should verify the following: 
• Patient has met all eligibility criteria within the protocol stated timeframes; and 
• All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 
Note: The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. Please print this confirmation for your records. 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ website. 
Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
Patient enrollment for this study will be facilitated using the Slot Reservation System in 
conjunction with the registration system in OPEN. Prior to discussing protocol entry with the 
patient, all site staff must use the CTSU OPEN Slot Reservation System to ensure that a slot on 
the protocol is available to the patient. Once a slot reservation confirmation is obtained, site staff 
may then proceed to enroll the patient to this study.  
 
4.4 
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 

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50 
 
may be canceled. The Clinical Research Site (CRS) must notify the CITN Coordinating Center 
of cancellations as soon as possible. 
5. 
TREATMENT PLAN 
5.1 
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. 
5.1.1 Mycosis Fungoides/Sézary Syndrome (Treatment Group 1) 
Treatment Plan 
• MK-3475 (pembrolizumab) will be administered at a dose of 200 mg every 3 weeks by IV 
infusion. No dose modification will be allowed. 
• IFN-gamma will be initiated at 50 mcg/m2 administered subcutaneously 3 times a week (e.g., 
M/W/F or T/Th/Sat).  
Regimen Description (Treatment Group 1) 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
MK-3475 
(pembrolizumab) 
None 
200 mg 
Intravenous 
Refer to section 
8.1.1 for 
compatible infusion 
set materials 
including in-line 
filter. 
Every 3 
weeks (Day 1 
of each cycle) 
3 weeks 
Interferon-
gamma-1b 
Antihistamines, 
analgesics, 
nonsteroidal anti-
inflammatory 
drugs (NSAIDs), 
anti-depressants. 
Refer to Section 
6.1.5 
50 mcg/m2 
(Dose Varies, 
see below) 
Subcutaneous 
Three times 
weekly 
(e.g., M/W/F 
or T/Th/Sat) 
Variable 
 

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The combination will be administered following the schema above: 
• IFN-gamma lead-in treatment x 1 week = > opportunity to obtain correlative biomarkers after 
IFN-gamma monotherapy for correlative studies  
• Combination of MK-3475 (pembrolizumab) 200mg every 3 weeks and IFN-gamma 50 
mcg/m2 3 doses per week for 12 weeks 
• Followed by MK-3475 (pembrolizumab) continued every 3 weeks up to 2 years. IFN-gamma 
boost (3 weeks) blocks every 2 cycles (6 weeks) of MK-3475 (pembrolizumab). IFN-gamma 
will be given 3 weeks on followed by 3 weeks off. If patients are experiencing intolerable 
toxicities and need additional time off, the investigator may increase time off in 1 week 
increments up to 3 weeks. A re-assessment of symptoms is made during this time period. The 
decision to increase time off is at the discretion of the investigator in consultation with the 
patient. If a patient is tolerating IFN-gamma well, IFN-gamma can be given continuously 
without break at the discretion of the investigator and in consultation with the patient starting 
at cycle 7.  This option is intended for patients who experienced worsening of disease or 
associated symptoms during the cycles off of IFN-gamma, or in cases where the investigator 
believes the patient would otherwise benefit from continuous IFN-gamma therapy.   
• Intra-patient dose increase for IFN-gamma: dose increases by 25 mcg/m2 can be considered 
at each boost event if a CR cannot be confirmed at a global clinical assessment, to a max 
IFN-gamma dose of 100 mcg/m2. If toxicity seen at higher IFN-gamma dose is deemed 
intolerable by the treating physician, the IFN-gamma dose can be reduced to the previously 
tolerable dose.  
IFN 
50 
mcg/m
2 
sc 3 
doses  
over 7 
days 
Pembrolizumab 200mg IV every 3 weeks 
IFN 50 mcg/m
2 3 x wk, for 12 
wks 
IFN  
TIW  
3 
wks 
Off 
IFN 
3 
wks 
Off 
IFN 
3 
wks 
IFN  
TIW  
3 
wks 
Repe
at 
On/Of
f IFN 
Lead-in Combination immunotherapy 12 wks 
 IFN Immune boosts q 3 wks  
C1         C2            C3            C4           C5           C6            C7            C8            C9          C10          C11 
up to 2 
yrs 
Screening elements
Correlative skin (s) and/or Peripheral Blood (PB) (b) sampling time points: screening (s/b), post IFN-lead-in (C1D1; 
s/b), C2D1 (early combo effect; s/b), , C6D1 (b), C10D1 (b), then variable intervals (b), new tumor/PD (s/b), or EOT 
(s/b), at time of response, CR or PR, (blood only) and in the event of a Skin Flare Reaction (s/b). 

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• The dose of IFN-gamma will be reduced to 25 mcg/m2 for certain Gr 3 toxicities as outlined 
in  Section 6.1.4, and may be reduced at the investigator discretion to 25mcg/m2 for 
constitutional symptoms as in Section 5.1.1.2.  If patients are experiencing intolerable 
toxicities, IFN-gamma may be held for up to a period of 3 weeks at the discretion of the 
investigator and in consultation with the patient.  A re-assessment of symptoms is made 
during this time period, and treatment may be restarted at any point during the cycle.  If such 
a hold occurs after cycle 5, treatment would recommence at the next planned cycle on IFN-
gamma.  For example, if IFN-gamma were held throughout cycle 8, the next IFN-gamma 
treatment would be at the start of cycle 10.  
Disease Assessments 
• All patients: mSWAT at screening, pre-IFN-gamma lead-in, C1D1, C2D1, then every other 
cycle thereafter, and for CR/PR, PD or EOT, and in the event of a Skin Flare Reaction.  
• Presence of extracutaneous disease at enrollment: Sezary flow at pre-IFN-gamma lead-in, 
C2, C6, C10, then every 4 cycles and in the event of a Skin Flare Reaction; Imaging at 
screening, C5-6, C9-10, (before MK-3475 (pembrolizumab) is administered at cycle 6, and 
10) then every 4 cycles, both Sezary flow and imaging are performed to confirm PR and/or 
CR, when suspect PD and at EOT. 
• Absent extracutaneous disease at enrollment: Imaging at screening, Sezary flow at pre-IFN-
gamma lead-in, then both are performed to confirm PR and/or CR, when suspect PD, at EOT 
and in the event of a Skin Flare Reaction. 
5.1.1.1 
MK-3475 (pembrolizumab) 
Trial treatment of MK-3475 (pembrolizumab) will be administered on Day 1 of each 
3-week treatment cycle after all procedures/assessments have been completed. Trial 
treatment may be administered up to 7 days before or after the scheduled Day 1 of 
each cycle due to administrative reasons, beginning with Cycle 2. A 3-day window is 
allowed for Cycle 1. 
Note: Dosing interruptions are permitted in the case of medical / surgical events or 
logistical reasons (i.e., elective surgery, unrelated medical events, patient vacation, 
holidays) not related to study therapy. Patients should be placed back on study 
therapy within 3 weeks of the scheduled interruption. The reason for interruption 
should be documented in the patient’s study record. 
MK-3475 (pembrolizumab) will be administered as a dose of 200 mg using a 30-
minute IV infusion. Infusion timing should be as close to 30 minutes as possible; 
however, a window of -5 minutes and +10 minutes is permitted (i.e., infusion time is 
25 – 40 minutes). 
5.1.1.2 
Interferon-gamma (Actimmune) 
IFN-gamma will be administered subcutaneously per the approved package insert 
instructions, self-administered by the patient whenever possible. The optimum sites of 
subcutaneous injection are the abdomen, right and left deltoid and anterior thigh. 
Appropriate counseling in the administration of subcutaneous injections must occur 

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before patients are allowed to self-administer IFN-gamma. If the patient is unable to 
self-administer, a family member or caregiver may administer IFN-gamma to the 
patient after proper counseling in the administration of subcutaneous injections. 
Dosages will be increased for inadequate response as described above and will be 
decreased for toxicities as described above. Since toxicities may be constitutional in 
nature, investigator discretion will be necessary to determine the appropriate dose, the 
goal being to find a tolerable dose to keep patients on study.  
5.1.2 Synovial Sarcoma 
Regimen Description (Treatment Group 2) 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
MK-3475 
(pembrolizumab) 
None 
Patients ≥18 
years of age: 200 
mg 
 
Patients <18 
years of age: 2 
mg/kg (max= 
200 mg) 
Intravenous 
Every three weeks starting on 
Day 1 of Cycle 1, followed by 
Day 1 of each 3-week cycle. 
 
Interferon-gamma-
1b 
Antihistamines, 
analgesics, nonsteroidal 
anti-inflammatory 
drugs (NSAIDs), anti-
depressants. 
100 mcg/m2 
Subcutaneous 
Once per week starting one 
week prior to the first dose of 
MK-3475 (pembrolizumab). 
 
5.1.2.1 
MK-3475 (pembrolizumab) 
MK-3475 (pembrolizumab) will be administered on Day 1 of each 3-week cycle after all 
procedures/assessments have been completed. MK-3475 (pembrolizumab) may be administered 
up to 7 days before or after the scheduled Day 1 of each cycle, if needed due to logistical 
reasons, beginning with Cycle 2. A 3 day window is allowed for Cycle 1. 
 
Note: Dosing interruptions are permitted in the case of medical/surgical events or logistical 
reasons (e.g., elective surgery, unrelated medical event, patient vacations or holidays) not related 
to study therapy. Patients should be placed back on study therapy within 3 weeks of the 
scheduled interruption. The reason for interruption should be documented in the patient’s study 
record. 
In patients ≥18 years of age, MK-3475 (pembrolizumab) will be administered at a fixed dose of 
200 mg using a 30-minute IV infusion.  
In patients <18 years of age, MK-3475 (pembrolizumab) will be administered at a dose of 2 
mg/kg (max=200 mg) using a 30-minute IV infusion. 

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Infusion timing should be as close to 30 minutes as possible. However, a window of -5 minutes 
and +10 minutes is permitted (i.e., infusion time is 25-40 minutes). 
 
5.1.2.2 
Interferon Gamma-1b (ACTIMMUNE®) 
Interferon gamma-1b will be administered at a dose of 100 mcg/m2 once per week, starting one 
week prior to initiating pembrolizumab. Interferon gamma-1b will be administered 
subcutaneously per the approved package insert instructions, self-administered by the patient 
whenever possible. If the patient is unable to self-administer, a family member or caregiver may 
administer interferon gamma-1b to the patient. Appropriate counseling in the administration of 
subcutaneous injections must occur prior to the start of treatment. Patients will be given an 
injection log to record drug self-administration and to make note of toxicities. If substantial 
toxicity occurs, interferon gamma-1b, but not pembrolizumab, will be dose de-escalated.  The 
dose of interferon gamma-1b will be reduced to for certain Gr 3 toxicities as outlined in  Section 
6.1.4.  
NOTE: For synovial sarcoma patients the dose of interferon gamma-1b will be reduced by 50 
mcg/m2 (50%). Grade 3 flu-like symptoms including fevers, fatigue, myalgias, or other patient 
reported symptoms that resolve to grade 1 within 48 hours should not trigger an interferon 
gamma-1b dose change. 
 
5.2 
Study Design, Interim Futility, and Safety Evaluation 
5.2.1 Mycosis Fungoides/Sézary Syndrome (Treatment group 1) 
This is a single arm, open label, interventional study to evaluate the efficacy and safety of the 
combination immunotherapy with MK-3475 (pembrolizumab) and IFN-gamma in Mycosis 
Fungoidesor Sézary Syndrome, stages IB-IV, who have relapsed, progressed or otherwise failed 
after at least one standard systemic therapy. There is no planned stratification. 30 patients will be 
enrolled on a continuous basis.  
MK-3475 (pembrolizumab) will be a 200-mg flat dose administered intravenously every 3 
weeks, remaining unchanged throughout the study. 
In this single stage phase II open label trial, we will have an interim futility analysis. When 12 
patients have been followed for 6 months, we will perform the interim futility analysis. If ORR is 
less than 33% (4 or less CR+PR), the trial will stop and we will accept the null that combination 
therapy is no better than monotherapy. Otherwise, trial will continue until 30 patients accrue. If 
ORR is at least 57% (17 or more CR+PR) at the final analysis, we will accept the alternative that 
combination therapy is significantly better than monotherapy. 
There is a planned interim safety review after the first 12 patients are enrolled. If 4 or more out 
of 12 patients experience a study drug related SAE within the first 10 weeks of therapy, the trial 
will not be allowed to continue further enrollment and treatment unless or until reviewed and 
approved by the CITN and NCI CTEP. 

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5.2.2 Synovial Sarcoma (Treatment Group 2) 
The study is a single arm, open label trial of interferon gamma-1b and MK-3475 
(pembrolizumab) for patients with advanced (unresectable or metastatic) synovial sarcoma. Both 
adult and pediatric patients are eligible to participate in this trial. Patients will receive interferon 
gamma-1b at a dose of 100 mcg/m2 weekly, as this dose has been found to be relatively well 
tolerated and successful at inducing MHC expression and T cell infiltration into synovial 
sarcoma tumors. Interferon gamma-1b will begin one week prior to initiating MK-3475 
(pembrolizumab). MK-3475 (pembrolizumab) will be given at a standard fixed dose of 200 mg 
administered every 3 weeks. Thus patients will receive one dose of interferon gamma-1b priming 
their tumors for checkpoint blockade using MK-3475 (pembrolizumab). If substantial toxicity 
occurs, interferon gamma-1b, but not MK-3475 (pembrolizumab), will be dose de-escalated. 
The primary endpoint of the study will be the overall response rate (ORR) based on RECIST v. 
1.1. The ORR is defined as the complete response rate (CR) combined with the partial response 
rate (PR). Based on historical controls, we estimate the ORR of single agent pembrolizumab is 
less than 5%. Twelve patients will be enrolled initially. If one or more of these patients respond, 
an additional four patients will be enrolled.  If three or more patients respond the treatment will 
be considered promising.  
Toxicity will be assessed by CTCAE v. 5.0. Although interferon gamma-1b in combination with 
MK-3475 (pembrolizumab) has previously been seen to be safe, its side effect profile has not 
been confirmed in a synovial sarcoma patient population or in a population of patients with cold 
tumors. There is no reason to suspect there would be additional toxicity in these patients 
however, we will adopt CTEP’s data safety monitoring plan of every two week teleconferences 
attended by all participating site principal investigators, CTEP staff and CITN Coordinating 
Center staff to oversee the safety of the trial. During each activated protocol teleconference all 
patient toxicities, including all serious adverse events (SAE) and all other clinical data will be 
reviewed. Any SAE suspected to be attributed to the study regimen will be distributed to all 
participating site principal investigators and their staff on an urgent basis. If necessary, an ad hoc 
teleconference may be convened to discuss any adverse event determined to be a patient safety 
issue or if the adverse event is suspected of being related to study treatment. 
Radiographic assessment by CT scan will occur every 12 weeks. Response and progression will 
be determined using RECIST v1.1. All patients with either a CR, PR or stable disease (SD) will 
continue therapy for up to two years. Patients will be followed for up to two years after study 
discontinuation for disease status and survival. Patients with radiographic progression but who 
are otherwise stable without symptomatic progression may continue treatment up until 
confirmation at the next radiographic imaging time point in order to assess for possible pseudo 
progression. ORR based on immune related response criteria (IRRC) will also be noted as an 
exploratory endpoint.  
 

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5.3 
General Concomitant Medication and Supportive Care Guidelines (Treatment 
Group 1 and 2) 
5.3.1 MK-3475 (pembrolizumab) 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 any medication or 
vaccination 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 patient’s primary physician; however, the decision to continue the 
patient on trial therapy or vaccination schedule requires the mutual agreement of the 
Investigator, CTEP, and the patient. 
5.3.1.1 
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 30 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 serious adverse events (SAEs). 
5.3.1.2 
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: 
– Antineoplastic systemic chemotherapy or biological therapy.  
– Immunotherapy not specified in this protocol. 
– Chemotherapy not specified in this protocol. 
– Investigational agents other than MK-3475 (pembrolizumab) and Interferon-
gamma (Actimmune). 
– Radiation therapy  
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be 
considered on an exceptional case by case basis after consultation with CTEP. 
The patient must have clear measurable disease outside the radiated field. 
Administration of palliative radiation therapy will be considered clinical 
progression for the purposes of determining PFS. 
– Live vaccines within 30 days before the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited 

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to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, 
Bacillus Calmette–Guérin (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. 
– Systemic glucocorticoids for any purpose other than to modulate symptoms 
from an event of suspected immunologic etiology or for physiologic 
replacement using 10mg/day or less of Prednisone or equivalent. The use of 
physiologic doses of corticosteroids may be approved after consultation with 
the study PI and CTEP.  
– NOTE: For the synovial sarcoma patients in this trial, systemic 
glucocorticoids used for ≤ 10 days for acute inflammatory symptoms (e.g., 
allergic reaction), or used at a low dose (prednisone ≤ 10 mg/day or 
equivalent) for physiologic replacement may be administered at the discretion 
of the treating physician. 
 
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. 
5.4 
Duration of Therapy (Treatment Group 1 and 2) 
In the absence of treatment delays due to AE(s), treatment may continue for up to two years or 
until 1 of the following criteria applies: 
• Disease progression warranting alternative systemic therapy and without evidence of clinical 
benefit from continued MK-3475 (pembrolizumab) + Interferon-gamma. Patients who 
continue MK-3475 (pembrolizumab) + Interferon-gamma 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 
• Adverse event(s) which require(s) treatment discontinuation (see also Section 6): 
➢ Any dosing interruption lasting >12 weeks with the following exceptions: Dosing 
interruptions >12 weeks that occur for non-drug-related reasons may be allowed if 
approved by the Principal Investigator. Before re-initiating treatment in a patient 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. 
• Any patient requiring systemic steroid or other immunosuppressive treatment. (Steroids may 
be allowed if they can be tapered, see section 6.1.3. 

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• Patient decides to withdraw from the study 
• General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
• Patient noncompliance 
• Pregnancy 
➢ All women of child bearing potential should be instructed to contact the investigator 
immediately if they suspect they might be pregnant (e.g., missed or late menstrual period) 
at any time during study participation. 
➢ The investigator must immediately notify CTEP in the event of a confirmed pregnancy in 
a patient participating in the study. 
• Termination of the study by sponsor 
• The drug manufacturer can no longer provide the study agent 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
5.5 
Duration of Follow-Up (Treatment Group 1 and 2) 
All patients, regardless of reason for discontinuation from study, will be followed for AE/SAE 
resolution for 30 days after removal from study. All patients will be followed for survival either 
by in-person visit or by telephone assessment every 12 weeks until 1 year after EOT. 
Disease status and overall survival data will be collected and reported every 12 weeks, either by 
in-person visit or by telephone assessment.  
After disease progression or start of new anticancer treatment, patient will be followed for 
overall survival only. Survival follow-up will continue until death or 1 year after the end of 
treatment, whichever occurs first. 
In subjects who discontinue study therapy without documented disease progression, every effort 
should be made to continue monitoring their disease status by Olsen assessment (for patients 
with Mycosis Fungoides) or by CT scan (for patients with synovial sarcoma) 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 before the date of discontinuation, then an additional assessment at treatment 
discontinuation isn’t mandatory. 
Patients removed from study for unacceptable AE(s) will be followed until resolution or 
stabilization of AE; in addition the patients will be followed for disease status and overall 
survival, as described above. 

