Phase II Study of Epacadostat (INCB024360) in Combination With Pembrolizumab in Patients With Locally Advanced/Metastatic Sarcoma
Phase: PHASE2
Conditions: Sarcoma
Sponsor: Memorial Sloan Kettering Cancer Center

Memorial Sloan Kettering Cancer Center 
IRB Number: 17-508 A(S) 
Approval date: 07-May-2024 
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MSKPROTOCOLCOVERSHEET 
 
Phase II Study of Epacadostat (INCB024360) in Combination with Pembrolizumab 
in Patients with Locally Advanced/Metastatic Sarcoma 
 
Principal Investigator/Department: Sandra P. D' Angelo, MD/ Medicine 

Memorial Sloan Kettering Cancer Center 
IRB Number: 17-508 A(8) 
Approval date: 07-May-2024 
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Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ...................................................................... 3 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ............................................................................... 5 
3.0 
BACKGROUND AND RATIONALE .................................................................................... 6 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ........................................................... 18 
4.1 
Design ........................................................................................................................... 18 
4.2 
Intervention .................................................................................................................... 19 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS .......................................................................... 19 
5.1 Epacadostat ........................................................................................................................ 19 
5.2 Pembrolizumab ................................................................................................................... 20 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .......................................................................... 22 
6.1 
Subject Inclusion Criteria ................................................................................................ 22 
6.2 
Subject Exclusion Criteria............................................................................................... 24 
7.0 
RECRUITMENT PLAN ...................................................................................................... 26 
8.0 
PRETREATMENT EVALUATION ..................................................................................... 26 
9.0 
TREATMENT/INTERVENTION PLAN ............................................................................... 27 
10.0 EVALUATION DURING TREATMENT/INTERVENTION ................................................... 33 
11.0 TOXICITIES/SIDE EFFECTS ............................................................................................ 40 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ...................... 74 
13.0 CRITERIA FOR REMOVAL FROM STUDY ...................................................................... 84 
14.0 BIOSTATISTICS ............................................................................................................... 87 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES90 
15.1 Research Participant Registration .................................................................................. 90 
15.2 Randomization ............................................................................................................... 90 
16.0 DATA MANAGEMENT ISSUES ........................................................................................ 90 
16.1 
Quality Assurance .......................................................................................................... 90 
16.2 Data and Safety Monitoring ............................................................................................ 91 
16.3 Regulatory Documentation ............................................................................................. 92 
17.0 PROTECTION OF HUMAN SUBJECTS ........................................................................... 93 
17.1 Privacy ........................................................................................................................... 93 
17.2 
Serious Adverse Event (SAE) Reporting ........................................................................ 95 
18.0 INFORMED CONSENT PROCEDURES ........................................................................... 96 
19.0 REFERENCES .................................................................................................................. 97 

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IRB Number: 17-508 A(8) 
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20.0 APPENDICES ................................................................................................................. 100 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
Sarcomas comprise a very diverse group of malignancies including more than 50 subtypes 
of bone and soft tissue origin. Despite optimal approach, approximately 30-80% of patients 
will develop recurrent and metastatic disease after receiving initial therapy with curative 
intent. In this setting, responses to standard cytotoxic chemotherapy occur in 10-30% of the 
cases and median survival is 10-18 months. 
Sarcomas are immunogenic neoplasms with a need for more therapeutic options. Prior 
immunotherapeutic agents have shown promise in select sarcoma patients. Using a 
combination of epacadostat, an IDO-1 inhibitor administered concurrently with the anti-PD1 
monoclonal antibody pembrolizumab to treat patients with sarcomas and our planned 
scientific correlates, we believe we can assess the safety and efficacy of immune activating 
therapy and better understand the effects of combined therapy in antitumoral immune 
response. 
This is an open-label, single-center, phase II study to evaluate the efficacy of epacadostat 
in combination with pembrolizumab in patients with locally advanced/metastatic, grade 
sarcoma (Figure 1. Study Schema). One treatment cycle will consist of 21 days. Patients 
will start both study drugs on day one of the first cycle. They will receive epacadostat 100mg, 
orally, twice daily, continuously for 21 days (Table 1). They will receive 200mg of 
pembrolizumab intravenously on day 1 of every three week cycle (Table 1). Patients will be 
reassessed with CT scans at week 8 and every 8 weeks thereafter. Treatment will be 
repeated until the patient develops progressive disease or unacceptable toxicity. 
A total of 30 patients will be enrolled onto the study. Patients will be enrolled onto one of 4 
cohorts. Each cohort will enroll a prespecified number of patients with certain sarcoma 
histological subtype(s). The 4 patient cohorts and the number of patients eligible to enroll 
per cohort in this study are as follows: 
A) Undifferentiated Pleomorphic Sarcoma (UPS), Liposarcoma (dedifferentiated or 
pleomorphic liposarcoma), or Myxofibrosarcoma (n=10) 
B) Leiomyosarcoma (n= 5) 
C) Vascular 
Sarcoma 
Subtypes 
(includingangiosarcoma 
,and 
Epithelioid 
Hemangioendothelioma (EHE)) (n=5) 
D) Other (n=10) 

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IRB Number: 17-508 A(8) 
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Sarcoma 
 
 
 
 
*Mandatory biopsies for research purposes will be performed at baseline (within 3 weeksof the first dose ofepacadostat and/or pembrolizumab) and at Week 7 
where feasible. An optional research biopsy will be offered at the time of progression 
** The maximum duration of therapy is 2 years. In the case of patients benefiting from study therapy who discontinue treatmet after the maximal therapy 
duration of 2years and subsequently experience disease progression, rechallenge with study therapy will be permitted 
 
 
 
 
 
 
Phase II Study of Epacadostat in Combination with Pembrolizumab in 
 
 
 
Table 1 Study Treatment 
 
Study Drug 
Dose 
Dose 
Frequency 
Regimen/Treatment 
Period 
Route of 
Administration 
Epacadostat 
100mg 
Twice daily 
Continuously days 
1-21 of each 3 week 
cycle 
Oral 
Pembrolizumab 
200mg 
Every 3 
weeks 
Day 1 of each 3 
week cycle 
IV infusion 
Figure 1. Study Schema 
 
 
 
Post treatmlrt 
Biopsy 
Document 
Progression* 
Disease 
Progression 
 
 
 
 
 
 
 
 
 
 
 
 
 
The hypotheses for this study include: 
Primary hypothesis 

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IRB Number: 17-508 A(8) 
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1. 
Epacadostat given in combination with pembrolizumab, will ellicit an enhanced 
immune response in patients with advanced sarcoma with antitumoral effect, as assessed 
by RECIST 1.1. 
Secondary hypotheses 
1. 
Epacadostat, given in combination with pembrolizumab will be safe and well 
tolerated in patients with advanced sarcomas. 
2. 
Epacadostat, given in combination with pembrolizumab, will improve progression 
free survival and overall survival in patients with advanced sarcoma as assessed by 
RECIST 1.1 and irRECIST. 
3. 
Epacadostat, given in combination with pembrolizumab, will ellicit an enhanced 
immune response in patients with advanced sarcoma with antitumoral effect, as assessed 
by irRECIST. 
Exploratory hypotheses 
1. 
Baseline characteristics of the immune micorenvironment of sarcoma tumor tissue 
will vary depending on the sarcoma histological subtype. 
2. 
Epacadostat given in combination with pembrolizumab, will alter immune related 
characteristics of tumor tissue in ways that may correlate with clinical outcome. 
3. 
Epacadostat given in combination with pembrolizumab, will alter immune related 
characteristics of peripheral blood in ways that may correlate with clinical outcome 
4. 
Epacadostat, given in combination with pembrolizumab, will benefit a substantial 
portion of patients with advanced sarcomas. Baseline tumor mutational burden and 
neoantigen production and and patient-specific immune characteristics,may correlate with 
clinical efficacy of the study therapy 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
Primary Objective: 
To evaluate the efficacy of epacadostat in combination with pembrolizumab in patients with 
advanced sarcoma, as assessed by the best objective response rate (complete response+ 
partial response) by 24 weeks using RECIST 1.1. 
 
Secondary Objectives: 
1) To assess the safety of epacadostat in combination with pembrolizumab in patients 
with advanced sarcoma using CTCAE v4.03 criteria for toxicity assessment. 

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IRB Number: 17-508 A(8) 
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2) To determine the progression free survival (PFS) rate at 24 weeks by RECIST 1.1 
and irRECIST and overall survival (OS) for patients treated with epacadostat in 
combination with pembrolizumab. 
3) To evaluate the efficacy of epacadostat in combination with pembrolizumab in 
patients with advanced sarcoma, as assessed by the best objective response rate 
(complete response + partial response) by 24 weeks by immune-related response 
evaluation criteria in solid tumors (irRECIST). 
 
Exploratory Objectives: 
i) 
To determine the baseline characteristics of sarcoma tumors (pre-treatment biopsy 
sample) evaluated in this study including the level of IDO1, kynurenine and PD-1/PD-L1 
expression, presence of tumor infiltrating lymphocytes (Tlls) and tumor antigens, gene 
expression profile, and the T-cell receptor clonality in tumor-infiltrating lymphocytes (TIL). 
ii. 
To assess the potential effect of epacadostat and pembrolizumab on selected 
biomarker expression measured in pre- and post-treatment tumor tissue and the 
association between these biomarkers (baseline level of expression and the change in 
biomarker level of expression following treatment) and clinical outcome, including 
characterization of IDO-1 expression, PD-1/PD-L1 expression, kynurenine expression, 
tumor infiltrating lymphocytes (Tlls) and tumor antigens, gene expression profiling, and 
characterization of T-cell receptor clonality in tumor-infiltrating lymphocytes (TIL). 
iii. 
To evaluate associations between selected biomarkers measured in serial 
peripheral blood and with clinical efficacy, including immunophenotyping and functional 
analyses, evaluation of serum levels of chemokines, cytokines and other immune 
mediators, and characterization of T-cell receptor clonality in peripheral blood. 
iv. 
To evaluate the association between baseline tumor mutational burden and 
neoantigen production with clinical efficacy of the study therapy. 
 
3.0 
BACKGROUND AND RATIONALE 
Sarcomas: New therapies are desperately needed 
Sarcomas represent a collection of rare, heterogeneous tumors of mesenchymal origin. 
There are more than 50 distinct sarcoma subtypes. Approximately 13,000 patients are 
diagnosed with bone and soft tissue sarcomas every year in the United States. Surgery is 
the cornerstone of treatment for patients with localized, resectable sarcomas. Adjuvant 
radiation and chemotherapy are considered in very particular situations. However, despite 
combined modailty treatment 25-50% of patients develop a recurrence and/or metastatic 
disease.1•2 The median survival for patients with metastatic sarcoma is 10-15 months.3.4 
Standard cytotoxic chemotherapy agents such as doxorubicin, ifosfamide, and dacarbazine 
result in objective responses in 10-30% of the patients, and this is significantly influenced by 

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IRB Number: 17-508 A(8) 
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histologic variant.5 The development of novel and effective therapies is desperately needed 
for patients with advanced/metastatic sarcomas. 
Sarcoma: an immunogenic tumor 
lmmunotherapeutic strategies may be a promising approach to treating this disease. The 
role of the immune system as a mechanism of cancer therapy was first observed in a 
sarcoma patient who had a response after an erysipelas infection.6 Sarcomas are more 
common in patients who are immunosuppressed.7 Infiltration of lymphocytes has been 
demonstrated in sarcomas.8 Furthermore, tumor-infiltrating lymphocytes have been 
associated with improved survival in Ewing's sarcoma and GIST.9-11 Spontaneous 
regression of primary tumors has been seen in desmoid tumors and osteosarcomas.12,13 
There have been multiple clinical trials evaluating the role of immune stimulants such as 
IL-2, interferon, and liposomal-muramyl tripeptide phosphatidylethanolamine showing 
some benefit in sarcoma patients.14-18 T cells genetically engineered to target NY-ESO-1 
expressing synovial sarcoma have shown some promise.19 In patients with GIST, tyrosine 
kinase inhibitors such as imatinib can have stimulating effects on multiple immune cells.11 
lmmunotherapy in Sarcoma 
The results of two clinical trials evaluating the efficacy of single agent PD-1 blockade in the 
setting of advanced sarcoma were recently presented in 2016 at the annual meeting of the 
American Society of Clinical Oncology. The first trial, a phase II study investigated the role 
of pembrolizumab in patients with patients with advanced soft tissue and bone sarcomas. 
A signal of efficacy for pembrolizumab monotherapy was observed in patients with 
undifferentiated pleomorphic sarcoma, liposarcoma, osteosarcoma and chondrosarcoma. 
However, no efficacy was observed in other subtypes such as leiomyosarcoma, synovial 
sarcoma and ewing's sarcoma.20 Nivolumab monotherapy was also deemed to be 
ineffective in the setting of patients advanced uterine leiomyosarcoma.21 lmmunotherapy 
research efforts in sarcoma are now focusing on combination immunotherapy strategies. 
Sarcoma: Microenvironment Immune Infiltrate is Susceptible to Manipulation 
The sarcoma microenvironment is a critical factor that contributes to tumor growth and 
progression. Sharma A, et al, demonstrated this point when they retrospectively analyzed 
the expression of immune response-related genes by quantitative RT-PCR and 
immunohistochemistry on paired tumor samples taken before and after radiotherapy from 
38 patients with sarcoma.22 They observed that radiotherapy caused up-regulation of 
transcripts specific for several immune effector cells and concomitantly resulted in down 
regulation of various transcripts related to immune suppression including IDO1, PD-1 and 
PD-L1 in many patients. (Figure 2) They validated their findings at the protein level using 
immunohistochemistry by demonstrating that radiotherapy increased the expression of CT- 
antigens, MHC-I and lymphocyte infiltration. They also demonstrated that patients with 
prolonged survival greater than 3 years after radiotherapy had a clear down regulation of 

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IRB Number: 17-508 A(8) 
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genes associated with immune suppression compared to patients who died within three 
years of radiation therapy. This supports the hypothesis that radiotherapy promotes a 
durable protective immunity within the tumor microenvironment. This study importantly 
highlights the susceptibility of the sarcoma microenvironment to manipulation, particularly 
with respect to the immune infiltrate. 
 
 
 
 
 
 
Diagnosis 
N 
Angiosarcoma 
1 
Leiomyosarcoma 
4 
MPNST 
2 
Myxoflbrosarcoma 
3 
Myxoidliposarcoma 
10 
Pleomorphicliposarcoma 
2 
Pleomorphicsarcoma NOS 
10 
Pleomorphicsarcoma withRhabdomyosarcoma 
Rhabdomyosarcoma 
1 
Synovial sarcoma 
2 
Sclerosing epithelial flbrosarcoma 
Spindle cellsarcoma withpleomorphic Liposarcoma 
 
 
 
 
 
 
 
 
Figure 2: Radiotherapy-induced changes of immune response-related gene 
expression in human sarcoma - Thirty-seven paired FFPE sarcoma samples before/after 
radiotherapy were subjected to qR-PCR analysis for 35 different immune response-related 
genes. Genes displayed on the left side of the vertical dotted line are associated with 
immune effectors and those on the right with immune suppressors. Each symbol 
represents an individual patient. 
lndolamine 2, 3-dioxygenase (ID01) 
ID01 is a rate-limiting, intracellular enzyme responsible for oxidation of tryptophan into 
kynurenine. ID01 activity reduces tryptophan that starves cytotoxic T-cells within the 
tumor microenvironment and causes their arrest in the G1 phase of the cell cycle. 

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Tryptophan metabolites activate regulatory T-cells, which further suppresses the immune 
response to the tumor enabling the tumor to evade the immune system.23 (Figure 3) 
 
 
 
 
Figure 3: ID01 is one of several immune checkpoints involved in tumor immune 
escape. The ID01 enzyme, activated in dendritic cells (DC) and macrophages (Mcj>), 
helps create an environment that favors suppression and tolerance. 
 
 
A study in melanoma has shown that infiltrating COB+ T cells elicit several 
immunosuppressive effects within the tumor microenvironment, including upregulation of 
1001 and of PD-L1.24 1001 acts as a critical molecular switch driving mature, quiescent 
Tregs into diametrically opposite functional states. In the setting of a stimulated innate 
immune response 1001 is active and Tregs are maintained in their normal potently 
suppressive state. However, when 100 is blocked, Tregs undergo an inflammation- 
induced, IL-6 dependent conversion into a proinflammatory phenotype similar to effector, 
T-helper-17 cells.22•25  1001 inhibition increases and restores proliferation and activation 
of immune cells; including dendritic cells, NK cells, and T-lymphocytes, IFN production and 
causes a reduction in tumor associated regulatory T cells. A combination of 1001 
inhibition and stimulation of the immune system through anti-PD1 and PD-L1 therapies 
may inhibit the growth of 1001 expressing tumors by manipulating the tumor 
microenvironment from an immune-suppressive state towards an immune activated state. 
ID01 in Sarcoma: 
In the setting of human sarcoma, Uyttenhove et al demonstrated 1001 expression in 20% 
of the sarcoma cell lines evaluated.23 Vanderstraeten et al, determined 14% of uterine 
sarcomas (n=22) to express a high level of 1001.26 Another study has shown 1001 

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expression levels as high as 41% in tumor cells of soft tissue sarcoma specimens. There 
was significant consistency in the joint expression of POL1 and IDO on tumor cells, POL1 
and kynurenine, and kynurenine and IDO on tumor cells, in 70% (p<0.0001 ), 53% 
(p=0.0004) and 53% (p=0.05) of samples, respectively.27 The level of IDO1 expression 
has also been evaluated in 47 patients with high grade osteosarcoma arising from an 
extremity. IDO1 expression was determined using immunohistochemistry (IHC) performed 
on pretreatment pathology specimens. Two observers without knowledge of the clinic- 
pathological information evaluated the results of the IHC staining on the basis of a five- 
point scale: 0% for positive stainable cell number(-), 1-24% (1+), 25-49% (2+), 50-74% 
(3+), 75-100% (4+). The majority of cases (96%) showed positive immune-reactivity for 
IDO1 in malignant cells. The IDO1 level of expression was 22+ in 78% of cases. Patients 
with high IDO1 expression (4+, n=19) had a significantly lower metastasis free survival 
(p=0.016) and overall survival (p=0.005).28 This data supports the hypothesis that immune 
tolerance mediated through IDO1 may have an important role in the tumorigenesis of 
osteosarcoma and other sarcomas and may exert a negative impact on clinical outcome 
and lends itself as a therapeutic target that warrants investigation in this group of tumors. 
It is important to remember that IDO1 can be induced by IFNy and that IDO1 negative 
tumors may start expressing IDO1 when exposed to an inflammatory context such as that 
resulting from an immune response induced by anti-PD-1 or PD-L1 antibodies. In a 
Ewings sarcoma model, IDO1 was shown to be expressed in tumor cells as a 
consequence of IFNy produced by lymphocytes in response to IL2. In this preclinical study 
the impact of the cluster of differentiation 137 (CD137)/CD137 ligand (CD137L) on 
expression of IDO1 and other cytokines was analyzed in vivo and in vitro. Depending on 
the concentration of IL2, stimulation of CD137 produced a variation in expression of IDO1. 
At low IL2 concentrations IDO1 was reduced in the presence of the antibody against 
CD137. However, at high IL2 concentrations IDO1 was more highly expressed in the 
presence of CD137 antibodies. The cytokine analysis showed a correlation between IDO 
expression by tumor cells and IFNy secretion by peripheral blood mononuclear cells.29 
Hence, In IDO1 negative tumors, immunotherapies such as anti-PD1 and PD-L1 
antibodies that stimulate the immune response may lead to the development of IDO1 
expressing tumor cells that aim to suppress the immune response. In this setting, the 
addition of an IDO1 inhibitor could lead to an enhanced anti-tumor effect by blocking the 
immunosuppressive effects of IDO1. Tumor-induced IDO1 acts as a fundamental 
antagonist to anti-tumor immune responses generated by immunotherapy and may explain 
why only a minority of patients responds to checkpoint inhibition if administered as 
monotherapy. 
Epacadostat 
Overview 

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Epacadostat represents a novel, potent, and selective inhibitor of the enzyme IDO1. IDO1 
mediates the catabolism of the essential amino acid tryptophan (Trp) to kynurenine (Kyn) 
within immune cells and a subset of tumor cells. This catabolism of Trp results in the 
inhibition of antitumor cell-mediated immune responses. Histologic evaluation of most 
human cancers shows extensive infiltration by inflammatory and immune cells, suggesting 
that the immune system does recognize and respond to the presence of the malignancy, 30 
but in most cases the immune response is ineffective in inhibiting or eradicating tumor 
growth. Many tumor cells or the infiltrating immune cells overexpress IDO1, and there have 
been multiple lines of evidence to suggest that IDO1 is a key regulator in the 
immunosuppressive mechanisms responsible for tumor escape from immune 
surveillance.31 Therefore, inhibition of this enzyme may provide a unique method to treat 
malignancies, either alone or in combination with chemotherapeutics or other immune- 
based therapies. 
Refer to the Investigator's Brochure (IB)/approved labeling for detailed background 
information on epacadostat. 
Clinical experience 
As of 29 OCT 2016, 12 lncyte-sponsored clinical studies have either been completed or 
are ongoing (11 Phase 1 and 2 studies and 1 Phase 3 study). Three clinical studies have 
been completed (Studies INCB 24360-101, INCB 24360-102, and INCB 24360210). Seven 
ongoing studies (INCB 24360-201, INCB 24360-202, INCB 24360-203, INCB 24360-204, 
INCB 24360301, and INCB 24360-110, and INCB 39110-106) are combination therapy 
studies. Two ongoing studies (INCB 24360-103 and INCB 24360-104) are monotherapy 
studies. As of the cutoff date, 898 unique subjects have been exposed to INCB024360 in 
lncyte sponsored studies as monotherapy (149 subjects) and/or in combination with 
checkpoint inhibitors anti-programmed cell death protein-1 (PD-1) targeted therapy (543 
subjects), anti-programmed death-ligand 1 (PD-L1) targeted therapy (124 subjects), 
anti-CTLA-4 targeted therapy (50 subjects), and a Janus kinase (JAK) inhibitor with JAK1 
selectivity (32 subjects). 
The safety profile of epacadostat monotherapy has been investigated in early phase 
clinical trials in the setting of advanced solid tumors. Epacadostat was generally well 
tolerated in subjects with refractory solid tumors at doses of up to 700 mg BID, and there 
appeared to be no correlation of dose with toxicity. Of the 52 subjects who were 
administered epacadostat, the median duration of treatment was 51.5 days. Eight subjects 
(15.4%) had an AE leading to death; of these 8 subjects, the cause of death was disease 
progression for 7 subjects and hypoxia for the remaining subject. Twenty-five subjects 
(48.1%) had an SAE during the study. Serious adverse events were observed in all 8 
treatment groups. The most frequently reported SAE was disease progression (4 subjects, 
7.7%), followed by abdominal pain, nausea, and hypoxia (3 subjects each, 5.8%). 
Treatment-emergent AEs were reported in all subjects. Fatigue was the most frequently 

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reported TEAE (36 subjects, 69.2%). The majority of subjects (90.4%) had treatment- 
related TEAEs. Fatigue and nausea were the most frequently reported treatment-related 
TEAEs (25 subjects each, 48.1%). The incidence and severity of fatigue were not dose 
related. Thirty subjects (57.7%) had TEAEs 
Grade 3 in severity and 7 subjects (13.5%) 
had a TEAE leading to discontinuation of study drug and withdrawal from the study. Two 
DLTs occurred; 1 DLT of radiation pneumonitis at the 300 mg BID dose level and 1 DLT of 
fatigue at the 400 mg BID dose level. A maximum tolerated dose was not determined. 
There were no clinically meaningful changes or trends noted in clinical hematology, 
chemistry, or urinalysis results or for vital signs, electrocardiograms, or physical 
examinations. 
The safety profile of epcadostat in combination with pembrolizumab has been explored in 
a phase I study in the setting of patients with advanced melanoma and select solid tumors. 
This study included cohorts with escalating dose levels of epacadostat (25 mg BID (n = 4), 
50 mg BID (n = 20), 100 mg BID (n = 18), and 300 mg BID (n = 18)) in combination with 
pembrolizumab 2 mg/kg or 200 mg IV administered every 3 weeks. A dose expansion 
portion of the study also enrolled patients to 4 dose levels of epacadostat (epacadostat 
50, 100, and 300 mg BID) in combination with pembrolizumab 200mg IV every 3 weeks. 
Enrollment to both study portions has completed. The preliminary safety results of this 
phase I study were presented at ESMO 2016 (these data have a cutoff of July 7th 2016). 
The maximum tolerated dose has not been established. Across all treatment groups, 
treatment-related AEs were reported in 50 subjects (81%). The most common ( 15%) all- 
grade treatment-related AEs (TRAEs) included fatigue (29%), rash (29%), arthralgia, 
pruritus, diarrhea, and nausea. Grade 3 TRAEs were observed in 18% of participants 
(rash [8%] and increased lipase [3%] were the most commonly experienced grade 3 
treatment related adverse events). No treatment-related deaths occurred. A favorable 
objective response rate (58%), CR rate (26%), and a disease control rate (74%) among 
treatment-naive subjects with melanoma was observed. Responses were observed in all 
epacadostat dose cohorts 50 mg BID and all sites of target lesions including liver, lung, 
and lymph nodes. Objective responses were also observed in patients with previously 
treated advanced solid tumors other than melanoma.51 
The safety profile for the 300mg bid dose of epacadostat in combination with 
pembrolizumab in the Phase 1/11 study did not exceed the MTD in that study. While there 
was a higher incidence of grade 3 rash in the 300mg bid cohort compared to the 100mg 
bid cohort, these did not qualify as protocol-specified DLTs. A phase Ill randomized, 
double-blind, placebo-controlled study of pembrolizumab in combination with epacadostat or 
placebo in subjects with unresectable or metastatic melanoma is underway. The dose of 
100mg epacadostat in combination with pembrolizumab will be used in this study. 
Other phase 1/11 studies examining epacadostat in combination with other checkpoint 
inhibitors such as nivolumab, atezolizumab and durvalumab are ongoing. 