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5.6 
Criteria to Resume Treatment (Treatment Group 1 and 2) 
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.  
• Non-drug-related toxicity including hepatic, pulmonary toxicity, diarrhea, or colitis, must 
have resolved to baseline before treatment is resumed. 
• Drug-related endocrinopathies (not including drug-related adrenal insufficiency or 
hypophysitis) adequately controlled with only physiologic hormone replacement may resume 
treatment after replacement correction and clinically stable regimen. 
If the criteria to resume treatment are met, the patient should restart treatment no sooner than the 
next scheduled time point per protocol. However, if the treatment is delayed past the next 
scheduled time point per protocol, the treatment should resume at the earliest convenient point 
that is within the 12-week delay period.  
If treatment is delayed >12 weeks, the patient must be permanently discontinued from study 
therapy, except as specified in Section 5.4 (Duration of Therapy). 
5.7 
Contraception and Pregnancy (Treatment Group 1 and 2) 
5.7.1 Contraception 
MK-3475 (pembrolizumab) may have adverse effects on a fetus in utero. Furthermore, it 
is not known if MK-3475 (pembrolizumab) has transient adverse effects on the 
composition of sperm.  
For this trial, male patients will be considered to be of nonreproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying 
medical condition).  
Female patients will be considered of nonreproductive potential if they are either:  
1. Postmenopausal (defined as at least 12 months with no menses without an 
alternative medical cause; in women <45 years of age, a high follicle-stimulating 
hormone [FSH] level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy. In the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.);  
OR 
2. Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy 
or bilateral tubal ligation/occlusion, at least 6 weeks before screening;  
OR 
3. Has a congenital or acquired condition that prevents childbearing. 
Female and male patients of reproductive potential must agree to avoid becoming 
pregnant or impregnating a partner, respectively, while receiving study drug and for 120 
days after the last dose of study drug by complying with one of the following:  

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1. Practice abstinence† from heterosexual activity;  
OR  
2. Use (or have their partner use) acceptable contraception during heterosexual 
activity.  
Acceptable methods of contraception are‡: 
Single method (1 of the following is acceptable): 
• intrauterine device (IUD) 
• vasectomy of a female patient’s male partner  
• contraceptive rod implanted into the skin 
Combination method (requires use of 2 of the following): 
• diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• cervical cap with spermicide (nulliparous women only)  
• contraceptive sponge (nulliparous women only)  
• male condom or female condom (cannot be used together) 
• hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection 
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the patient’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and Ethics 
Review Committees (ERCs)/Institutional Review Boards (IRBs). Periodic 
abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, 
etc.) and withdrawal are not acceptable methods of contraception.  
‡If a contraceptive method listed above is restricted by local 
regulations/guidelines, then it does not qualify as an acceptable method of 
contraception for patients participating at sites in this country/region. 
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, patients of childbearing potential must adhere to the 
contraception requirement (described above) from the day of study medication initiation 
(or 14 days before the initiation of study medication for oral contraception) throughout 
the study period up to 120 days after the last dose of trial therapy. 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. 
5.7.2 Use in Pregnancy 
If a patient inadvertently becomes pregnant while on treatment with MK-3475 
(pembrolizumab), 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 

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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.  
5.7.3 Use in Nursing Women 
It is unknown whether MK-3475 (pembrolizumab) 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. 
5.8 
Treatment Beyond Progression 
5.8.1 Mycosis Fungoides/Sézary Syndrome (Treatment Group 1) 
Immunotherapeutic agents such as MK-3475 (pembrolizumab) 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 ≥4 
weeks later in order to confirm PD with the option of continuing treatment per the instructions 
below while waiting 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: 

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• Absence of signs and symptoms (including worsening of laboratory values) indicating 
disease progression 
• No decline in ECOG performance status 
• Absence of rapid progression of disease 
• Absence of progressive tumor at critical anatomical sites (e.g., cord compression) requiring 
urgent alternative medical intervention 
Continuation after confirmation of progression: 
Patients who are determined to have confirmed progression may continue to receive study 
treatment if they are clinically stable as defined by the following criteria:  
• Absence of signs and symptoms (including worsening of laboratory values) indicating 
disease progression 
• No decline in ECOG performance status 
• Absence of rapid progression of disease 
• Absence of progressive tumor at critical anatomical sites (e.g., cord compression) requiring 
urgent alternative medical intervention 
The following assessment and stopping criteria apply to patients who continue study treatment 
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.  
 
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 
study therapy, repeat 
mSWAT every cycle. 
mSWAT, CT scans, for 
measurable disease, and 
CSC, for patients who 
are positive, will be 
repeated every 4 cycles 
Patient may 
continue therapy 
with MK-3475. 
No additional 
assessments 
required 
N/A 

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(every 12 weeks) Must 
stop if any compartment 
increases by 25% or 
more. 
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 
** Note: Mycosis Fungoides and Sézary Syndrome may not be measurable by CT or PET/CT 
scan. Disease assessments will include CT or PET/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 Mycosis Fungoides/Sézary Syndrome. 
In the table above PD, SD, PR and CR will be determined by Global Response Assessment as 
described in section 11.  
5.8.2 Synovial Sarcoma (Treatment Group 2) 
Immunotherapeutic agents such as MK-3475 (pembrolizumab) 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. 
Patients with radiographic progression but who are otherwise stable without symptomatic 
progression may continue treatment up until confirmation. Confirmation imaging may be done as 
early as 6 weeks and up to 12 weeks later in order to assess for possible pseudo progression.  
Confirmation of progression means that tumor growth has continued. If a progressing patient has 
a repeat scan that shows tumor regression from the previous scan this does not count as 
confirmation even if it is still progressive disease compared to baseline. 
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 (including worsening of laboratory values) indicating 
disease progression 
• No decline in ECOG performance status 
• Absence of rapid progression of disease 
• Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention 

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5.9 
Guidelines for Management of Skin Flare Reaction in Patients with Mycosis 
Fungoides/Sézary Syndrome (Treatment Group 1) 
In this trial the term “Skin Flare Reaction” will be used to describe skin changes that are felt by 
the investigator to be due to a MK-3475 (pembrolizumab)/Interferon-gamma immune related 
process. Patients may have dermatologic adverse events that are not immune related. We will 
not use the term “Skin Flare Reaction” to describe these reactions. Instead, other terms such as 
erythroderma or maculo-papular rash may be used, as applicable, to describe these non-immune-
related dermatologic adverse events. The immune mediated, study drug related AE’s will be 
termed “Skin Flare Reactions” for consistency.  
If a patient has a Skin Flare Reaction they may be seen at a regular protocol visit or, if timing 
does not permit, they will be seen for an unscheduled visit. All patients with Skin Flare 
Reactions will have medical photography (mSWAT) performed for documentation purposes. 
Skin biopsies will be performed in accordance with section 9.1 with tissue being sent for local 
pathology review and tissue sent for research purposes to the CITN Central Lab. The tissue sent 
for local pathology will be used to help differentiate between an immune mediated flare reaction 
and progressive disease. In addition, all correlative studies except whole exome sequencing and 
neoantigen prediction, and microbiome analyses will be repeated. (See Study Calendars Section 
10).  
If it is not clear whether the event is a Skin Flare Reaction or Progressive disease the investigator 
is encouraged to consider TCR High Throughput Sequencing to determine whether the increase 
in T-cell density is from a rise in the original dominant tumor TCR sequence versus something 
new or reactive.  
Patients with Skin Flare Reaction grade 1-2 should be managed with supportive care including 
the use of mild or moderate potency topical steroids for up to two weeks and diphenhydramine. 
Patients with grade 3-4 Skin Flare Reaction may receive at investigator’s discretion a two week 
course of prednisone (30mg for 3 days, 20mg for 3 days, 10mg for 3 days, 5mg for 3 days).  
5.10 
Discontinuation of Treatment Following Complete Response (Treatment Group 1 
and 2) 
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 
(pembrolizumab) in combination with interferon gamma-1b and had at least two treatment cycles 
beyond the date when the initial CR was declared.  
5.11 
Treatment Up to 2 Years (Treatment Group 1 and 2) 
Treatment with MK-3475 (pembrolizumab) in combination with interferon gamma-1b will 
continue for up to 2 years, or until documented disease progression, 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. 

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6. 
DOSING DELAYS/DOSE MODIFICATIONS 
6.1 
Dose Modifications and Supportive Care Guidelines for Drug-Related Adverse 
Events (Treatment Group 1 and 2) 
6.1.1 MK-3475 (pembrolizumab) Dose Modifications 
Adverse events (both nonserious and serious) associated with MK-3475 exposure may 
represent an immunologic etiology. These AEs may occur shortly after the first dose or 
several months after the last dose of treatment. MK-3475 must be withheld for drug-
related toxicities and severe or life-threatening AEs as the table in Section 6.1.3. 
Dosing interruptions are permitted in the case of medical/surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, 
patient vacation, and/or holidays). Patients should be placed back on study therapy within 
3 weeks of the scheduled interruption. The reason for interruption should be documented 
in the patient’s study record. 
6.1.2 MK-3475 (pembrolizumab) Supportive Care Guidelines 
Patients should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs 
with potential immunologic etiology are also outlined in the table in Section 6.1.3. Where 
appropriate, these guidelines include the use of oral or IV treatment with corticosteroids 
as well as additional anti-inflammatory agents if symptoms do not improve with 
administration of corticosteroids. Note that several courses of steroid tapering may be 
necessary as symptoms may worsen when the steroid dose is decreased. For each 
disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines are intended to be applied when the investigator determines the events to be 
related to MK-3475. 
Note: If after the evaluation the event is determined not to be related, the investigator 
does not need to follow the treatment guidance (as outlined below). 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, 
or skin photography as part of the evaluation of the event. 

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6.1.3 Dose Modification and Toxicity Management Guidelines for Immune-related AEs 
Associated with MK-3475 (pembrolizumab)  
 
General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other 
immunosuppressive treatment should begin if the irAEs are not controlled by corticosteroids.  
2. Pembrolizumab must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not 
≤10 mg/day within 12 weeks of the last pembrolizumab treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If pembrolizumab has been withheld, pembrolizumab may resume after the irAE decreased to ≤ Grade 1 after 
corticosteroid taper. 
irAEs 
Toxicity grade 
(CTCAE V5.0) 
Action with 
pembrolizumab 
Corticosteroid and/or 
other therapies  
Monitoring and follow-up  
Pneumonitis  
Grade 2 
Withhold  
•  Administer 
corticosteroids (initial 
dose of 1 - 2 mg/kg 
prednisone or 
equivalent) followed 
by taper 
•  Add prophylactic 
antibiotics for 
opportunistic 
infections 
•  Monitor participants for 
signs and symptoms of 
pneumonitis 
•  Evaluate participants with 
suspected pneumonitis 
with radiographic imaging 
and initiate corticosteroid 
treatment 
Recurrent Grade 2,  
Grade 3 or 4  
Permanently 
discontinue 
Diarrhea / Colitis  
Grade 2 or 3 
Withhold 
•  Administer 
corticosteroids (initial 
dose of 1 - 2 mg/kg 
prednisone or 
equivalent) followed 
by taper 
•  Monitor participants for 
signs and symptoms of 
enterocolitis (ie, diarrhea, 
abdominal pain, blood or 
mucus in stool with or 
without fever) and of 
bowel perforation (ie, 
peritoneal signs and ileus) 
•  Participants with ≥Grade 2 
diarrhea suspecting colitis 
should consider GI 
consultation and 
performing endoscopy to 
rule out colitis 
•  Participants with 
diarrhea/colitis should be 
advised to drink liberal 
quantities of clear fluids. If 
sufficient oral fluid intake 
is not feasible, fluid and 
electrolytes should be 
substituted via IV infusion 
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue 

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

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Grade 3 or 4 
Permanently 
discontinue 
•  Based on severity of 
AE administer 
corticosteroids 
etiology and/or exclude 
other causes 
 
All Other immune-
related AEs 
Persistent Grade 2 
Withhold 
•  Based on severity of 
AE administer 
corticosteroids 
•  Ensure adequate 
evaluation to confirm 
etiology or exclude other 
causes 
Grade 3 
Withhold or 
discontinue based 
on the event e  
Recurrent Grade 3 
or Grade 4  
Permanently 
discontinue 
a AST/ALT: >3.0 - 5.0 x ULN if baseline normal; >3.0 - 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 - 3.0 x ULN if baseline normal; >1.5 - 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 - 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 - 10.0 x 
ULN if baseline normal; >3.0 - 10.0 x baseline if baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating 
physician. If control achieved or ≤ Grade 2, pembrolizumab may be resumed. 
e Events that require discontinuation include but are not limited to: Guillain-Barre Syndrome, encephalitis, Stevens-
Johnson Syndrome and toxic epidermal necrolysis. 
 
 
 

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6.1.4 MK-3475 (pembrolizumab) and Interferon Gamma-1ba, b Dose Modification and Toxicity Management for Other Drug-
Related Adverse Events 
 
Dose Modification Guidelines 
Supportive Care Guidelines 
Toxicity 
Hold treatment 
for Grade 
Timing for 
Restarting 
Treatment 
Treatment 
Discontinuation 
CTCAE v5.0 
Grade 
Action / Supportive Care Guidelines 
Infusion Reaction 
(MK-3475) 
General Considerations across all Grades: Signs and symptoms usually develop during or shortly after drug infusion and generally resolve completely 
within 24 hours of completion of infusion. 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug administration. 
 
1c 
Increase monitoring of vital signs as medically 
indicated until the patient is deemed medically 
stable in the opinion of the investigator. 
No premedication at subsequent dosing: 
2d 
Toxicity resolves to 
Grade 0-1 
Permanently discontinue if 
toxicity develops despite 
adequate premedication 
2e 
Stop infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include, but is not limited to:  
• 
IV fluids 
• 
Antihistamines 
• 
NSAIDS 
• 
Acetaminophen 
• 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the patient is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within 1 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: Before 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 patient should be 
premedicated for the next scheduled dose. 
Patients who develop Grade 2 toxicity upon 
rechallenge despite adequate premedication 
should be permanently discontinued from 
further trial treatment administration. 
Patient may be premedicated 1.5h (± 30 minutes) 
before infusion of pembrolizumab with:  

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Dose Modification Guidelines 
Supportive Care Guidelines 
Toxicity 
Hold treatment 
for Grade 
Timing for 
Restarting 
Treatment 
Treatment 
Discontinuation 
CTCAE v5.0 
Grade 
Action / Supportive Care Guidelines 
• 
Diphenhydramine 50 mg PO (or 
equivalent dose of antihistamine). 
• 
Acetaminophen 500-1000 mg PO (or 
equivalent dose of antipyretic). 
3-4 
Permanently 
discontinue 
Permanently discontinue 
3f or 4g 
Stop Infusion. 
Additional appropriate medical therapy may include 
but is not limited to: 
• 
IV fluids 
• 
Antihistamines 
• 
NSAIDS 
• 
Acetaminophen 
• 
Narcotics 
• 
Oxygen 
• 
Pressors 
• 
Corticosteroids 
• 
Epinephrine 
Increase monitoring of vital signs as medically 
indicated until the patient is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Patient is permanently discontinued from further 
trial treatment administration. 
Neutropenia, 
Thrombocytopenia 
3 
Hold MK-3475 and 
Interferon gamma 
until toxicity resolves 
to grade 0-1 and 
reduce Interferon 
gamma by 50% when 
restarting treatment 
Toxicity >7 days or 
associated with bleeding 
requires discontinuation 
 
 
4 
Permanently 
discontinue 
Permanently discontinue 
 
 
Hematologic AE other 
than neutropenia, 
thrombocytopenia or 
lymphopenia 
3 
Hold MK-3475 and 
Interferon gamma 
until toxicity resolves 
to Grade 0-1 
Toxicity does not resolve 
within 12 weeks of last 
dose or inability to reduce 
corticosteroid to 10 mg or 
less of prednisone or 
equivalent per day within 
12 weeks 
 
 

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Dose Modification Guidelines 
Supportive Care Guidelines 
Toxicity 
Hold treatment 
for Grade 
Timing for 
Restarting 
Treatment 
Treatment 
Discontinuation 
CTCAE v5.0 
Grade 
Action / Supportive Care Guidelines 
4 
Permanently 
discontinue 
Permanently discontinue 
 
 
Skin-only Toxicity 
 
2-4 
Treat with topical corticosteroids (including high 
potency corticosteroids) and/or systemic 
corticosteroids. If systemic steroids are given, a 
steroid taper should start once symptoms improve to 
Grade 1 or less. For treatment group 1, if symptoms 
are consistent with a skin flare reaction, then 
management should follow the guidelines in section 
5.9.   
Drug-related neurologic 
sequelae including 
seizure, altered mental 
status or gait disturbance. 
3-4 
Permanently 
discontinue 
Permanently discontinue 
 
 
All Other Drug-Related 
Toxicityh 
3 or Severe 
Hold both MK-3475 
and Interferon gamma 
until toxicity resolves 
to Grade 0-1 
Toxicity does not resolve 
within 12 weeks of last 
dose or inability to reduce 
corticosteroid to 10 mg or 
less of prednisone or 
equivalent per day within 
12 weeks 
 
 
4 
Permanently 
discontinue 
Permanently discontinue 
 
 
a. 
As described in section 5.1, the dose of Interferon-gamma will be increased at specified time points if patients have had less than a CR and are tolerating their current 
dose. The dose of Interferon-gamma may also need to be reduced, most likely for constitutional symptoms for patient tolerability. Interferon-gamma may also need to be 
held for up to a period of 3 weeks at the discretion of the investigator and in consultation with the patient   (as described in section 5.1) if necessary for patient tolerance. 
Close communications between the patient and treating investigator will be needed to determine a tolerable and hopefully effective dose of Interferon-gamma.  
b. 
In the event of an irAE (Table 6.1.3) Interferon-Gamma-1b will be withheld when MK-3475 is withheld, resumed when MK3475 is resumed and discontinued when MK-
3475 (pembrolizumab) is discontinued.  
c. 
Mild reaction; infusion interruption not indicated; intervention not indicated 
d. 
If symptoms resolve within 1 hour of stopping drug infusion, the infusion may be restarted at 50% of the original infusion rate (e.g., from 100 mL/hr to 50 mL/hr). 
Otherwise dosing will be held until symptoms resolve and the patient should be premedicated for the next scheduled dose. 
e. 
Requires infusion interruption but responds promptly to symptomatic treatment (e.g., antihistamines, NSAIDS, narcotics, IV fluids); prophylactic medications indicated 
for < =24 hrs 
f. 
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) 
g. 
Life-threatening; pressor or ventilatory support indicated 
h. 
Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion. Permanently discontinue study drug for persistent 
Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose. 
 

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Dose Modification Guidelines 
Supportive Care Guidelines 
Toxicity 
Hold treatment 
for Grade 
Timing for 
Restarting 
Treatment 
Treatment 
Discontinuation 
CTCAE v5.0 
Grade 
Action / Supportive Care Guidelines 
 
 
NOTE: For synovial sarcoma patients (Treatment group 2) the dose of interferon gamma-1b will be reduced by 50 mcg/m2 (50%). For Treatment Group 2 (synovial sarcoma) grade 
3 flu-like symptoms including fevers, fatigue, myalgias, or other patient reported symptoms that resolve to grade 1 within 48 hours should not trigger an interferon gamma-1b dose 
change. 

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6.1.5 Interferon-gamma Supportive Care Guidelines 
• Acetaminophen 325 mg orally PRN per patient preference can be taken 30-60 
minutes before injection for fevers and myalgias and may be used supportively at a 
dose of 325-650 mg orally Q6H PRN (≤ 3 gm/day). 
• Anti-depressant medication in the form of a selective serotonin re-uptake inhibitor 
(SSRI) or next generation anti-depressant medication may be taken orally by patient 
to start up to two weeks prior or at any point during therapy to treat or protect against 
the development of depression. This should be decided between the patient and 
treating clinician. 
• Ibuprofen 200 mg orally to 400 mg orally Q4-6H PRN (≤ 1200 mg/day) may be taken 
prophylactically or for supportive purposes for fevers and myalgias assuming 
adequate renal function as viewed by the treating clinician 
• Diphenhydramine 25 to 50 mg orally Q4-6H (</= 300mg/day) 
7. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
(TREATMENT GROUP 1 AND 2) 
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 and 
7.3) will determine whether the event requires expedited reporting via the CTEP Adverse Event 
Reporting System (CTEP-AERS) in addition to routine reporting. 
7.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (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 (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: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using 
multiple investigational agents and has an AE listed on different SPEERs, use the lower 
of the grades to determine if expedited reporting is required. 
 

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7.1.1 CAEPRs for CTEP IND Agent(s) 
7.1.1.1 
CAEPR for CTEP IND Agent(s) MK-3475 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
MK-3475 (pembrolizumab, NSC 776864) 
 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for further clarification. Frequency is provided based on 3793 patients. Below is the CAEPR for MK-3475 
(pembrolizumab). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 
 
 
 
       Version 2.5, December 27, 20191 
 
 Adverse Events with Possible  
 Relationship to MK-3475 (pembrolizumab) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
 
 
Anemia2 
 
 
 
 
Lymph node pain2 
 
 
 
 
Thrombotic thrombocytopenic 
purpura2 
 
 
 

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 Adverse Events with Possible  
 Relationship to MK-3475 (pembrolizumab) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
CARDIAC DISORDERS 
 
 
 
 
Myocarditis2 
 
 
 
 
Pericarditis2 
 
 
ENDOCRINE DISORDERS 
  
 
Adrenal insufficiency2 
 
  
 
Endocrine disorders - Other 
(thyroiditis)2 
 
  
 
Hyperthyroidism2 
 
  
 
Hypohysitis2 
 
  
 
Hypopituitarism2 
 
  
 
Hypothyroidism2 
 
  
EYE DISORDERS 
  
 
 
Uveitis2 
  
 
 
Eye disorders - Other (Vogt-
Koyanagi-Harada syndrome) 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
 
Colitis2 
 
  
 
Diarrhea2 
 
 Diarrhea2 (Gr 2) 
 
Mucositis oral2 
 
  
 
Nausea 
 
 Nausea (Gr 2) 
 
Pancreatitis2 
 
  
 
Small intestinal mucositis2 
 
  
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills2 
 
  

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 Adverse Events with Possible  
 Relationship to MK-3475 (pembrolizumab) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
Fatigue 
 
 
 Fatigue (Gr 2) 
 
Fever2 
 
  
HEPATOBILIARY DISORDERS 
  
 
Hepatobiliary disorders - Other 
(autoimmune hepatitis)2 
 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Anaphylaxis2 
  
 
 
Cytokine release syndrome2 
  
 
 
Immune system disorders - 
Other (acute graft-versus-host-
disease)2,3 
  
 
 
Immune system disorders - 
Other (hemophagocytic 
lymphohistiocytosis)2 
  
 
Immune system disorders - Other 
(pseudoprogression/tumor 
inflammation)2 
 
  
 
Immune system disorders - Other 
(sarcoidosis)2 
 
  
 
 
Serum sickness2 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection4 
 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
 
 Infusion related reaction 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased2 
 
  
 
Alkaline phosphatase increased 
 
  

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 Adverse Events with Possible  
 Relationship to MK-3475 (pembrolizumab) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Aspartate aminotransferase 
increased2 
 
  
 
Blood bilirubin increased 
 
  
 
CPK increased 
 
  
 
 
GGT increased 
  
 
 
Serum amylase increased 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
  
 
Hyponatremia 
 
  
 
 
Metabolism and nutrition 
disorders - Other (diabetic 
ketoacidosis)2 
  
 
 
Metabolism and nutrition 
disorders - Other (type 1 
diabetes mellitus)2 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia2 
 
 Arthralgia2 (Gr 2) 
 
Arthritis2 
 
  
 
Avascular necrosis2 
 
  
 
Back pain 
 
  
 
Joint effusion2 
 
  
 
Joint range of motion decreased 
 
  
 
Musculoskeletal and connective 
tissue disorder - Other 
(tenosynovitis)2 
 
  
 
Myalgia2 
 
  
 
Myositis2 
 
  
NERVOUS SYSTEM DISORDERS 
  

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 Adverse Events with Possible  
 Relationship to MK-3475 (pembrolizumab) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
 
Guillain-Barre syndrome2 
  
 
 
Nervous system disorders - 
Other (myasthenic syndrome)2 
  
 
 
Nervous system disorders - 
Other (neuromyopathy)2 
  
 
 
Nervous system disorders - 
Other (non-infectious 
encephalitis)2 
  
 
 
Nervous system disorders - 
Other (non-infectious 
meningitis)2 
  
 
 
Nervous system disorders - 
Other (non-infectious myelitis) 
  
 
 
Nervous system disorders - 
Other (polyneuropathy)2 
  
 
 
Paresthesia 
  
 
 
Peripheral motor neuropathy2 
  
RENAL AND URINARY DISORDERS 
  
 
 
Renal and urinary disorders - 
Other (autoimmune nephritis)2 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
 Cough 
 
  
 
 Pleuritic pain2 
 
  
 
 Pneumonitis2 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Bullous dermatitis2 
 
  
 
 
 Erythema multiforme2 
  
 
Erythroderma 
 
  

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 Adverse Events with Possible  
 Relationship to MK-3475 (pembrolizumab) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
 
Palmar-plantar 
erythrodysesthesia syndrome 
  
 
Pruritus2 
 
 Pruritus2 (Gr 2) 
 
Rash acneiform2 
 
  
 
Rash maculo-papular2 
 
 Rash maculo-papular2 (Gr 2) 
 
Skin and subcutaneous tissue 
disorders - Other (dermatitis)2 
 
  
 
Skin hypopigmentation2 
 
  
 
 
Stevens-Johnson syndrome2 
  
 
 
Toxic epidermal necrolysis 
  
 
Urticaria2 
 
  
VASCULAR DISORDERS 
  
 
 
Vasculitis2 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Immune-mediated adverse reactions have been reported in patients receiving MK-3475 
(pembrolizumab).  Adverse events potentially related to MK-3475 (pembrolizumab) may be 
manifestations of immune-mediated adverse events. In clinical trials, most immune-mediated adverse 
reactions were reversible and managed with interruptions of MK-3475 (pembrolizumab), administration of 
corticosteroids and supportive care. 
 
3Acute graft-versus-host disease has been observed in patients treated with MK-3475 (pembrolizumab) 
who received hematopoeitic stem cell transplants. 
 
4Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 

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Adverse events reported on MK-3475 (pembrolizumab) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that MK-3475 (pembrolizumab) caused 
the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(pancytopenia); Disseminated intravascular coagulation; Hemolysis 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Chest pain - cardiac; Heart failure; Myocardial 
infarction; Pericardial effusion; Pericardial tamponade; Ventricular arrhythmia 
EYE DISORDERS - Eye pain 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Constipation; Duodenal 
hemorrhage; Dysphagia; Gastritis; Gastrointestinal disorders - Other (diverticulitis); Gastrointestinal 
disorders - Other (intestinal obstruction); Gastrointestinal disorders - Other (intussusception); Oral pain; 
Rectal hemorrhage; Small intestinal perforation; Upper gastrointestinal hemorrhage; Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; Edema limbs; 
Facial pain; Gait disturbance; General disorders and administration site conditions - Other (general 
physical health deterioration); Generalized edema; Malaise; Non-cardiac chest pain; Pain 
INVESTIGATIONS - Cholesterol high; Creatinine increased; Fibrinogen decreased; Lymphocyte count 
decreased; Neutrophil count decreased; Platelet count decreased; Weight loss; White blood cell 
decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperglycemia; 
Hyperkalemia; Hypertriglyceridemia; Hyperuricemia; Hypoalbuminemia; Hypokalemia; 
Hypophosphatemia; Metabolism and nutrition disorders - Other (failure to thrive); Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Generalized muscle 
weakness; Musculoskeletal and connective tissue disorder - Other (groin pain); Pain in extremity 
NERVOUS SYSTEM DISORDERS - Aphonia; Depressed level of consciousness; Dysarthria; Edema 
cerebral; Encephalopathy; Headache; Hydrocephalus; Lethargy; Meningismus; Nervous system disorders 
- Other (brainstem herniation); Seizure; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Agitation; Confusion 
RENAL AND URINARY DISORDERS - Acute kidney injury; Nephrotic syndrome; Proteinuria; Renal and 
urinary disorders - Other (hydronephrosis); Urinary incontinence; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Pelvic pain 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Dyspnea; Hypoxia; Laryngeal 
inflammation; Pleural effusion; Pneumothorax; Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Skin and subcutaneous tissue 
disorders - Other (drug eruption) 
VASCULAR DISORDERS - Hypertension; Peripheral ischemia; Thromboembolic event 
 
 

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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. 
 
 
 
 
 
7.1.1.2 
Common Adverse Events for Interferon-gamma (Actimmune Package Insert)  
The following data on adverse reactions are based on the subcutaneous administration 
of ACTIMMUNE at a dose of 50 mcg/m2, three times weekly, in patients with CGD 
during a clinical trial in the United States and Europe.  
The most common adverse reactions observed in patients with CGD are shown in the 
following table: 
Adverse Reactions Occurring in 2 % or Greater of Chronic Granulomatous Disease (CGD) 
Patients Receiving ACTIMMUNE in Clinical Trials 
 
Percent of Patients 
Adverse Reactions 
ACTIMMUNE CGD 
(n=63) 
Placebo CGD 
(n=65)  
Fever  
52  
28  
Headache  
33  
9  
Rash  
17  
6  
Chills  
14  
0  
Injection site erythema or tenderness  
14  
2  
Fatigue  
14  
11  
Diarrhea  
14  
12  
Vomiting  
13  
5  
Nausea  
10  
2  
Myalgia  
6  
0  
Arthralgia  
2  
0  
The most common adverse reactions include constitutional symptoms such as fever, 
headache, chills, myalgia or fatigue which may decrease in severity as treatment 
continues. 
7.1.1.3 
Less Common Adverse Reactions  
The following adverse reactions are assessed as potentially related to ACTIMMUNE 
(interferon gamma-1b) therapy:  

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Blood and Lymphatic System—neutropenia (reversible), febrile neutropenia, 
leukopenia, and thrombocytopenia.  
Cardiovascular— angina pectoris, arrhythmia, atrial fibrillation, atrioventricular 
block, cardiac failure (including congestive cardiac failure), tachyarrhythmia, heart 
block, (acute) myocardial infarction, myocardial ischemia, syncope, and tachycardia.  
Gastrointestinal—abdominal pain, dyspepsia, gastrointestinal bleeding, 
granulomatous colitis, hepatic insufficiency, and pancreatitis, including pancreatitis 
with fatal outcome.  
General Disorders and Administration Site Conditions—asthenia, chest 
pain/discomfort, influenza-like illness/flu-like symptoms, injection site hemorrhage, 
injection site pain, malaise, rigors, and weakness.  
Hepatobiliary Disorders—hepatic insufficiency and hepatomegaly. 
Immunological—hypersensitivity, increased autoantibodies, lupus-like syndrome 
(including systemic lupus erythematosus-flares and drug-induced lupus 
erythematosus), and Stevens-Johnson syndrome.  
Infections and Infestations—upper respiratory tract infection. 
Investigations—blood alkaline phosphatase increased, liver function tests abnormal/ 
elevation of hepatic enzymes, increased triglycerides, and weight decreased. 
Metabolic—hyponatremia, hypokalemia, hyperglycemia, and hypertriglyceridemia.  
Musculoskeletal—back pain, clubbing, and muscle spasms.  
Nervous System—dizziness (excluding vertigo), gait disturbance, headache, 
Parkinsonian symptoms, convulsion/seizure (including grand mal convulsions), and 
transient ischemic attacks.  
Psychiatric—confusion, depression, disorientation, hallucinations, mental status 
changes, and mental status decreased.  
Pulmonary—tachypnea, bronchospasm, pulmonary edema, and interstitial 
pneumonitis. 
Renal—acute renal failure (which may be reversible) and proteinuria.  
Skin and Subcutaneous Tissue Disorders—atopic dermatitis, (exacerbation of) 
dermatomyositis, transient cutaneous rash, and urticaria.  
Vascular Disorder—deep venous thrombosis, hypotension, pulmonary embolism.  
Abnormal Laboratory Test Values: Elevations of ALT and AST have been observed 

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7.1.2 Adverse Event List(s) for [Other Investigational Agent(s)]: N/A 
7.1.3 Adverse Event List(s) for Commercial Agent(s): N/A 
7.2 
Adverse Event Characteristics  
• CTCAE term (AE description) and grade: The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 will be utilized for AE reporting beginning April 1, 2018. All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0. 
A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:  
– AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed 
in the SPEER column, Section 7.1.1) should be reported through CTEP-AERS 
only if the grade is above the grade provided in the SPEER. 
– Other AEs for the protocol that do not require expedited reporting are outlined 
in section 7.3.4. 
• Attribution of the AE: 
– Definite – The AE is clearly related to the study treatment. 
– Probable – The AE is likely related to the study treatment. 
– Possible – The AE may be related to the study treatment. 
– Unlikely – The AE is doubtfully related to the study treatment. 
– Unrelated – The AE is clearly NOT related to the study treatment. 
7.3 
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. 

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7.3.2 Distribution of Adverse Event Reports 
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 or Lead Organization, the local treating 
physician, and the Reporter and Submitter. CTEP-AERS provides a copy feature for 
other e-mail recipients.  
7.3.3 Expedited Reporting Guidelines 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
Note: A death on study requires both routine and expedited reporting, regardless of 
causality. Attribution to treatment or other cause must be provided. 
Death due to progressive disease should be reported as Grade 5 “Disease progression” 
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 CTEP AERS 
recognizes this event as a patient death. 
A neonatal death should be reported expeditiously as Grade 4, “Death neonatal” under 
the general disorders and administration SOC.  
Phase 1 and Early Phase 2 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/Intervention 1, 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 

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require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 
312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5  
Timeframes 
Resulting in Hospitalization 
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar Days 
Not resulting in 
Hospitalization 
≥ 24 hrs 
Not required 
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific Protocol 
Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of learning of the 
AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention 
and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, rounded UP 
to the nearest whole day, after the agent/intervention was last administered. Footnote “1” above applies after this 
reporting period. 
Effective Date: May 5, 2011 
 
7.3.4 Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions N/A 
7.4 
Routine Adverse Event Reporting 
All Adverse Events must be reported in routine study data submissions. AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents. AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave. For this trial the Adverse Event CRF is used for routine AE 
reporting in Rave. 
7.5 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 

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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.  
7.6 
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. 
8. 
PHARMACEUTICAL INFORMATION (TREATMENT GROUP 1 AND 2) 
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 7.1. 
8.1 
CTEP IND Agent(s) 
8.1.1 MK-3475 (pembrolizumab) (NSC 776864) 
Other Names: SCH 900475, pembrolizumab 
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 (pembrolizumab) 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 (pembrolizumab) is a humanized MAb of the IgG4/kappa 
isotype. 
How Supplied: 
MK-3475 (pembrolizumab) is supplied by Merck & Co., Inc. and distributed by the 
Pharmaceutical Management Branch, CTEP/DCTD/NCI as single-use 100 mg vials 
containing a sterile, non-pyrogenic, clear to opalescent aqueous solution (25 mg/mL). 

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Proteinaceous particles may be present. MK-3475 (pembrolizumab) solution for infusion 
is formulated in 10mM histidine buffer, pH 5.2-5.8, containing 7% sucrose and 0.02% 
polysorbate 80, supplied in Type I glass vials with a cap color of red, salmon, or blue.  
Preparation:  
MK-3475 (pembrolizumab) solution for infusion must be diluted before administration. . 
Do not shake the vials. Do not use if opaque or extraneous particulate matter other than 
translucent to white proteinaceous particles is observed. Do not use if discolored. To 
prepare the infusion solution add the dose volume of MK-3475 (pembrolizumab) to an 
infusion bag containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, 
USP. Gently invert the bag 10-15 times to mix the solution. The final concentration must 
be between 1 mg/mL to 10 mg/mL. 
Compatible IV bag materials:  
PVC plasticized with DEHP, non-PVC (polyolefin), EVA, or PE lined polyolefin 
Storage:  
Store intact vials between 2°C-8°C (36°F-46°F). Do not freeze. Protect from light by 
storing in the original box.  
If a storage temperature excursion is identified, promptly return MK-3475 
(pembrolizumab) vials to 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 24 hours. MK-3475 
(pembrolizumab) solutions may be stored at room temperature for a cumulative time of 
up to 6 hours. This includes room temperature storage of liquid drug product solution in 
vials, room temperature storage of infusion solution in the IV bag, and the duration of 
infusion. 
Route 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 patient has a central venous catheter in place, it is recommended that it be 
used for the infusion. Do not co-administer other drugs through the same infusion line. 
Following the infusion, flush the IV line with normal saline. 
Compatible infusion set materials:  

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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 (pembrolizumab) is an investigational agent supplied to investigators by the 
Division of Cancer Treatment and Diagnosis (DCTD), NCI. 
MK-3475 (pembrolizumab) is provided to the NCI under a Collaborative Agreement 
between the Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.3).  
Investigator Brochure Availability: 
The current version of the Pembrolizumab IB will be accessible to site investigators and 
research staff through the PMB Online Agent Order Processing (OAOP) application. 
Access to OAOP requires the establishment of a CTEP Identity and Access Management 
(IAM) account and the maintenance of an “active” account status, a “current” password, 
and active person registration status. Questions about IB access may be directed to the 
PMB IB coordinator via email. 
8.1.2 Interferon-gamma-1b injection (NSC# 600662) 
Other Names: Actimmune 
Classification: An Interferon-gamma 
Mode of Action:  
Interferons bind to specific cell surface receptors and initiate a sequence of intracellular 
events that lead to the transcription of interferon-stimulated genes. The three major 
groups of interferons (alpha, beta, gamma) have partially overlapping biological activities 
that include immunoregulation such as increased resistance to microbial pathogens and 
inhibition of cell proliferation. Type 1 interferons (alpha and beta) bind to the alpha/ beta 
receptor. Interferon gamma binds to a different cell surface receptor and is classified as 
Type 2 interferon. Specific effects of interferon gamma include the enhancement of the 
oxidative metabolism of macrophages, antibody dependent cellular cytotoxicity (ADCC), 
activation of natural killer (NK) cells, and the expression of Fc receptors and major 
histocompatibility antigens. 
Description:  
ACTIMMUNE (Interferon gamma-1b), an interferon gamma, is a single-chain 
polypeptide containing 140 amino acids. Production of ACTIMMUNE is achieved by 
fermentation of a genetically engineered Escherichia coli bacterium containing the DNA 
which encodes for the recombinant protein. Purification of the product is achieved by 
conventional column chromatography. ACTIMMUNE is a highly purified sterile solution 
consisting of non-covalent dimers of two identical 16,465 Dalton monomers; with a 

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specific activity of 20 million International Units/mg (2x106 International Units/0.5 mL) 
which is equivalent to 30 million units/mg. 
How Supplied:  
ACTIMMUNE (interferon gamma-1b) is supplied by Horizon Pharma and distributed by 
the Pharmaceutical Management Branch, CTEP/DCTD/NCI as a sterile, clear, colorless 
solution filled in a single-use vial for subcutaneous injection. Each vial permits the 
extraction of up to 0.5 mL of ACTIMMUNE with additional volume to facilitate solution 
withdrawal. Each 0.5 mL of ACTIMMUNE contains: 100 mcg (2 million International 
Units) of interferon gamma-1b. 
Preparation:  
Actimmune solution is withdrawn from the vial and is administered by the patient or a 
caregiver as a subcutaneous injection. 
Storage:  
Store vials in the refrigerator at 2°C to 8°C (36 °F-46 °F). Do Not Freeze. 
Avoid excessive or vigorous agitation. Do Not Shake.  
Stability:  
Refer to the package label for product expiration. An unused vial of ACTIMMUNE can 
be stored at room temperature up to 12 hours before use. Discard vials if not used within 
the 12-hour period. Do not return to the refrigerator. 
Route of Administration: Subcutaneous 
Patient Care Implications: See section 6.1.5 (Supportive Care Guidelines) 
Availability: 
Commercial supplies of Interferon Gamma-1b (ACTIMMUNE) are supplied to 
investigators by the Division of Cancer Treatment and Diagnosis (DCTD), NCI. 
Interferon-gamma is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.3). 
8.1.3 Agent Ordering and Agent Accountability 
NCI-supplied agents may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution. The CTEP-assigned protocol 
number must be used for ordering all CTEP-supplied investigational agents. The eligible 
participating investigators at each participating institution must be registered with CTEP, 
DCTD through an annual submission of FDA Form 1572 (Statement of Investigator), 
NCI Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF). If there are 
several participating investigators at one institution, CTEP-supplied investigational 
agents for the study should be ordered under the name of one lead investigator at that 
institution. 