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Pembrolizumab 
Overview 
Pembrolizumab is a highly selective humanized monoclonal lgG4-kappa isotype antibody 
against PD-1 currently approved by the Food and Drug Administration (FDA) for the 
treatment of patients with advanced melanoma at a dose of 2mg/kg given every 3 
weeks.32-35 Pembrolizumab has also received FDA approval for the treatment of patients 
with PD-L1 positive advanced non-small cell lung cancer36 and patients with advanced 
head and neck squamous cell carcinoma. 37 Refer to the Investigator's Brochure 
(IB)/approved labeling for detailed background information on pembrolizumab. 
Clinical Experience 
The first dose-escalation phase 1 study involving patients with solid tumors showed that 
pembrolizumab was safe across 3 tested dose levels (1mk/kg; 3mg/kg and 10mg/kg) 
administered every 2 weeks; of note, the maximum tolerated dose was not reached and 
clinical responses were observed at all of the dose levels.32 Subsequent studies confirmed 
the clinical activity of pembrolizumab. Hamid et al. initially investigated pembrolizumab at 
doses of 2mg/kg every 3 weeks and 10mg/kg given every 2 or 3 weeks in a melanoma- 
only cohort in a non-randomized fashion in the KEYNOTE-001 trial.35 Objective responses 
occurred in 38% of 135 included patients. Grade 3 or 4 adverse events occurred in only 
13% of the patients. In a subsequent cohort of the same KEYNOTE-001 phase I trial,33173 
patients with advanced melanoma were randomized to receive pembrolizumab at 2mg/kg 
every 3 weeks or 10mg/mg every 3 weeks. ORR was 26% at both doses after a median 
follow up of 8 months, with no difference in OS between different doses (estimated OS at 1 
year 58% vs 63%, 95% Cl 0.68-1.75). In the expansion cohort of the same trial including a 
total of 411 patients, pembrolizumab resulted in objective responses in 40% of treatment 
naive patients. In the phase II study (KEYNOTE 002) patients with ipilimumab refractory 
advanced melanoma were randomized to receive pembrolizumab or investigator's choice 
of chemotherapy. A total of 540 patients were enrolled. Progression free survival was 
superior in the pembrolizumab arms compared to the chemotherapy arm. Efficacy was 
similar between pembrolizumab administered at a dose of 2mg/kg every 3 weeks versus 
10mg/kg every 3 weeks and toxicity was less at the lower dose.38 KEYNOTE-006 was a 
randomized phase Ill pivotal trial, designed to test whether pembrolizumab (10 mg/kg 
Q2W or 10 mg/kg Q3W) was superior to ipilimumab (IPl)(3 mg/kg Q3W) in the co-primary 
efficacy endpoints of progression-free survival (PFS) and OS in IPl-na'i've subjects with 
unresectable or metastatic melanoma. This trial demonstrated statistically significant 
improvements in OS and PFS for subjects randomized to pembrolizumab compared with 
subjects randomized to ipilimumab. The OS hazard ratio was 0.65 (95% Cl: 0.52, 0.83) for 
the pembrolizumab arms combined over the IPI arm with a one-sided p-value of 0.0002. 

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The 12-month OS rate was 71.3% (95% Cl: 67.3, 74.9) for the pembrolizumab arms 
combined. The HR PFS was 0.58 (95% Cl: 0.46, 0.72) and 0.58 (95% Cl: 0.47, 0.72) in 
the pembrolizumab 10 mg/kg Q2W arm and the pembrolizumab 10 mg/kg Q3W arm, 
respectively, versus the IPI arm, favoring the pembrolizumab arms.34 Pembrolizumab 
treatment demonstrated superior efficacy compared to available treatment options (IPI, 
investigator's choice chemotherapy) in subjects with advanced melanoma who were 
treatment-na·1ve, as well as those who progressed on prior therapy, including IPI. 
Two clinical trials were conducted to evaluate the efficacy of pembrolizumab in the 
treatment of NSCLC: KN001, KN010 KN024. 
• KN001 was an open-label, Phase 1, first-in-human trial conducted to evaluate clinical 
activity of pembrolizumab as a single agent in solid relapsed/refractory 
malignancies, including NSCLC. 
 
• KN010 was a randomized, adaptively designed Phase 2/3 trial of pembrolizumab at 2 
dose levels versus docetaxel in subjects with NSCLC with PD-L1 positive tumors 
who had experienced disease progression after platinum-containing systemic 
therapy. Subjects were randomized according to their tumor proportion score (TPS) 
(extent of PD-L1 expression) defined as follows: a TPS 50% was considered 
strongly positive and a TPS = 1% to 49% was considered weakly positive.39 
 
In the KN-001 trial the overall response rate by RECIST 1.1 among all subjects treated 
was 42.6%. For the KN010 Intent-to-treat (ITT) Population (TPS 50%), the HR for OS 
was 0.54(95% Cl: 0.38, 0.77) with a one-sided p-value of 0.00024 in the pembrolizumab 2 
mg/kg Q3W arm vs. the docetaxel arm. The HR for OS was 0.50 (95% Cl: 0.36, 0.70) with 
a one-sided p-value of 0.00002 in the pembrolizumab 10 mg/kg Q3W arm vs. the 
docetaxel arm. The median OS was 14.9 months in the 2 mg/kg Q3W arm and 17.3 
months in the 10 mg/kg Q3W arm compared with 8.2 months in the docetaxel arm. For the 
KN010 ITT population with TPS 1 %, the OS HR for pembrolizumab 2 mg/kg versus 
docetaxel was 0.71 (95% Cl: 0.58, 0.88), with a p-value of 0.00076. The OS HR for 
pembrolizumab 10 mg/kg vs docetaxel was 0.61 (95% Cl: 0.49, 0.75), with a p-value 
<0.00001.39 
 
Overall, the results from KN001 and KN010 demonstrated that pembrolizumab provided 
substantial, clinically meaningful benefits in OS, PFS, and ORR in subjects with NSCLC 
who progressed after platinum-containing chemotherapy and whose tumor cells expressed 
PD-L1. The PD-L1 selection employed in KN010 identified patients more likely to benefit 
from pembrolizumab and resulted in favorable HRs in OS compared with docetaxel. In 
previously treated subjects with NSCLC with PD-L1 TPS 1 % and disease progression 
following platinum-containing chemotherapy, pembrolizumab provides a statistically 

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significant and clinically meaningful OS benefit compared with standard docetaxel 
chemotherapy. Pembrolizumab was subsequently explored in a randomized, phase Ill 
study examining pembrolizumab compared to platinum-based chemotherapy in patients 
with treatment-na·1ve, advanced, NSCLC with PO-L1 expression on at least 50% of tumor 
cells without evidence of sensitizing EGFR mutation or ALK gene fusion. Pembrolizumab 
was shown to produce a significantly longer PFS, OS and improve response rates 
compared to chemotherapy (Keynote-024).36 
 
 
KEYNOTE_012 trial was a non-randomized trial exploring the safety and anti-tumor activity 
of pembrolizumab monotherapy in patients with advanced solid tumors including head and 
neck, triple negative breast cancer, gastric cancer and urothelial cancer. This trial enrolled 
192 patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). 
Robust anti-tumor activity was demonstrated in this cancer subtype with an objective 
response rate of 21.9% in HPV+ve patients and 15.9% in HPV -ve patients. The median 
overall survival was 8.5 months and the 6-month progression free survival rate was 24.9%.40 
Pembrolizumab has a positive benefit-risk profile and is well tolerated in the approved 
indications, as evidenced by a low rate of toxicity Grade 3 to 5 drug-related AEs (13.8%), 
discontinuations due to AEs (11.9%), and deaths due to drug-related AEs (0.4%). 
Furthermore, the frequency of immune-mediated AEOSls is low, and these events are 
readily managed in the clinical setting. The safety and efficacy data generated to date 
provide a favorable benefit-risk assessment for the use of pembrolizumab as a treatment 
for subjects with advanced/metastatic melanoma, NSCLC, and HNSCC 
 
Identifying predictive biomarkers to immunotherapy 
One major challenge to harnessing immune checkpoint inhibitors in sarcomas is identifying 
patients who have the highest chance of benefiting from this modality of therapy. To address 
this question, lessons can be extrapolated from other tumor types and applied to sarcomas. 
We believe the heterogeneity inherent to sarcomas makes them an ideal group of tumors to 
validate a prospective biomarker for response to immune activating agents. 
It is unclear how best to predict which patients will benefit from immune checkpoint inhibitors. 
Expression of PO-L1 on tumor cells can predict benefit to anti-PO-1 therapy however; PO- 
L1 negativity does not preclude durable responses to anti-PO-1 agents in patients with 
melanoma. In the Keynote-006 study that explored the role of pembrolizumab in patients 
with advanced, ipilimumab-na"i"ve, melanoma, 80% of the patients had tumors that were PO- 
L1 positive, 18% were PO-L1 negative and PO-L1 status was unknown in 2%. Progression 
free survival (PFS) and objective response rate (ORR) were improved with pembrolizumab 
irrespective of the PO-L1 status. However, overall survival was improved only in PO-L1 
positive patients. The disproportionate representation of PO-L1 positive versus negative 
patients in this study should be considered when interpreting this result.41 

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In the Keynote-001 study Daud et al, has explored the relationship between anti-PD-1 
activity and PD-L1 expression in patients with advanced melanoma. The ORR was highest 
in the PD-L1 strong group (41.0%) compared to other treatment groups.42 
In the case of non-small cell lung cancer, data from Keynote-001 and Keynote-010 studies 
indicated that patients with a PD-L1 tumor proportion score of 50% or greater were more 
likely than those with lower tumor proportion scores to respond to pembrolizumab. Similarly, 
in Keynote-024, patients with advanced, treatment-na"i"ve, NSCLC with PD-L1 tumor 
proportion score of 50% had longer PFS and OS than patients randomized to and treated 
with platinum-based chemotherapy.36 Pembrolizumab obtained FDA approval for the 
treatment of advanced, treatment refractory, PD-L1 positive, NSCLC, in association with a 
companion diagnostic tool, the PO-L1 IHC 22C3 pharmOx test, the first test designed to 
detect PO-L1 expression in non-small cell lung tumors. 
It is known that PO-L1 expression remains a dynamic marker that can change over time 
and under different conditions in the microenvironment. Tumor heterogeneity can also 
contribute to varied PO-L1 expression.43 These data suggest that PO-L1 expression may 
change as a result of therapy with immune checkpoint inhibitors or that other mechanisms 
underlie the response to immune checkpoint blockade. There remains the need to further 
define the role of PO-L1 as a biomarker predictive of response to PO-1 blockade in all 
tumor types in which it is investigated. 
Tumor Neoantigens May Underlie Response to Immune Checkpoint Inhibition 
Van Rooij et al associated a response to ipilimumab in a patient with melanoma with T cell 
recognition of a tumor-specific mutant protein, termed a 'neoantigen' .44 To do this, they 
performed whole exome sequencing of the melanoma tumor tissue and tumor infiltrating 
lymphocytes (TlLs) and identified >1000 tumor-specific mutations. They then utilized 
NetMHC, an online predictor of Class I major histocompatibility complex (MHC)-specific 
affinities for specific sequences of 9-11 amino acids, to narrow the mutant sequences to 448 
peptides predicted to bind with medium to high affinity to the patient's COB+ T cells.45 These 
peptides were screened for binding with patient Tlls, and they identified 3.3% of all patient 
COB+ T cells reacted with a specific mutated epitope in the ataxia-telangiectasia and Rad3- 
related protein (ATR) pathway, suggesting this resulted in the clinical benefit seen in this 
patient. 
Further support for neoantigen-specific immune surveillance has come from in vivo models 
of sarcoma. In a murine model of chemically-induced sarcomas arising in immune-deficient 
Rag2-1- mice, Matsushita et al reported that implantation into an immunocompetent murine 
host resulted in "immune editing" of the tumor, and tumors with a greater neoantigen load 
were frequently rejected by the new host.46 Similar results were seen in a conditional Kras- 
p53 knockout mouse model. Whereas the work of van Rooij et al and Matsushita et al 

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suggests that certain key mutations predict response, DuPage et al and other authors imply 
that a higher overall mutational load and resulting neoantigen burden may lead to efficacy.47 
The Chan lab at MSKCC has proprietary data supporting the association between this 
patient-specific neoantigen analysis in melanoma with individual clinical benefit from 
ipilimumab and tremelimumab. Whole exome sequencing was performed on tumor tissue 
and matched blood samples from 64 patients with melanoma who were treated with anti- 
CTLA-4 blockade (ipilimumab or tremelimumab). A neoantigen signature incorporating both 
mutational load and patient-specific neoantigens was shown to separate patients with 
prolonged clinical benefit from patients with progressive disease. They then validated this 
signature in another set of 39 patients with melanoma who were treated with anti-CTLA-4 
antibodies. In this validation set predicted neoantigens activated T cells from patients treated 
with ipilimumab. This work defines a genetic basis for benefit to anti-CTLA-4 blockade in 
melanoma and provides strong rationale for examining exomes of patients receiving other 
immunotherapies to similarly see if a genetic basis can be defined for response or resistance 
to these immunotherapies.48 
 
Sarcoma is an ideal tumor subtype in which to test this hypothesis prospectively. The Singer 
laboratory at MSKCC has shown that different histologies show markedly different amounts 
of genetic alteration.86 It is perhaps not surprising that a previous pilot study of ipilimumab 
in synovial sarcomas, a translocation-positive, genetically "simpler" tumor, produced no 
clinical responses.49 There are currently no published whole exome mutation studies in 
sarcoma, which underscores how important this research will be to the sarcoma community. 
Summary Statement 
MSKCC is a leading sarcoma research center with the expertise, resources, and high 
clinical volume to conduct scientifically sound clinical studies. Sarcoma is an immunogenic 
malignancy with a need for more therapeutic options. Prior immunotherapeutic agents 
have shown promise in select sarcoma patients. Using a combination of epacadostat, an 
IDO inhibitor, and the anti-PD1 monoclonal antibody, pembrolizumab, to treat patients with 
sarcomas and our planned scientific correlates, we believe we can assess the safety and 
efficacy of dual checkpoint inhibition and better understand the effects of combined 
immunotherapy in antitumoral immune response. The safety of this combination therapy 
has been explored in a phase I study in the setting of patients with advanced (checkpoint 
inhibitor na·1ve) melanoma and select solid tumors. The combination therapy was safe and 
well tolerated. The recommended phase II dose of epacadostat was identified as 100mg 
bid in combination with pembrolizumab delivered at a dose of 200mg intravenously on a 
three weekly basis. The combination also showed promising clinical activity.50 
Consequently, enrollment in tumor-specific cohorts is ongoing in phase 2 of this study and 
a phase 3 study in patients who are treatment-naive for advanced melanoma has been 
initiated (NCT0275207 4). 

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4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
This is a single-center, phase II study to evaluate the efficacy of the 1001 inhibitor, 
epacadostat, given in combination with the anti-PD1 monoclonal antibody, pembrolizumab, 
for patients with metastatic and/or locally advanced grade sarcomas. 
A total of 30 patients will be enrolled onto the study. Patients will be enrolled onto one of 4 
cohorts. Each cohort will enrol a prespecified number of patients with certain sarcoma 
histological subtype(s). The 4 patient cohorts and the number of patients eligible to enrol 
per cohort in this study are as follows: 
A) Undifferentiated Pleomorphic Sarcoma (UPS), 
Liposarcoma (dedifferentiated or 
pleomorphic liposarcoma), or Myxofibrosarcoma (n=10) 
B) Leiomyosarcoma (n=5) 
 
C) Vascular 
Sarcoma 
Subtypes 
Hemangioendothelioma (EHE))) (n= 5) 
D) Other (n=10) 
(including 
angiosarcomaEpithelioid 
This study will be conducted using a one-stage design. Patients will receive the 
recommended phase II dose (100mg bid) of epacadostat, when administered in combination 
with pembrolizumab. Epacadostat 100mg will be administered orally, twice daily, 
continuously for 21 days. Pembrolizumab will be administered at a dose of 200mg every 21 
days (±3 days). Treatment with epacadostat and pembrolizumab will start on day 1 of the 
first cycle. Each cycle will consist of 21 days. 
Patients will be evaluated radiographically at baseline, week 8 (+/- 7 days) and every 8 
weeks(+/- 7 days) subsequently until week 56 and then every 12 weeks thereafter or as 
per the discretion of the treating investigator. Response will be assessed using RECIST 
v1.1 (primary response assessment) and immune-related response evaluation criteria of 
solid tumors (irRECIST) (secondary response assessment). 
 
All study participants where feasible will undergo mandatory tumor biopsies at baseline 
and week 7. Optional biopsies at progression will be offered. Biopsies must be collected 
within +/- 7 days of the originally scheduled timepoint.Serial blood samples will be 
obtained at baseline, during, and at the end of study treatment. 
 
Study therapy should continue once there is no evidence of progression of disease per 
RECIST 1.1, no clear clinical deterioration and the patient is able to tolerate the treatment. 
Treatment beyond progression will be allowed at the discretion of the clinical investigator 

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as long as patient is clinically benefitting, is tolerating the drug well and continues to meet 
all study treatment criteria. 
The safety of the combination of epacadostat and pembrolizumab in patients with 
advanced sarcoma will be determined using CTCAE v4.03 criteria for toxicity assessment. 
Safety data will be collected for up to 90 days following the last dose of the study drugs. 
Therapy will be discontinued due to confirmed progression of disease or clinical 
progression, intercurrent illness that prevents further administration of treatment or 
intolerance of study treatment. Study personnel will attempt to collect survival status for all 
patients after the end-of-study visit every 3 months via telephone, email, or another 
method for up to 1 year. 
 
4.2 
Intervention 
Patients will start both study drugs on day one of the first and subsequent treatment 
cycles. One treatment cycle consists of 21 days. 
100mg tablets of epacadostat will be administered orally, twice daily continuously for 21 
days (Table 1). 
Pembrolizumab will be administered at a dose of 200mg every 21 days (±3 days). 
Pembrolizumab infusion should be administered in 30 minutes, with a window of -5 and 
+10 minutes, using an infusion pump. 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
5.1 Epacadostat (formerly known as INCB024360) 
5.1.1 Mechanism of Action of Epacadostat 
Epacadostat represents a novel, potent, and selective inhibitor of the enzyme IDO1. IDO1 
catabolism of Trp inhibits T-cell-mediated immune responses. IDO1 expression has been 
shown to be elevated in many human cancers, including sarcomas. IDO1 inhibition may 
restore an effective antitumor immune response and may provide a method to treat 
malignant diseases either alone or in combination with chemotherapeutics and/or 
immunotherapy-based strategies. In cell-based assays, epacadostat potently inhibits IDO1 
in both human tumor cells and human dendritic cells (DCs) resulting in reduced Trp to Kyn 
conversion (IC50 values= 7.1-12.7 nM). Epacadostat does not significantly inhibit other 
proteins that could impact Trp catabolism. 
5.1.2 Formulation, Storage and Packaging 
Epacadostat will be supplied as an immediate release tablet in two strengths (25 mg, 100 
mg) for oral use. The tablets contain the active drug (epacadostat) along with commonly 
used compendia! excipients (lactose monohydrate, microcrystalline cellulose, povidone, 
croscarmellose sodium, colloidal silicon dioxide, magnesium stearate). 