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In general, sites may order initial agent supplies when a subject is being screened for 
enrollment onto the study. 
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online Agent Order 
Processing (OAOP) application. Access to OAOP requires the establishment of a CTEP 
Identity and Access Management (IAM) account and the maintenance of an “active” 
account status and a “current” password. For questions about drug orders, transfers, 
returns, or accountability, call or email PMB any time. Refer to the PMB’s website for 
specific policies and guidelines related to agent management.  
8.1.3.1 
Agent Inventory Records 
The investigator, or a responsible party designated by the investigator, must maintain 
a careful record of the receipt, dispensing and final disposition of all agents received 
from the PMB using the appropriate NCI Investigational Agent (Drug) Accountability 
Record (DARF) available on the CTEP forms page. Store and maintain separate NCI 
Investigational Agent Accountability Records for each agent, strength, formulation 
and ordering investigator on this protocol. 
8.1.4 Useful Links and Contacts 
• CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/  
• NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov  
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm 
• PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP/ 
• CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/  
• CTEP IAM account help: ctepreghelp@ctep.nci.nih.gov 
• PMB email: PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET) 
• IB Coordinator: IBCoordinator@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET) 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
9.1 
Mycosis Fungoides/Sézary Syndrome (Treatment Group 1) 
The study calendars and lab manual describe blood draws for safety labs, research labs, and 
storage of leftover samples in 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 (safety labs drawn 

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for screening will used for this purpose before the first blood draws for research). The results of 
the CBC will be reviewed and the following blood volumes will be drawn based upon the 
patient’s hemoglobin level: 
• For a hemoglobin over 10.0 g/dL, draw the full volume of blood for safety labs, flow 
cytometry for Circulating Sézary Cells, research labs and the biorepository. 
• For a hemoglobin between 9.0 and 10.0, draw the full volume of blood for safety labs, flow 
cytometry for Circulating Sézary Cells, and research labs. Do not draw for the biorepository.  
• For a hemoglobin less than 9.0 g/dL, draw only the safety labs and flow cytometry for 
Circulating Sézary Cells.  
9.1.1 Biomarker Studies 
To assess the immune response and pre-determined correlative studies a skin biopsy will be 
collected and peripheral blood collected at baseline (screening). Skin and blood will then be 
required post IFN lead-in (C1D1). Skin and blood will then be required at C2D1 to detect an 
early combination effect. Blood samples will then be drawn at intervals specified in the study 
calendars. Skin and blood are required for new tumors or progressive disease, at EOT and for 
skin flare reactions.  
Table 9.1 Tumor Tissue and Blood Collection 
 
 
Response (PR/CR)/PD 
EOT and Skin Flare Rxn 
5 mm punch biopsies* 
Required at baseline– 
(Sent to CITN Central 
Lab in formalin) and at 
C1D1 and C2D1  
Required at 
progression or 
appearance of a new 
lesion –(Sent to CITN 
Central Lab in 
formalin) 
Optional at response 
(PR/CR) 
Required – (Sent to CITN 
Central Lab in formalin) 
Image guided Core 
Biopsy (subjects with 
known LN disease 
only) 
Optional – (Core 
biopsy to CITN Central 
Laboratory in 
Formalin) 
Optional – (Core 
biopsy to CITN Central 
Laboratory in 
Formalin) 
Optional – (Core biopsy to 
CITN Central Laboratory 
in Formalin)  
Biomarkers (blood) 
Required (Sent to 
CITN Central Lab) 
timing of specific 
biomarkers are 
variable, see study 
calendar 
Required for both 
response and PD (Sent 
to CITN Central Lab) 
Required (Sent to CITN 
Central Lab) 
Biorepository: 30 mL 
total volume. (20 mL 
for PBMCs and 
10 mL for Serum) 
Optional (Sent to CITN 
Central Lab) at 
screening, then every 
3rd cycle 
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.  

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**All blood that is drawn for storage in the Biorepository will be shipped to the CITN Central Laboratory 
Biorepository for storage and future testing. 
 
9.1.1.1 
Biopsy Instructions 
Two side-by-side 5 mm (minimal) punch biopsies per lesion should be obtained if at 
all possible. If the skin lesion is too small for side-by-side biopsies, one 6-8 mm 
punch can be obtained and bisected for handling. Samples from more than one lesion 
type (patch, plaque, tumor) or anatomic site (if all same type of lesion) are strongly 
encouraged. If diagnostic tissue is needed (to send to clinical/surgical pathology), 
bisected half of a punch biopsy can be sent; the remaining skin samples should be 
handled per lab manual.  
9.1.1.2 
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 may be sent to the CITN Central 
Laboratory where slides will be made and tested for Chromogenic (Single-Color) 
IHC for PD-L1 and for Multiparametric (Two-Color) IHC. The CITN Central Lab 
will also test archival tissue for Transcriptional Analyses using the Nanostring 
platform. If archival tissue is not available it is important to review the pathology 
report and confirm the diagnosis.  
9.1.1.3 
Image Guided Core Biopsy 
If a patient has known lymph node disease an optional image-guided core biopsy of 
the lymph node may be obtained at the other biopsy time points. Patients may refuse 
the lymph node biopsies and still participate in the trial. Lymph node core biopsies 
will be obtained at the respective Cancer Center according to their clinical SOP’s.  
9.1.1.4 
Circulating Tumor Cells 
Circulating Tumor Cells will be referred to as circulating Sézary cells or CSCs in this 
protocol). Sézary cells are typically CD4+CD26- and/or CD4+CD7- however in rare 
cases the phenotype is CD8+ or loss of CD3 expression. For an individual patient 
only one of the phenotypes will be used. We will follow the defined Sézary cell 
phenotype over time using the Olsen Criteria for response assessment. [Olsen 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 and absolute number of Circulating Sézary Cells). The 
flow cytometry testing for Sézary Cell Quantification will be performed locally at the 
individual research sites.  
9.1.2 Exploratory/Ancillary Correlative Studies 
9.1.2.1 
Chromagenic (Single-Color) immunohistochemistry for PD-1 
PD-L1 expression has emerged as the leading biomarker for response to anti-PD1 
therapy, but studies thus far have found this to be far from a perfect biomarker. This 
may be due at least in part to the dynamic nature of PD-L1 expression. Interferon 

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gamma is known to upregulate PD-L1 expression in some tumor cells and frequently 
on tumor infiltrating leukocytes. With this biomarker we will explore the predictive 
value of PD-L1 expression before treatment as well as the inducible expression after 
interferon gamma treatment. FFPE skin biopsies will be stained with the FDA 
approved 22C3 assay. Staining will be assess both pre-treatment and after interferon 
gamma treatment. We will test whether PD-L1 expression (baseline and/or inducible) 
correlates with MK-3475 (pembrolizumab) response in the Mycosis 
Fungoides/Sézary Syndrome population. 
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. 
Handling of Specimens(s) 
Biopsy samples will be placed in formalin and shipped to the CITN Central 
Laboratory. 
Shipping of Specimen(s) 
Participating sites will send biopsy tissue in formalin for overnight delivery to the 
CITN Central Laboratory. The CITN Central Laboratory will prepare FFPE blocks 
then prepare slides.  
Site(s) Performing Correlative Study 
The CITN Central Laboratory will coordinate the Chromagenic IHC testing using 
shared resources of the Fred Hutchinson Cancer Research Center (FHCRC) under the 
direction of Dr. Rob Pierce.  
9.1.2.2 
Multiparametric Immunohistochemistry 
The skin microenvironment plays a critical role in the development and progression 
of cutaneous T cell lymphomas (CTCL). There are a number of potentially 
suppressive immune populations, such as regulatory T cells and M2 macrophages, 
present within CTCL involved skin that may blunt response to immunotherapy. 
Conversely, the presence of a tumor infiltrating lymphocyte population has been 
correlated with response to immune checkpoint blockade in other malignancies. To 
better define the spatial relationship between CTCL cells and the other key 
microenvironment residents, we will employ multiparametric immunohistochemistry 
for CD3, CD4, CD8, Foxp3, and CD163. In addition, we will co-stain for PD1, PD-
L1, PD-L2, to define expression of these key markers on the relevant immune 
subsets. 
Collection of Specimen(s) 
Specimens will include archived and prospectively obtained tumor biopsies from skin 
and/or lymph nodes including possible punch and/or core biopsies 
Handling of Specimens(s) 
Biopsy samples will be placed in formalin and shipped to the CITN Central 
Laboratory. 

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Shipping of Specimen(s) 
Participating sites will send biopsy tissue in formalin to the CITN Central Laboratory. 
The CITN Central Laboratory will prepare FFPE blocks then prepare the slides.  
Site(s) Performing Correlative Study 
The CITN Central laboratory will coordinate the multiparametric 
immunohistochemical assays using shared resources of the FHCRC under the 
direction of Dr. Rob Pierce to identify and enumerate key cellular components and 
immunoregulatory molecules to include PD-1, PD-L1, among other analytes.  
9.1.2.3 
Multiplexed Ion Beam Imaging 
The skin microenvironment of CTCL includes CD8+ tumor infiltrating T cells, 
dendritic cells, macrophages, mast cells, and non-malignant CD4+ T cells including 
regulatory T cells. While the above studies will provide essential data with standard 
methodologies, they are unable to discriminate many critical cell populations due to 
the limitation of simultaneously detectable parameters. As a relevant example, in 
CTCL, the malignant T cells themselves can only be reliably identified by the 
expression pattern of a minimum of two parameters, typically CD4 and either CD7 or 
CD26. Until recently, there has been no imaging technology available capable of 
providing sufficient dimensionality to both discriminate relevant immune populations 
and simultaneously detect expression of other key markers. 
A mass spectrometry based approach dubbed multiplexed ion beam imaging (MIBI) 
is a novel approach to antibody-mediated labeling and imaging of tissue. The use of 
heavy metal isotope labels enables high dimensional multiplexing with minimal 
overlap between metals from formalin-fixed paraffin embedded tissue samples 
resulting in a theoretical limit of over 100 parameters collected per image. Currently, 
access to MIBI technology is very limited, with only two systems available 
worldwide. In collaboration with researchers at Stanford University, we have the 
opportunity to apply MIBI technology to study the CTCL skin microenvironment in 
unprecedented detail from primary patient samples collected before and during 
therapy. Through high dimensional analysis, we will decipher the complex 
interactions between tumor cells and the diverse immune residents within their local 
microenvironment. MIBI is uniquely capable of simultaneously discerning both the 
spatial relationship between CTCL cells and interacting immune cells and their 
relative expression of relevant immunomodulatory molecules such as PD-1 and PD-
L1. Applying MIBI to paired will provide an unparalleled glimpse into the 
perturbation of the immune microenvironment induced by immune checkpoint 
blockade. 
Collection of Specimen(s) 
Specimens will include archived and prospectively obtained tumor biopsies including 
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Handling of Specimens(s) 
Biopsy samples will be placed in formalin and shipped to the CITN Central 
Laboratory.  
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 Stanford for testing.  
Site(s) Performing Correlative Study 
Stanford University, under the direction of Dr. Jinah Kim.  
9.1.2.4 
Transcriptional Analyses 
The Nanostring platform will be used to profile mRNA expression of approximately 
730 genes in an attempt to define a gene set predictive for clinical response to MK-
3475 (pembrolizumab). The utility of this assay is two-fold. First, it will test the 
hypothesis that there is an immune related gene expression signature that predicts 
response to MK-3475 (pembrolizumab) and interferon gamma. Second, it will assess 
for Th1 polarization by interferon gamma of helper T cells in the tumor site. Profiling 
will be performed on RNA extracted from FFPE skin biopsies and may also be 
performed on peripheral blood mononuclear cells. 
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 
Handling of Specimens(s) 
Biopsy samples will be placed in formalin and shipped to the CITN Central 
Laboratory. 
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 Nanostring Technologies in Seattle for Nanostring gene 
panel 
Site(s) Performing Correlative Study 
The CITN Central lab will perform the analyses of testing results from Nanostring. 
9.1.2.5 
Whole Exome Sequencing and Neoantigen Prediction 
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 

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malignancies. Somatic mutations identified by whole exome sequencing will be 
analyzed for predicted formation of neoantigens. Neoantigen specific T cells will be 
detected by a combination of peptide-MHC tetramer staining and functional assays 
such as upregulation of CD137, OX-40, and interferon-gamma production after 
stimulation with candidate neoantigen peptides.  
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.  
Handling of Specimens(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. 
Shipping of Specimen(s) 
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.  
Site(s) Performing Correlative Study 
The Stanford Laboratory of Dr. Paul Khavari, or an equivalent laboratory, will 
perform the Exome Sequencing and neoantigen identification.  
9.1.2.6 
Immunophenotyping 
CyTOF is a mass spectrometry-based method of single cell analysis analogous to 
flow cytometry that is capable of collecting >30 parameters for each cell. CyTOF and 
multiparametric flow cytometry will be employed to extensively immunophenotype 
circulating peripheral lymphocytes before treatment, after 1 week of interferon 
gamma treatment and after the treatment with a combination of MK-3475 
(pembrolizumab) and interferon gamma. In addition to standard immunophenotyping, 
cells will be analyzed with and without TCR stimulation (either by PMA/ionomycin 
or anti-CD3) to assess for function defects in T cells. 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 Mycosis Fungoides/Sézary 
Syndrome. Flow cytometry will also be used to evaluate peripheral blood 
mononuclear cells. 
Collection of Specimen(s) 
Whole blood will be collected into heparinized tubes.  

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Handling of Specimens(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.  
Shipping of Specimen(s) 
Frozen PBMCs will be shipped to Stanford University. 
Site(s) Performing Correlative Study 
Analysis to be performed at Stanford University in the laboratory of Dr. Michael 
Khodadoust. 
9.1.2.7 
Cytokine/Chemokine Analysis (serum 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 (before treatment) and on treatment. Exploratory analysis will be 
performed to determine whether any cytokines/chemokines correlate with response to 
therapy. These assays will also provide a glimpse into the systemic immune 
perturbations caused by systemic interferon gamma therapy.  
Collection of Specimen(s) 
Whole blood will be collected into red-top tubes.  
Handling of Specimens(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, 
Khodadoust Laboratory. Aliquots will be thawed and analyzed by Luminex. 
Shipping of Specimen(s) 
Frozen serum will be shipped by the CITN Central Laboratory to Stanford University. 
Site(s) Performing Correlative Study 
All sites will provide samples for analysis to be performed at Stanford University in 
the laboratory of Dr. Michael Khodadoust. 
9.1.2.8 
T cell Receptor High Throughput Sequencing 
High throughput sequencing of TCR genes is emerging as a valuable disease marker 
and measure of minimal residual disease in cutaneous T cell lymphomas. In addition 
to providing a measurement of the burden of the malignant clone, high throughput 
sequencing allows interrogation of the entire T cell repertoire. This correlate will 
enable an exploratory analysis of the TCR repertoire as a potential biomarker for 
response to therapy. Characteristics such as repertoire diversity and clonal dynamics 
will be correlated to clinical responses. We will also utilize TCR-HTS to identify and 
quantify Sézary Cells and we will compare the utility of this testing methodology to 
Flow Cytometry.  

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Collection of Specimen(s) 
Specimens will include archived and prospectively obtained tumor skin biopsies and 
blood samples. 
Handling of Specimen(s) 
Biopsy samples will be placed in formalin and shipped to the CITN Central 
Laboratory. Whole blood will be shipped directly to the CITN Central Laboratory for 
processing and testing. 
Shipping of Specimen(s) 
All samples will be shipped to the CITN Central Laboratory for testing.  
Site(s) Performing Correlative Study 
The CITN Central Lab will coordinate the TCR-HTS testing using shared resources 
of the FHCRC or Adaptive Biosciences.  
9.1.3 Special Studies  
9.1.3.1 
Special Correlative Study #1: Whole Blood Kyn/Trp Ratios 
It is postulated that enhanced IDO expression may occur in patients who fail anti-PD-
1 therapy. Thus, Kyn/Trp ratios will be assayed as measured in peripheral blood at 
baseline and at specified intervals throughout the trial. Evidence of this mechanism of 
resistance would suggest that some anti-PD-1 failures could potentially be overcome 
with an IDO inhibitor. 
Collection of Specimens 
Whole blood will be collected into heparinized tubes and processed to frozen plasma 
at the local lab.  
Handling of Specimen(s)  
Frozen vials of plasma will be batch shipped to the CITN Central Laboratory.  
Shipping of Specimens 
Frozen vials of plasma will be shipped from the CITN Central Laboratory to the 
Incyte Corporation for testing. 
Site(s) Performing Correlative Study  
The Kyn/Trp analysis will be conducted at Incyte Corporation 
9.1.3.2 
Special Correlative Study #2: Microbiome Analyses 
The impact and importance of the gut microbiome in human cancer patients’ 
responses to immunotherapy has not yet been well-characterized and will be 
important to determine. We will collect microbiome samples from patients at baseline 
and perform taxonomic profiling via 16S rRNA gene sequencing and metagenomic 
whole genome shotgun (WGS) sequencing. Sequencing data will be analyzed and 
compared to clinical responses to determine whether response or non-response to 
treatment can be correlated with specific microbiota.  