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Once received by a designated staff member at the study site, epacadostat must be 
handled and stored safely and properly and kept in a secured location to which only the 
investigator and designated assistants have access to. Upon receipt, epacadostat should 
be stored according to the instructions specified on the drug labels. In general 
epacadostat tablets should be stored at ambient conditions (15°C-30°C or 59°F-86°F). 
5.1.3 Administration of Epacadostat 
Epacadostat be taken orally twice daily on a continuous dosing schedule at the 
recommended phase II dose for epacadostat when administered in combination with 
pembrolizumab. Epacadostat will be administered as a flat-fixed dose, and not by body 
weight or body surface area. Patients will be provided with a 3 week supply of epacadostat 
for self-administration at home until at least their next scheduled study visit. Patients will be 
instructed to return unused study drug to the site at each visit. A study medication diary will 
be completed by the patients for each dose of epacadostat. 
Epacadostat will be taken twice daily orally without regard to food morning and evening, 
approximately 12 hours apart. There is no priority to the order of administration of 
epacadostat and pembrolizumab when given in combination; however, th dose of 
epacadostat should be taken as close to the regularly scheduled 12-hour dosing interval 
as possible. Patients will be instructed not to chew or crush tablets of study drug. If a 
patient vomits at any time after dosing, the dose of study drug should not be re- 
administered. Doses of study drug omitted for AEs or any other reason should not be 
made up later in the day, or at the end of the dosing period. If a dose of epacadostat is 
missed, the subject should take it as soon as possible within 4 hours of the missed dose. If 
4 hours passes, the subject should skip the missed dose and take the next dose as 
scheduled. All missed doses and schedule deviations should be recorded in the pill diary. 
Doses of epacadostat will be self-administered except on the days scheduled to be given 
at the time of a study visit. 
5.2 Pembrolizumab 
5.2.1 Mechanism of Action of Pembrolizumab 
Pembrolizumab (formerly known as MK-3475 or lambrolizumab ), is a highly selective 
humanized monoclonal lgG4-kappa isotype antibody against PD-1, that acts by blocking 
its interaction with PD-L1 and PD-L2. Pembrolizumab is currently approved by the FDA for 
the treatment of patients with unresectable or metastatic melanoma as i) initial first-line 
therapy34 and ii) following disease progression on ipilimumab and/or , if BRAF V600 
mutation positive, a BRAF inhibitor.33,38 Pembrolizumab is also approved by the FDA for 
the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose 
tumors express PD-L1 as determined by an FDA-approved test in the first-line setting or 
with disease progression on or after platinum-containing chemotherapy. Patients with 
epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic 

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tumor aberrations should have disease progression on FDA-approved therapy for these 
aberrations prior to receiving pembrolizumab. Pembrolizumab is approved for use with a 
companion diagnostic, the PD-L1 IHC 22C3 pharmDx test, the first test designed to detect 
PD-L1 expression in NSCLC tumors.36 The FDA approved pembrolizumab 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.37 
Pembrolizumab is currently being explored both as monotherapy and in combination with 
other therapies across more than 30 tumor types. The combination of pembrolizumab and 
epacadostat has been investigated in a phase I study including patients with advanced 
melanoma or other select solid tumors. The combination was safe, well tolerated and 
showed promising clinical activity in melanoma and other tumor types. Based on this data 
enrollment in tumor-specific cohorts is ongoing in phase 2 of this study and a phase 3 
study in treatment na·1ve patients with advanced melanoma has been initiated. 51 
 
 
Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits 
T cell proliferation and cytokine production. Upregulation of PD-1 ligands occur in some 
tumors and signaling through this pathway can contribute to inhibition of active T-cell 
immune surveillance of tumors. Pembrolizumab is a monoclonal antibody that binds to the 
PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway- 
mediated inhibition of the immune response, including the anti-tumor immune response. In 
syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth. 
 
The theoretical molecular weights of the heavy and light chains derived from the amino acid 
sequences, excluding glycosylation, are 49.4 kDa and 23.7 kDa, respectively. The antibody 
is heterogeneously glycosylated at asparagine 297 within the Fe domain of each heavy 
chain, yielding molecular weights typically ranging between 148.9 and 149.5 kDa, depending 
on the attached glycan chains. 
 
5.2.2 Formulation, Storage and Packaging of Pembrolizumab 
Pembrolizumab will be manufactured by Merck. 
 
Pembrolizumab is supplied as pembrolizumab 50 mg lyophilized powder in a single-use vial 
for reconstitution or as Pembrolizumab 100 mg/4ml Solution for Injection 
 
Reconstituted and diluted solutions of pembrolizumab should be stored either: 
 
• 
At room temperature for no more than 4 hours from the time of reconstitution. This 
includes room temperature storage of reconstituted vials, storage of the infusion 
solution in the IV bag, and the duration of infusion. 

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• 
Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the 
time of reconstitution. If refrigerated, allow the diluted solution to come to room 
temperature prior to administration. 
 
Product should not be frozen. 
 
 
5.2.3 Administration of Pembrolizumab 
Pembrolizumab must be prepared and administered by a qualified healthcare 
professional. 
 
Pembrolizumab at a dose of 200 mg will be administered intravenously on Week 1 of 
treatment cycle 1 and every 3 weeks (±3 days) thereafter. 
 
Pembrolizumab infusion will be administered as a 30-minute intravenous infusion. 
Investigators should make every effort to target infusion timing to be as close to 30 
minutes as possible. However, given the variability of infusion pumps from site to site, 
a window of -5 and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+ 
10 min). A central catheter is not required for infusion; however if a subject has a 
central venous catheter in place, it is recommended that it be used for the infusion. A 
0.2 or 0.22 µm in-line filter made of polyethersulfone (PES) must be used during 
administration to remove any adventitious particles. If the infusion set does not 
contain a 0.2 or 0.22 µm in-line filter, it is recommended to use an extension line 
containing the filter. 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
6.1 
Subject Inclusion Criteria 
Patients must fulfill all of the following criteria to be eligible for admission to the study: 
 
 
• 
Male or female age 
18 years at the time of informed consent 
• 
Be willing and able to provide written informed consent/assent for the trial 
• 
Be willing to comply with treatment protocol 
• 
Subjects must have a histologically confirmed metastatic and/or locally advanced 
sarcoma 
• 
Adequate performance status: ECOG O or 1/KPS 100-70% 
• 
 Subjects must have at least one prior line of systemic therapy (e.g. chemotherapy, 
immunotherapy, targeted or biological therapy) for their sarcoma. An exception to this 
criterion will be made for patients with sarcoma histological subtypes for which there is 

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no known standard systemic therapy (e.g., chondrosarcoma). Any patient that refuses 
standard chemotherapy for the treatment of their disease is also considered eligible. Prior 
adjuvant therapy will not count provided it was completed more than 6 months previously. 
• 
Presence of measureable disease per RECIST v1.1.Target lesions must not be chosen 
from a previously irradiated field unless there has been radiographically and/or 
pathologically documented tumor progression in that lesion prior to enrollment. 
• 
 All subjects must agree to pre-treatment tumor biopsy. Subjects in whom biopsy is 
technically not feasible or in whom would result in unacceptable risk, in the opinion of 
the investigator, may be exempted from the biopsy requirement with discussion with 
the principal investigator. 
 
• 
 Adequate organ function determined within 21 days of treatment initiation, defined as 
per Table 2: 
 
 
Table 2: Definition of Adequate Organ Function 
 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
1,000 Imel 
Platelets 
75,000 I mcl 
Hemoglobin 
l B g/dl or 5.0 mmol/L 
Renal 
I 
Serum creatinine OR 
Measured or calculated8 creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCI) 
S1.5 X upper limit of normal (ULN) OR 
60 ml/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
Serum total bilirubin 
1.5 X ULN OR 
Direct bilirubin s ULN for subjects with total bilirubin levels 
> 1.5 ULN 
AST (SGOT) and ALT (SGPT) 
s 2.5 X ULN OR 
S 5 X ULN for subjects with liver metastases 
Albumin 
2.5 mg/dl 
Coagulation 
International Normalized Ratio 52 or 
Prothrombin Time 53 
Activated Partial Thromboplastin Time 
(aPTT) 
s1.5 X ULN unless subject is receiving anticoagulant 
therapy 
as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants 
s1.5 X ULN unless subject is receiving anticoagulant 
therapy 
as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants 
acreatinine clearance should be calculated per institutional standard. 
 
• 
Women of childbearing potential must have a negative serum pregnancy test at 
screening and :5 72 hours prior to day 1 of study treatment. 

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• 
Male and female subjects of childbearing potential must be willing to use an adequate 
method of contraception as outlined in Section 11.7, 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 subject. 
 
 
6.2 
Subject Exclusion Criteria 
Patients who fulfil any of the following criteria are not eligible for admission to the study: 
 
• 
Uncontrolled intercurrent illness including current active infection requiring systemic 
therapy or symptomatic congestive heart failure within 6 months 
• 
Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by imaging for at least four 
weeks prior to the first dose of trial treatment and any neurologic symptoms have 
returned to baseline), have no evidence of new or enlarging brain metastases, and 
are not using steroids for at least 7 days prior to trial treatment. This exception does 
not include carcinomatous meningitis which is excluded regardless of clinical stability. 
• 
Evidence of clinically significant immunosuppression such as the following: 
 
Primary immunodeficiency state such as Severe Combined 
Immunodeficiency Disease 
- 
Concurrent opportunistic infection 
Receiving systemic immunosuppressive therapy(> 2 weeks) including 
oral steroid doses > 10 mg/day of prednisone or equivalent within 7 days 
prior to enrollment. However, in the setting of non-immune mediated 
indications for steroid use, chronic/active low dose steroid use may be 
permitted at the discretion of the principal investigator. The dose of 
steroid allowed in this setting is also at the discretion of the principal 
investigator. (Use of inhaled or topical steroids is permitted.) 
 
• 
History or evidence of symptomatic autoimmune disease (e.g., pneumonitis, 
glomerulonephritis, vasculitis, or other), or history of active autoimmune disease 
that has required systemic treatment (i.e., use of corticosteroids, 
immunosuppressive drugs or biological agents used for treatment of autoimmune 
diseases) in past 2 years prior to enrollment. Replacement therapy (e.g., thyroxine 
for hypothyroidism, insulin for diabetes or physiologic corticosteroid replacement 

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therapy for adrenal or pituitary insufficiency) is not considered a form of systemic 
treatment for autoimmune disease. 
• 
Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies) disease 
• 
Has known active Hepatitis B (e.g., Hepatitis B Virus PCR is detected) or Hepatitis C 
(e.g., HGV RNA [qualitative] is detected). 
 
 
• 
Patients who have received a live vaccine within 30 days of the start date of the 
planned study therapy. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, Bacillus 
Calmette-Guerin (BCG), and typhoid vaccine. 
Note: Seasonal influenza vaccines 
for injection are generally inactivated flu vaccines and are allowed; however 
intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are 
not allowed. 
• 
Has a known history of active TB (Bacillus Tuberculosis) 
• 
Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 2 weeks of the first dose of treatment. 
• 
Has had a prior chemotherapy, immunotherapy, biological therapy, targeted small 
molecule therapy, or radiation therapy within 3 weeks prior to study Day 1 or who has 
not recovered (i.e., $ Grade 1 or at baseline) from adverse events due to previously 
administered agent. 
o Note: Subjects with$ Grade 2 neuropathy, alopecia or hypothyroidism are an 
exception to this criterion and may qualify for the study. 
o Note: If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy events due to a previously administered agent. 
• 
Presence of a gastrointestinal condition that may affect drug absorption 
• 
Known allergy or reaction to any component of either study drug formulation 
• 
Women who are pregnant or breast feeding 
• 
Subjects expecting to conceive or father children within the projected duration of the 
trial, starting with the pre-screening or screening visit through 120 days after the last 
dose of study treatment(s). 
• 
Inability to comply with protocol required procedures 

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• 
 Subjects receiving Monoamine Oxidase Inhibitors (MAOls) or drug which has 
significant MAOI activity (meperidine, linezolid, methylene blue) within the 21 days 
before screening. 
• 
Any history of Serotonin Syndrome (SS) after receiving serotonergic drugs. 
• 
History or presence of an abnormal electrocardiogram (ECG) that, in the 
investigator's opinion, is clinically meaningful. Screening QTc interval z 480 
milliseconds is excluded. In the event that a single QTc is z 480 milliseconds, the 
subject may enroll if the average QTc for the 3 ECGs is< 480 milliseconds. For 
subjects with an intraventricular conduction delay (QRS interval > 120 milliseconds), 
the JTc interval may be used in place of the QTc with the approval of the principal 
investigator. The JTc must be < 340 milliseconds if JTc is used in place of the QTc. 
Subjects with left bundle branch block are excluded. 
Note: QTc prolongation due to pacemaker may enroll if the JTc is normal. 
• 
Use of any UGT1A9 inhibitor from screening through follow-up period, including the 
following: diclofenac, imipramine, ketoconazole, mefenamic acid, and probenecid. 
• 
History of prior therapy with an IDO1 inhibitor in combination with an anti-PD-1/anti- 
PD-L1 agenUany other drug specifically targeting checkpoint pathways. Patients 
who have received prior therapy with single agent anti-PD-1/anti-PD-L1 therapy or 
single agent IDO1 inhibitor will be eligible for this study. 
• 
Presence of any other concurrent active malignancy 
 
 
7.0 
RECRUITMENT PLAN 
Both men and women and members of all races and ethnic groups are eligible for this trial. 
The clinical trial will be listed on the clinicaltrials.gov website and on the websites of 
participating institutions. Patients will be identified through internal referrals and external 
referrals by Medical and Surgical Oncologists, nationally and internationally. Patients will be 
recruited through the Sarcoma Disease Management Team of the Memorial Sloan Kettering 
Cancer Center. The Sarcoma Service and the Sarcoma Disease Management Tearn each 
hold weekly interdepartmental meetings to identify study participants for open clinical trials. 
We will also discuss the trial and patient recruitment with several Sarcoma patient support 
groups. The principal investigator will be available to all patients for further questions and 
information through a contact number, which will be provided on the consent form. 
8.0 
PRETREATMENT EVALUATION 
Screening 
All aspects of the screening evaluation should be completed prior to entering the study, 
unless otherwise noted. Pretreatment evaluations include: 
Informed consent 

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Confirmation of disease: documented presence of metastatic and/or locally 
advanced sarcoma with RECIST v1.1 measureable disease. 
Pathologic confirmation of the presence of a sarcoma at the study 
site 
All patients enrolled in this study will undergo a new baseline biopsy where 
feasible 
Full medical history, physical exam, assessment of performance status by 
KPS or ECOG status 
Review of concomitant medications 
Complete vital signs (pulse, blood pressure, temperature, respiratory rate, 
oxygen saturation) as well as weight and height. Height may be 
documented at any time prior to registration. 
Standard baseline imaging of chest, abdomen, pelvis (CT or MRI), with CT 
scan or MRI of brain or other site if applicable. 
12-lead electrocardiogram (ECG) 
Echocardiogram (ECHO) 
Serum pregnancy test for women with child-bearing potential. 
Complete blood count with differential. 
PT (or INR) and aPTT 
Comprehensive metabolic panel (glucose, blood urea nitrogen, creatinine, 
sodium, potassium, chloride, bicarbonate, calcium, total protein, albumin, 
serum bilirubin, alkaline phosphatase, ASL, AST), phosphorus, 
magnesium, 
TSH, T4 free, T3 
Amylase, lipase. 
Review of inclusion and exclusion criteria 
 
Baseline assessments including biopsy must be done within 3 weeks of starting protocol 
therapy. Note, previous pathologic confirmation of the presence of sarcoma at the study 
site prior to within 3 weeks of starting protocol therapy allowed. 
Please refer to Study Calendar in Section 10 for additional information. 
 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
9.1 
Study drugs 
Treatment will be administered on an outpatient basis. Reported adverse events and 
potential risks are described in section 11.0. Modifications and dose delays due to toxicity 
are described further in section 11.4. The schedule of evaluations and interventions is 
described in Section 10. 

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Patients will be treated with epacadostat (100mg tablet), administered orally in tablet form, 
twice daily, continuously for the 21 days of each treatment cycle, beginning on day 1. 
Pembrolizumab 200mg/dose will be administered by intravenous infusion on day 1 of cycle 
one and every three weeks thereafter (±3 days). Pembrolizumab infusion should be 
administered in 30 minutes, with a window of -5 and +10 minutes, using an infusion pump. 
 
 
The treatment period with the combination therapy or pembrolizumab will continue every 
21days for up to 35 cycles (approximately 2 years) as long as subjects are receiving benefit 
from treatment and have not had disease progression or met any criteria for study withdrawal 
and are tolerating therapy. In the case of a patient benefiting from study therapy who 
discontinue study treatment after the maximal therapy duration of 2 years and subsequently 
experience disease progression, re-challenge with study therapy will be permitted. 
No additional investigational or commercial agents or therapies other than those described 
below may be administered with the intent to treat the patient's malignancy 
9.2 
Dose rationale 
The dose combination of 100mg bid epacadostat plus pembrolizumab for the ongoing 
phase Ill melanoma study is based upon a benefit/risk assessment made specifically in 
melanoma in collaboration with Merck. In the phase 1/11 study examining this combination, 
there was evidence of improved efficacy in melanoma subjects at all doses of epacadostat 
from 50 to 300mg bid. The same dose of the combination therapy of epacadostat and 
pembrolizumab will be use in this phase II study as is being used in the melanoma specific 
phase Ill study. 
9.3 Duration of Therapy 
 
Study treatment may continue until one of the following criteria applies: 
Until a total of 35 cycles (approximately 2 years) of treatment has been administered as 
long as subjects are receiving benefit from treatment and have not had disease 
progression or met any criteria for study withdrawal outlined below 
Clinical or radiographic disease progression as defined by RECIST 1.1. Patient may be 
allowed to continue treatment after progression if they are deriving clinical benefit (section 
9.4). 
lntercurrent illness that prevents further administration of treatment 
Intolerance of study treatment 
Patient decides to withdraw from the study 

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Physician decides to withdraw a patient from the study for a reason not listed here 
Pregnancy in patient 
The patient is lost to follow-up 
Inability of the patient to comply with the requirement of the protocol for treatment or 
evaluation. 
End of study, whichever occurs first. 
 
9.4 Treatment Beyond Initial RECIST 1.1 Defined Progression of Disease 
 
Due to the mechanism of action, subjects may experience growth in existing tumors or the 
appearance of new tumors prior to maximal clinical benefit of the combination therapy of 
epacadostat and pembrolizumab. The patient may be allowed to continue study treatment 
after initial RECIST 1.1 defined progression if they are assessed by the treating physician 
to be deriving clinical benefit and tolerating study treatment. The treating physician may 
consult with the overall study Pl for help with assessing the patient. Patients who decide 
to continue study therapy on protocol after initial radiolgic evidence of disease progression 
will need to provide written informed consent at the time of the decision to treat beyond 
initial evidence of progression of disease on study therapy. Such patients should 
discontinue study therapy upon further evidence of progression at the discretion of the 
treating physician. 
9.5 
General Concomitant Medication and Supportive Care Guidelines 
 
 
Supportive Care: Best supportive care and treatment will be given as appropriate 
to each subject as per Clinical Center and ASCO guidelines 
(antiemetics, antibiotics, packed red blood cell and platelet 
transfusions, 
nutritional 
support, 
non-radiation 
palliative 
treatment for pain). 
Steroids: Doses up to 10mg of prednisone daily (or equivalent) will be 
allowed concurrently with continuous treatment with epacadostat 
and/or pembrolizumab. 
If the subject requires corticosteroid dosing of >10 mg 
prednisone 
daily 
(or 
equivalent) 
and/or 
other 
immunosuppressive 
medication 
for 
related 
toxicities, 
epacadostat and pembrolizumab dosing must be held until the 
corticosteroid dose has decreased to 10 mg prednisone daily 
(or  equivalent)  and  the  administration  of  the  other 

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immunosuppressive medication has discontinued. Higher doses 
of prednisone (.i.e., >10mg) may potentially be allowed in 
combination with the study therapy if they are prescribed for non- 
immune mediated indications at the discretion of the principal 
investigator. 
Radiation: Radiation therapy are only allowed during the study if required 
for palliation of symptoms due to underlying sarcoma. 
Non-Surgical 
Local Interventions: 
study 
Surgery: 
 
Non-surgical local interventions are only allowed during the 
if required for palliative of symptoms due to underlying sarcoma 
Subjects must not schedule any elective surgeries during 
the treatment period and for at least 30 days after the last 
administration of study drugs. If a subject undergoes any 
unexpected surgery or local intervention during the course of 
the study, all study treatments must be withheld and the 
investigator or designee should notify the sponsor' as soon as 
possible. A subject may be allowed to resume study drugs if 
both the investigator and sponsor's medical monitor agree to 
restart study therapy 
 
Other supportive measures and specific treatments/guidelines recommended for the 
management of toxicities are detailed in Appendix B. 
9.6 Drug Interactions 
9.6.1  Epacadostat 
 
 
 
9.6.1.1 Restricted Medications/Treatment 
- 
Systemic steroids may be used at doses 
10 mg/day prednisone or equivalents. 
However, in the setting of non-immune mediated indications for use, 
chronic/active low dose steroid use at doses >10mg/day prednisone or 
equivalents, may be permitted at the discretion of the principal investigator. 
Use of coumarin-based anticoagulants (eg, Coumadin) is discouraged. Low-dose 
Coumadin® (1 mg) is acceptable; however, doses that increase the INR are 
discouraged and will require dose modification. If an alternative to coumarin-based 
anticoagulants cannot be used, dose modifications of the Coumadin® may be 
needed. Based on the observed magnitude of epacadostat/warfarin PK interaction 
and PK/PD modeling results, for an epacadostat dose of 100 mg BID, the dose of 

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warfarin should be maintained and close INR monitoring is recommended. Based 
on PK/PD modeling, recommendations for warfarin dose modifications for subjects 
receiving epacadostat :s; 100 mg BID are summarized in Table 3 below based on 
the INR prior to starting epacadostat. 
Table 3. Recommendations for Warfarin dose modification in setting of concomitant 
epacadostat 
 
Stable Baseline INR 
Epacadostat Dose 
:S 100 mg BID 
INR ::;2.5 
Close INR monitoring 
INR > 2.5 
Close INR monitoring 
• 
Use of the anticonvulsant carbamazepine (a UGT1A9 inducer) is discouraged. 
Because there is a potential interaction that could result in lower epacadostat 
exposures, an alternative to carbamazepine should be used, if possible. 
9.6.1.2 Prohibited Medications/Treatment 
Subjects are prohibited from receiving the following therapies starting from screening 
through end of treatment phase of this study unless otherwise noted below: 
• 
Any investigational medication other than the study drugs. 
• 
Use of any anticancer medications, including chemotherapy or biologic therapy 
other than the study medications. 
• 
 Any chronic immunological-suppressive treatment. (Note: Inhaled or topical 
steroids are allowed, and systemic steroids at doses :510 mg/day prednisone or 
equivalents are allowed and immune suppressants are allowed for short-term 
treatment for immune toxicities or as prophylaxis for contrast allergy for imaging 
procedures. Steroid use at doses >10mg/day prednisone or equivalents for non- 
immune mediated indications may be permitted at the discretion of the principal 
investigator) 
• 
Radiation therapy 
Note: In the presence of a mixed response (some lesions improving or stable 
and other lesions progressing), radiation therapy to a symptomatic solitary lesion 
or to the brain is allowed. 
• 
 Administration of a live attenuated vaccine within 30 days before the first dose of 
study treatment and while participating in the study. Examples of live vaccines 
include, but are not limited to, the following: measles, mumps, rubella, chicken 
pox, yellow fever, rabies, BCG, and typhoid vaccine. Seasonal influenza 
vaccines for injection are generally killed virus vaccines and are allowed; 

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however, intranasal influenza vaccines (eg, FluMist®) are live attenuated 
vaccines and are not allowed. 
• 
Use of any MAOI or drug associated with significant MAOI activity agents is 
prohibited from 21 days prior to Day 1 through 2 weeks after the final dose of 
epacadostat has been administered 
• 
Use of any immunological-based treatment for any reason from screening 
through follow-up visit is prohibited. 
Note: Completed adjuvant therapy (eg, vaccines) with medical monitor 
approval, inhaled or topical steroids, and systemic steroids at doses 
10 mg/day prednisone equivalents are allowed, as described in Restricted 
Medications. 
• 
 Any UGT1A9 inhibitor, including acitretin, amitriptyline, androsterone, 
cyclosporine, dasatinib, diclofenac, diflunisal, efavirenz, erlotinib, estradiol (17- 
beta), flutamide, gefitinib, gemfibrozil, glycyrrhetinic acid glycyrrhizin, imatinib, 
imipramine, ketoconazole, linoleic acid supplements, mefenamic acid, 
mycophenolic acid, niflumic acid, nilotinib, phenobarbital, phenylbutazone, 
phenytoin, probenecid propofol, quinidine, ritonavir, sorafenib, sulfinpyrazone, 
valproic acid, and verapamil. 
Subjects may receive other medications that the investigator deems to be medically 
necessary. 
The exclusion criteria describe other medications that are prohibited during this study. 
There are no prohibited therapies during the post-treatment follow-up phase. 
 
 
9.6.2  Pembrolizumab 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for one of these or other 
medications or vaccinations specifically prohibited during the trial, discontinuation from trial 
therapy or vaccination may be required. The investigator should discuss any questions 
regarding this with the Merck Clinical team. The final decision on any supportive therapy 
or vaccination rests with the investigator and/or the subject's primary physician. 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded. Concomitant 
medications administered after 30 days after the last dose of trial treatment should be 
recorded for SAEs and ECls. 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 

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• 
Antineoplastic systemic chemotherapy or biological therapy 
• 
lmmunotherapy not specified in this protocol 
• 
Chemotherapy not specified in this protocol 
• 
lnvestigational agents other than pembrolizumab 
• 
Radiation therapy 
o Note: Radiation therapy to a symptomatic lesion or to the brain may be 
allowed at the investigator's discretion. 
• 
Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine. 
• 
 Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology. The use of physiologic 
doses or higher of corticosteroids for non-immune mediated indications may be 
approved after consultation with the principal investigator. 
Subjects 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. 
Subjects 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. 
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
10.1 - Pre-treatment diagnosis confirmation 
All patients will have histological confirmation of their diagnosis prior to treatment. Baseline 
clinical and radiologic evaluations are to be conducted within 3 weeks of starting protocol 
therapy. In addition, a mandatory baseline biopsy will be performed within 3 weeks of first 
dose of the study drugs for all patients enrolled in the study where feasible. 
10.2 - Standard evaluations 
Evaluations at clinic visits will occur on day 1 (± 3 days) of cycle 1 and every cycle thereafter. 
The clinical evaluations are delineated further in the study calendar (Table 5) and include: 

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- 
Full medical history, physical exam, assessment of performance status by KPS or 
ECOG status 
- 
Review of concomitant medications 
Complete vital signs (pulse, blood pressure, temperature, respiratory rate, and 
oxygen saturation)  as well as weight and height. Height may be documented at 
any time prior to registration. 
All patients will undergo a baseline staging CT scan of the chest (with or without contrast), 
abdomen and pelvis (with or without contrast), and MRI of the affected area if deemed 
necessary by the treating physician. Response evaluations will occur at week 8 and every 8 
weeks subsequently (± 1 week window) until 56 weeks, and then every 12 weeks thereafter 
or as per the discretion of the treating investigator. 
Routine/standard blood samples will be obtained at screening, day 1 of cycle 1 and then 
prior to every scheduled treatment visit (± 3 days) thereafter. All routine blood samples 
should be obtained prior to the daily dose epacadostat and/or pembrolizumab. These 
samples will be used for routine tests and are part of standard of care. The following 
analyses will be assessed at various time points during the study: 
Hematology: Complete blood count with differential 
Chemistry: phosphorus, magnesium 
Serum pregnancy test for women with child-bearing potential 
Comprehensive metabolic panel (sodium, potassium, chloride, bicarbonate, 
calcium, glucose, blood urea nitrogen, creatinine, total protein, albumin, 
serum bilirubin, alkaline phosphatase, ASL, AST) 
TSH, T4 free, T3 
Amylase and lipase 
Additional tests if clinically indicated 
 
 
10.3 Required Laboratory Parameters for Treatment 
A new dose of therapy may be initiated provided that the patient meets the following criteria 
on the day of treatment: 
• 
ANC  1,000/µL 
• 
Platelets> 75,000/µL 
• 
All grade 2 non-hematologic adverse events (except for fatigue, 
nausea and vomiting, or laboratory values that are not clinically 
significant) must have resolved to CTCAE grade  1 
 
10.4 - Tumor and blood samples for correlative/companion studies 

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All patients enrolled on this study will undergo paired biopsies/blood samples for research 
purposes (correlative/companion studies) where feasible 
Blood samples for research purposes will be obtained at week 1 (before treatment), 4, 7, 13, 
and 22 and at the date of the off study visit (± 3 days). This is detailed in Table 5 (Study 
calendar). Research blood collection procedures will be performed as outlined in Appendix 
A. 
Biopsies for research purposes will be done at baseline (within 3 weeks of the first dose of 
epacadostat and/or pembrolizumab) and at Week 7 in all patients enrolled in this study 
where feasible. Up to 6 cores from each tumor biopsy site should be taken where feasible 
and safe to do so. An optional biopsy will be offered to all patients at the time of progression. 
Biopsy procedures will otherwise be performed in accordance with institutional guidelines 
and the biopsy protocol outlined in Appendix A. 
10.4.1 Tumor Based Biomarkers 
Interrogation of immune responses within the tumor microenvironment of sarcomas 
before and after treatment with epacadostat and PD-1 checkpoint blockade. 
For each resected specimen, up to 6 cores of tissue will be obtained for tumor immune 
correlative studies. 
 
 
a) Density of immune infiltration and immune checkpoint and kynurenine 
expression of sarcomas: IHC will be used to assess the number and 
composition of immune infiltrates in order to define the immune cell subsets 
present within the tumor before and after exposure to epacadostat and 
pembrolizumab. PD-L1, PD-1, ID0-1 and kynurenine expression within the tumor 
before and after exposure to epacadostat and pembrolizumab will also be 
determined by IHC. 
The IHC assays will be performed using but are not limited to the following 
markers: CD3, CD4, CDS, CD25, CD28 CD45RA, CD68, CD69, CCR?, ID0-1, 
kynurenine, PD-L1, PD-1, CD137, FOXP3, LAG-3, TIM-3, and ICOS. PD-L1 
expression by immunohistochemistry staining of archival tumor specimens will be 
performed with using a QualTek immunohistochemistry-based assay. 
b) Phenotype and function of TIL in human sarcomas: 
Multiparameter flow cytometry (MFC) performed on freshly dissociated tumor 
tissue will be used to characterize the tissue T cell populations. We will study the 
functional significance of PD-1 expression and ID0-1 expression on T cells 
isolated from sarcomas. Using intracellular cytokine staining (ICS) and MFC 
analysis on freshly isolated TIL, we will identify the T cell cytokine profiles in 

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accordance to their immune checkpoint profile (PD-1, LAG-3, TIM-3) and level of 
IDO-1 expression. A range of cytokines representing key lymphocyte subgroups 
(e.g., Th1, 2 or 17) such as IL-2, TNF-a, IFN-y IL-17 among other inflammatory 
mediators will be assessed. Functional T cell markers including granzyme Band 
perforin as well as activation markers such as CD62L, CD44, CD69 will be also 
included in our analysis. 
 
c) Tumor Biopsy gene expression profiling: Fresh tumor biopsy will be examined 
for RNA gene and protein expression by NanoString technology (nCounter® RNA: 
Protein, PanCancer Immune Profiling Panel) and/or qRT-PCR to detect 
expression of immune related genes. This panel includes 770 immune related 
genes including: 109 genes related to cell surface markers for 24 different immune 
cell types and populations, 30 genes for commonly studied cancer/testis (CT) 
antigens, over 500 genes for measuring immune response and 40 reference 
genes. 
 
d) Neoantigen analysis: Massively parallel sequencing of the whole exome of the 
tumor tissue and normal blood will be performed for patients who opt in. Genomic 
DNA will be captured via solution-based hybrid selection and sequenced on the 
lllumina HiSeq platform by the Genomics Core at MSKCC. The sequencing data 
will be aligned by the Bioinformatics Core Tumor, using Somatic Sniper, Somatic 
lndel Detector and Mutect softwares. 
 
e) Next generation sequencing for T-cell receptor clonality in tumor-infiltrating 
lymphocytes (TIL): Samples will be analyzed using highthroughput sequencing 
of the variable 13-chain of the T cell receptor (TCR) to characterize the expansion 
and clonality of the T-cell repertoire in Tlls. 
 
10.4.2 Peripheral blood studies 
 
Blood samples will be taken prior to initiation of study therapy and on designated time 
points post-treatment. These samples will be analyzed for: 
 
a.) lmmunophenotyping and Functional Analyses: 
1. Samples will be analyzed by flow cytometry to study the effects of epacadostat 
and pembrolizumab on various peripheral blood immune cell subsets including, 
but not limited to T cell subsets (activated, memory and regulatory T cells). 
2. To explore whether inhibition of both PD-1 and IDO-1 in combination will restore 
T cell activation and function, peripheral blood mononuclear cells (PBMCs) will be 
isolated and cryopreserved. Assays of the functional status of effector T cells will 

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be performed, including, but not limited to assays for interferon-gamma (IFN-y) 
and granzyme B. This assay will use a non-specific stimulus including but not 
limited to anti-CD3 and anti-CD28 and would allow for the comparison of the effect 
of PD-1 blockade alone on T cell function. 
 
b.)  Soluble Factors: Baseline and on-treatment serum levels of chemokines, 
cytokines and other immune mediators will be assessed by techniques that may 
include but are not limited to ELISA or multiplex assays. Analytes may include, 
but are not limited to IFN-y, IL-12, IL-10, soluble MICA, C-reactive protein, soluble 
PD-1 and soluble PD-L1. 
 
c.) Next generation sequencing for T-cell receptor clonality in peripheral blood: 
Samples will be analyzed using highthroughput sequencing of the variable 13-chain 
of the T cell receptor (TCR) to characterize the expansion and clonality of the T- 
cell repertoire in peripheral blood mononuclear cells. 
 
 
 
Table 4. Exploratory Biomarkers 
 
Biomarker name 
Assay 
Tissue/Body Fluid Tested 
and Timing of Assay 
Peripheral Blood Cells 
1. 
 Flow cytometric analyses to 
evaluate activated (HLA- 
DR+) and memory 
(CD45RA-) T cells 
2. 
 Flow cytometric analyses to 
evaluated peripheral blood 
leucocytes including 
CD4/CD25/FoxP3, 
CD4/CD8/CD45RA/CCR7, 
CD4/CD8/LAG3/PD-1/PD- 
L1, CD4/CD8/CD137/IDO-1 
3. 
Functional Status of 
effector T cells assays for 
interferon-gamma and 
granzyme B. 
4. 
T-cell subsets and their 
activation status (CDS+ 
Teff/Treg ratio and ICOS 
expression 
Blood (Weeks 1(before treatment), 4, 7, 
13, 22 and off-study) 
Soluble Factors, Serum 
Treatment modulation of serum 
levels of chemokines, cytokines and 
other immune mediators by ELISA 
or other multiplex-based assay 
methods. Primary analysis includes 
interferon-gamma and IL-10. 
Blood Serum (Weeks 1(before 
treatment), 4, 7, 13, 22 and off-study) 
Characterization of Tumor 
infiltrating lymphocytes 
1. IHC to assess number and 
composition of immune 
infiltrates to define immune 
cell subsets present within 
Tumor biopsy at: 
Baseline 

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tumor before and after 
exposure to treatment. 
CD3, CD4, CD8 and 
FOXP3 will be evaluated. 
2. 
Immune cell phenotyping of 
freshly isolated TIL to 
evaluate Treg/Teff ratio 
(CD8+/FoxP3+ cells) and 
activations markers (ICOS, 
PD-1, CD69). 
Week 7 
Progression (optional) 
100- 1, PD-L1 & kynurenine 
expression by IHC 
Qualtek immunohistochemistry- 
based assay for PD-L1 
Tumor biopsy at: 
Baseline 
Week 7 
Progression (optional) 
Tumor Biopsy neoantigen 
analysis 
Fresh frozen tumor biopsy will be 
utilized for massively parallel whole 
exome sequencing. Available 
databases such as SNP effect 
(http://snpeff.sourceforge.neUwill be 
used to determine which mutations 
are in coding regions and will affect 
amino acid sequence. NetMHC and 
the Immune Epitope Database will 
be utilized to predict MHC Class I 
binding and T cell interactions, 
respectively. 
Tumor biopsies at baseline 
Paired normal peripheral blood 
mononuclear cells at baseline 
T-cell receptor sequencing 
Highthroughput sequencing of the 
variable (3 chain of the T-cell 
receptor. 
Tumor biopsy at: 
Baseline 
Week 7 
Progression (optional) 

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study 
 
 
 
 
 
 
 
 
 
I' 
IIBiopsy 
X 
X 
X 
X 
 
X 
ECHO 
X 
X 
X 
ECGF 
X 
X 
Pregnancy TestE 
X 
 
X 
X 
X 
X 
Research blood 
tests0 
X 
X 
X 
X 
X 
Routine laboratory 
testsc 
 
X 
X 
X 
X 
X 
Physical exam 
 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
concomitant 
medications 
 
X 
Pathologic 
Confirmation at 
study siteJ 
 
 
 
 
 
 
 
X 
Informed consent 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
EpacadostatA 
 
 
 
Wk1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 5. Study calendar - 
 
A. Epacadostat will be administered twice daily, orally, continuously from day 1-21 (inclusive) of each 
treatment cycle, each treatment cycle consists of 21 days 
B. Pembrolizumab will be administered once at a dose of 200mg, intravenously, on day 1 of cycle 1 and 
every 3 weeks (±3 days) thereafter 
C. Routine laboratory tests at screening, day 1 of cycle 1 and then prior to every scheduled treatment 
visit(± 3 days) thereafter. All routine blood samples should be obtained prior to the daily dose 
epacadostat and/or pembrolizumab. routine laboratory tests include: cbc with differential, PT/INR 
and a PTT, comprehensive metabolic panel, magnesium and phosphorus, fT4, TSH, T3, lipase and 
amylase 
D. Research blood samples will be collected at week 1 (before treatment), 4, 7,13, 22 and at the date of 
the off study visit(± 3 days) 

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E. Serum pregnancy test (Female subject of childbearing potential should have a negative serum 
pregnancy at screening and within 72 hours prior to receiving the first dose of both study drugs and 
at the off study visit.) 
F.  An ECG will be performed at baseline, week 8, every 8 weeks subsequently((± 1 week window) and 
at the off study visit((± 1 week window) 
 
G. Standard Imaging studies will be performed at baseline, week 8 and every 8 weeks subsequently (± 
1 week window) until 56 weeks, and then every 12 weeks thereafter or as per the discretion of the 
treating investigator and will include CT of chesUabdomen/pelvis and MRI of the affected area if 
deemed necessary by the study investigator. 
H. Optional biopsy at progression. 
I. 
The off study visit will take place 30 days(+/- 7 days) after the last dose of study therapy 
J. Pathologic confirmation of the presence of sarcoma at the study site may take place during or before 
the screening period. 
 
11.0 
TOXICITIES/SIDE EFFECTS 
Toxicity will be assessed using the NCI CTCAE (version 4.03). 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm). 
 
Patients who have received at least one dose of the epacadostat and/or pembrolizumab are 
available for the safety assessment. Patients who discontinue the study before receiving their first 
dose of the study treatments will not be available for safety assessment and should be replaced. 
Patients whose treatment is interrupted or permanently discontinued due to an adverse 
event or clinically significant laboratory value must be followed until resolution or stabilization 
of the event. 
A dose delay >6 weeks from the date of the planned dose (i.e., approximately 9 weeks since 
the previous dose) may require the patient to be discontinued from the study, with exception 
of patients who undergo surgery. A dose delay >6 weeks from the date of the planned dose 
(i.e., approximately 9 weeks since the previous dose) due to the occurrence of an adverse 
event that is considered related to epacadostat and/or pembrolizumab, the subject should 
be taken off study treatment. 
11.1 
Adverse Event Characteristics and Definitions 
11.1.1 Definition of an AE 
Any untoward medical occurrence in a subject or clinical investigation subject, temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of a medicinal product. For marketed medicinal products, this also includes failure 
to produce expected benefits, abuse, or misuse. Examples of events meeting the definition 
of an AE include: 

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• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or grade of the condition 
• New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study 
• Signs, symptoms, or the clinical sequelae of a suspected interaction 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE). 
Events that do not meet the definition of an AE include: 
• Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE. 
• Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease or condition present or 
detected at the start of the study that do not worsen. 
• The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
subject's condition. 
11.1.2 Definition of a SAE 
A serious adverse event is any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe. 
c. Requires hospitalization or prolongation of existing hospitalization 
NOTE: In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician's office or out- 
patient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 

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serious. When in doubt as to whether "hospitalization" occurred or was necessary, 
the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an SAE. 
d. Results in disability/incapacity, or 
NOTE: The term disability means a substantial disruption of a person's ability to 
conduct normal life functions. This definition is not intended to include experiences of 
relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may 
interfere or prevent everyday life functions but do not constitute a substantial 
disruption. 
e. Is a congenital anomaly/birth defect. 
f. All grade 4 laboratory abnormalities 
g. Specific liver function abnormalities and pregnancy 
Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other outcomes 
listed in the above definition. These should also be considered serious. Examples of such 
events are invasive or malignant cancers, intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse. 
11.1.3 Laboratory and Other Safety Assessment Abnormalities Reported as AEs and 
SAEs 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis), or other 
safety assessments (e.g., ECGs, radiological scans, vital signs measurements) including 
those that worsen from baseline, and events felt to be clinically significant in the medical and 
scientific judgment of the investigator are to be recorded as an AE or SAE, in accordance 
with the definitions provided. 
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject's condition, are not to be reported as AEs or SAEs. 
11.1.4 Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
SAEs 

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Disease Related Events are events (serious or non-serious) anticipated to occur in the 
study population due to the underlying disease. These could include overall disease 
progression or pain or discomfort caused by growing tumors. Such events do not meet the 
definition of an Adverse Event unless assessed to be more severe than expected for the 
subject's condition. 
An event which is part of the natural course of the disease under study (i.e., disease 
progression) does not need to be reported as an SAE. Deaths and hospitalizations related 
to disease (other than for study procedures) during the study period and 30 days after 
completion must be reported as SAEs. 
Disease Related Events that would qualify as an Adverse Event or Serious Adverse Event: 
 
• 
An event based on the underlying disease that is worse than expected as assessed by 
the investigator for the subject's condition 
The investigator believes there is a causal relationship between the investigational 
product33/study treatment/protocol required therapies and disease worsening 
 
11.2 Risks, toxicities and adverse drug reactions - Epacadostat 
Epacadostat dosing likely will produce side effects, and not all side effects may be known. 
Specific identified risks and potential risks are highlighted below, as well as adverse drug 
reactions observed in clinical trials. 
See the investigation brochure for complete list of possible adverse events related to 
epacadostat. 
11.2.1 Identified Risks - Epacadostat 
Monotherapy 
In the Phase 1 clinical study in subjects with refractory solid tumors (INCB 24360-101), 
epacadostat was well tolerated at doses ranging from 50 mg QD to 700 mg BID. Twenty- 
five (48.1%) of the 52 subjects administered epacadostat had a single SAE. The most 
frequently reported SAEs were disease progression (4 subjects, 7.7%), followed by 
abdominal pain, nausea, and hypoxia (3 subjects each, 5.8%). Treatment-emergent 
adverse events (TEAEs) were reported in all subjects. The most commonly reported 
treatment-related TEAEs were fatigue and nausea (25 subjects, 48.1%). The incidence 
and severity of fatigue were not dose-related. Two DLTs occurred: 1 DLT of radiation 
pneumonitis at the 300 mg dose level and 1 DLT of fatigue at the 400 mg BID dose level. 
Data from Study INCB 24360-210 (600 mg BID of epacadostat versus 20 mg BID of 
tamoxifen in Stage Ill or IV epithelial ovarian cancer) are available as of the data cutoff on 
29 OCT 2014. At the time of the cutoff, 42 subjects were enrolled (22 in the 
epacadostat-treated group and 20 in the tamoxifen-treated group). Based on the 
preliminary unaudited data through that date, no subject had an AE leading to death. Two 

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subjects (4.8%) had an SAE. One SAE was reported in the epacadostat group (abdominal 
pain), and 1 SAE was reported in the tamoxifen group (ascites). Treatment-emergent AEs 
were reported in 32 subjects (76.2%) with 17 subjects (77.3%) in the epacadostat group 
and 15 subjects (75.0%) in the tamoxifen group. Fatigue was the most frequently reported 
TEAE in the epacadostat group (8 subjects, 36.4%), followed by nausea (6 subjects, 
27.3%) and abdominal distention, constipation, and vomiting (4 subjects each, 18.2%). 
This study has been terminated by lncyte. No new safety concerns with epacadostat were 
identified. 
 
Combination Therapy 
Preliminary data from Study INCB 24360-201 (evaluating the combination of epacadostat 
and ipilimumab) suggest that epacadostat 50 mg BID is well tolerated with ipilimumab 
based on evaluation of subjects in 50 mg BID continuous cohort. Only 4 of the 18 
evaluable subjects reported DLTs, which included a Grade 3 diarrhea (n = 1), a Grade 3 
ALT/AST elevation (n = 1), a Grade 3 colitis (n = 1), and a Grade 3 pneumonitis (n = 1). 
One of the 9 subjects enrolled in 50 mg BID intermittent cohort reported Grade 3 colitis as 
a DLT. The most common irAEs with Grade 3 were AST elevation and colitis (n = 4, 
9.5% each) and ALT elevation (n = 3, 7.1%). Other irAEs with Grade 3 observed in only 
1 subject were idiopathic thrombocytopenic purpura, diarrhea, acute renal failure, 
pneumonitis, pruritus, and rash (2.4% each). Common treatment emerging AEs reported 
included fatigue (n = 29, 69%), constipation and nausea (n = 13, 31% each), decreased 
appetite and headache (n = 11, 26% each), and vomiting (n = 10, 24%). This study is 
currently closed to enrollment. 
The initial evaluation of epacadostat 300 mg BID in combination with ipilimumab was 
terminated because of the occurrence of Grade 3 or 4 alanine aminotransferase 
(ALT)/aspartate aminotransferase (AST) elevation in 5 of 7 subjects treated at this dose. 
The most common Grade 1 or 2 AEs reported at 25 mg BID (N = 8) were fatigue (n = 6, 
75%), abdominal pain (n = 6, 75%), headache (n = 5, 62.5%), rash (n = 4, 50%), nausea 
(n = 4, 50%), cough (n = 4, 50%), and diarrhea (n = 3, 37.5%). Grade 3 or 4 AEs that 
occurred in > 1 subject at 25 mg BID were colitis (Grade 3) and elevated alkaline 
phosphatase (Grade 3), with n = 2 each (25%). 
As of the data cut off (28 MAR 2016), 60 subjects have been enrolled in INCB 24360-202 
(epacadostat 25 mg, 50 mg, 100 mg, and 300 mg BID in combination with 
pembrolizumab). Based on the preliminary unaudited safety data (unaudited), no Grade 4 
treatment related AEs were reported. Three subjects (5%) discontinued for a treatment- 
related AE: Grade 3 arthralgia, Grade 3 AST elevation, and Grade 2 nervous system 
disorder. No treatment-related deaths occurred. Treatment-emergent AEs were reported 
in 44 subjects (73.0%). The most frequently reported AEs were rash (27%) followed by 
fatigue (23%). Rash includes the preferred terms rash, rash generalized, rash 
maculopapular, rash pruritic, and rash follicular. As of the data cutoff (28 MAR 2016), 18 
subjects in the Phase 1 portion of the INCB 24360-202 study and 119 subjects in the 
Phase 2 portion of the study have received combination treatment with pembrolizumab 
and the 100 mg BID dose of epacadostat, the recommended dose for the Phase 3 study. 
The data for Phase 2 presents a subset of 99 subjects who had at least 1 month of safety 
data. The most frequently reported ( 15%) AEs of any grade for the combined Phase 1 

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and Phase 2 subjects treated with epacadostat 100 mg BID were fatigue (35.0%), 
constipation (24.8%), diarrhea (20.5%), nausea (20.5%), vomiting (18.8%), pyrexia 
(16.2%), and dyspnea (15.4%). Fatigue (13.7%) and rash (11.1%; including the preferred 
terms rash, rash maculopapular, rash generalized, and rash macular) were the only 
treatment-related AEs reported in > 10% of subjects. Treatment-related AEs of rash were 
only reported in Phase 2. Treatment-related AEs 2: Grade 3 occurring in more than 1 subject 
who received epacadostat 100 mg BID in Phase 1 or Phase 2 included rash (5 subjects, 
4.3%) and dehydration, lipase increased, AST increased, and nausea (2 subjects [1.7%] 
each). Theoretically, inhibition of IDO1 could cause an increase in serotonin levels that 
could precipitate a cluster of AEs termed serotonin syndrome (SS) when administered 
alone or in combination with other serotonergic agents. This rare syndrome has been 
associated with some monoamine oxidase inhibitors (MAOls) and combinations of 
serotonergic drugs. The clinical manifestations of SS range from barely perceptible to 
lethal; onset is rapid (within 12 hours of drug[s] administration). Based on preliminary 
studies in the rat, concentrations of epacadostat in the cerebrospinal fluid were below the 
quantifiable limit of detection (2 nM) after IV dosing, and total brain homogenate 
concentrations were approximately 15% of corresponding plasma concentrations. 
Therefore, epacadostat exhibits apparent limited penetration across the blood-brain barrier 
and is likely not associated with significant effects on tryptophan metabolism in the brain 
that might affect brain serotonin levels. In the INCB 24360-201 study, 12 of the 48 
subjects enrolled as of 29 OCT 2014 received concomitant treatment with an SSRI and 
epacadostat, and O of 12 subjects exhibited SS. Although this represents a hypothetical 
risk only and has not been observed in clinical studies of epacadostat, use of MAOls will 
be prohibited during the study, and all subjects will be assessed for SS symptoms at an 
appropriate timeframe after dose administration. Subjects will be provided with an 
informative subject leaflet describing the signs and symptoms of the syndrome along with 
instructions to seek immediate medical care if any of these signs or symptoms is observed. 
 