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Assays will be performed in collaboration with Dr. David Fredricks at FHCRC or 
other agreed upon collaborator. 
Collection of Specimen(s) 
Enrolled study subjects will be provided with fecal swab/storage devices and SOPs. 
Fecal samples will be collected by patients before initiating therapy using standard, at 
home stool-collection procedures using standardized fecal swab/storage devices. 
Handling of Specimens(s) 
Samples will be initially stored frozen or at 4°C at home by patients and returned to 
the clinical research site at the first study visit and stored at the local site at -80°C. 
Shipping of Specimen(s) 
Frozen samples will be batch shipped overnight on dry ice to the CITN Central 
Laboratory (CIML). Sites will utilize a web-based specimen system (BSI) to 
communicate with the CIML. The CIML will coordinate the shipment of samples to 
Dr. David Fredricks at FHCRC. 
Site(s) Performing Correlative Study  
Assays will be performed in collaboration with Dr. David Fredricks at FHCRC, or a 
CIMAC or other collaborator. 
 
9.2 
Synovial Sarcoma (Treatment Group 2) 
9.2.1 Blood Draws in Anemic and Pediatric Patients 
The study calendar and lab manual describe blood draws for safety- and research labs. In the 
interest of patient safety, we are including a provision to draw less blood if patients are anemic or 
<18 years of age.  
 
9.2.1.1 
Blood Draw Instructions based on Hemoglobin Level 
A complete blood count (CBC) will be performed as part of the safety labs at each study visit. 
The results of the CBC will be reviewed and the following blood volumes will be drawn based 
upon the patient’s hemoglobin level: 
 
• 
For a hemoglobin value over 10.0 g/dL, draw the full volume of blood for safety labs and 
research labs. 
 
• 
For a hemoglobin value between 9.0 and 10.0 g/dL, draw blood for safety labs and research labs 
for Flow Cytometry and Cytokines only (Do not draw blood for ELISPOT).   
 
• 
For a hemoglobin less than 9.0 g/dL, draw only the safety labs. 
 

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9.2.1.2 
Blood Draw instructions based on patient weight if <18 years of age 
For patients <18 years of age, blood draws will be prioritized as follows: 
• 
For patients weighing ≥30 kg (66 lbs) draw the full volume of safety labs and research labs (up to 
165 mL total volume). 
 
• 
For patients weighing <30 kg (<64 lbs) only draw blood for safety labs and cytokines (up to 25 
mL total volume). 
 
 
9.2.2 Research Biopsies for Correlative Studies 
A mandatory research biopsy will occur prior to the initiation of study therapy. There is no time 
limit on the pretreatment biopsy. However, the patient cannot have undergone a different therapy 
since its collection. Archival tissue can be used in lieu of a pretreatment biopsy if the patient has 
not undergone any treatment since that tissue was collected. Archival tissue may also be used in 
lieu of a fresh biopsy for patients <18.  The second biopsy is mandatory for participant ≥18 years 
of age, but will be performed only if deemed safe by the principal investigator. For participants 
<18 years of age a second biopsy is optional and will only be performed if deemed safe by the 
principal investigator. The second biopsy will be performed after Week 8 but before the patient’s 
first scan which will occur 12 weeks after starting treatment. Multiplex immunohistochemistry of 
tumor biopsy samples will test whether clinical outcomes correlate with the level of increased 
MHC expression, T cell infiltration and the presence of other immune infiltrates on paired biopsy 
specimens. Gene expression using the NanoString platform will be used to determine whether 
increased expression of inflammatory markers at 8-12 weeks correlates with clinical outcomes. 
 
9.2.3 Biopsy Instructions 
A biopsy will be performed on a safely accessible lesion to be chosen by the patient’s treating 
physician. This lesion should not have received prior radiation or any other locally directed 
therapy (e.g., hepatic artery ablation, clinical trial of intra-tumor therapy). When possible, four 
cores will be pulled so long as the treating physician thinks this can be done safely and with high 
quality. In general, all cores should be fixed in formalin immediately after they are pulled and 
sent to the CITN Immune Monitoring Lab (CIML). However, the PI may select samples where 
there is particular scientific interest for cores to be processed differently, such as placed in RPMI 
for digestion and flow cytometric analysis or cell culture. In those special cases the PI will give 
specific instructions for handling those samples. 
 
9.2.4 Archival Tissue 
Archival tissue is not mandatory, however if it is available and if the patient has given permission in the 
consent form a formalin-fixed paraffin-embedded (FFPE) block will be sent to the CITN Central 
Laboratory for storage and analysis.  

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9.2.5 Blood Sampling for Correlative studies 
Blood samples for correlative studies, including peripheral blood mononuclear cells (PBMC) and serum, 
will be drawn prior to starting treatment and then as indicated in the Study Calendar. Patients will be 
tested for HLA-A*0201 and HLA-A*2402 and in patients expressing the alleles, MHC tetramers will be 
used to test for increased antigen specific populations. We hypothesize that large, central memory T cell 
populations with specificity for NY-ESO-1, PRAME and MAGE family antigens will result in improved 
clinical outcomes. Furthermore, robust expansion of highly activated T central memory cell derived 
populations after starting treatment will correlate with better clinical outcomes. 
 
 
9.2.6 Integrated/Exploratory Correlative Studies 
9.2.6.1 
Flow Cytometry for Selected Class I HLA Alleles and Tetramer Analyses for Antigen-
Specific T Cell Phenotyping on PBMC (Flow Cytometry) 
Collection of Specimens 
Whole blood will be collected into heparinized tubes. Blood draws will be performed by venipuncture on 
study subjects just before, during and at end of treatment. 
Handling and Shipping of Specimens 
Blood Samples will be collected at room temperature and shipped ambient to the CIML the same day as 
the blood draw. The sample must be received at the CIML within 24 hours of blood draw. Blood samples 
will be shipped to the CIML for processing to PBMC and stored in liquid nitrogen. Clinical sites will 
utilize a web-based specimen system (BSI) to communicate with the CIML. 
Site(s) Performing Correlative Study 
Analysis will be performed at the Fred Hutchinson Cancer Research Center (FHCRC) in the laboratory of 
Dr. Seth Pollack and/or at the CIML under the direction of Dr. Steven Fling.  
 
9.2.6.2 
Immune Phenotype Panel (Multispectral Immunohistochemistry) 
Collection of Specimens 
Tumor biopsy tissue will be collected prior to and during therapy as described in sections 9.2.2, 9.2.3 and 
9.2.4. 
Handling and Shipping of Specimens 
Tissue will be placed in formalin for overnight shipping to the CIML where they will be embedded in 
paraffin. For archival samples, clinical sites will arrange for the formalin-fixed, paraffin-
embedded tumor blocks or FFPE slide to be shipped at ambient temperature to the CIML. 
Clinical sites will utilize a web-based specimen system (BSI) to communicate with the CIML. Paraffin 
blocks (or FFPE slides) will be stored at 4oC under desiccant. The CIML will coordinate shipment to the 
FHCRC immunopathology lab or other vendor.   

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Site(s) Performing Correlative Study 
Analysis will be performed in the laboratory of Dr. Rob Pierce at the FHCRC Core Laboratory, and 
FHCRC shared services.  
 
9.2.6.3 
Immune Gene Expression Signature (NanoString®Gene Expression using the 
nCounter® Human Immunology V2 Panel and the nCounter®PanCancer Immune 
Profiling Panel) 
Collection of Specimens 
Tumor biopsy tissue will be collected prior to and during therapy as described in sections 9.2.2, 
9.2.3 and 9.2.4. 
Handling and Shipping of Specimens 
Tissue will be placed in formalin for overnight shipping to the CIML where they will be embedded in 
paraffin. Clinical sites will utilize a web-based specimen system (BSI) to communicate with the CIML. 
For archival samples, clinical sites will arrange for the formalin-fixed, paraffin-embedded tumor 
blocks or FFPE slide to be shipped at ambient temperature to the CIML. Paraffin blocks (or FFPE 
slides) will be stored at 4oC under desiccant. The CIML will coordinate shipment to Nanostring or 
designated Cancer Immune Monitoring and Analysis Center (CIMAC).   
Site(s) Performing Correlative Study 
Analysis to be performed at NanoString Corp.and at the CIML/FHCRC or at a designated vendor or 
CIMAC. 
 
9.2.6.4 
T Cell Receptor (TCR) Clonality (TCR ImmunoSeq) 
Collection of Specimens 
Tumor biopsy tissue will be collected prior to and during therapy as described in sections 9.2.2, 
9.2.3 and 9.2.4. 
Handling and Shipping of Specimens 
Biopsy samples will be placed in formalin and shipped to the CIML. For biopsies done as part of this 
protocol, tissue in formalin will be shipped overnight at ambient temperature to the CIML where they will 
be embedded in paraffin. For archival samples, clinical sites will arrange for the formalin-fixed, 
paraffin-embedded tumor blocks or FFPE slide to be shipped at ambient temperature to the 
CIML. Clinical sites will utilize a web-based specimen system (BSI) to communicate with the CIML. 
Paraffin blocks (or FFPE slides) will be stored at 4oC under desiccant. The CIML will coordinate 
shipment to Adaptive Biotechnologies or designated CIMAC. 
Site(s) Performing Correlative Study 
Analysis to be performed at Adaptive Biotechnologies or designated CIMAC. 
 
 

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9.2.7 Exploratory/Ancillary Correlative Studies 
9.2.7.1 
PD-L1 Baseline and Post-Treatment (Immunohistochemistry)  
Collection of Specimens 
Tumor biopsy tissue will be collected prior to and during therapy as described in sections 9.2.2, 
9.2.3 and 9.2.4. 
Handling and Shipping of Specimens 
Biopsy samples will be placed in formalin and shipped to the CIML. For biopsies done as part of this 
protocol, tissue in formalin will be shipped overnight at ambient temperature to the CIML where they will 
be embedded in paraffin. For archival samples, clinical sites will arrange for the formalin-fixed, 
paraffin-embedded tumor blocks or FFPE slide to be shipped at ambient temperature to the 
CIML. Clinical sites will utilize a web-based specimen system (BSI) to communicate with the CIML. 
Paraffin blocks (or FFPE slides) will be stored at 4oC under desiccant. The CIML will coordinate 
shipment to the FHCRC immunopathology lab or other vendor. 
Site(s) Performing Correlative Study 
These analyses will be performed using qualified analytes and analytic tools at the 
immunopathology lab and shared resources of the FHCRC under the direction of Dr. Rob Pierce, 
or at a vendor to be determined or at Merck. 
 
9.2.7.2 
Whole Blood Lymphocyte and Monocyte Immunophenotyping (Whole Blood 
Multiparametric Flow Cytometry) 
Collection of Specimens 
Whole blood will be collected into heparinized tubes. Blood draws will be performed by venipuncture on 
study subjects just before, during, and at end of treatment. 
Handling and Shipping of Specimens 
Blood Samples will be collected at room temperature and shipped ambient to the CIML the same day as 
the blood draw. The sample must be received at the CIML within 24 hours of blood draw. Clinical sites 
will utilize a web-based specimen system (BSI) to communicate with the CIML. Blood samples will be 
shipped to the CIML for processing and the Whole Blood Assay. 
Site(s) Performing Correlative Study 
Analysis will be done at FHCRC/CIML under the direction of Dr. Steven Fling. 
 
9.2.7.3 
Anti-Tumor Immune T cell Responses (ELISPOT) 
Collection of Specimens 
Whole blood will be collected into heparinized tubes. Blood draws will be performed by venipuncture on 
study subjects just before, during, and at end of treatment. 
Handling and Shipping of Specimens 
Blood Samples will be collected at room temperature and shipped ambient to the CIML the same day as 
the blood draw. The sample must be received at the CIML within 24 hours of blood draw. Clinical sites 

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will utilize a web-based specimen system (BSI) to communicate with the CIML. Blood samples will be 
shipped to the CIML for processing to PBMC and stored in Liquid Nitrogen. 
Site(s) Performing Correlative Study 
Analysis will be done at the FHCRC at the CIML under the direction of Dr. Steven Fling.  
 
9.2.7.4 
Multiplex Cytokines (Affymatrix or Luminex) 
Collection of Specimens 
Whole blood will be collected into red-top tubes by venipuncture. Blood draws will be performed by 
venipuncture on study subjects just before, during, and at end of treatment. 
Handling and Shipping of Specimens 
Blood samples will be processed to frozen serum at the local labs and stored frozen at -80°C.  Frozen 
serum vials will be shipped in Batch from clinical sites to the CIML. Clinical sites will utilize a web-
based specimen system (BSI) to communicate with the CIML. The CIML will coordinate shipments of 
serum to the FHCRC Shared Resource facility, to CIMAC collaborator, as needed.  
Site(s) Performing Correlative Study 
Analysis will be done at FHCRC shared services, or at a CIMAC collaborator. 
 
9.2.7.5 
Microbiome Analyses 
 
Collection of Specimens 
Enrolled study subjects will be provided with fecal swab/storage devices and SOPs.  Fecal 
samples will be collected by patients prior to initiating therapy using standard, at home stool-
collection procedures using standardized fecal swab/storage devices. 
 
Handling and Shipping of Specimens 
Samples will be initially stored frozen or at 4°C at home by patients and returned to the clinical 
research site at the first study visit and stored at the local site at -80°C. Frozen samples will be 
batch shipped overnight on dry ice to the CITN Central Laboratory (CIML). Sites will utilize a 
web-based specimen system (BSI) to communicate with the CIML. The CIML will coordinate 
the shipment of samples to Dr. David Fredricks at FHCRC or to designated CIMAC. 
 
Site(s) Performing Correlative Study 
Assays will be performed in collaboration with Dr. David Fredricks at FHCRC or other CIMAC 
collaborator. 
 
 
9.2.8 Special Studies 
9.2.8.1 
HLA Class I and Class II Typing 
DNA will be extracted from residual blood collected at baseline and processed as described in 
9.2.6. Extracted DNA will be assayed at the laboratory of Dr. Dan Geraghty (FHCRC). The 
CIML will coordinate sample shipping to the Geraghty Lab. 

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10. 
STUDY CALENDAR 
Baseline evaluations are to be conducted within 1 week before start of protocol therapy. Safety Labs are to be drawn within 10 days before the 
start of therapy. Scans and x-rays must be done <4 weeks before the start of therapy.  
10.1 
Mycosis Fungoides/Sézary Syndrome (Treatment Group 1) 
Treatment Cyclea 
(Cycle Number) 
Screen
ing 
Base
line/I
FN 
Lead
-Ins 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
Response/ 
PD Assess 
or EOT b,c 
Skin Flare 
Reactionq 
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 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
 
MK-3475 AdministrationA 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Interferon-G 
Administrationt 
 
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 
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 
X 
Limited Physical exam 
 
X 
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 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogramg 
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 
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 
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 
X 
Urinalysisk 
Xh 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
T3, FT4 and TSHk 
Xh 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
Pregnancy Testj,k 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

NCI Protocol #: CITN-13 
Version Date: March 03, 2020  
 
106 
 
Treatment Cyclea 
(Cycle Number) 
Screen
ing 
Base
line/I
FN 
Lead
-Ins 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
Response/ 
PD Assess 
or EOT b,c 
Skin Flare 
Reactionq 
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 or 
CT/PET) for pts with 
extracutaneous  diseasen 
X 
 
 
 
 
 
 
X* 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Tumor Imaging for pts with 
cutaneous  disease only 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Circulating Sézary cells** 
 
X 
 
X 
 
 
 
X* 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
mSWAT 
Scoring/Photography 
X 
X 
X 
X 
 
X 
 
X* 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Tumor Biopsy/Correlative Blood and Stool Samples,l 
Skin Biopsy (See Section 
9.1)o     
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Xr 
Lymph Node 
Biopsy(Optional)p  
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Transcriptional Analysis 
(10mL) 
 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
WES, Neoantigens (90mL) 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Peripheral 
Immunophenotyping 
(CyTOF) (20mL) 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Cytokines/Chemokines 
(10mL) 
 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
TCR Sequencing (10mL) 
 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Kyn/Trp Ratio (10mL) 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Microbiome Analyses*** 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biorepository (Sec. 9) 
(30mL) 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
A. The dose of MK-3475 is 200mg by IV infusion every 21 days. Interferon-gamma dose starts at 50mcg/m2 thrice weekly (e.g., MWF or TTHS).  Dose in mcg/m2 may vary, see section 5.1.  
a.  In general, safety labs, assessments/procedures are to be performed on Day 1 and prior to the dose of MK-3475 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 (+/- 1 week) 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. 
g.  Electrocardiogram at screening.  Repeat only if clinically indicated.  

NCI Protocol #: CITN-13 
Version Date: March 03, 2020  
 
107 
 
Treatment Cyclea 
(Cycle Number) 
Screen
ing 
Base
line/I
FN 
Lead
-Ins 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
Response/ 
PD Assess 
or EOT b,c 
Skin Flare 
Reactionq 
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  
 
h.  Laboratory tests for screening are to be performed within 10 days prior to the first dose of trial treatment. 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 include:  Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total protein,    
SGOT [AST], SGPT [ALT], sodium.  
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.  Baseline correlative samples may be obtained any time after confirmation of eligibility and before the first dose of IFN-G 
m. PFT required at baseline for patients with a history of significant pulmonary disease, prolonged smoking history, or symptoms of respiratory dysfunction.  
n.  Presence of extracutaceous disease at screening:  Scans will be performed at screening, C5-6 (before cycle 6), , C9-10 (before cycle 10), then every 4 cycles, to confirm CR/PR when suspect  PD, 
EOT.  Absent extracutaneous disease:  Scans will be performed at screening, to confirm PR/CR, when suspect Progressive Disease and at EOT.   
o.  Skin biopsies will be performed prior to IFN-G lead-in, after IFN-G lead-in (C1D1), C2D1, for PD or appearance of a new lesion, skin flare & EOT.  Biopsy for response (PR/CR) is optional. 
p.  Lymph node biopsies are at the same time points as skin biopsies however they are optional.   
q.  Visit for flare reaction may be scheduled or unscheduled.  If flare is noticed during a regular visit the additional correlative studies and assessments must be performed at the time of the visit.     
r. A research biopsy of the skin flare reaction is mandatory.  Tissue for local review and patient management is also mandatory.  
s. Procedures, assessments and tests for pre-IFN Lead-In only need to be performed once, prior to the first dose of IFN. 
t. Interferon-gamma may be continued without break starting on cycle 7, according to Section 5.1.1 
* The first global clinical assessment including mSWAT, CSCs (if indicated), and CT or PET/CT (for those with measurable or extracutaneous disease) will occur at Cycle #6 (before Pembro #6 is 
administered). For those with PD at Cycle #6 the same assessments will be repeated in a confirmatory fashion in ≥ 4 weeks. Those who do not have PD at Cycle #6 will have the same assessments 
repeated at Cycle  #10, then every 4 cycles thereafter. 
**CSC Testing:  For extracutaneous disease at enrollment:  CSC testing will be performed at  pre-IFN, C2D1, C6D1, C10D1, then every 4 cycles thereafter then to confirm PR/CR, when suspect PD, 
EOT, skin flare.  For patients with NO extracutaneous disease at enrollment perform CSC only at  pre-IFN to confirm PR/CR, when suspect PD, EOT, skin flare.   
***Fecal swab/storage devices and instructions must be given to patient; sample collection to be performed at home by patient and returned to clinical research site at the next study visit. 
 