 
Risk: Serotonin Syndrome 
 
Procedure for Subjects Exhibiting Serotonin Syndrome 
There is a theoretical chance that epacadostat could cause an increase in serotonin levels 
in the brain that might trigger SS (http://www.nejm.org/doi/full/10.1056/NEJMra041867) 
when administered in combination with other serotonergic agents. This syndrome has 
been most closely associated with use of MAOls, Demerol®, linezolid, or methylene blue; 
all of these agents are prohibited during the study. Selective serotonin reuptake inhibitors 
(SSRls) and serotonin/norepinephrine reuptake inhibitors (SNRls) are permitted in the 
study. The following procedures will be implemented if subjects exhibit the 
signs/symptoms of SS described in Table 6, including tremor; hyperreflexia; and 
spontaneous, ocular, or inducible clonus, together with agitation, fever, diaphoresis, or 
muscle rigidity: 
• 
Immediately interrupt epacadostat administration. Administration of 
pembrolizumab may continue. 

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• 
Immediately interrupt any SSRI or SNRI administration. 
• 
Provide appropriate medical management of the subject until all signs/symptoms 
are resolved (eg, IV fluids and/or sympathomimetic amines for hypotension, 
benzodiazepines for agitation, administration of 5-hydroxytryptamine 
antagonists, such as cyproheptadine). 
• 
If subject chooses to remain in the study, restart treatment with epacadostat 
after the SSRI or SNRI has been discontinued, no sooner than 5 half-lives have 
elapsed for the specific SSRI or SNRI in question and after resolution of 
signs/symptoms of SS. The SSRI or SNRI treatment MAY NOT be restarted. 
• 
If subject chooses to withdraw from the study or must restart treatment with 
SSRI or SNRI, the subject should be scheduled for a follow-up visit. Treatment 
with SSRI or SNRI may be initiated 2 weeks after resolution of signs and 
symptoms of SS. 
Table 6: 
Sign and Symptoms of Serotonin Syndrome 
 
Tremor and hyperreflexia 
Spontaneous clonus 
Muscle rigidity, temperature> 38°C (100.4°F), and either ocular clonus or 
inducible clonus 
Ocular clonus and either agitation or diaphoresis 
Inducible clonus and either agitation or diaphoresis 
 
Adverse Drug Reactions - Epacadostat 
As of 29 Oct 2016, 898 unique subjects have been exposed to INCB024360 in lncyte 
sponsored studies as monotherapy (149 subjects) and/or in combination with checkpoint 
inhibitors (anti-PD-1 targeted therapy [543 subjects]); PD-L1-targeted therapy (124 
subjects); anti-CTLA-4 targeted therapy (50 subjects); and a JAK inhibitor with JAK1 
selectivity (32 subjects). 
Table 7. contains a list of expected treatment-emergent adverse events for epacadostat 
monotherapy 
Table 7: Expected Treatment-Emergent Adverse Events for Epacadostat 
Monotherapy 

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System. Organ Class 
MedDRA Preforred Term 
OveraU Frequency 
All Grades 
N(%} 
G1·ad1'3 or Gr:acle 4 
N{%) 
Frequency of 
Serious E,,ents 
N(%>) 
Gasfroiotl'sfinal di<Jordl't·s 
Dianhea 
Very common -19 (12. .8) 
- 
- 
Nausea 
Very common- 44 (29.5) 
Common-5 (3.4) 
Connnon.- 3 (2.0) 
Vomiting 
Vei:ycommon-27 (18.1) 
Common - 4 ,(2.7) 
Common - 2 (1.3) 
Gen.eraJ dirorde1·s and adminisfration. site c,onditions 
Asthenia 
Comm.on - 2 (L3) 
- 
- 
Fatigue 
Very common- 50 (33_6) 
Common - 6 (4.0) 
- 
lnves1ti.gatioos 
Al.mine aminotransferase increased 
Common - 4 (2.7) 
Common - 2 (1.3) 
- 
Aspartate aminotnmsfense incre.as:ed 
Common - 4 (2_7) 
Uncommon - 1 (0.7) 
- 
1\{usculoskeletal and c .ollD.ectrive tissue disorders 
Arthralgia 
Co:mmon - 6 (4.0) 
- 
- 
Skin and subcutaneous tissue diso ,rders 
Pruritus 
Common - 4 (2_7) 
- 
- 
Rash 
Common - 5 (3.4) 
- 
- 
Rash maculo-papular 
Common - 5 (1.4) 
Common - 2 (1.3) 
- 
Rash papnlar 
Common - 2 (1-3) 
- 
- 
'"-" =:not expected. 
 
Table 8. Expected TEAEs for Epacadostat and Anti-PD-1 Combination Therapy 
(n=543) 
 
 
 
System. Organ Class 
M:l'dDRA P:n fen:ed Term 
Overall Fl·equency 
All Grades 
- (%) 
Grade 3 or G1·ade 4 
(%) 
Fn:iquency of Serious 
Events 
- (%) 
Endocrine cli.sm·der:s 
Adcenal insufficiency 
Unco.mmon-2 (0.4) 
Uncomm.011-  I (0.2) 
- 
Hypothyroidism 
Common-16 (4.8) 
- 
- 
G3sh·ointestinal disorders 
DiMrhea 
Verycommon-103 (19.0) 
Common - 8 (1.5) 
Uncommon - 4 (0.7) 
Nausea 
VeryCOllllllOll- 145(26.7) 
Common - 9 (1.7) 
Comm.on-13 (2.4) 
Vomiting 
Veryaommon-101 (l&.6) 
Common-10 (L&) 
Common - 9 {L 7) 
GeneraJ disordea·s and 3 dminisjration site conditions 
Astheni.a 
Comwon-31 (:'.i7) 
Common- 7 (1.3) 
Common- 6(1.1) 
Fatigue 
Veryaommon-230 (42.4) 
Common-11 (20) 
Uncommon - 5 ,(0.9) 

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Preliminary safety results for the phase I study INCB 24360-202, of epacadostat in 
combination with pembrolizumab) were presented in a poster presentation and are 
presented in Table 9; these data have a data cutoff of 07 JUL 2016.50 
Phase 1 has completed enrollment with a total of 62 subjects. Subjects were treated with 
epacadostat 25 mg BID (n = 4), 50 mg BID (n = 20), 100 mg BID (n = 18), and 300 mg BID 
(n = 20) in combination with pembrolizumab 2 mg/kg or 200 mg IV every 3 weeks. 
Treatment-related AEs were reported in 50 subjects (81%). Table 9 presents treatment- 
related AEs 
5% or Grade 3/4 AEs in 
1 subject in the Phase 1 portion of the study. The 
most frequently reported treatment-related AEs were fatigue and rash (29% each). Rash 
includes the preferred terms rash, rash erythematous, rash generalized, rash maculo- 
papular, rash pruritic, and rash follicular. The most frequently reported Grade 3 
treatment-related AE was rash (8%). 
Five subjects (8%) discontinued for a treatment-related AE: Grade 3 arthralgia, Grade 3 
AST increased/Grade 2 ALT increased, Grade 3 lipase increased, Grade 3 aseptic 
meningitis, and Grade 2 nervous system disorder. No treatment-related deaths occurred 
as of 07 JUL 2016. 

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Table 9: Related TEAEs 
5% or Grade 3 I 4 TEAEs in 
1 subject in the phase I 
population in study INCB 24360-202 
 
 
The combination of epacadostat and pembrolizumab is under investigation in the setting of 
melanoma, in a phase Ill study, INCB 24360-301. The recommended phase Ill dose for this 
study was based on findings from phase I and phase II of study INCB 24360-202. The 
preliminary safety results summarized below are the basis for the initial recommended dose 
in melanoma of epacadostat 100 mg BID in combination with pembrolizumab 200 mg IV 
Q3W; these data have a data cutoff of 28 MAR 2016. 
Eighteen subjects in the Phase 1 portion of the study and 119 subjects in the Phase 2 
portion of the study have received at least 1 dose of combination treatment with 
pembrolizumab and the 100 mg BID dose of epacadostat. The data for Phase 2 provides a 
subset of 99 subjects who had at least 1 month of safety data. Subjects were included in 
the data presented below if they were enrolled and received at least 1 dose of study 
medications on or before 28 FEB 2016 with a data cutoff of 28 MAR 2016 for all subjects. 
Of the 119 subjects, 115 had the following cancers: melanoma (n = 7), PD-L1-positive 
NSCLC (n = 5), PD-L1-negative/indeterminate NSCLC (n = 4), transitional cell carcinoma 
of the genitourinary tract (n = 21), TNBC (n = 24), ovarian cancer (n = 35), DLBCL (n = 3), 
and SCCHN (n = 16). At the time of the data cutoff, the disease history information for the 
4 remaining subjects had not yet been specified in the database. 

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Table 10 presents an overall summary of TEAEs for subjects administered epacadostat 100 
mg BID in the Phase 1 or Phase 2 cohorts of the study. 
Table 10: Summary of Treatment-Emergent Adverse Events in Study INCB 24360-202 
(Data Cutoff 28 MAR 2016) 
 
For subjects receiving 100 mg BID in the Phase 1 and Phase 2 portion of the study, 3 
subjects died because of AEs. One subject with SCCHN was admitted to the intensive care 
unit with worsening mental status and prior aspiration pneumonia, and the subject had upper 
airway hemorrhage and died. A second subject with metastatic urothelial cancer was found 
unresponsive at home and had been hypoxic for an estimated 35 minutes. The subject was 
admitted to the hospital and placed on a ventilator (Grade 4 respiratory distress). The subject 
was later removed from life support and died. A third subject with ovarian cancer reported 
dehydration and failure to thrive (Grade 4) as AEs with fatal outcome. 
Treatment-related TEAEs per investigator occurred in 16 subjects (88.9%) in Phase 1 and 
46 subjects (46.5%) in Phase 2. In Phase 2, treatment-related rash (including the preferred 
terms rash, rash maculopapular, rash generalized, and rash macular) occurred in 13 
subjects (13.1%). Other frequently reported treatment-related TEAEs in Phase 2 were 
fatigue (11.1%); pyrexia (6.1%); and nausea, AST increased, pruritus, and vomiting (4.0% 
each). Diarrhea, chills, ALT increased, decreased appetite, and arthralgia were each 
observed in 3 subjects (3.0%). Frequently reported (> 15%) treatment-related AEs in 
Phase 1 were fatigue (27.8%), AST increased (22.2%), diarrhea (22.2%), vomiting 
(22.2%), arthralgia (22.2%), nausea (16.7%), and ALT increased (16.7%). Treatment- 
related TEAEs 
Grade 3 occurring in more than 1 subject in Phase 2 included rash (5.1%) 
and dehydration (2.0%). In Phase 1, the only treatment-related TEAE Grade 3 occurring 
in more than 1 subject was lipase increased in 2 subjects. 
The overall incidence of SAEs was 23.1% subjects treated with epacadostat 100 mg BID, 

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with 44.4% occurring in Phase 1 subjects and 19.2% occurring in Phase 2 subjects. The 
overall incidence of treatment-related SAEs was 6.8% subjects treated with epacadostat 
100 mg BID, with 16.6% occurring in Phase 1 subjects and 5% occurring in the Phase 2 
subjects. 
Adverse events that were treatment-related and potentially immune-related were observed 
less frequently in the 99 subjects in Phase 2 in this analysis, except for rash (13.1%) and 
pruritus (4.0%), compared with the 18 Phase 1 subjects. Of note, no cases of pneumonitis, 
colitis, or adrenal insufficiency were observed in either the Phase 1 or 2 subjects receiving 
epacadostat 100 mg BID in combination with pembrolizumab (see Table 11). As of 28 
MAR 2016, the Phase 1 group had 1 additional immune-related AE, a single report of 
Grade 1 hypothyroidism. 
Liver enzyme abnormalities, which may be symptoms of a potential immune-mediated liver 
event, were reported as AST increased in 4 subjects (22%) in Phase 1 and 4 subjects 
(4.0%) in Phase 2. Three (2.6%) of 8 AST increases were Grade 3. Alanine 
aminotransferase increased was reported in 3 subjects (16.7%) in Phase 1 and 3 subjects 
(3.0%) in Phase 2 with only 1 (0.9%) Grade 3 ALT increase. Blood alkaline phosphatase 
increased was reported in 1 subject (5.6%; Grade 2) in Phase 1 and none in Phase 2. Two 
subjects required dose interruptions due to ALT or AST increases and 2 subjects required 
dose discontinuation due to ALT or AST increases. One of the 2 subjects who 
discontinued treatment due to ALT/AST increases received corticosteroids. 
Although the incidence of AEs is lower in the subjects in the Phase 2 portion of the study, it 
is important to note that subjects in the Phase 1 portion of the study have had a longer 
duration of exposure (mean 222.0 days vs 62.0 days). 
Table 11: Summary of Treatment-Related Potential Immune-Related Adverse Events at 
100 mg BID (Data Cutoff 28 MAR 2016) 
 
With the additional 5 months of follow-up for the subjects treated with 100 mg BID in Phase 
1 (median duration of treatment= 222 days), the AE profile remains similar to that originally 
described. No new safety trends were observed, and the data supports the selected dose of 

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epacadostat 100 mg BID in combination with pembrolizumab 200 mg IV Q3W in the Phase 
3 INCB 24360-301 study. 
 
 
11.3 - Risks, toxicities and adverse drug reactions - Pembrolizumab 
 
 
Pembrolizumab dosing likely will produce side effects, and not all side effects may be 
known. Specific identified risks and potential risks are highlighted below, as well as adverse 
drug reactions observed in clinical trials: 
Information extracted from Pembrolizumab Prescribing Information, available at: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125514lbl.pdf 
11.3.1 - Identified risks - Pembrolizumab 
 
 
Risk: Immune-Mediated Pneumonitis 
Pneumonitis occurred in 12 (2.9%) of 411 melanoma patients, including Grade 2 or 3 cases 
in 8 (1.9%) and 1 (0.2%) patients, respectively, receiving pembrolizumab. The median time 
to development of pneumonitis was 5 months (range 0.3 weeks-9.9 months). The median 
duration was 4.9 months (range 1 week-14.4 months). Five of eight patients with Grade 2 
and the one patient with Grade 3 pneumonitis required initial treatment with high-dose 
systemic corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) 
followed by a corticosteroid taper. The median initial dose of high-dose corticosteroid 
treatment was 63.4 mg/day of prednisone or equivalent with a median duration of treatment 
of 3 days (range 1-34) followed by a corticosteroid taper. Pneumonitis led to discontinuation 
of pembrolizumab in 3 (0.7%) patients. Pneumonitis completely resolved in seven of the 
nine patients with Grade 2-3 pneumonitis. 
 
Risk: Immune-Mediated Colitis 
Colitis (including microscopic colitis) occurred in 4 (1%) of 411 patients, including Grade 2 
or 3 cases in 1 (0.2%) and 2 (0.5%) patients, respectively, receiving pembrolizumab. The 
median time to onset of colitis was 6.5 months (range 2.3-9.8). The median duration was 
2.6 months (range 0.6 weeks-3.6 months). All three patients with Grade 2 or 3 colitis were 
treated with high-dose corticosteroids (greater than or equal to 40 mg prednisone or 
equivalent per day) with a median initial dose of 70 mg/day of prednisone or equivalent; the 
median duration of initial treatment was 7 days (range 4-41), followed by a corticosteroid 
taper. One patient (0.2%) required permanent discontinuation of pembrolizumab due to 
colitis. All four patients with colitis experienced complete resolution of the event. 
 
Risk: Immune-Mediated Hepatitis 

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Hepatitis (including autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients, including a 
Grade 4 case in 1 (0.2%) patient, receiving pembrolizumab. The time to onset was 22 days 
for the case of Grade 4 hepatitis which lasted 1.1 months. The patient with Grade 4 hepatitis 
permanently discontinued pembrolizumab and was treated with high-dose (greater than or 
equal to 40 mg prednisone or equivalent per day) systemic corticosteroids followed by a 
corticosteroid taper. Both patients with hepatitis experienced complete resolution of the 
event. 
 
Risk: Immune-Mediated Hypophysitis 
Hypophysitis occurred in 2 (0.5%) of 411 patients, consisting of one Grade 2 and one Grade 
4 case (0.2% each), in patients receiving pembrolizumab. The time to onset was 1.7 months 
for the patient with Grade 4 hypophysitis and 1.3 months for the patient with Grade 2 
hypophysitis. Both patients were treated with high-dose (greater than or equal to 40 mg 
prednisone or equivalent per day) corticosteroids followed by a corticosteroid taper and 
remained on a physiologic replacement dose. 
 
Risk: Renal Failure and Immune-Mediated Nephritis 
Nephritis occurred in 3 (0.7%) patients, consisting of one case of Grade 2 autoimmune 
nephritis (0.2%) and two cases of interstitial nephritis with renal failure (0.5%), one Grade 3 
and one Grade 4. The time to onset of autoimmune nephritis was 11.6 months after the first 
dose of pembrolizumab (5 months after the last dose) and lasted 3.2 months; this patient 
did not have a biopsy. Acute interstitial nephritis was confirmed by renal biopsy in two 
patients with Grades 3-4 renal failure. All three patients fully recovered renal function with 
treatment with high-dose corticosteroids (greater than or equal to 40 mg prednisone or 
equivalent per day) followed by a corticosteroid taper. 
 
Risk: Immune-Mediated Hyperthyroidism and Hypothyroidism 
Hyperthyroidism occurred in 5 (1.2%) of 411 patients, including Grade 2 or 3 cases in 2 
(0.5%) and 1 (0.2%) patients, respectively, receiving pembrolizumab. The median time to 
onset was 1.5 months (range 0.5-2.1). The median duration was 2.8 months (range 0.9 to 
6.1). One of two patients with Grade 2 and the one patient with Grade 3 hyperthyroidism 
required initial treatment with high-dose corticosteroids (greater than or equal to 40 mg 
prednisone or equivalent per day) followed by a corticosteroid taper. One patient (0.2%) 
required permanent discontinuation of pembrolizumab due to hyperthyroidism. All five 
patients with hyperthyroidism experienced complete resolution of the event. Hypothyroidism 
occurred in 34 (8.3%) of 411 patients, including a Grade 3 case in 1 (0.2%) patient, receiving 
pembrolizumab. The median time to onset of hypothyroidism was 3.5 months (range 0.7 
weeks-19 months). All but two of the patients with hypothyroidism were treated with long- 
term thyroid hormone replacement therapy. The other two patients only required short-term 
thyroid hormone replacement therapy. No patient received corticosteroids or discontinued 
pembrolizumab for management of hypothyroidism. 

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Risk: Infusion reactions 
 
Pembrolizumab infusion reactions may consist of fever, chills/rigor, nausea, pruritus, 
angioedema, hypotension, headache, bronchospasm, urticaria!, rash, vomiting, myalgia, 
dizziness, or hypertension. Severe reactions may include acute respiratory distress 
syndrome, myocardial infarction, ventricular fibrillation, and cardiogenic shock. Patients 
should be closely monitored for such reactions. Guidelines for patients who experience an 
infusion related or allergic reaction during or after infusion with pembrolizumab are detailed 
in Table 17.. 
Risk: Other Immune-Mediated Adverse Reactions 
Other clinically important immune-mediated adverse reactions can occur. The following 
clinically significant, immune-mediated adverse reactions occurred in less than 1% of 
patients treated with pembrolizumab: exfoliative dermatitis, uveitis, arthritis, myositis, 
pancreatitis, hemolytic anemia, partial seizures arising in a patient with inflammatory foci in 
brain parenchyma, and adrenal insufficiency. Other adverse events of interest have been 
reported in patients after treatment with pembrolizumab including myocarditis, Stevens 
Johnson Syndrome (SJS) and Toxic Epidernal Necrolysis (TEN). Of note fatal outcomes 
have been reported in some of the cases of SJS and TEN that occurred in patients treated 
with pembrolizumab. 
 
Across clinical studies with pembrolizumab in approximately 2000 patients, the following 
additional clinically significant, immune-mediated adverse reactions were reported in less 
than 1% of patients: myasthenic syndrome, optic neuritis, and rhabdomyolysis. 
 
11.3.2 - Adverse Drug Reactions - Pembrolizumab 
 
Adverse drug reactions observed in an uncontrolled, open-label, multiple cohort trial in which 
411 patients with unresectable or metastatic melanoma received pembrolizumab at either 2 
mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks (Trial 1). The median duration of 
exposure to pembrolizumab was 6.2 months (range 1 day to 24.6 months) with a median of 
10 doses (range 1 to 51). 
 
Pembrolizumab was discontinued for adverse reactions in 9% of the 411 patients. Adverse 
reactions, reported in at least two patients that led to discontinuation of pembrolizumab were: 
pneumonitis, renal failure, and pain. Serious adverse reactions occurred in 36% of patients 
receiving pembrolizumab. The most frequent serious adverse drug reactions reported in 2% 
or more of patients in Trial 1 were renal failure, dyspnea, pneumonia, and cellulitis. Table 
12 presents adverse reactions identified from analyses of the 89 patients with unresectable 
or metastatic melanoma who received pembrolizumab 2 mg/kg every three weeks in one 

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cohort of Trial 1. This cohort of Trial 1 excluded patients with severe immune-related toxicity 
related to ipilimumab, defined as any Grade 4 toxicity requiring treatment with corticosteroids 
or Grade 3 toxicity requiring corticosteroid treatment (greater than 10 mg/day prednisone or 
equivalent dose) for greater than 12 weeks; a medical condition that required systemic 
corticosteroids or other immunosuppressive medication; a history of pneumonitis or 
interstitial lung disease; or any active infection requiring therapy, including HIV or hepatitis 
B or C. Of the 89 patients in this cohort, the median age was 59 years (range 18-88), 33% 
were age 65 years or older, 53% were male, 98% were white, 44% had an elevated LOH, 
84% had Stage M1c disease, 8% had brain metastases, and 70% received two or more prior 
therapies for advanced or metastatic disease. The median duration of exposure to 
pembrolizumab was 6.2 months (range 1 day to 15.3 months) with a median of nine doses 
(range 1 to 23). Fifty-one percent of patients were exposed to pembrolizumab for greater 
than 6 months and 21% for greater than 1 year. Pembrolizumab was discontinued for 
adverse reactions in 6% of the 89 patients. The most common adverse reactions (reported 
in at least 20% of patients) were fatigue, cough, nausea, pruritus, rash, decreased appetite, 
constipation, arthralgia, and diarrhea. 
 