 
Treatment Cyclea 
(Cycle Number) 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
Response/ 
PD Assess 
or EOT b,c 
Skin Flare 
Reactionq 
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) 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
 
Study Drug Administration 
MK-3475 AdministrationA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Interferon-G Administration 
 
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 

NCI Protocol #: CITN-13 
Version Date: March 03, 2020  
 
108 
 
Treatment Cyclea 
(Cycle Number) 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
Response/ 
PD Assess 
or EOT b,c 
Skin Flare 
Reactionq 
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 
 
 
Vital Signs & Weightf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogramg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
 
T3, FT4 and TSHk 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
Efficacy Measurements 
Tumor Imaging (CT or CT/PET) 
for pts with extracutaneous  
diseasen 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
Tumor Imaging for pts with 
cutaneous  disease only 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Circulating Sézary cells** 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
mSWAT Scoring/Photography 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X  
Tumor Biopsy/Correlative Blood Samples,l 
Skin Biopsyo  (See Section 9.1) o 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Xr 
Lymph Node Biopsy(Optional)p 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Transcriptional Analysis (10mL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
WES, Neoantigens (90mL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Peripheral Immunophenotyping 
(CyTOF) (20mL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Cytokines/Chemokines (10mL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
TCR Sequencing (10mL) 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
Kyn/Trp Ratio (10mL) 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
Biorepository (Sec. 9) (30mL) 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
A. The dose of MK-3475 is 200mg by IV infusion every 21 days. Interferon-gamma dose starts at 50mcg/m2 thrice weekly (e.g., M/W/F or T/TH/S).  Dose in mcg/m2 may vary, see 
section 5.1. 
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. 
g.  Electrocardiogram at screening.  Repeat only if clinically indicated.  

NCI Protocol #: CITN-13 
Version Date: March 03, 2020  
 
109 
 
Treatment Cyclea 
(Cycle Number) 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
Response/ 
PD Assess 
or EOT b,c 
Skin Flare 
Reactionq 
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 
 
 
h.  Laboratory tests for screening are to be performed within 10 days prior to the first dose of trial treatment. 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 include:  Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, 
total protein, SGOT [AST], SGPT [ALT], sodium.  
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.  Baseline correlative samples may be obtained any time after confirmation of eligibility and before the first dose of IFN-G 
m. PFT required at baseline for patients with a history of significant pulmonary disease, prolonged smoking history, or symptoms of respiratory dysfunction.  
n.  Presence of extracutaceous disease at screening:  Scans will be performed at screening C5-6 (before cycle 6),  C9-10 (before cycle 10), then every 4 cycles, to confirm CR/PR when 
suspect  PD, EOT.  Absent extracutaneous disease:  Scans will be performed at screening, to confirm PR/CR, when suspect Progressive Disease and at EOT.   
o.  Skin biopsies will be performed prior to INF-G lead-in, after IFN-G lead-in (C1D1), C2D1, for PD, or appearance of a new lesion,  skin flare & EOT.  Biopsy for response (PR/CR) is 
optional. 
p.  Lymph node biopsies are at the same time points as skin biopsies however they are optional   
q. Visit for flare reaction may be scheduled or unscheduled.  If flare is noticed during a regular visit the additional correlative studies and assessments must be performed at the time of 
the visit.     
r. A research biopsy of the skin flare reaction is mandatory.  Tissue for local review and patient management is also mandatory.  
* The first global clinical assessment including mSWAT, CSCs (if indicated), and CT or PET/CT (for those with measurable or extracutaneous disease) will occur at Cycle #6 (before 
Pembro #6 is administered). For those with PD at Cycle #6 the same assessments will be repeated in a confirmatory fashion in ≥ 4 weeks. Those who do not have PD at Cycle #6 will 
have the same assessments repeated at Cycle #10, then every 4 cycles thereafter. 
**CSC Testing:  For extracutaneous disease at enrollment:  CSC testing will be performed at  pre-IFN, C2D1, C6D1, , C10D1, then every 4 cycles thereafter then to confirm PR/CR, 
when suspect PD, EOT, skin flare.  For patients with NO extracutaneous disease at enrollment perform CSC only at  pre-IFN to confirm PR/CR, when suspect PD, EOT, skin flare.  
 
 
 
 
 
 
 
 
 

NCI Protocol #: CITN-13 
Version Date: March 03, 2020  
 
110 
 
10.2 
Synovial Sarcoma (Treatment Group 2) 
Treatment Cycle 
Screening 
Base
line/
IFN 
lead-
in 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Subsequ
ent 
Cycles 
(up to 2 
years) 
End of 
Tx and 
at 
docume
nted 
progres
sion 
Post Treatment Follow-up 
Weeks  
 
 
1-3 
4-6 
7-9 
10-12 
13-15 
16-18 
19-21 
22-24 
25-27 
28-30 
 
At the 
time of 
D/C 
Safety FU 
Disease 
Assessmenta 
Survival 
FU 
Scheduling window 
(days) 
Within 7 
days 
 
+/-3d 
+/- 7d 
+/- 7d 
+/- 7d 
+/- 7d 
+/- 7d 
+/- 7d 
+/- 7d 
+/- 7d 
+/- 7d 
 
 
30 d +/-
5d post 
D/C 
Every 12 
+/- 1 weeks  
Every 12 
+/- 1 
weeks 
Interferon-gamma 
(ACTIMMUNE)b 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
MK-3475 
(pembrolizumab)c 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Administrative procedures 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Procedures/Assessment 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital signs and 
weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG Performance 
status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
EKGd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event 
assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pulmonary function 
testinge 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Assessments (Safety Labs) 
CBC w/diff 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Serum chemistryf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Pregnancy test (urine 
or serum HCG)g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
X 
 
 
 
 
Xh 
 
 
 
 
T3, FT4 and TSH 
X 
 
 
 
 
 
 
X 
 
 
 
 
Xh 
 
 
 
 

NCI Protocol #: CITN-13 
Version Date: March 03, 2020  
 
111 
 
Treatment Cycle 
Screening 
Base
line/
IFN 
lead-
in 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Subsequ
ent 
Cycles 
(up to 2 
years) 
End of 
Tx and 
at 
docume
nted 
progres
sion 
Post Treatment Follow-up 
Weeks  
 
 
1-3 
4-6 
7-9 
10-12 
13-15 
16-18 
19-21 
22-24 
25-27 
28-30 
 
At the 
time of 
D/C 
Safety FU 
Disease 
Assessmenta 
Survival 
FU 
Scheduling window 
(days) 
Within 7 
days 
 
+/-3d 
+/- 7d 
+/- 7d 
+/- 7d 
+/- 7d 
+/- 7d 
+/- 7d 
+/- 7d 
+/- 7d 
+/- 7d 
 
 
30 d +/-
5d post 
D/C 
Every 12 
+/- 1 weeks  
Every 12 
+/- 1 
weeks 
Efficacy Measurements 
Radiologic 
evaluation 
Xi 
 
 
 
 
 
X 
 
 
 
X 
 
Xj 
X 
 
X 
 
Tumor Biopsies/Archival Tissue Collection 
Tumor biopsy 
Xk 
 
 
 
 
Xl 
 
 
 
 
 
 
 
 
 
 
 
Correlative Studies Blood Draws 
Tetramer analyses by 
Flow Cytometrym 
 
Xn 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
Whole Blood 
Multiparametric 
Flow cytometrym 
 
Xn 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
ELISPOTm 
 
Xn 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
Multiplex cytokinesm 
 
Xn 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
HLA Typingo 
 
Xn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stool Sample 
Microbiomep 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a. Disease assessment per standard of care 
b. Interferon Gamma-1b: 100 mcg/m2 once per week, starting one week prior to the first MK-3475 (pembrolizumab) dose. 
c. MK-3475 (pembrolizumab): 200 mg (≥18 years of age)/2 mg/kg (max=200mg) (<18years of age) every 3 weeks, starting cycle 1, week 1, day 1. 
d. Electrocardiogram will be performed at screening. Repeat only if clinically indicated. 
e. Pulmonary function testing required at baseline only for patients with a history of significant pulmonary disease, prolonged smoking history, or symptoms of respiratory dysfunction. 
f. Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], 
sodium. 
g. Pregnancy test (women of childbearing potential) must be performed within 72 hours of the initiation of study treatment. 
h. Urinalysis and thyroid (T3, FT4 and TSH) function tests will be performed every 6th cycle. 
i. Baseline radiographic assessment by CT scan must be done <2 weeks (14 days) before the initiation of study treatment.  
j. Radiographic assessment by CT scan will occur every 12 weeks (+/- 1 week). 
k. Baseline tumor biopsy (archival or fresh) is mandatory. Although there is no time limit on the pretreatment biopsy, the patient cannot have undergone a different therapy since its 
collection. Archival tissue can be used in lieu of a pretreatment biopsy if the patient has not undergone any treatment since that tissue was collected. If a fresh baseline biopsy is 

NCI Protocol #: CITN-13 
Version Date: March 03, 2020  
 
112 
 
Treatment Cycle 
Screening 
Base
line/
IFN 
lead-
in 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Subsequ
ent 
Cycles 
(up to 2 
years) 
End of 
Tx and 
at 
docume
nted 
progres
sion 
Post Treatment Follow-up 
Weeks  
 
 
1-3 
4-6 
7-9 
10-12 
13-15 
16-18 
19-21 
22-24 
25-27 
28-30 
 
At the 
time of 
D/C 
Safety FU 
Disease 
Assessmenta 
Survival 
FU 
Scheduling window 
(days) 
Within 7 
days 
 
+/-3d 
+/- 7d 
+/- 7d 
+/- 7d 
+/- 7d 
+/- 7d 
+/- 7d 
+/- 7d 
+/- 7d 
+/- 7d 
 
 
30 d +/-
5d post 
D/C 
Every 12 
+/- 1 weeks  
Every 12 
+/- 1 
weeks 
obtained this should be collected any time after confirmation of eligibility and before the first dose of interferon gamma-1b. 
l. The second biopsy is mandatory for participant ≥18 years of age, but will be performed only if deemed safe by the principal investigator. For participants <18 years of age a second 
biopsy is optional, and will be performed only if deemed safe by the principal investigator. The second biopsy will be performed after week 8, but before the patient’s first scan at week 
12. 
m. Correlative blood samples must be drawn prior to administration of study agents on a dosing day.  
n. Baseline correlative samples to be collected prior to the first dose of Interferon Gamma-1b. 
o. HLA-typing is performed on residual material from the flow cytometry blood draws. There is no additional blood draw for this test.  
p. Fecal swab/storage instructions must be given to patient; sample collection to be performed at home by patient and returned to clinical research site at the next study visit. 
 
 

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11. 
MEASUREMENT OF EFFECT 
11.1 
Mycosis Fungoides/Sézary Syndrome (Treatment Group 1) 
11.1.1 Antitumor Effect – Solid Tumors 
Mycosis Fungoides and Sézary Syndrome 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 with measurable disease will have scans at the 
intervals specified in the study calendar. 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 
CR, PR, PD/EOT. 
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 or PET/CT), Visceral Disease 
(CT or PET/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. 
Patients will be assessed (including scans for measurable disease, mSWAT and CSC, for 
extracutaneous disease) before study drug at Cycle 6, 10, then every 4 cycles thereafter. If 
progression is noted at an assessment, a confirmatory assessment will be repeated in ≥4 weeks. 
Assessments will also be performed at the time of CR/PR confirmation, PD and at EOT. 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 CR, 
PR, PD/EOT.  
If a CR is achieved patients may stop study drug therapy after 2 additional cycles (each cycle is 3 
weeks) 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 received additional therapy in the interim, if they are still eligible for the 
trial and the trial is still open to enrollment.  
11.1.1.1 
Definitions 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of 
their first treatment with Interferon-gamma (given first as run-in before MK-3475 
(pembrolizumab)). 
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 

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be objectively evaluated for disease response using parameters unique to Mycosis 
Fungoides/Sézary Syndrome.  
11.1.1.2 
Disease Parameters: N/A 
11.1.1.3 
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. 
Measurement Methods 
• Skin: mSWAT. 
• 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 
• 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. 
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. 
Digital copies of mSWAT photographs will be retained at sites for quality assurance or 
secondary review purposes.  
Regardless of treatment delays, response assessment including mSWAT, circulating 
sézary cell count 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 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 
(pembrolizumab), (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. 
11.1.1.4 
Initial Tumor Imaging 
Initial tumor imaging with a CT or PET/CT must be performed within 28 days before 
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 

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diagnostic quality and performed within 28 days before 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 (pembrolizumab) 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.  
11.1.1.5 
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 if possible 
progression is considered or to confirm response. Imaging should not be delayed for 
delays in cycle starts or extension of MK-3475 (pembrolizumab) cycle intervals. 
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. 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness. MRI is also acceptable in certain situations (e.g., for body 
scans).  
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.  
11.1.1.6 
Response Criteria 
Primary outcome measure is clinical response rate as assessed by the standard 
response criteria used in Mycosis Fungoides and Sézary Syndrome (skin, LN, viscera, 
blood, global). 

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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 Mycosis Fungoides/Sézary 
Syndrome (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 
Relapse 
Any new lymph node >1.5cm in long axis diameter in those with CR 
* Peripheral and central lymph nodes. 
†Whichever criterion occurs first. 

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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 measurable 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 

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Global 
Score* 
Definition 
Skin 
Nodes 
Blood 
Viscera 
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 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. 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, including 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:  
• 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 
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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11.1.1.7 
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. 
ORR12: Patients who have a response duration of at least 12 months.  
11.1.1.8 
Progression-Free Survival 
PFS is defined as the duration of time from start of treatment to time of progression or 
death, whichever occurs first. 
11.1.1.9 
Response Review 
No review of response rate is contemplated. Investigator determined responses will be 
chronicled.  
11.2 
Synovial Sarcoma (Treatment Group 2) 
11.2.1 Tumor Imaging and Assessment of Disease 
The primary endpoint of the study will be the ORR. Clinical CT scans of the chest, abdomen and pelvis 
will be assessed and evaluated based on RECIST v. 1.1. If additional imaging is clinically necessary (e.g., 
MRI humerus) in addition to this CT scan, it should also be evaluated by RECIST criteria. If a patient’s 
treating physician has a specific documented clinical reason to use a different imaging modality instead of 
CT chest, abdomen and pelvis, for a particular patient this will be allowed. Patients will come in for chest 
and/or abdomen scans, depending on clinical presentation, prior to treatment (within 14 days) and then at 
12 week intervals at the discretion of the site principal investigator. 
 
11.2.2 Response Criteria 
CR 
Disappearance of all lesions and no new lesion 
PR 
30% reduction in tumor size and no new lesions 
SD 
Fails to attain the criteria for CR, PR and PD 
PD 
20% increase in tumor size or at least one new lesion 
Relapse 
Any disease recurrence in those with CR 
 
 

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11.2.3 Progression-free Survival 
Progression free survival (PFS) is defined as the duration of time from start of treatment to time of 
progression or death, whichever occurs first. 
12. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS (TREATMENT GROUP 1 AND 2) 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
12.1 
Study Oversight 
This protocol is monitored at several levels, as described elsewhere in this section. The Protocol 
Principal Investigator is responsible for monitoring the conduct and progress of the clinical trial, 
including the ongoing review of accrual, patient-specific clinical and laboratory data, and routine 
and serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s). The Protocol Principal Investigator and 
statistician have access to the data at all times. 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via the mechanism described elsewhere in this section. 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
12.2 
Data Reporting 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments. To access Rave via iMedidata:  
• 
Site staff will need to be registered with CTEP and have a valid and active CTEP-IAM 
account; and  
• 
Assigned one of the following Rave roles on the relevant Lead Protocol Organization 
(LPO) or Participating Organization roster at the enrolling site: Rave CRA, Rave Read 
Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator. Refer to 
https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required. 
o To hold Rave CRA or Rave CRA (Lab Admin) role, site staff must hold a 
minimum of an AP registration type; 
o To hold Rave Investigator role, the individual must be registered as an NPIVR or 
IVR; and 
o To hold Rave Read Only role, site staff must hold an Associates (A) registration 
type. 

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If the study has a Delegation of Tasks Log (DTL), individuals requiring write access to Rave 
must also be assigned the appropriate Rave tasks on the DTL. 
Upon initial site registration approval for the study in Regulatory Support System (RSS), all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail 
from iMedidata. To accept the invitation, site staff must log 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. Site staff will not be able 
to access the study in Rave until all required Medidata and study specific trainings are 
completed. Trainings will be in the form of electronic learnings (eLearnings), and can be 
accessed by clicking on the link in the upper right pane of the iMedidata screen. If an eLearning 
is required and has not yet been taken, the link to the eLearning will appear under the study name 
in iMedidata instead of the Rave EDC link; once the successful completion of the eLearning has 
been recorded, access to the study in Rave will be granted, and a Rave EDC link will display 
under the study name.  
Site staff that have not previously activated their iMedidata/Rave account at the time of initial 
site registration approval for the study in RSS will also receive a separate invitation from 
iMedidata to activate their account. Account activation instructions are located on the CTSU 
website, in the Rave section under the Rave resource materials (Medidata Account Activation 
and Study Invitation Acceptance). Additional information on iMedidata/Rave is available on the 
CTSU members’ website in the Data Management >  Rave section at www.ctsu.org/RAVE/ or 
by contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com. 
12.2.1 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 by FTP burst of data. 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). 
Note: If your study has been assigned to CDUS-Complete reporting, all adverse events 
(both routine and expedited) that have occurred on the study and meet the mandatory 
CDUS reporting guidelines must be reported via the monitoring method identified above. 
If your study has been assigned to CDUS-Abbreviated reporting, no adverse event 
reporting (routine or expedited) is required to be reported via CDUS, but expedited 
adverse events are still required to be submitted via CTEP-AERS. 
12.2.2 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.  

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Data are to be submitted via Medidata Rave to the CITN on a real-time basis, but no less 
than 72 hours after the data has been collected. 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 trials, which may be 
found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
) and CTSU websites. 
The CITN data management organization will utilize a core set of eCRFs that are Cancer 
Data Standards Registry and Repository (caDSR) compliant 
(http://cbiit.nci.nih.gov/ncip/biomedical-informatics-resources/interoperability-and-
semantics/metadata-and-models). Customized eCRFs will be included when appropriate 
to meet unique study requirements. The 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 12.2.1 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.  
12.3 
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. 
• 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 

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the initial IRB approval for the site has been forwarded by the Coordinating Center to the 
CTEP PIO (PIO@ctep.nci.nih.gov) except for Group studies. 
12.4 
Collaborative Agreements Language 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
1. 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study. 
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) 
and shall be maintained as such by the investigators. The protocol documents for 
studies utilizing Agents contain confidential information and should not be shared or 
distributed without the permission of the NCI. If a copy of this protocol is requested 
by a patient or patient’s family member participating on the study, the individual 
should sign a confidentiality agreement. A suitable model agreement can be 
downloaded from: http://ctep.cancer.gov. 
2. 
For a clinical protocol where there is an investigational Agent used in combination 
with (an)other Agent(s), each the subject of different Collaborative Agreements, the 
access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as “Multi-Party Data”): 
a. NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with NCI, 
the design of the proposed combination protocol, and the existence of any 
obligations that would tend to restrict NCI’s participation in the proposed 
combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow said 
other Collaborator to develop, obtain regulatory approval or commercialize its 
own Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing before 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 

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disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects, including, if applicable, the Standards for Privacy of 
Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
4. 
When a Collaborator wishes to initiate a data request, the request should first be sent 
to the NCI, who will then notify the appropriate investigators (Group Chair for 
Cooperative Group studies, or PI for other studies) of Collaborator’s wish to contact 
them. 
5. 
Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with 
the guidelines and policies of the responsible Data Monitoring Committee (DMC), if 
there is a DMC for this clinical trial. 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to CTEP 
by the Group office for Cooperative Group studies or by the principal investigator for 
non-Cooperative Group studies for immediate delivery to Collaborator(s) for advisory 
review and comment before submission for publication. Collaborator(s) will have 30 
days from the date of receipt for review. Collaborator shall have the right to request 
that publication be delayed for up to an additional 30 days in order to ensure that 
Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s 
intellectual property rights, are protected. Copies of abstracts must be provided to 
CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible and 
preferably at least three (3) days before submission, but in any case, before 
presentation at the meeting or publication in the proceedings. Press releases and other 
media presentations must also be forwarded to CTEP before 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 
13.1 
Mycosis Fungoides/Sézary Syndrome (Treatment group 1) 
13.1.1 Study Design/Endpoints 
13.1.1.1 
Primary Objective 
To assess the overall response rate (ORR) of MK-3475 (pembrolizumab) and IFN-
gamma (Actimmune®) combination immunotherapy in subjects with previously 
treated Mycosis Fungoides or Sézary Syndrome. 
In this single stage phase II open label trial, we will have an interim futility analysis. 
When 12 patients have been followed for 6 months, we will perform the interim 
futility analysis. If ORR is less than 33% (4 or less CR+PR), the trial will stop and we 
will accept the null that combination therapy is no better than monotherapy. 
Otherwise, trial will continue until 30 patients accrue. If ORR is at least 57% (17 or 

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more CR+PR) at the final analysis, we will accept the alternative that combination 
therapy is significantly better than monotherapy. 
Hypothesis: Administration of MK-3475 (pembrolizumab) and IFN-gamma 
(Actimmune®) as a combination immunotherapy regimen to subjects with previously 
treated Mycosis Fungoides or Sézary Syndrome will result in a clinically meaningful 
ORR that is an improvement over the ORR of MK-3475 (pembrolizumab) or IFN-
gamma as monotherapy.  
13.1.1.2 
Secondary Objectives 
To explore the safety/tolerability and clinical activity of MK-3475 (pembrolizumab) 
and IFN-gamma (Actimmune®) in subjects with previously treated Mycosis 
Fungoides or Sézary Syndrome with respect to the following secondary endpoints:  
Safety and tolerability  
Interim safety review based on distinct patient SAE’s following the first 3 doses of 
pembrolizumab (10 weeks of therapy) that are attributable to study drugs; We will 
allow 10% or less of patients to develop study drug related SAEs. If 4 or more 
patients amongst the first 12 evaluable patients for toxicity at pre-C4 (week 10) have 
experienced study drug related serious adverse events (SAEs), we will conclude that 
the combination immunotherapy regimen is too toxic and accrual will stop. If accrual 
is not stopped for either interim futility or safety reasons, a final safety evaluation will 
be conducted based on the percentage of the 30 patients who have experienced SAEs. 
We will consider the safety profile being acceptable if less than 6 patients have 
experienced study drug related SAEs. Otherwise, we will evaluate the tradeoff 
between safety and efficacy benefits based on the magnitude of ORR improvements.  
Time to response (TTR) 
Duration of response (DOR) 
is defined as the time interval between the date of first response (CR/PR) and the date 
of progression. 
Progression-free survival (PFS) 
is defined as the time from enrollment to PD or death, whichever occurs earlier, based 
upon investigator assessment. Patients without documented PD/death will be 
censored at the last disease assessment date.  
Event-free survival 
(EFS events defined as termination due to toxicity, initiation of next significant 
treatment, progressive disease, or death of any cause) 
ORR12 
Percentage of all patients who have a response duration of at least 12 months 
(ORR12)  

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Hypothesis: Combination immunotherapy of MK-3475 (pembrolizumab) and IFN-
gamma (Actimmune®) will have acceptable safety/tolerability profile in previously 
treated Mycosis Fungoides/Sézary Syndrome population and meaningful clinical activity 
will be reflected in other clinical outcome parameters including DOR, PFS, EFS and 
ORR12. 
13.1.1.3 
Exploratory Objectives 
To investigate the relationship between the following putative biomarkers for 
combination immunotherapy of MK-3475 (pembrolizumab) and IFN-gamma 
(Actimmune®) and clinical outcomes (as measured by safety/tolerability and ORR, 
DOR, PFS, EFS) in subjects with previously treated Mycosis Fungoides/Sézary 
Syndrome, including tumor/microenvironment (PD-1/PD-L1/PD-L2 expression, 
CTLs, Tregs, macrophages, DCs; nanostring gene expression profile), systemic 
immune response (flow cytometry, CyTOF, Luminex multiplexed cytokine profile), 
and molecular/genomic immune correlates (exome sequencing, high throughput 
sequencing (HTS) for TCR). 
Hypothesis: The putative biomarkers and immune regulators tested will be related to 
clinical response induced by combination immunotherapy of MK-3475 (pembrolizumab) 
and IFN-gamma (Actimmune®) and will help define actionable causes of not achieving 
CR. 
The primary and key secondary endpoints, primary analysis population, and statistical 
methods that will be employed for the efficacy analyses are presented in the Table below. 
Summary Analysis Strategy for Efficacy Endpoints 
Endpoint/Variable 
(Description, Time 
Point) 
Statistical Method 
Analysis 
Population 
Missing Data Approach 
Primary: 
 
 
 
Overall response rate 
(ORR) per global 
assessment of Mycosis 
Fungoides and Sézary 
Syndrome (confirmed & 
investigator assessed) 
Binomial proportion 
Evaluable 
population as 
defined 
Subjects without any efficacy 
evaluation will be excluded; if 
one compartment is missing 
data, that compartment will be 
considered non-response 
Secondary: 
 
 
 
Time to Response (TTR) Simple statistics 
All responders 
Non-responders are excluded in 
analysis 
Duration of Response 
(DOR) 
Kaplan-Meier method 
All responders 
Non-responders are excluded in 
analysis; censored at last f/u or 
start of new significant therapy 
Progression-free 
survival 
Kaplan-Meier method 
All efficacy or 
safety 
evaluable 
patients 
Censored at last f/u or start of 
new significant therapy 

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Endpoint/Variable 
(Description, Time 
Point) 
Statistical Method 
Analysis 
Population 
Missing Data Approach 
Event-free survival 
Kaplan-Meier method 
All efficacy or 
safety 
evaluable 
patients 
Event is defined by early 
termination due toxicity, start 
of new significant therapy, PD, 
or death of any cause 
Rate of overall response 
duration beyond 12 
months (ORR12) per 
global assessment of 
Mycosis Fungoides and 
Sézary Syndrome 
(confirmed & 
investigator assessed) 
Binomial distribution 
Evaluable DOR 
beyond 12 
months for 
evaluable 
population. 
Subjects without any efficacy 
evaluation will be excluded; 
The ORR12 is the proportion of 
ORR times conditional 
probability of DOR beyond 12 
months. If one compartment is 
missing data, that compartment 
will be considered non-
response. Censored at last f/u. 
Start of new significant therapy 
before 12 months will be 
considered as failures.  
13.1.1.4 
Interim Safety and Futility Analyses 
• One interim safety analysis will be performed in this study when 12 patients are 
evaluable for toxicity at pre-C4 (week 10) of the study. If at that time, 4 or more 
patients have experienced study drug related serious adverse events (SAEs), we will 
conclude that the combination immunotherapy regimen is too toxic and accrual will 
stop.  
• The properties of interim safety stopping rule are given in the table below. 
True Probability of Study Drug Related 
SAEs (ptox) 
Probability of Stopping Early 
(pstop) 
0.10 
0.026 
0.14 
0.075 
0.18 
0.155 
0.22 
0.261 
0.26 
0.382 
0.30 
0.507 
One interim futility analysis will be performed in this study. Results will be reviewed by 
the participating institutions/investigators, CITN, NCI/CTEP, and participating industry 
sponsors (Horizon and Merck). 
The statistical criterion for success requires ORR that is greater than 37% (null) and at 
least 65% (alternative). This is a single stage trial. Patients will be recruited continuously. 
We will perform the interim futility analysis when 12 patients have been followed for 6 
months. If ORR is less than 33% (4 or less CR+PR), the trial will stop and we will accept 
the null that combination therapy is no better than monotherapy. The probability of 

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stopping at interim futility analysis under the null and alternative are 52% and 2% 
respectively. 
Otherwise, the trial will continue until we reach 30 patients. If ORR is at least 57% (17 or 
more CR+PR) at the final analysis, we will accept the alternative that combination 
therapy is significantly better than monotherapy. The type I error rate is 2%. The power is 
87%. 
Summary of Interim Safety and Futility Analyses Strategy 
Key Endpoints for  
Interim Analysis 
Timing of Interim Analysis 
Purpose of Interim Analysis 
Study drug related serious 
adverse events (SAEs) 
12 subjects enrolled and 
received at least 1 dose of either 
IFN-g or MK-3475 
(pembrolizumab), with 12th pt 
evaluable through interim safety 
assessment time point at pre-
C4/week 10 
Stop for significant safety 
concerns. Enrollment will not 
stop in order to wait for the 12th 
patient to reach week 10. New 
patient enrollment will continue 
as long as there are less than 4 
study drug-related SAEs.  
Overall response rate (ORR) per 
global assessment of Mycosis 
Fungoides and Sézary 
Syndrome (confirmed & 
investigator assessed) 
12 subjects enrolled and 
received at least 1 dose of either 
IFN-g or MK-3475 
(pembrolizumab); all 12 
subjects followed for 6 months 
Stop for futility of combination 
therapy relative to monotherapy.  
13.1.2 Exploratory Correlative Analyses 
Clinical response (as measured by the primary and secondary endpoints) to combination 
immunotherapy regimen as a function of biomarkers will be evaluated. All biomarker 
assays will be run on the clinical trial samples in a blinded manner.  
Time to event endpoints (DOR, PFS, EFS) will be evaluated using Kaplan-Meier curves 
generated by biomarker scoring group using the log-rank test. 
Exploratory outcomes will be summarized with descriptive statistics (primarily 
proportions and medians) for all biomarkers described above, and additionally, serum IL-
10, regulatory T-cells, and activated CD8 T cells. Scatterplots and Kendall’s tau 
estimates will be produced for estimating correlation of PD-1, PDL1, or PD-L2 
expression measures and clinical outcome across compartments (skin, lymph node, 
blood). Comparison of tissue IHC markers between pre-treatment and with clinical 
response or disease progression will be assessed using Wilcoxon signed-rank test. A full 
panel of approximately ~600 mRNA transcripts will be measured using the Nanostring 
platform and will be evaluated using descriptive statistics.  
13.1.3 Sample Size/Accrual Rate 
13.1.3.1 
Power and Sample Size 
The statistical criterion for success requires ORR that is greater than 37% (null) and 
at least 65% (alternative). By adding an interim futility analysis, the sample size is 30 

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patients. The probability of stopping at interim futility analysis under the null and 
alternative are 52% and 2%, respectively. The type I error rate is 2%. The power is 
87%. The expected sample sizes under the null and alternative are 21 and 30, 
respectively. 
This is a single stage trial. Patients will be recruited continuously. We will perform 
the interim futility analysis when 12 patients have been followed for 6 months. If 
ORR is less than 33% (4 or less CR+PR), the trial will stop and we will accept the 
null that combination therapy is no better than monotherapy. Otherwise, the trial will 
continue until we reach 30 patients. If ORR is at least 57% (17 or more CR+PR) at 
the final analysis, we will accept the alternative that combination therapy is 
significantly better than monotherapy. 
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/Alaska Native 
 
 
 
 
 
Asian 
1 
1 
 
 
2 
Native Hawaiian or Other Pacific 
Islander 
 
 
 
 
 
Black or African American 
1 
1 
 
 
2 
White 
7 
17 
1 
1 
26 
More Than One Race 
 
 
 
 
 
Total 
9 
19 
1 
1 
30 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015) OMB No. 0925-0001/0002 
13.1.4 Stratification Factors 
There is no planned stratification.  
13.1.5 Reporting and Exclusions 
13.1.5.1 
Evaluation of Toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with 
Interferon-gamma or MK-3475 (pembrolizumab).  
13.1.5.2 
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) complete response, (2) partial 
response, (3) stable disease, (4) progressive disease, (5) early death from malignant 

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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 possible exception of 
those who received no study medication) should be included in the main analysis of 
the response rate. Patients in response categories 4-9 should be considered to have a 
treatment failure (disease progression). Thus, an incorrect treatment schedule or drug 
administration does not result in exclusion from the analysis of the response rate. 
Precise definitions for categories 4-9 will be protocol specific.  
All conclusions should be based on all eligible patients. Subanalyses may then be 
performed on the basis of a subset of patients, excluding those for whom major 
protocol deviations have been identified (e.g., early death due to other reasons, early 
discontinuation of treatment, major protocol violations, etc.). However, these 
subanalyses may not serve as the basis for drawing conclusions concerning treatment 
efficacy, and the reasons for excluding patients from the analysis should be clearly 
reported. The 95% confidence intervals should also be provided.  
13.2 
Synovial Sarcoma (Treatment Group 2) 
13.2.1 Study Endpoints 
The primary objective is to determine whether the combination of interferon gamma-1b 
(ACTIMMUNE®) and MK-3475 (pembrolizumab) improves the overall response rate (ORR) of 
pembrolizumab in patients with unresectable or metastatic synovial sarcoma. 
 
The ORR of single agent pembrolizumab is ≤ 5%. Accordingly, a Simon 2-stage design will be 
used:  Twelve patients will be enrolled initially. If 0 respond the study will be stopped for 
futility.  Otherwise, an additional four patients will be enrolled.  If three or more out of 16 
patients respond, the treatment will be considered promising and would likely lead to widespread 
use of this regimen in the clinic. 
The secondary objectives for the study are: 
• To determine the progression-free survival (PFS) and overall survival (OS) for patients 
with advanced synovial sarcoma receiving interferon gamma-1b and MK-3475 
(pembrolizumab). 
 
• To determine the tolerability of the combination of interferon gamma-1b and MK-3475 
(pembrolizumab) based on CTCAE version 5.0 
 
The exploratory objectives are to investigate paired, serial biopsy specimens from pre-treatment 
and 8-12 weeks after starting treatment for the following: 
 

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• MHC class I expression (scored by pathologist)  
• Number of infiltrating T cells per mm2 
• Tumor associated macrophage number and phenotype using multiplex 
immunohistochemistry 
• T cell clonality 
• Gene expression profiling 
 
Additionally, the exploratory objectives include investigating peripheral blood samples from 
patients to determine: 
• The number and phenotype of T cells specific for CT antigens and potential neo-antigens 
• The phenotype of circulating monocytes 
• Cytokines associated with response 
 
The primary and key secondary endpoints, primary analysis population, and statistical methods 
that will be employed for the efficacy analyses are presented in the table below. 
 
 
Summary Analysis Strategy for Efficacy Endpoints 
Endpoint/Variable 
Statistical Method 
Analysis Population 
Missing Data 
Approach 
Primary: 
Overall Response Rate 
(ORR) 
Binomial proportion 
Evaluable population 
as defined 
Subjects without any 
efficacy evaluation 
will be excluded; if 
one compartment is 
missing data, that 
compartment will be 
considered non-
response. 
Secondary: 
Progression-free survival 
(PFS) 
Kaplan-Meier method 
All efficacy or safety 
evaluable patients 
Censored at last 
follow-up or start of 
new significant 
therapy 
Overall survival (OS) 
Kaplan-Meier method 
All efficacy or safety 
evaluable patients 
Event is death due to 
any cause, otherwise 
it is considered 
censored at last 
follow-up 
Tolerability 
Binomial proportion 
All enrolled patients 
All AEs and SAEs 
will be summarized 

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13.2.2 Interim Safety and Futility Analyses 
One interim safety analysis will be performed in this study when 12 patients are evaluable for 
toxicity at pre-C4 (week 10) of the study. If at that time, 4 or more patients have experienced 
unexpected study drug related serious adverse events (SAEs), we will conclude that the 
combination immunotherapy regimen is too toxic and accrual will stop. 
The properties of interim safety stopping rules are given in the table below. 
 
True Probability of Study Drug-Related 
SAEs (ptox) 
Probability of Stopping Early 
0.10 
0.026 
0.14 
0.075 
0.18 
0.155 
0.22 
0.261 
0.26 
0.382 
0.30 
0.507 
 
One interim futility analysis will be performed in this study. A Simon 2-stage design will be 
used: Twelve patients will be enrolled initially. If 0 respond the study will be stopped for futility. 
The probabilities of stopping the trial for futility at this interim analysis are 54% and 3% under 
the null hypothesis (ORR=5%) and alternative hypothesis (ORR=25%) respectively. 
Otherwise an additional four patients will be enrolled. If three or more out of 16 patients 
respond, the treatment will be considered promising and would likely lead to widespread use of 
this regimen in the clinic. 
The overall type I error for the study is 4.3%, and the overall power of the study at the alternative 
hypothesis (ORR=25%) is 80.1%. 
 
 
13.2.3 Exploratory/Correlative Analyses 
The exploratory objectives are to investigate paired, serial biopsy specimens from pre-treatment 
and 8-12 weeks after starting treatment for the following: 
• MHC class I expression (scored by pathologist)  
• Number of infiltrating T cells per mm2 
• Tumor associated macrophage number and phenotype using multiplex 
immunohistochemistry 
• T cell clonality 
• Gene expression profiling 

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Additionally, the exploratory objectives include investigating peripheral blood samples from 
patients to determine: 
• The number and phenotype of T cells specific for CT antigens and potential neo-antigens 
• The phenotype and activation state of circulating monocytes and PBMC 
• Cytokines associated with response 
 
The exploratory outcomes will be summarized with descriptive statistics for all the biomarkers 
described above. 
 
13.2.4 Sample Size and Power 
A Simon 2-stage design will be used:  Twelve patients will be enrolled initially. If 0 respond the 
study will be stopped for futility. The probabilities of stopping the trial for futility at this interim 
analysis are 54% and 3% under the null hypothesis (ORR=5%) and alternative hypothesis 
(ORR=25%) respectively. 
 