Table 12: Adverse Reactions in 10% of patients with unresectable or metastatic 
melanoma treated with pembrolizumab 2mg/kg every 3 weeks. 
 
Adverse Reaction 
All Grades 
(%) 
Grade 3* 
(%) 
General Disorders and Administration Site Conditions 
Fatigue 
47 
7 
Peripheral Edema 
17 
1 
Chills 
14 
0 
Pyrexia 
11 
0 
Gastrointestinal Disorders 
Nausea 
30 
0 
Constipation 
21 
0 
Diarrhea 
20 
0 
Vomiting 
16 
0 
Abdominal pain 
12 
0 
Respiratory, Thoracic And Mediastinal Disorders 
Cough 
30 
1 
Dyspnea 
18 
2 
Skin And Subcutaneous Tissue Disorders 
Pruritus 
30 
0 
Rash 
29 
0 
Vitiligo 
11 
0 
Metabolism and Nutrition Disorders 
Decreased appetite 
26 
0 
Musculoskeletal and Connective Tissue Disorders 
Arthralgia 
20 
0 
Pain in extremity 
18 
1 
Myalgia 
14 
1 
Back pain 
12 
Nervous System Disorders 
Headache 
16 
0 
Dizziness 
11 
0 
Blood and Lymphatic System Disorders 
Anemia 
14 
5 
Psychiatric Disorders 
Insomnia 
14 
0 

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I Infections and Infestations 
I 
Upper respiratory tract infection 
11 
 
There were no Grade 5 adverse reactions reported. Of the 10% adverse reactions, 
none was reported as Grade 4. 
 
Other clinically important adverse reactions observed in up to 10% of patients treated with 
pembrolizumab were: Infections and infestations: sepsis 
 
Table 13: Laboratory Abnormalities Increased from baseline in 20% of patients with 
unresectable or metastatic melanoma treated with pembrolizumab 2mg/kg every 3 
weeks. 
 
Laboratory Test 
All Gradesl 
Grades 3-4 
% 
% 
Chemistry 
Hyperglycemia 
40 
2* 
Hyponatremia 
35 
9 
Hypoalbuminemia 
34 
0 
Hypertriglyceridemia 
25 
0 
Increased Aspartate 
Aminotransferase 
24 
2* 
Hypocalcemia 
24 
1 
Hematology 
Anemia 
55 
8* 
* 
Grade 4 abnormalities in this table limited to hyperglycemia, increased 
aspartate aminotransferase, and anemia (one patient each) 
 
11.4 
Dose adjustments, delays, rules for withholding and restarting treatment and 
permanent discontinuation. 
11.4.1 Epacadostat 
Dose reductions/Interruptions - Epacadostat 
In some circumstances, it may be necessary to temporarily interrupt both study treatments 
as a result of AEs that may have an unclear relationship to study drug. If an interruption is 
necessary both study treatments should be interrupted. 
Any interruptions of> 2 weeks or for LFT abnormalities must be discussed with the 
medical monitor before resuming treatment. Treatment with both study drugs should be 
withheld for drug-related Grade 4 hematologic toxicities, nonhematological toxicity Grade 
3 (including laboratory abnormalities), and severe or life-threatening AEs. 
Epacadostat may be dose reduced according to the guidelines and dose levels described 
in Table 14. 
Dosing interruptions may be permitted in the case of medical/surgical events or logistical 
reasons not related to study therapy (eg, elective surgery, unrelated medical events, 

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subject vacation, and/or holidays). Subjects will be placed back on study therapy within 3 
weeks of the scheduled interruption. The reason for interruption should be documented in 
the subject's study record. 
 
 
For patients who do not tolerate the RP2D of epacadostat in combination with pembrolizumab, 
three dose reductions are permitted (Table 14) in order to allow the patient to continue on study 
drug. The following guidelines need to be applied and these changes must be recorded on the 
Dosage Administration Record. Please refer to Table 15 for dose reduction steps and criteria for 
interruption and re-initiation of epacadostat for drug-related toxicities. Doses held during the study 
will not be made up. When toxicity that resulted in a dose reduction improves to grade 1 or less, 
the dose can be re-escalated at the investigators discretion provided there are no other 
concomitant toxicities. 
Table 14 Dose Modification Algorithm for Adverse Events Associated with Epacadostat 
 
Epacadostat Dose 
Levels 
Dose Level 1 
(starting dose) 
Dose Level -1 
Dose Level -2 
Actual Dose 
100mg bid 
50mg bid 
25mg bid 
 
 
 
 
Table 15. Dose Modification Guidelines for Epacadostat Related Adverse Effects without 
Immune Etiology 
 
 
 
 
 
 
 
 
. 
Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing for 
Treatment 
Restart 
Dose for 
Treatment 
Restart 
Discontinue 
Subject (after 
discussion 
with Pl) 
Hematologic 
Toxicity 
1,2,3 
No 
N/A 
N/A 
N/A 
4 
Yes 
Permanently 
discontinue 
treatment 
N/A 
Permanently 
discontinue 
study 
treatment 
Non 
Hematologic 
Toxicity 
1 
No 
N/A 
N/A 
N/A 

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Note: 
Exception to 
be treated to 
similar Grade 
1 toxicity: 
-G2 alopecia 
-G2 fatigue 
2 
Consider 
holding for 
persistent 
symptoms 
Toxicity 
resolves to ::;; 
grade 1 or 
baseline 
Restart at 
same dose 
Toxicity does 
not resolve 
within 12 
weeks of last 
dose of 
treatment 
3,4 
Yes 
Toxicity 
Restart at 1 
resolves to ::;; 
 dose level 
grade 1 or 
lower 
baseline. 
Subjects with 
AEs that 
stabilize at 
grade 2 ( such 
as neuropathy) 
may resume 
treatment 
upon principal 
investigator 
approval. 
Permanent 
discontinuation 
of epacadostat 
in setting of 
grade 4 
toxicities with 
the exception 
of grade 4 
laboratory 
abnormalities 
that are 
deemed 
clinically 
insignificant 
Toxicity does 
not resolve 
within 12 
weeks of last 
dose of 
treatment. 
Permanent 
discontinuation 
should be 
considered for 
any severe or 
life threatening 
event. 
With principal investigator agreement, subjects with a laboratory AE still at grade 2 after 12 
weeks may continue treatment in the study only if asymptomatic and controlled. 
Adverse events of a potential immunologic etiology or immune-related AEs (irAEs) may be 
defined as an AE of unknown etiology, associated with drug exposure and consistent with 
an immune phenomenon. Immune-related AEs may be predicted based on the nature of 
the compounds, their mechanism of action, and reported experience with immunotherapies 
that have a similar mechanism of action. Special attention should be paid to AEs that may 

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Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
be suggestive of potential irAEs. An irAE can occur shortly after the first dose or several 
months after the last dose of treatment. 
If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, 
toxin, or other etiologic causes prior to labeling an AE as an irAE. 
Immune-related adverse events may be attributable to epacadostat alone, pembrolizumab 
alone, or the combination of both agents. If the event is clearly related to one of the 
agents, follow the instructions specific for that agent. If the event is related to both agents, 
follow the action taken instructions for both. 
Suggested supportive care measures for the management of adverse events with potential 
immunologic etiology are outlined in Table 16. below. Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, 
or skin photography as part of evaluation of the event. 
 
 
Table 16:   Dose Modification Guidance Epacodostat and Pembrolizumab. 
 

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Immune-related 
AEs 
Toxicity 
Grade or 
Conditions 
(CTCAEv4.0) 
Study 
Medication 
Action 
Taken with 
Study 
Medication 
irAE 
Management 
with 
Corticosteroid 
and/or Other 
Therapies 
Monitor and 
Follow-up 
Grade 3 or 4, 
or recurrent 
grade 2 
Pembrolizuma 
b 
Permanent! 
y 
discontinue 
Epacadostat or 
matching 
placebo 
Permanent! 
y 
discontinue 
Diarrhea / colitis 
Grade 2 or 3 
Pembrolizuma 
b 
Withhold 
until Grade 
0-1 
• Administer 
corticosteroids 
(initial dose of 
l-2mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
• 
Monitor 
participants for 
signs and 
symptoms of 
enterocolitis 
(i.e. diarrhea, 
abdominal 
pain, blood or 
mucus in stool 
with or without 
fever) and of 
bowel 
perforation (i.e. 
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 
Epacadostat 
Withhold 
until Grade 
0-1 
Related: 
Reduce by 
1 dose 
level. 
Not Related: 
Same dose 
level. 
Grade 4 
Pembrolizuma 
b 
Permanent! 
y 
discontinue 
Epacadostat 
Permanent! 
y 
discontinue 

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Immune-related 
AEs 
Toxicity 
Grade or 
Conditions 
(CTCAEv4.0) 
Study 
Medication 
Action 
Taken with 
Study 
Medication 
irAE 
Management 
with 
Corticosteroid 
and/or Other 
Therapies 
Monitor and 
Follow-up 
substituted via 
IV infusion. 
AST/ ALT 
Elevation or 
Increased 
Bilirubin 
Grade 2* 
Pembrolizuma 
b 
Withhold 
until Grade 
0-1 
• Administer 
corticosteroids 
(initial dose of 
0.5- lmg/kg 
• 
Monitor with 
liver function 
tests (consider 
weekly or more 
Epacadostat 
Withhold 
until Grade 
0-1 
Related: 
Reduce by 
1 dose 
level. 
Not Related: 
Same dose 
level. 
prednisone or 
equivalent) 
followed by 
taper 
frequently until 
liver enzyme 
value returned 
to baseline or is 
stable 
Grade 3 or 4 
Pembrolizuma 
b 
Permanent! 
y 
discontinue 
• Administer 
corticosteroids 
(initial dose of 
l-2mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
Epacadostat 
Permanent! 
y 
discontinue 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemiab 
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemi 
a associated 
with evidence 
of p-cell 
failure 
Pembrolizuma 
b 
Withhold 
until Grade 
0-1 
• Initiate insulin 
replacement 
therapy for 
participants 
with TlDM 
• Administer 
anti- 
hyperglycemic 
in participants 
with 
hyperglycemia 
• 
Monitor 
participants for 
hyperglycemia 
or other signs 
and symptoms 
of diabetes. 
Epacadostat 
Withhold 
until Grade 
0-1 
Related: 
Reduce by 
1 dose 
level. 

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Immune-related 
AEs 
Toxicity 
Grade or 
Conditions 
(CTCAEv4.0) 
Study 
Medication 
Action 
Taken with 
Study 
Medication 
irAE 
Management 
with 
Corticosteroid 
and/or Other 
Therapies 
Monitor and 
Follow-up 
Not Related: 
Same dose 
level. 
Hypophysitis 
Grade 2 
Pembrolizuma 
b 
Withhold 
until Grade 
0-1 
• Administer 
corticosteroid 
s and initiate 
hormonal 
replacements 
as clinically 
indicated. 
•  Monitor for 
signs and 
symptoms of 
hypophysitis 
(including 
hypopituitaris 
m and adrenal 
insufficiency) 
Epacadostat 
Withhold 
until Grade 
0-1 
Related: 
Reduce by 
1 dose 
level. 
Not Related: 
Same dose 
level. 
Pembrolizuma 
b 
Withhold 
until Grade 
0- 1 or 
permanently 
discontinuea 
Grade 3 or 4 
Epacadostat 
Withhold 
until Grade 
0- 1 or 
permanently 
discontinuea 
Related: 
Reduce by 
1 dose 
level. 

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Immune-related 
AEs 
Toxicity 
Grade or 
Conditions 
(CTCAEv4.0) 
Study 
Medication 
Action 
Taken with 
Study 
Medication 
irAE 
Management 
with 
Corticosteroid 
and/or Other 
Therapies 
Monitor and 
Follow-up 
Not Related: 
Same dose 
level. 
Grade 2 
Pembrolizuma 
b 
Continue 
• Treat with 
non-selective 
beta-blockers 
(e.g. 
propranolol) 
or thionamides 
as appropriate 
• 
Monitor for 
signs and 
symptoms of 
Epacadostat 
Continue 
thyroid 
disorders. 
Hyperthyroidism 
b 
Grade 3 or 4 
Pembrolizuma 
b 
Withhold 
until Grade 
0- 1 or 
permanently 
discontinuea 
Epacadostat 
Withhold 
until Grade 
0- 1 or 
permanently 
discontinuea 
Related: 
Reduce by 
1 dose 
level. 
Not Related: 
Same dose 
level. 
Hypothyroidismb 
Grade 2-4 
Pembrolizuma 
b 
Continue 
• 
 Initiate 
thyroid 
replacement 
hormones 
(e.g. 
levothyroxine 
or 
liothyroinine) 
per standard 
of care 
• 
Monitor for 
signs and 
symptoms of 
thyroid 
disorders. 
Epacadostat 
Continue 

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Immune-related 
AEs 
Toxicity 
Grade or 
Conditions 
(CTCAEv4.0) 
Study 
Medication 
Action 
Taken with 
Study 
Medication 
irAE 
Management 
with 
Corticosteroid 
and/or Other 
Therapies 
Monitor and 
Follow-up 
Nephritis and 
Renal 
Dysfunction 
Grade 2 
Pembrolizuma 
b 
Withhold 
until Grade 
0- 1 
•  Administer 
corticosteroid 
s (prednisone 
l-2mg/kg or 
equivalent) 
followed by 
taper. 
• 
Monitor 
changes of 
renal function 
Epacadostat 
Withhold 
until Grade 
0-1 
Related: 
Reduce by 
1 dose 
level. 
Not Related: 
Same dose 
I. 
Grade 3 or 4 
Pembrolizuma 
b 
Permanent! 
y 
discontinue 
Epacadostat 
Permanent! 
y 
discontinue 
Rash 
Pembrolizmnab 
Continue 
• Manage with 
topical 
steroids with 
or without 
drug 
interruption. 
1 or 2 
Epacadostat 
Continue 
3 C 
Pembrolizumab 
Withhold 
until Grade 
0-1 
• Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper. 
• 
If toxicity does 
not resolve 
within 12 
weeks of last 
dose, or cannot 
taper below 10 
mg or less of 
prednisone or 
equivalent 
within 12 
weeks, must 
permanently 
discontinue. 
Epacadostat 
Withhold 
until Grade 
0-1 

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Immune-related 
AEs 
Toxicity 
Grade or 
Conditions 
(CTCAEv4.0) 
Study 
Medication 
Action 
Taken with 
Study 
Medication 
irAE 
Management 
with 
Corticosteroid 
and/or Other 
Therapies 
Monitor and 
Follow-up 
Related: 
Reduce by 
1 dose 
level. 
Not Related: 
Same dose 
level. 
• 
Restart 
epacadostat at 
same dose if 
rash is mild 
and assessed as 
Grade 3 based 
only on body 
surface area 
and resolves 
without oral 
steroids. If oral 
steroids are 
required, or 
rash is severe, 
decrease by 1 
dose level once 
resolved to 
Grade 0-1. 
4 
Pembrolizumab 
Permanently 
discontinue 
• Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper. 
Epacadostat 
Permanently 
discontinue 
Asymptomatic d 
Amylase or 
Lipase 
Increased 
3 
Pembrolizumab 
May continue 
treatment 
with medical 
monitor 
approval 
• 
Pennanently 
discontinue if 
clinical signs 
and symptoms 
of pancreatitis 
develop 
(abdominal 
pam, nausea, 
vomiting). 
• 
If toxicity does 
not resolve 
within 12 
weeks of last 
dose after an 
interruption, 
must 
pennanently 
discontinue 
unless 
approved by 
the medical 
monitor to 
continue. 
Epacadostat 
May continue 
treatment 
with medical 
monitor 
approval 
4 
Pembrolizumab 
Withhold 
until toxicity 
resolves to 
Grade 0-1e 
Epacadostat 
Withhold 
until toxicity 
resolves to 
Grade 0-1e 
Related: 
Reduce by 

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Immune-related 
AEs 
Toxicity 
Grade or 
Conditions 
(CTCAEv4.0) 
Study 
Medication 
Action 
Taken with 
Study 
Medication 
irAE 
Management 
with 
Corticosteroid 
and/or Other 
Therapies 
Monitor and 
Follow-up 
1 dose 
level. 
Not Related: 
Same dose 
level. 
• 
If Grade 4 
lipase/amylase 
elevation is 
asymptomatic 
and abdominal 
imaging 
suggests no 
pathology, 
study drug 
administration 
dosing may 
continue with 
medical 
monitor 
approval. 
All Other 
Immune-related 
AEs 
Grade 3, or 
intolerable/ 
persistent 
Grade 2 
Pembrolizuma 
b 
Withhold 
until Grade 
0- 1 
• Based on 
severity of AE 
administer 
corticosteroid 
• 
Ensure 
adequate 
evaluation to 
confirm 
s 
etiology or 
exclude other 
causes 
Epacadostat 
Withhold 
until Grade 
0-1 
Related: 
Reduce by 
1 dose 
level. 
Not Related: 
Same dose 
level. 
Grade 4 or 
recurrent 
Grade 3 
Pembrolizuma 
b 
Permanent! 
y 
discontinue 
Epacadostat 
Permanent! 
y 
discontinue 

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Immune-related 
AEs 
Toxicity 
Grade or 
Conditions 
(CTCAEv4.0) 
Study 
Medication 
Action 
Taken with 
Study 
Medication 
irAE 
Management 
with 
Corticosteroid 
and/or Other 
Therapies 
Monitor and 
Follow-up 
General Instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at 
least 4 weeks. 
2.  For situations where pembrolizumab and epacadostat have been withheld, pembrolizumab and 
epacadostat/placebo can be resumed after AE has been reduced to Grade 1 or O and corticosteroid has been 
tapered. Pembrolizumab and epacadostat/placebo should be permanently discontinued if AE does not 
resolve within 12 weeks of last dose or corticosteroids cannot be reduced to :S 10 mg prednisone or 
equivalent per day within 12 weeks. 
3.  For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. 
Other immunosuppressive treatment should be initiated ifirAEs cannot be controlled by corticosteroids. 
4. Pembrolizumab should be permanently discontinued if Stevens Johnson Syndrome (SJS) or Toxic 
Epidermal Necrolysis (TEN) occurs. 
NOTES: 
1. Withhold OR permanently discontinue pembrolizumab + epacadostat at the discretion of the Investigator. 
2.  For participants with Grade 3 or 4 immune-related endocrinopathy where withholding ofpembrolizumab 
and epacadostat is required, pembrolizumab and epacadostat may be resumed when AE resolves to :S Grade 
2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case ofTlDM) 
3.  Participants with Grade 3 rash in the absence of desquamation, no mucosa] involvement, does not require 
systemic steroids, and resolves to Grade 1 within 14 days does not have to hold study medication 
4. If Grade 4 lipase/amylase elevation is asymptomatic and abdominal imaging suggests no pathology, study 
drug administration dosing may continue (with or without dose reduction) with medical monitor approval. 
Abbreviations: AEs = adverse events; ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic 
transaminase); AST (SGOT) = aspartate aminotransferase (serum glutamic oxaloacetic transaminase); CTCAE = 
Common Terminology Criteria for Adverse Events; OKA= diabetic ketoacidosis; IV = intravenous; irAE = infusion- 
related adverse events; TlDM = Type 1 diabetes mellitus 
*For patients with liver metastases who begin treatment with Grade 2 AST or ALT, if AST or ALT levels remain 
grade 2 after study treatment the combination of pembrolizumab/epacadostat may continue at the same dose level 
without any need to withhold treatment. If AST/ALT resolve to grade 0/1 at any time point following initiation of 
study treatment and then subsequently increase to grade 2 the guidelines recommended in the section of this table 
entitled "AST I ALT Elevation or Increased Bilirubin" should be followed. 
 
Procedures for Other Immune-Mediated Adverse Reactions, Including Ocular 
Manifestations 
Epacadostat should be permanently discontinued for severe (Grade 4) irAEs. Systemic 
corticosteroids treatment should be initiated at a dose of 1 to 2 mg/kg per day of 
prednisone or equivalent for severe irAEs. 
Corticosteroid eye drops should be administered to subjects who develop uveitis, iritis, or 
episcleritis. Epacadostat should be permanently discontinued for immune-mediated ocular 
disease that is unresponsive to local immunosuppressive therapy. 

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11.4.2 Pembrolizumab 
Dose reductions - Pembrolizumab 
Dose reductions of pembrolizumab are not permitted. 
Dose Modification (Escalation/Titration/Other) 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure 
may represent an immunologic etiology. These adverse events may occur shortly after the 
first dose or several months after the last dose of treatment. Pembrolizumab must be 
withheld for drug-related toxicities and severe or life-threatening AEs as per table 16 
above. 
 
 
Other allowed dose interruption for pembrolizumab 
Dosing interruptions are permitted in the case of medical / surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, 
patient vacation, and/or holidays). Subjects should be placed back on study therapy within 
3 weeks of the scheduled interruption, unless otherwise discussed with the Sponsor. The 
reason for interruption should be documented in the patient's study record. 
11.5 
Guidelines for the management of specific and immune-related toxicities 
Subjects should receive appropriate supportive care measures for immune-related 
toxicities related to pembrolizumab as deemed necessary by the treating investigator (see 
Appendix B). 
Management of Infusion Reactions: Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Table 17 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475). 
 
 
Table 17 Infusion Reaction Treatment Guidelines 
 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
r 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab (MK- 
3475) with: 

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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
r 
dosing 
prophylactic medications indicated 
for< =24 hrs 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(e.g., from 100 mUhr to 50 ml/hr). 
Otherwise dosing will be held until symptoms 
resolve and the subject should be 
premedicated for the next scheduled dose. 
Subjects who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from further 
trial treatment administration. 
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine). 
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief interruption 
of infusion); recurrence of 
symptoms following initial 
improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
No subsequent dosing 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period 
of drug administration. 
 
11.6 
AE and SAE reporting 
11.6.1 Time Period and Frequency of Detecting AEs and SAEs 
The investigator or site staff is responsible for detecting, documenting and reporting events 
that meet the definition of an AE or SAE. See section below for the timeline for reporting 
SAEs. 
AEs and SAEs will be collected from the time the first dose of study treatment is administered 
until 90 days following discontinuation of study treatment regardless of initiation of a new 
cancer therapy or transfer to hospice. 