Otherwise, an additional four patients will be enrolled. If three or more out of 16 patients 
respond, the treatment will be considered promising and would likely lead to widespread use of 
this regimen in the clinic. The overall type I error for the study is 4.3%, and the overall power of 
the study at the alternative hypothesis (ORR=25%) is 80.1%. 
 
The patient demographics for the addendum is expected to be similar to the patient demographics 
of the original protocol. The planned enrollment report is given below. 
 
13.2.5 Planned Enrollment Report 
 
Racial 
Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American 
Indian/Alaska 
Native 
 
 
 
 
 
Asian 
1 
1 
 
 
2 
Native Hawaiian 
or other Pacific 
Islander 
 
 
 
 
 

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Black or African 
American 
1 
1 
 
 
2 
White 
5 
5 
1 
1 
12 
More than one 
race 
 
 
 
 
 
Total 
 
 
 
 
16 
 
 
 

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14. 
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Propper DJ, Chao D, Braybrooke JP, et al. Low-dose IFN-gamma induces tumor MHC expression in 
metastatic malignant melanoma. Clin Cancer Res. 2003;9: 84-92. 
Raphael BA, Shin DB, Suchin KR, et al. High clinical response rate of Sezary syndrome to 
immunomodulatory therapies: prognostic markers of response. Arch Dermatol 2011;147(12):1410-1415.   
Riley JL. PD-1 signaling in primary T cells. Immunol Rev 2009;229(1):114-125. PMCID: PMC3424066 
Robert C, Schachter J, Long GV, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N 
Engl J Med 2015;372(26):2521-2532.   
Rook AH, Wood GS, Yoo EK, et al. Interleukin-12 therapy of cutaneous T-cell lymphoma induces lesion 
regression and cytotoxic T-cell responses. Blood 1999;94(3):902-908.  
Samimi S, Benoit B, Evans K, et al. Increased programmed death-1 expression on CD4+ T cells in 
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1388. PMCID: PMC4467572 
Seo N, Tokura Y, Matsumoto K, et al. Tumour-specific cytotoxic T lymphocyte activity in Th2-type 
Sezary syndrome: its enhancement by interferon-gamma (IFN-gamma) and IL-12 and fluctuations in 
association with disease activity. Clin Exp Immunol 1998;112(3):403-409. PMCID: PMC1904995 
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therapy of interferon-gamma and narrowband UVB in patients with mycosis fungoides. J Dermatol Sci 
2008;50(3):217-225.   
Spaccarelli N, Rook AH. The Use of Interferons in the Treatment of Cutaneous T-Cell Lymphoma. 
Dermatol Clin 2015;33(4):731-745.   
Sugaya M, Tokura Y, Hamada T, et al. Phase II study of i.v. interferon-gamma in Japanese patients with 
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APPENDIX A 
PERFORMANCE STATUS CRITERIA (TREATMENT GROUP 1 
AND 2) 
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 (TREATMENT GROUP 1 
AND 2) 
If an institution wishes to collaborate with other participating institutions in performing a CTEP-
sponsored research protocol, then the guidelines below must be followed. 
Responsibility of the Protocol Chair  
• The Protocol Chair will be the single liaison with the CTEP Protocol and Information Office 
(PIO). The Protocol Chair is responsible for the coordination, development, submission, and 
approval of the protocol as well as its subsequent amendments. The protocol must not be 
rewritten or modified by anyone other than the Protocol Chair. There will be only one 
version of the protocol, and each participating institution will use that document. The 
Protocol Chair is responsible for assuring that all participating institutions are using the 
correct version of the protocol. 
• The Protocol Chair is responsible for the overall conduct of the study at all participating 
institutions and for monitoring its progress. All reporting requirements to CTEP are the 
responsibility of the Protocol Chair.  
• The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure 
safety of the patients. 
• The Protocol Chair will be responsible for the review of and timely submission of data for 
study analysis. 
Responsibilities of the Coordinating Center 
• Each participating institution will have an appropriate assurance on file with the Office for 
Human Research Protection (OHRP), NIH. The Coordinating Center is responsible for 
assuring that each participating institution has an OHRP assurance and must maintain copies 
of IRB approvals from each participating site.  
• Before the activation of the protocol at each participating institution, an OHRP form 310 
(documentation of IRB approval) must be submitted to the CTEP PIO. 
• The Coordinating Center is responsible for central patient registration. The Coordinating 
Center is responsible for assuring that IRB approval has been obtained at each participating 
site before the first patient registration from that site. 
• The Coordinating Center is responsible for the preparation of all submitted data for review by 
the Protocol Chair. 
• The Coordinating Center will maintain documentation of AE reports. There are 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 IRB approval documents, 

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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 
BIOASSAY TEMPLATES 
Mycosis Fungoides/Sézary Syndrome (Treatment Group 1) 
Biomarker Namea 
AND Lead PI and 
Site 
Assay 
(CLIA: Y/N) 
Use (Integral, Integrated, or 
Exploratory)AND Purpose b 
Tissue/Body Fluid 
Tested 
and Timing of Assay 
M/O  
Funding 
Source(s) c 
Tissue PDL1 
Expression 
PI: Dr. Rob Pierce 
Site:  Fred 
Hutchinson Cancer 
Research Center 
 
Chromagenic 
(Single-Color) IHC 
for PD-L1 
CLIA: N 
Exploratory 
Purpose: We will explore 
correlation of PDL1 
expression with response. 
Two hypotheses will be 
explored: 
1) Pre-treatment PDL1 
expression correlates with 
response 
2) Interferon-gamma 
mediated upregulation of 
PDL1 correlates with 
response 
Tissue: Skin biopsy 
Timing: 
(M) Prior to IFN-gamma 
lead-in, Prior to Cycle 1, 
Prior to Cycle 2, w at 
progression or 
appearance of a new 
lesion, at end of 
treatment, and in the 
event of a Skin Flare 
Reaction 
(O) At response (PR/CR),  
M 
Funding for 
biomarkers will be 
from CITN with 
co-funding from 
Merck and 
Horizon. 
Additional funds 
will be sought 
from foundations 
and CTEP’s 
CRADA with 
Merck 
Spatial association 
of tumor cells and 
components of the 
tumor 
microenvironment 
PI: Dr. Rob Pierce 
Site:  Fred 
Hutchinson Cancer 
Research Center 
 
Multispectral 
immunohistochemist
ry 
CLIA: N 
Exploratory 
Purpose: Hypothesis 
generating 
Multispectral 
immunohistochemistry IHC 
for PD1, PDL1, PDL2, CD3, 
CD4, CD8, Foxp3, CD163 will 
define the spatial relationship 
of the tumor infiltrate 
 
Tissue: Skin biopsy 
Timing: 
(M) Prior to IFN-gamma 
lead-in, Prior to Cycle 1, 
Prior to Cycle 2, at 
progression or 
appearance of a new 
lesion, r, at end of 
treatment, and in the 
event of a Skin Flare 
Reaction 
(O) At response (PR/CR),  
M 
(see above) 
High dimensional 
imaging of tumor 
microenvironment 
PI: Youn Kim 
Site: Stanford 
University 
Multiplexed Ion 
Beam Imaging 
CLIA: N 
Exploratory 
Purpose: Hypothesis 
generating 
Mass spectroscopy based 
imaging of ~30 parameters 
simultaneously to delineate 
expression of immune 
checkpoint molecules and 
activation markers on 
components of the tumor 
microenvironment 
Tissue: Skin biopsy 
Timing: 
(M) Prior to IFN-gamma 
lead-in, Prior to Cycle 1, 
Prior to Cycle 2, , at 
progression or 
appearance of a new 
lesion, at end of treatment 
and in the event of a Skin 
Flare Reaction 
(O) At response (PR/CR).  
M 
(see above) 

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Biomarker Namea 
AND Lead PI and 
Site 
Assay 
(CLIA: Y/N) 
Use (Integral, Integrated, or 
Exploratory)AND Purpose b 
Tissue/Body Fluid 
Tested 
and Timing of Assay 
M/O  
Funding 
Source(s) c 
Gene expression 
profiling  
PI: Dr. Rob Pierce 
Site:  Fred 
Hutchinson Cancer 
Research Center 
 
Nanostring immune 
panel 
CLIA: N 
Exploratory 
Purpose: Hypothesis 
generating and will assess 
Th1 skewing of T cells after 
interferon gamma treatment 
Tissue: Skin biopsy and  
peripheral blood 
mononuclear cells 
Timing: 
(M) Skin biopsy: Prior to 
IFN-gamma lead-in, Prior 
to Cycle 1, Prior to Cycle 
2, at progression or 
appearance of a new 
lesion, at end of treatment 
and in the event of a Skin 
Flare Reaction 
Blood draw: Prior to IFN-
gamma lead-in, Prior to 
Cycle 1, Prior to Cycle 2, 
Prior to Cycle 6, with a 
response, at progression 
or appearance of a new 
lesion, at end of treatment 
and in the event of a Skin 
Flare Reaction 
(O) Skin biopsy: At 
response (PR/CR),  
M 
(see above) 
Peripheral blood 
immunophenotypin
g 
PI:  Michael 
Khodadoust 
Site: Stanford 
University 
Multiparametric flow 
cytometry and 
CyTOF 
CLIA: N 
Exploratory 
Purpose: Hypothesis 
generating 
Phenotyping of normal T cell 
and Sezary cell populations 
pretreatment and post 
treatment. Functional 
phenotyping of T cells will be 
performed by testing cytokine 
production after stimulation. 
Tissue: Peripheral blood 
mononuclear cells 
Timing: 
(M) Prior to IFN-gamma 
lead-in, Prior to Cycle 1, 
Prior to Cycle 2, and in 
the event of a Skin Flare 
Reaction. 
 
M 
(see above) 
Serum cytokine 
and chemokine 
detection 
PI: Michael 
Khodadoust 
Site: Stanford 
University 
Luminex multiplexed 
ELISA-based 
cytokine assay 
CLIA: N 
Exploratory 
Purpose: Hypothesis 
generating 
Quantitative measurement of 
cytokines/chemokines pre 
and post treatment 
Tissue: Serum 
Timing: 
(M) Prior to IFN-gamma 
lead-in, Prior to Cycle 1, 
Prior to Cycle 2, prior to 
Cycle 6, with response, or 
progression, at EOT and 
in the event of a Skin 
Flare Reaction.  
M 
(see above) 

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Biomarker Namea 
AND Lead PI and 
Site 
Assay 
(CLIA: Y/N) 
Use (Integral, Integrated, or 
Exploratory)AND Purpose b 
Tissue/Body Fluid 
Tested 
and Timing of Assay 
M/O  
Funding 
Source(s) c 
Tumor genotyping 
and prediction of 
neoantigens  
PI: Michael 
Khodadoust 
Site: Stanford 
University 
Whole exome 
sequencing 
CLIA: N 
Exploratory 
Purpose: Hypothesis 
generating and will test the 
hypothesis that high 
neoantigen burden is 
associated with response 
Tissue: Skin biopsy and 
peripheral blood 
Timing: 
(M) Skin biopsy: Prior to 
IFN-gamma lead-in, prior 
to cycle 1, prior to cycle 2, 
at progression or 
appearance of a new 
lesion, at EOT, and in the 
event of a Skin Flare 
reaction. 
Blood draw: Prior to IFN-
gamma lead-in, Prior to 
Cycle 2, Prior to Cycle 6, 
with response, at 
progression, at EOT 
(O) Skin biopsy: At 
response (PR/CR).  
M 
(see above) 
T cell receptor 
sequencing 
PI: Dr. Steven 
Fling/Dr. Rob 
Pierce 
Site:  Fred 
Hutchinson Cancer 
Research Center 
 
High throughput 
sequencing of TCR 
CLIA: N 
Exploratory 
Purposes: Hypothesis 
generating and to assess 
responses through  
Response assessment 
through detection of 
malignant clone and 
characterization of the T cell 
repertoire.  
Tissue: Skin biopsy and 
peripheral blood 
mononuclear cells 
Timing: 
(M) Skin biopsy: Prior to 
interferon gamma lead-in, 
Prior to Cycle 1, prior to 
Cycle 2, at progression or 
appearance of a new 
lesion, EOT, and in the 
event of a skin flare 
reaction. 
Blood draw: Prior to IFN-
gamma lead-in, Prior to 
Cycle 1, Cycle 2, 6, 10, 
then every 4 cycles, with 
progression, response, 
EOT, and in the event of 
a Skin Flare Reaction. 
(O) Skin Biopsy: At 
response (PR/CR) 
M 
(see above) 
Kyn/Trp 
PI: Dr. Steven Fling 
and TBD 
Site:  Fred 
Hutchinson Cancer 
Research Center 
and Incyte Corp. 
Mass Spec  
CLIA: N 
Exploratory 
Purposes: Hypothesis 
generating and to assess 
whether IDO1 activity may be 
a mechanism leading to 
treatment failure.  
Timing: 
(M) Blood draw: Prior to 
IFN-gamma lead-in, Prior 
to Cycle 2, 6, 10, then 
every 4 cycles, with 
progression, response, 
EOT, and in the event of 
a Skin Flare Reaction. 
M 
(see above) 
Microbiome 
PIs: Dr. Steven 
Fling and Dr. David 
Fredricks 
Site:  Fred 
Hutchinson Cancer 
Research Center 
16S rRNA gene 
sequencing and 
WGS 
CLIA: N 
Exploratory 
Purposes: Hypothesis 
generating and to understand 
the role of the microbiome in 
responses to immunotherapy 
 
Timing: 
(M) Stool Sample: Prior to 
IFN-gamma 
M 
(see above) 
 
 
 

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Synovial Sarcoma (Treatment Group 2) 
Biomarker Namea 
AND Lead PI and Site 
Assay 
(CLIA: Y/N) 
Use (Integral, 
Integrated, or 
Exploratory)AND 
Purpose b 
Tissue/Body 
Fluid Tested 
and Timing of 
Assay 
M/O  
Funding Source(s) c 
Lymphocyte and Monocyte 
Phenotype 
 
Steven Fling, PhD 
CITN Central Immune 
Monitoring Laboratory 
(CIML) 
Multiparametric Flow 
Cytometry 
CLIA: No  
Exploratory 
To be used to assess the 
effect of IFNγ and 
pembrolizumab on 
circulating lymphocyte 
and monocyte numbers 
and phenotype 
Whole Blood and 
PBMC 
Prior first IFNγ 
dose, Cycle 1, 3 
and 7. 
M 
CITN/Horizon/Merck, 
possibly CIMAC  
Flow cytometry for selected 
Class I HLA-Alleles and for 
phenotype assessment of 
antigen specific T cells 
 
Steven Fling, PhD 
CITN CIML and TBD 
Seth Pollack, MD 
FHCRC 
Tetramer Flow 
cytometry 
 
CLIA: N 
Integrated/Exploratory 
To evaluate for a change 
in the phenotype of 
circulating tumor specific 
T cells 
Whole Blood and 
PBMC 
Prior first IFNγ 
dose, Cycle 3, 7 
and EOT, and at 
time of 
documented 
failure 
M 
 
Anti-Tumor Immune T cell 
Responses  Steven Fling, 
PhD 
CITN CIML and TBD 
Elispot 
CLIA: N 
Exploratory 
To evaluate for the 
emergence and/or 
expansion of T-cells 
reactive to known tumor 
antigens (e.g. MAGE-A4, 
MAGE-A-9, NY-ESO-1, 
LAGE-1, PRAME)  
Peripheral Blood 
Prior first IFNγ 
dose, Cycle 3, 7 
and EOT and at 
time of 
documented 
failure  
 
M 
 
 
 
 
 
 
Multiplex Cytokines  
FHCRC Shared Services 
and TBD or CIMAC 
 
Affymatrix or Luminex 
CLIA:  No 
Exploratory 
To be used to explore 
whether reactive 
changes in cytokine 
levels correlates with 
toxicity & efficacy of IFNγ 
and pembrolizumab 
 
Serum  
Prior first IFNγ 
dose, Cycle 1, 3, 
7 and EOT and at 
time of 
documented 
failure  
M 
 
PD-L1 baseline and post-
treatment 
FHCRC (Rob Pierce) or 
Merck 
IHC 
CLIA:  No 
Exploratory 
To be used to explore 
whether induction of this 
marker correlates with 
response  
Tumor biopsy 
tissue 
Pre-therapy 
biopsy and Week 
8-12 
 
 

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Biomarker Namea 
AND Lead PI and Site 
Assay 
(CLIA: Y/N) 
Use (Integral, 
Integrated, or 
Exploratory)AND 
Purpose b 
Tissue/Body 
Fluid Tested 
and Timing of 
Assay 
M/O  
Funding Source(s) c 
Slide-Based Immune 
Phenotype Panel  
Immunohistochemistry for 
CD80, Arginase-1, CD3, 
CD4, CD8, CD20, PD1, 
CD68, FOXP3, PDL1, 
CD11b, CD137, CD45RO, 
HLA-DR, MHC class I,  
Rob Pierce MD in the 
FHCRC Core Laboratory  
CITN CIML and FHCRC 
Shared services 
Multi-spectral 
Immunohistochemistry 
CLIA: N 
Integrated/Exploratory 
To evaluate for a change 
in the immune profile of 
the tumor 
microenvironment 
towards a pro-
inflammatory phenotype 
Tumor biopsy 
tissue 
Pre-therapy 
biopsy and Week 
8-12 
M 
 
Immune Gene Expression 
Signature 
Steven Fling, PhD 
CITN CIML and/or 
NanoString Corp or CIMAC 
NanoString® Gene 
Expression using the 
nCounter® Human 
Immunology V2 Panel 
and the nCounter® 
PanCancer Immune 
Profiling Panel 
CLIA: N 
Integrated/Exploratory 
To evaluate for a change 
in the immune profile of 
the tumor 
microenvironment 
towards a pro-
inflammatory phenotype  
Tumor biopsy 
tissue 
Pre-therapy 
biopsy and Week 
8-12 
M 
 
 
TCR Clonality 
 
Adaptive Biotechnologies 
or CIMAC 
 
 
 
TCR ImmunoSeq 
(Adaptive 
Biotechnologies) 
CLIA: N 
Integrated/Exploratory 
To evaluate for evidence 
of the emergence and/or 
expansion of tumor 
specific T-cells within the 
TME 
Tumor biopsy 
tissue 
Pre-therapy 
biopsy and Week 
8-12 
M 
 
Microbiome 
 
Dr. David Fredricks 
(FHCRC) or CIMAC 
 
16S Ribosomal 
Sequencing and WGS  
CLIA: N 
Integrated/Exploratory 
To evaluate the potential 
role of the microbiome in 
response to therapy and 
hypothesis generating 
Fecal Stool 
Sample 
 
Pre-therapy 
M 
 
HLA Class I and Class II 
Typing 
Dr. Dan Geraghty 
(FHRCR) 
HLA Class I and Class 
II Typing 
 
 
Peripheral Blood 
Pre-therapy 
M 
 
 
 
 
 

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APPENDIX D 
STANDARDIZED MEDICAL PHOTOGRAPHY (TREATMENT 
GROUP 1) 
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 E 
MODIFIED SEVERITY-WEIGHTED ASSESSMENT TOOL 
(MSWAT) (TREATMENT GROUP 1) 
The mSWAT is an objective, quantitative, severity- weighted method to assess the extent of 
Mycosis Fungoides 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 
Mycosis Fungoides 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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