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After discontinuation of study treatment, the investigator will monitor all AEs/SAEs that are 
ongoing until resolution or stabilization of the event or until the subject is lost to follow-up. At 
any time after treatment discontinuation the investigator may report any adverse event that 
they believe possibly related to study treatment. 
11.6.2 Prompt Reporting of Serious Adverse Events and Other Events to MSKCC IRB 
Please see section 17.2 for SAE reporting guidelines. 
11.6.3 CTCAE term (AE description) and grade 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.03 will be utilized for AE reporting. All appropriate 
treatment areas should have access to a copy of the CTCAE version 4.03. A copy of the 
CTCAE 
version 
4.03 
can 
be 
downloaded 
from 
the 
CTEP 
web 
site 
http://ctep.cancer.gov/protocolDevelopmenUelectronic_applications/ctc.htm. 
11.6.4 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. 
11.7 
Pregnancy Testing, Prevention and Lactation Reporting 
Epacadostat should not be used by pregnant women. Studies to evaluate the potential for 
embryotoxicity and teratogenicity have not been performed. Pembrolizumab may have 
adverse effects on a fetus in utero. Furthermore, it is not known if pembrolizumab has 
transient adverse effects on the composition of sperm. 
For this trial, male subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying 
medical condition). 
The need for a screening pregnancy test depends on whether a female subject is of 
childbearing potential or non-childbearing potential. 
Female subjects will be considered of non-reproductive 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) 

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level in the postmenopausal range may be used to confirm a post-menopausal 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 prior to screening; 
OR 
Has a congenital or acquired condition that prevents childbearing. 
A female of child-bearing potential is defined as any female who does not meet the criteria 
of non-childbearing potential as described in the previous paragraph. 
If a female subject is of childbearing potential, she must have a serum -HCG or urine 
pregnancy test performed within 72 hours of the first dose of study treatment. If the urine 
test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 
Subjects with positive pregnancy test result must be excluded from the study. 
Female and male subjects 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 both epacadostat and pembrolizumab by complying with one of 
the following: 
(1) practice abstinencet from heterosexual activity; 
OR 
(2) use (or have their partner use) acceptable contraception during heterosexual activity. 
 
 
Acceptable methods of contraception are+: 
 
 
Single method (one of the following is acceptable): 
• 
intrauterine device (IUD) 
• 
vasectomy of a female subject's male partner 
• 
contraceptive rod implanted into the skin 

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Combination method (requires use of two 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 
 
 
tAbstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject's preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and ERCs/lRBs. 
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 subjects 
participating at sites in this country/region. 
 
 
Subjects 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 subjects of childbearing potential must adhere to the contraception 
requirement (described above) from the day of study medication initiation (or 14 days prior 
to 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 subject of 
childbearing potential will not reliably comply with the requirements for contraception, that 
subject should not be entered into the study. 
If a female subject is suspected to be pregnant during the study, a serum pregnancy test 
must be performed. If pregnancy is confirmed, subject must stop study treatment 
immediately and the pregnancy must be reported. A report confirming a female subject to 
be pregnant or lactating has to be reported to lncyte and Merck within 24hours of sponsor 
awareness and submitted within 10 days of sponsor awareness. The site will contact the 
pregnant subject at least monthly and document the subject's status until the pregnancy has 

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been completed or terminated. The outcome of the pregnancy will be reported to the study 
sponsor and to Merck and lncyte without delay and within 24 hours to the Sponsor and within 
2 working days to Merck and lncyte 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 to the 
Sponsor. 
11.8 Additional Information Related to Pembrolzumab and Reporting 
11.8.1 Definition of a Pembrolizumab Overdose for This Protocol and Reporting of 
Pembrolizumab Overdose to the Sponsor and to Merck 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 
1,000 mg or greater ( 5 times the indicated dose). No specific information is available on 
the treatment of overdose of pembrolizumab. Appropriate supportive treatment should be 
provided if clinically indicated. In the event of overdose, the subject should be observed 
closely for signs of toxicity. 
If an adverse event33 is associated with ("results from") the overdose of a Merck product, 
the adverse event33 is reported as a serious adverse event, even if no other seriousness 
criteria are met. 
If a dose of Merck's product meeting the protocol definition of overdose is taken without 
any associated clinical symptoms or abnormal laboratory results, the overdose is reported 
as a non-serious Event of Clinical Interest (ECI), using the terminology "accidental or 
intentional overdose without adverse effect." 
All reports of overdose with and without an adverse event must be reported within 24 
hours to the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) 
11.8.2 Events of Clinical Interest 
Reporting to lncyte 
Selected non-serious and serious adverse events are also known as Events of Clinical 
Interest (ECI) and must be reported within 24 hours to lncyte. 
All Serious Adverse Events ("SAE") required to be reported pursuant to the Protocol shall 
be provided to lncyte and its representatives by Institution or Principal Investigator within 
twenty-four (24) hours of learning of the event as well as any additional reports agreed 
upon by Institution or Principal Investigator and lncyte. SAE Reports will be sent to 
lncytePhVOpslST@incyte.com. By sending to this e-mail address, the lncyte 
Pharmacovigilance group will receive copies of the reports. This process will be tested 

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and established before the first patient is enrolled in the Study. Notwithstanding anything to 
the contrary herein, Institution will have the primary responsibility of reporting adverse 
events ("AE'') to regulatory authorities. 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must 
be reported within 24 hours to lncyte and within 2 working days to Merck Global Safety if it 
causes the subject to be excluded from the trial, or is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, 
whether or not related to Merck product, must be reported within 24 hours to lncyte and 
within 24 hours to Merck Global Safety. 
Events of clinical interest for this trial include: 
1. an overdose of Merck product, as defined in Section 11.8.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.* 
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology. 
 
 
 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
12.1 
Antitumor effect 
All patients will undergo a baseline staging CT scan of the chest (with or without contrast), 
abdomen and pelvis (with or without contrast), and MRI of the affected area if deemed 
necessary by the treating physician. Response evaluations will occur at week 8 and every 8 
weeks subsequently (± 1 week window) until week 56, and then less frequently at the 
discretion of the treating investigator. 

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Response and progression will be evaluated in this study using the international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline, 
version 1.1 (Primary response criteria).54 Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
In addition, patients will also be evaluated using the Immune-related Evaluation Response 
Criteria (irRECIST), which will not be used for treatment decisions (Secondary Response 
Criteria) and are discussed separately in section 12.12 
In subjects who have initial evidence of progressive disease (PD) as per RECIST criteria or 
irRECIST criteria, it is at the discretion of the investigator to continue a subject on study 
treatment until confirmation of PD 4 weeks. This clinical judgment decision should be 
based on the subject's overall clinical condition, including performance status, clinical 
symptoms, and laboratory data. 
 
Subjects will receive treatment if they are clinically stable as defined by the following criteria: 
• 
Absence of signs and symptoms indicating PD. 
• 
No decline in the Eastern Cooperative Oncology Group (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 
 
Patients who decide to continue study therapy on protocol after initial radiolgic evidence of 
disease progression will need to provide written informed consent at the time of the decision 
to treat beyond initial evidence of progression of disease on study therapy. 
12.2 
Definitions 
Evaluable for toxicity - Patients evaluable for safety analysis will include all patients who 
have received at least one dose of epacadsotat and pembrolizumab. Patients will be 
evaluable for toxicity from the time of their first treatment with epacadostat and 
pembrolizumab. 
Evaluable for efficacy - Only those patients who have a measurable disease based on 
RECIST 1.1 criteria will be eligible for this study, as highlighted in Section 6.0. These patients 
will have their response classified according to the definitions stated below. 
Only those patients who have measurable disease present at baseline, have received at 
least one cycle of the combination therapy, and have had their disease re-evaluated will be 
considered evaluable for response. (Note: Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable and determined to 

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be non-responders. Note: one cycle of therapy consists of 21 days where the study therapy 
(epacadostat and pembrolizumab) is administered at the start of the cycle on day 1) 
 
12.2.1 Disease Parameters 
Measurable disease - Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded for non-nodal lesions 
and short axis for nodal lesions) as >20mm by chest x-ray, as >10mm with CT scan or MRI, 
or >10mm with calipers by clinical exam. All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
 
To be considered pathologically enlarged and measurable, a lymph node must be > 15 mm 
in short axis when assessed by CT scan (CT scan slice thickness recommended to be no 
greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and 
followed. 
 
Note: Tumor lesions that are situated in a previously irradiated area are not considered 
measurable unless there is evidence of progression after radiation therapy. 
 
Non-measurable disease - All other lesions (or sites of disease), including small lesions 
(longest diameter <10mm or pathological lymph nodes with 10 to <15mm short axis) are 
considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardia! effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease and 
abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
Target lesions - All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target lesions 
and recorded and measured at baseline. Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated measurements. A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. The baseline sum 
diameters will be used as a reference to further characterize any objective regression in the 
measurable dimension of the disease. 
Non-target lesions - All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline. Measurements of these lesions are not required, but the 
presence, absence or in rare cases unequivocal progression of each should be noted 
throughout follow-up. 

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12.3 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers. 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up portion of study. 
Imaging-based evaluation is preferred to evaluation by clinical examination unless the 
lesion33 being followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions - Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed 
using calipers (e.g., skin nodules). In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended. 
Chest x-ray - Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
 
Conventional CT and MRI - This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness. MRI is also acceptable in certain situations (e.g. for body scans). 
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease. Furthermore, as with CT, the modality used at follow-up should be 
the same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe specific 
MRI pulse sequence parameters for all scanners, body parts, and diseases. Ideally, the 
same type of scanner should be used and the image acquisition protocol should be followed 
as closely as possible to prior scans. Body scans should be performed with breath-hold 
scanning techniques, if possible. 
 
12.3.1 Primary Response Criteria (RECIST 1.1) 
 
12.3.1.1 
Evaluation of Target Lesions 

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Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if that 
is the smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more 
new lesions is also considered progressions). 
 
Stable Disease 1: Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 
12.3.1.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion33. 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally 
trump target lesion status. It must be representative of overall disease status change, not a 
single lesion increase. 
 
Although a clear progression of "non-target" lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should 
be confirmed at a later time by the review panel (or MSKCC Principal Investigator). 
 
12.3.1.3 
Evaluation of Best Response 
The best response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response 
assignment will depend on the achievement of both measurement and confirmation criteria. 
Table 18. Evaluation of Best Response - RECIST criteria 

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Target 
Lesions 
Non- 
Target 
Lesions 
New 
Lesions 
Best 
Response 
Best Response for This 
Category also 
Requires: 
CR 
CR 
No 
CR 
4 wks. Confirmation 
CR 
Non-CR/ 
Non-PD 
No 
PR 
4 wks. Confirmation 
PR 
Non-CR/ 
Non-PD 
No 
PR 
SD 
Non-CR/ 
Non-PD 
No 
SD 
documented at least 
once 4 wks. from 
baseline 
PD 
Any 
Yes or 
No 
PD 
Any 
PD* 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
Any 
Yes 
PD 
* In exceptional circumstances, unequivocal progression in non-target lesions 
may be accepted as disease progression. 
Note: Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as "symptomatic 
deterioration." Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
12.4 
Confirmation of response 
 
Complete or partial response may only be claimed if the criteria for each are met at a 
subsequent time point ( 4 weeks later) in studies with a primary endpoint that include 
response rate. 
 
12.4.1 Special note on target lesions that become "too small to measure" 
 
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their 
actual measurements recorded at each subsequent evaluation, even when very small (e.g. 

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2mm). However, sometimes, lesions or lymph nodes which are recorded as target lesions 
at baseline become so faint on CT scan that the radiologist may not feel comfortable 
assigning an exact measure and may report them as being "too small to measure". When 
this occurs, it is important that a value be recorded on the D2M form. If it is the opinion of 
the radiologist that the lesion has likely disappeared, the measurement should be recorded 
as O mm. If the lesion is believed to be present and is faintly seen but too small to measure, 
a default value of 5 mm should be assigned. 
 
12.5 
Not evaluable (NE) 
 
When no imaging/measurement is done at all at a particular time point, the patient is 
considered not evaluable (NE) at that time point. 
 
12.6 
Early death 
 
If the patient has no repeat tumor assessments following initiation of study therapy resulting 
from the death of the patient due to disease or treatment, it is considered early death. 
 
12.7 
Symptomatic Deterioration 
 
Patients with global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time be recorded as "symptomatic 
deterioration". Every effort should be made to document objective progression even after 
discontinuation of treatment. 
 
12.8 
Duration of response 
 
Defined as the time measurement criteria are first met for CR/PR until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurement recorded on study). 
 
12.9 
Duration of stable disease 
 
Measured from the start of the treatment until the criteria for progression are met, taking as 
reference the smallest sum on study (if the baseline sum is the smallest, this is the reference 
for calculation of PD). 
 
12.10 Progression-Free Survival (PFS) 
 
PFS is defined as the period from start of study treatment until recurrent or progressive of 
disease (POD) is objectively documented (taking as reference for progressive disease the 
smallest measurement recorded on study), death, or date of last study visit involving 
assessment of disease status. 

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12.11 Overall Survival (OS) 
 
OS is defined as the observed length of life from start of study treatment to death or the date 
of last contact. 
 
12.12 Secondary Response Criteria - Immune-related Response Evaluation Criteria 
in Solid Tumors (irRECIST) 
 
In 2013, Nishina et al. demonstrated that immune-related response criteria using 
unidimensional measurements were highly concordant with the bidimensional results of 
irRC, but with less measurement variability. 55 Based on these findings and in order to 
utilize both the established criteria of irRC and RECIST 1.1, the two systems have been 
adapted, modified, and combined into the Immune-related Response Evaluation Criteria in 
Solid Tumors (irRECIST). The adapted irRECIST criteria are modifications to the irRC, 
incorporating the findings of Nishina et al. and the advantages of RECIST 1.1 while 
overcoming the shortcomings of each of the other guidelines. 
irRECIST 
Immune-related RECIST (irRECIST) guidelines according to Bohnsack et al. are presented 
below. 
 
I. Baseline Assessments in irRECIST 
 
In irRECIST, baseline assessment and measurement of measurable/non-measurable and 
target/non-target lesions and lymph nodes are in line with RECIST 1.1. 
 
One new definition is added: If a subject has no measurable and no non-measurable 
disease at baseline the radiologist will assign 'No Disease' (irND) as the overall tumor 
assessment for any available follow-up time points unless new measurable lesions are 
identified and contribute to the total measured tumor burden (TMTB). irND is a valid 
assessment in studies with adjuvant setting where the protocol and study design allow the 
inclusion of subjects with no visible disease 
 
Follow-up Assessments in irRECIST 
 
A. Follow-up recording of target and new measurable lesions 
 
The key difference in irRECIST is that the appearance of new lesions does not 
automatically indicate progression. Instead, all measured lesions (baseline-selected target 
lesions and new measurable lesions) are combined into the total measured tumor burden 
(TMTB) at follow up. Baseline-selected target lesions and new measurable lesions are 

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NOT assessed separately. Measurements of those lesions are combined into the TMTB, 
and one combined assessment provided. 
 
In order to be selected as new measurable lesions (:5 2 lesions per organ, :5 5 lesions total, 
per time point), new lesions must meet criteria as defined for baseline target lesion 
selection and meet the same minimum size requirements of 10 mm in long diameter and 
minimum 15 mm in short axis for new measurable lymph nodes. New measurable lesions 
should be prioritized according to size, and the largest lesions elected as new measured 
lesions. 
 
B. Follow-up non-target assessment 
 
RECIST 1.1 definitions for assessment of non-target lesions apply. The response of non- 
target lesions primarily contributes to the overall response assessments of irCR and irNon- 
CR/Non-PO (irNN). Non-target lesions do not affect irPR and irSO assessments. Only a 
massive and unequivocal worsening of non-target lesions alone, even without progress in 
the TMTB is indicative of irPO. In alignment with RECIST 1.1, baseline selected non-target 
lesions can never convert to measurable lesions, not even if they increase in size at 
subsequent time points and become measurable. Only true new lesions can be measured 
and contribute to the TMTB. 
 
C. Follow-up for New Non-Measurable Lesions 
All new lesions not selected as new measurable lesions are considered new non- 
measurable lesions and are followed qualitatively. Only a massive and unequivocal 
progression of new non-measurable lesions leads to an overall assessment of irPO for the 
time point. Persisting new non-measurable lesions prevent irCR. 
 
Overall Assessments for irRECIST 
 
The irRECIST overall tumor assessment is based on TMTB of measured target and 
new lesions, non-target lesion assessment and new non-measurable lesions. 
 
At baseline, the sum of the longest diameters (SumO) of all target lesions (up to 2 lesions 
per organ, up to total 5 lesions) is measured. At each subsequent tumor assessment (TA), 
the Sumo At each subsequent tumor assessment (TA), the Sumo of the target lesions and 
of new, measurable lesions (up to 2 new lesions per organ, total 5 new lesions) are added 
together to provide the total measurable tumor burden (TMTB). In the setting where 
treatment is continued beyond progression further assessments using irRECIST will use 
the first scan showing progressive disease as the new baseline scan to which all 
subsequent scans are compared. 

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Table 18. Overall Assessment by irRECIST 
 
 
 
Complete Response (irCR) 
Complete disappearance of all measurable 
and non-measurable lesions. Lymph nodes 
must decrease to < 10 mm in short axis. 
Partial Response (irPR) 
Decrease of 
30% in TMTB relative to 
baseline, non-target lesions are irNN, and no 
unequivocal progression of new non- 
measurable lesions 
• 
If new measurable lesions appear in 
subjects with no target lesions at 
baseline, irPD will be assessed. That 
irPD time point will be considered a 
new baseline, and all subsequent time 
points will be compared to it for 
response assessment. irPR is possible 
if the TMTB of new measurable lesions 
decreases by 
30% compared to the 
first irPD documentation 
• 
irRECIST can be used in the adjuvant 
setting, in subjects with no visible 
disease on CT/MRI scans. The 
appearance of new measurable 
lesion(s) automatically leads to an 
increase in TMTB by 100% and leads 
to irPD. These subjects can achieve a 
response if the TMTB decreases at 
follow-up, as a sign of delayed 
response. 
• 
Based on the above, sponsors may 
consider enrolling subjects with no 
measurable disease and/or no visible 
disease in studies with response 
related endpoints. 
Stable Disease (irSD) 
Failure to meet criteria for irCR or irPR in the 
absence of irPD 
Progressive Disease (irPD) 
Minimum 20% increase and minimum 5 mm 
absolute increase in TMTB compared to nadir, 
or irPD for non-target or new non-measurable 
lesions. Confirmation of progression is 
recommended minimum 4 weeks after the first 

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irPD assessment. An irPD confirmation scan 
may be recommended for subjects with a 
minimal TMTB %-increase over 20% and 
especially during the flare time-window of the 
first 12 weeks of treatment, depending on the 
compound efficacy expectations, to account 
for expected delayed response. 
• 
In irRECIST a substantial and 
unequivocal increase of non-target 
lesions is indicative of progression. 
• 
 lrPD may be assigned for a subject 
with multiple new non-measurable 
lesions if they are considered to be a 
sign of unequivocal massive worsening 
Other 
irNE: used in exceptional cases where 
insufficient data exist. 
irND: in adjuvant setting when no disease is 
detected 
irNN:, no target disease was identified at 
baseline, and at follow-up the subject fails to 
meet criteria for irCR or irPD 
 
 
 
 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
Patients will be removed from the study when any of the criteria listed below applies. The 
reason for removal from the study and the date the patient was removed must be 
documented in the Clinical Research Database system. Patients who come off study before 
their first radiological assessment from baseline for reasons other than disease progression 
or treatment related toxicities may be replaced. 
All patients who have received at least one dose of both study treatments will be assessable 
for safety of the combination therapy. Patients evaluable for efficacy analysis will include all 
patients who have received at least one cycle of treatment with both epacadostat and 
pembrolizumab and assessable for response. Patients who are missing an assessment of 
response post baseline will not be considered evaluable for response unless they missed 

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the assessment due to progression of disease or treatment related toxicities in which case 
they will be considered non-responders for that time point. 
In the absence of treatment delays due to adverse events, treatment with epacadostat 
and/or pembrolizumab may continue until one of the following criteria applies: 
 
• 
lntercurrent illness that prevents further administration of treatment 
 
• 
Intolerance of study treatment 
 
• 
Patient decides to withdraw from the study 
 
• 
Physician decides to withdraw a patient from the study for a reason not listed here 
 
• 
Pregnancy in patient 
 
• 
The patient is lost to follow-up 
 
• 
Inability of the patient to comply with the requirement of the protocol for treatment or 
evaluation. 
• 
End of study, whichever occurs first. 
 
 
Due to the mechanism of action, subjects may experience growth in existing tumors or the 
appearance of new tumors prior to maximal clinical benefit of epacadostat and pembrolizumab. 
The patient may be allowed to continue study treatment after initial RECIST 1.1 defined 
progression if they are assessed by the treating physician to be deriving clinical benefit 
and tolerating study treatment. The treating physician may consult with the overall study 
Pl for help with assessing the patient. Such patients should discontinue study therapy 
upon further evidence of progression at the discretion of the treating investigator. 
Safety follows up and End of Study visit 
Upon permanent discontinuation from the study treatment for any reason, the following 
procedures will be performed approximately 30 (+7) days after the last dose of epacadostat 
or the last dose of pembrolizumab, whichever is later. 
Full medical history, physical exam, assessment of performance status by 
KPS or ECOG status 
Review of concomitant medications 
Complete vital signs (pulse, blood pressure, temperature, respiratory rate, 
oxygen saturation) as well as weight and height. Height may be documented 
at any time prior to registration. 
12-lead electrocardiogram (ECG) 

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Serum -HCG or urine pregnancy test for women with child-bearing 
potential. If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required. 
Complete blood count with differential, including lymphocyte and eosinophil 
count. 
Comprehensive metabolic panel (glucose, blood urea nitrogen, creatinine, 
sodium, potassium, chloride, bicarbonate, calcium, total protein, albumin, 
serum bilirubin, alkaline phosphatase, ASL, AST) 
phosphorus, magnesium 
TSH, T4 free, T3 
Amylase and lipase 
An optional biopsy will be offered at progression of disease. 
Patients whose treatment is interrupted or permanently discontinued due to an adverse 
event or clinically significant laboratory value must be followed until resolution or stabilization 
of the event. 
 
Reporting of adverse events will occur for up to 90 days for serious adverse events (within 
90 [+7] days after the last administration of epacadostat or pembrolizumab, whichever is 
later), Events of Clinical Interest (within 90 [+7] days after the last administration of 
epacadostat or pembrolizumab, whichever is later), and documentation of concomitant 
medications. 
Long-Term Follow-up Procedures: 
 
All subjects who permanently discontinue study drug for any reason other than withdrawal 
of full consent will be contacted by clinic visit or telephone to assess survival and initiation 
of additional sarcoma therapy. Contact for all subjects will be attempted every 12 weeks 
(±28 days) following the safety follow-up visit until death, subject withdraws full consent, or 
up to 12 months after the end of treatment. 

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14.0 
BIOSTATISTICS 
14.1 Primary Endpoint 
The primary objective is to evaluate the efficacy, as assessed by the best objective response 
rate (complete response + partial response) by 24 weeks by RECIST 1.1. The study will 
use a one stage design based on the exact binomial test. A 10% response rate will be 
considered not promising; a 30% response rate will be considered promising.There will be 
a maximum accrual of 30 patients to this study. It will be concluded that the true response 
rate is > 10% if there are 6 or more patients with an objective response among 30 
patients. The design has a type I error rate of 0.07 and a type II error rate of 0.08. This 
design provides 92% probability of a positive result if the true response rate is at least 30%, 
and a 93% probability of a negative result if the true response rate is 10% or lower. 
 
The patient population in this study represents patients with locally advanced/metastatic 
sarcoma that have received at least one line of previous therapy. The data supporting the 
10% null rate comes from the SARC028 study that evaluated the efficacy of 
pembrolizumab monotherapy among patients with advanced/metastatic sarcoma which is 
discussed further below. In assessing the efficacy of a combination therapy incorporating 
pembrolizumab in this study population a response rate of> 10% would be preferred to 
determine the therapy as having a signal of efficacy. 
Patients evaluable for efficacy analysis will include all patients who have received at least 
one cycle of treatment with epacadostat and pembrolizumab and are assessable for 
response. Patients who are missing an assessment of response post baseline will not be 
considered evaluable for response unless they missed the assessment due to progression 
of disease or treatment related toxicities in which case they will be considered non- 
responders for that time point. Patients who miss an assessment of response post baseline 
for any reason other than progression of disease and treatment related toxicity will be 
replaced. 
Are knowledge regarding the efficacy of immunotherapy in sarcoma is evolving. As 
previously outlined, two studies evaluating the role of anti-PD1 monotherapy in patients with 
sarcoma were presented at the ASCO annual meeting in 2016. One study confirmed that 
no responses were seen among 12 patients with uterine LMS treated with nivolumab.21 The 
second study evaluated pembrolizumab in bone and soft tissue sarcomas (SARC028).20 
Signals of efficacy were observed in patients with UPS, liposarcoma (poorly 
differentiated/defferentiated) and chondrosarcoma. The objective response rates observed 
in this study was 19% for soft tissue sarcoma and was 5% for bone sarcoma. The objective 
response rates observed in this study for specific histologic subtypes were as follows: UPS 
-44%; liposarcoma -22%; synovial sarcoma 11%; leiomyosarcoma -  0%; chondrosarcoma 
- 17%; ewing's sarcoma - 0%; osteosarcoma - 5%. In relation to this trial design, patients 
with sarcoma subtypes where limited benefit from anti-PD1 monotherapy was observed in 

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previous studies may benefit from the combination immunotherapy approach offered in this 
study. Therefore, patients will be accrued based on histological sarcoma subtype into one 
of 4 cohorts. This will ensure that we enroll patients with an adequate spead of sarcoma 
histologies. Each cohort will enroll a prespecified number of patients with specific sarcoma 
histological subtypes. Due to the small sample size in each cohort, a sufficiently-powered 
efficacy analysis for each cohort is not possible however, the objective response rate for i) 
soft tissue sarcomas ii) bone sarcomas (if applicable depending on enrolment), and iii) within 
each cohort +/ each histological sarcoma subtype will be examined to look for a potential 
signal of efficacy. 
We expect to accrue approximately 1-2 patients each month and hence expect to finish 
enrollment in 15-20 months. 
The anticipated accrual rate for each cohort is as follows: 
 
A) Undifferentiated Pleomorphic Sarcoma (UPS)/ Liposarcoma (dedifferentiated or 
pleomorphic liposarcoma) - one patient every month 
B) Leiomyosarcoma - one patient every second month 
 
C) Vascular 
Sarcoma 
Subtypes 
(including 
angiosarcoma, 
Hemangioendothelioma (EHE),)- one patient every 3-4 months 
D) Other - one patient every second month 
Epithelioid 
 
 
 
14.2 Secondary Endpoints 
 
Secondary endpoints include: 
1. Safety 
Patients evaluable for safety analysis will include all patients who have received at least 
one dose of epacadsotat and pembrolizumab. Adverse events will be graded according to 
the NCI CTCAE v4.03, presented on an individual basis and summarized using descriptive 
statistics. 
 
2. Survival 
Progression free survival (PFS) rate at 24 weeks, median PFS, overall survival (OS) 
and progression-free survival intervals will be estimated using Kaplan-Meier methodology 
 
3. Best Objective Response Rate by irRECIST 
Best objective response rate (complete response + partial response) by 24 weeks by 
immune-related response criteria (irRECIST), of epacadostat in combination with 
pembrolizumab in patients with metastatic and/or locally advanced, sarcoma. 

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14.3 Correlative Endpoints Statistical Considerations 
The study is not powered to detect specific hypotheses. Due to the small sample size, the 
correlative studies will be exploratory and hypothesis generating in nature. These analyses 
will help better identify patients having the potential to benefit from this therapy and aid in 
designing larger phase Ill studies. 
I. 
 To evaluate the baseline characteristics of sarcoma tumors (pre-treatment biopsy 
sample) evaluated in this study including the level of 1001, kynurenine and PD-1/PD- 
L1 expression, presence of tumor infiltrating lymphocytes (TlLs) and tumor antigens, 
gene expression profile, and the T-cell receptor clonality in tumor-infiltrating 
lymphocytes (TIL). Descriptive statistics will be used to report the baseline tumor 
characteristics with respect the level of 1001, kynurenine and PD-1/PD-L1 
expression, presence of tumor infiltrating lymphocytes (Tlls) and tumor antigens, 
gene expression profile, and the T-cell receptor clonality in tumor-infiltrating 
lymphocytes (TIL). 
II. 
To assess the potential effect of epacadostat and pembrolizumab on selected 
biomarker expression measured in pre- and post-treatment tumor tissue and the 
association between these biomarkers and with clinical outcome, including 
characterization of 100-1, PD-1/PD-L1, kynurenine expression, tumor infiltrating 
lymphocytes 
(Tlls) 
and 
tumor 
antigens, 
gene 
expression 
profiling, 
and 
characterization of T-cell receptor clonality in tumor-infiltrating lymphocytes (TIL). 
The pre- and post-treatment measurements will be compared using the paired t-test 
for each of these biomarkers. The associations with the selected biomarkers, in terms 
of both the pre-treatment measurement and the difference between pre- and post- 
treatment measurements, will be evaluated using the two-sample t-test for clinical 
outcome such as response and clinical benefit, and using survival data analysis 
(including Kaplan-Meier curve and Cox Proportional Hazards models) for survival 
outcomes such as progression-free survival and survival. More specifically, Kaplan- 
Meier curve and Cox Proportional Hazards models will be used for analyzing pre- 
treatment measurement; Kaplan-Meier curve at a landmark time point and Cox 
Proportional Hazards models allowing for time varying coefficients will be used for 
analyzing the difference between pre-and post treatment measurements. 
III. 
 To evaluate associations between selected biomarkers measured in serial peripheral 
blood over time with clinical efficacy, including immunophenotyping and functional 
analyses, evaluation of serum levels of chemokines, cytokines and other immune 
mediators, and characterization of T-cell receptor clonality in peripheral blood. 
Summary statistics will be used to for describing changes across time. In addition the 
time course of biomarker measurements will be investigated graphically, by summary 
plots or individual patient plots; their trends over time will be categorized either by 
visual inspection (if there are clear trend groups such as monotonically increasing or 

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monotonically decreasing) or by pattern recognition methods such as K-means 
clustering. The associations with the observed trend in selected biomarkers analyzed 
will be evaluated using categorical data analysis (including Fisher's exact test 
and logistic regression) for clinical outcome such as response and clinical benefit, 
and using survival data analysis (including Kaplan-Meier curve and Cox Proportional 
Hazards models) for survival outcomes such as progression-free survival and 
survival. 
 
 
IV. 
To evaluate the association between baseline tumor mutational burden and 
neoantigen production with clinical efficacy of the study therapy. 
The associations with baseline tumor mutational burden and neoantigen production will be 
evaluated using categorical data analysis (including Fisher's exact test and logistic 
regression) for clinical outcome such as response and clinical benefit, and using survival 
data analysis (including Kaplan-Meier curve and Cox Proportional Hazards models) for 
survival outcomes such as progression-free survival and survival. 
 
 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
15.1 Research Participant Registration 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. Obtain 
informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. During the registration process registering individuals will be required to 
complete a protocol specific Eligibility Checklist. The individual signing the Eligibility 
Checklist is confirming whether or not the participant is eligible to enroll in the study. Study 
staff are responsible for ensuring that all institutional requirements necessary to enroll a 
participant to the study have been completed. See related Clinical Research Policy and 
Procedure #401 (Protocol Participant Registration). 
15.2 Randomization 
N/A 
 
 
 
 
16.0 
DATA MANAGEMENT ISSUES 
A Clinical research coordinator (CRC) will be assigned to the study. The responsibilities of 
the CRC include project compliance, data collection, abstraction and entry, data reporting, 

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regulatory monitoring, problem resolution and prioritization, and coordinate the activities of 
the protocol study team. 
The data collected for this study will be entered into a secure database. 
Source 
documentation will be available to support the computerized patient record. 
16.0.1 Data 
 
 
 
16.1 
Quality Assurance 
Weekly registration reports will be generated to monitor patient accruals and 
completeness of registration data. Routine data quality reports will be generated to 
assess missing data and inconsistencies. Accrual rates and extent and accuracy of 
evaluations and follow-up will be monitored periodically throughout the study period 
and potential problems will be brought to the attention of the study team for 
discussion and action 
 
Random-sample data quality and protocol compliance audits will be conducted by 
the study team, at a minimum of two times per year, more frequently if indicated. 
16.2 
Data and Safety Monitoring 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer 
Center were approved by the National Cancer Institute in September 2001. The plans 
address the new policies set forth by the NCI in the document entitled "Policy of the 
National Cancer Institute for Data and Safety Monitoring of Clinical Trials" which can 
be found at: http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The DSM 
Plans at MSKCC were established and are monitored by the Office of Clinical 
Research. The MSKCC Data and Safety Monitoring Plans can be found on the 
MSKCC Intranet at: http://mskweb5.mskcc.org/intranet/html/99074.cfm 
There are several different mechanisms by which clinical trials are monitored for data, 
safety and quality. There are institutional processes in place for quality assurance 
(e.g., protocol monitoring, compliance and data verification audits, therapeutic 
response, and staff education on clinical research QA) and departmental procedures 
for quality control, plus there are two institutional committees that are responsible for 
monitoring the activities of our clinical trials programs. The committees: Data and 
Safety Monitoring Committee (DSMC) for Phase I and II clinical trials, and the Data 
and Safety Monitoring Board (DSMB) for Phase Ill clinical trials, report to the Center's 
Research Council and Institutional Review Board. 
During the protocol development and review process, each protocol will be assessed 
for its level of risk and degree of monitoring required. Every type of protocol (e.g., 

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NIH sponsored, in-house sponsored, industrial sponsored, NCI cooperative group, 
etc.) Will be addressed and the monitoring procedures will be established at the time 
of protocol activation 
Final data sets for publication are required to be locked and stored centrally for 
potential future access requests from outside entities. 
16.3 
Regulatory Documentation 
Prior to implementing this protocol at MSKCC, the protocol, informed consent form, 
HIPAA authorization and any other information pertaining to participants must be 
approved by the MSKCC Institutional Review Board/Privacy Board (IRB/PB). There 
will be one protocol document and each participating site will utilize that document. 
 
Participating sites that are conducting data analysis should submit this protocol to 
their IRB according to local guidelines. Copies of any site IRB correspondence 
should be forwarded to MSK. 
 
Role of Stanford University as the participating site is as follows: 
Data analysis being performed by the site: Diagnosis, Age, Gender, ECOG, 
Prior therapies, All efficacy response parameters (ORR, DOR, PFS, OS) will 
be shared with Stanford 
The data will be shared via secure file transfer system 
The data will be shared at the end of the study 
Participant identifiers will not be shared 
Role of MD Anderson Cancer Center as the participating site is as follows: 
Data analysis being performed by the site: Computational analysis of any 
tumor sequencing available and combining it with sequencing data available 
through MD Anderson cohorts. Also, genomic correlates of response to 
immunotherapy, histology-specific determinants of response to ICB 
Data will be shared via Secure File Transfer System 
Data will be shared as soon as possible since the study has been completed. 
Participant identifiers will not be shared. Only clinical data and demographics 
will be shared. 
 
16.3.1 Amendments 
 
Each change to the protocol document must be organized and documented by MSKCC and 
approved by the MSKCC IRB/PB. 
Prospective and Retrospective deviations 

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A protocol deviation on this study is defined as a request to treat a research participant who 
does not meet all the eligibility criteria, pretreatment evaluation, or who requires alteration 
in their study plan. If a deviation from this protocol is proposed for a potential or existing 
participant at MSKCC, approval from the MSKCC IRB/PB is required prior to the action. A 
protocol violation is anything that occurs with a participant, which deviated from the protocol 
without prior approval from the MSKCC IRB/PB. The MSKCC Pl will in turn report the 
violation to the MSKCC IRB/PB. 
 
16.3.3 Document maintenance 
 
The MSKCC Pl will maintain adequate and accurate records to enable the implementation 
of the protocol to be fully documented and the data to be subsequently verified. 
 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
Participation in this trial is voluntary. The patients will be explained e extent of the 
risks, benefits, toxicities/side effects, alternatives/options for treatment, financial 
costs/burdens, and the voluntary nature of the study. All patients will be required to 
sign a statement of informed consent, which must conform to Institutional Review 
Board guidelines. 
Inclusion of Women and Minorities: Memorial Sloan Kettering Cancer Center has filed 
forms: HHS 441 (civil rights), HHS (handicapped individual), 639-A (sex 
discrimination), and 680 (age discrimination); we also take due notice of the NIH 
policy concerning inclusion of women and minorities in clinical research populations. 
Patients of all races, both male and female, will be accepted into the protocol. The 
proposed study population is as described in section 6.0. 
Exclusion of Lactating or Pregnant Women: Lactating and pregnant women are also 
excluded because of unknown effects of epacadostat and/or pembrolizumab that may 
be harmful to the developing fetus or nursing infant. 
Inclusion of Children in Research: The protocol/project does not include patients 
younger than the age of 18. Although sarcomas are the most common solid tumor in 
children, pediatric sarcomas are treated with specific protocols. 
Benefits: It is possible that this treatment will result in shrinkage of the tumor or in a 
stabilization of an otherwise progressing disease. It is not known, of course, whether 
these or any other favorable events will occur. It is not known whether this treatment 
will affect the overall survival of the patients. 

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Costs: The patient will be responsible for the costs of standard medical care, 
including all drug administration fees and all hospitalizations, even for complications 
charge. 
Research-only biopsies and laboratory tests will no be charged to the patient. 
Research testing on tissue will not be charged to the patient. 
Incentives: No incentives will be offered to the patients/subjects for participation in 
the study. 
Alternatives: For patients with locally advanced and/or metastatic sarcomas 
alternative treatments may include conventional cytotoxic chemotherapies including, 
but not limited to: doxorubicin, ifosfamide, gemcitabine in combination with docetaxel, 
liposomal doxorubicin, dacarbazine, temozolomide, vinorelbine; and also tyrosine 
kinase inhibitors depending on the histology, including, but not limited to: imatinib, 
sorafenib, sunitinib, pazopanib. Epacadostat and pembrolizumab are not yet 
approved by the Food and Drug Administration, but may be part of the treatment in a 
different clinical trial. 
Confidentiality: Every effort will be made to maintain the patient confidentiality. 
Research and hospital records are confidential. Patient's name or any other 
personally identifying information will not be used in reports or publications resulting 
from this study. The Food and Drug Administration or other authorized agencies (e.g., 
qualified monitors from MSKCC or collaborating institutions) may review patients' 
records and pathology slides, as required. 
17.1 Privacy 
MSK's Privacy Office may allow the use and disclosure of protected health 
information pursuant to a completed and signed Research Authorization form. The 
use and disclosure of protected health information will be limited to the individuals 
described in the Research Authorization form. A Research Authorization form must 
be completed by the Principal Investigator and approved by the IRB and Privacy 
Board (IRB/PB). 
The consent indicates that individualized de identified information collected for the 
purposes of this study may be shared with other qualified researchers. Only 
researchers, and members of the research teams at participating sites who have 
received approval from MSK will be allowed to access this information which will not 
include protected health information, such as the participant's name, except for 
dates. It is also stated in the Research Authorization that their research data may be 
shared with other qualified researchers. 

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The consent indicates that samples and genetic information collected may be 
shared with other qualified researchers and placed in online databases. An example 
of an online database is the NIH dbGAP database, which is monitored by the 
National Institutes of Health, and may be made accessible to investigators approved 
by the U.S. government. Such information will not include identifying information 
such as name. It is also stated in the Research Authorization that research data 
(e.g. genomic sequence) may be shared with regulators. The requirements for 
submission of genotype/phenotype data into the NIH dbGAP or any other public 
database will be followed as per the IRB SOP for Genomic Data Sharing. 
 
17.2 
Serious Adverse Event (SAE) Reporting 
An adverse event is considered serious if it results in ANY of the following 
outcomes: 
• Death 
• A life-threatening adverse event 
• An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• A congenital anomaly/birth defect 
• 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 participant and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition 
Note: Hospital admission for a planned procedure/disease treatment is not 
considered an SAE. 
SAE reporting is required as soon as the participant starts investigational 
treatment/intervention. SAE reporting is required for 30-days after the participant's 
last investigational treatment/intervention. Any event that occur after the 30-day 
period that is unexpected and at least possibly related to protocol treatment must be 
reported. 
 
Please note: Any SAE that occurs prior to the start of investigational 
treatment/intervention and is related to a screening test or procedure (i.e., a 
screening biopsy) must be reported. 

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All SAEs must be submitted in PIMS. If an SAE requires submission to the HRPP 
office per IRB SOP RR-408 'Reporting of Serious Adverse Events', the SAE report 
must be submitted within 5 calendar days of the event. All other SAEs must be 
submitted within 30 calendar days of the event. 
 
The report should contain the following information: 
The date the adverse event occurred 
• The adverse event 
• The grade of the event 
• Relationship of the adverse event to the treatment(s) 
• If the AE was expected 
• Detailed text that includes the following 
o An explanation of how the AE was handled 
o A description of the participant's condition 
o Indication if the participant remains on the study 
• If an amendment will need to be made to the protocol and/or consent form 
• If the SAE is an Unanticipated Problem 
The SAE report should be completed as per above instructions. If appropriate, the 
report will be forwarded to the FDA by the IND Office 
All Serious Adverse Events ("SAE") required to be reported pursuant to the Protocol shall 
be provided to lncyte and its representatives by Institution or Principal Investigator within 
twenty-four (24) hours of learning of the event as well as any additional reports agreed 
upon by Institution or Principal Investigator and lncyte. SAE Reports will be sent to 
lncytePhVOpslST@incyte.com. By sending to this e-mail address, the lncyte 
Pharmacovigilance group will receive copies of the reports. This process will be tested and 
established before the first patient is enrolled in the Study. Notwithstanding anything to the 
contrary herein, Institution will have the primary responsibility of reporting adverse events 
("AE") to regulatory authorities. 
 
 
18.0 
INFORMED CONSENT PROCEDURES 
Before protocol-specified procedures are carried out, consenting professionals will 
explain full details of the protocol and study procedures as well as the risks involved 

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to participants prior to their inclusion in the study. Participants will also be informed 
that they are free to withdraw from the study at any time. All participants must sign 
an IRS/PB-approved consent form indicating their consent to participate. This 
consent form meets the requirements of the Code of Federal Regulations and the 
Institutional Review Board/Privacy Board of this Center. The consent form will 
include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of 
supportive care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions 
and to withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting 
professional will fully explain the aspects of patient privacy concerning research 
specific information. In addition to signing the IRB Informed Consent, all patients 
must agree to the Research Authorization component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The 
participant must receive a copy of the signed informed consent form. 
 
 
 
19.0 
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Schwinger W, Klass V, Benesch M, et al. Feasibility of high-dose interleukin-2 in heavily 
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Robbins PF, Morgan RA, Feldman SA, et al. Tumor regression in patients with metastatic 
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Tawbi HA-H, Burgess MA, Crowley J, et al. Safety and efficacy of PD-1 blockade using 
pembrolizumab in patients with advanced soft tissue (STS) and bone sarcomas (BS): Results of 
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Ben-Ami E, Barysauskas CM, Solomon S, et al. lmmunotherapy with single agent 
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Sharma A, Bode B, Studer G, et al. Radiotherapy of human sarcoma promotes an 
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Uyttenhove C, Pilotte L, Theate I, et al. Evidence for a tumoral immune resistance 
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Urakawa H, Nishida Y, Nakashima H, Shimoyama Y, Nakamura S, lshiguro N. Prognostic 
value of indoleamine 2,3-dioxygenase expression in high grade osteosarcoma. Clin Exp 
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29. 
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an immunotherapy model for Ewing sarcoma. Anticancer Res 2014;34:6431-41. 
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Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells 
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Liu X, Newton RC, Friedman SM, Scherle PA. lndoleamine 2,3-dioxygenase, an emerging 
target for anti-cancer therapy. Curr Cancer Drug Targets 2009;9:938-52. 
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Patnaik A, Kang SP, Rasco D, et al. Phase I Study of Pembrolizumab (MK-3475; Anti-PD-1 
Monoclonal Antibody) in Patients with Advanced Solid Tumors. Clin Cancer Res 2015;21:4286-93. 
33. 
Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with 
pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison 
cohort of a phase 1 trial. Lancet (London, England) 2014;384:1109-17. 
34. 
Robert C, Schachter J, Long GV, et al. Pembrolizumab versus lpilimumab in Advanced 
Melanoma. The New England journal of medicine 2015;372:2521-32. 
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Hamid 0, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti- 
PD-1) in melanoma. N Engl J Med 2013;369:134-44. 
36. 
Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for 
PD-L1-Positive Non-Small-Cell Lung Cancer. The New England journal of medicine 
2016;375:1823-33. 
37. 
Seiwert TY, Burtness B, Mehra R, et al. Safety and clinical activity of pembrolizumab for 
treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE- 
012): an open-label, multicentre, phase 1b trial. The Lancet Oncology 2016;17:956-65. 
38. 
Ribas A, Puzanov I, Dummer R, et al. Pembrolizumab versus investigator-choice 
chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, 
phase 2 trial. The Lancet Oncology 2015;16:908-18. 
39. 
Herbst RS, Baas P, Kim OW, et al. Pembrolizumab versus docetaxel for previously treated, 
PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled 
trial. Lancet (London, England) 2016;387:1540-50. 
40. 
Mehra R ST, Mahipal A, et al. Efficacy and safety of pembrolizumab in recurrenUmetastatic 
head and neck squamous cell carcinoma (R/M HNSCC): Pooled analyses after long-term follow-up 
in KEYNOTE-012. ASCO annual meeting; 2016. 
41. 
Daud A BC, Robert C et al. . KEYNOTE-006 study of pembrolizumab (pembro) versus 
ipilimumab (ipi) for advanced melanoma: Efficacy by PD-L1 expression and line of therapy.. 
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Daud Al, Wolchok JD, Robert C, et al. Programmed Death-Ligand 1 Expression and 
Response to the Anti-Programmed Death 1 Antibody Pembrolizumab in Melanoma. Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology 2016;34:4102-9. 
43. 
Merelli B, Massi D, Cattaneo L, Mandala M. Targeting the PD1/PD-L1 axis in melanoma: 
biological rationale, clinical challenges and opportunities. Crit Rev Oncol Hematol 2014;89:140-65. 
44. 
van Rooij N, van Buuren MM, Philips D, et al. Tumor exome analysis reveals neoantigen- 
specific T-cell reactivity in an ipilimumab-responsive melanoma. J Clin Oncol 2013;31:e439-42. 
45. 
Lundegaard C, Lamberth K, Harndahl M, Buus S, Lund 0, Nielsen M. NetMHC-3.0: 
accurate web accessible predictions of human, mouse and monkey MHC class I affinities for 
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Matsushita H, Vesely MD, Koboldt DC, et al. Cancer exome analysis reveals a T-cell- 
dependent mechanism of cancer immunoediting. Nature 2012;482:400-4. 
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DuPage M, Mazumdar C, Schmidt LM, Cheung AF, Jacks T. Expression of tumour-specific 
antigens underlies cancer immunoediting. Nature 2012;482:405-9. 
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Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 
blockade in melanoma. N Engl J Med 2014;371:2189-99. 
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50. 
Gangadhar TC, Hamid, 0, Smith, D.C, . Epacadostat plus pembrolizumab in patients with 
advanced melanoma and select solid tumors: Updated phase 1 results from ECHO- 
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Gangadhar TC H, 0, Smith, D.C. Epacadostat plus pembrolizumab in patients with 
advanced melanoma and select solid tumors: Updated phase 1 results from ECHO- 
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common language for tumor response to immunotherapy: immune-related response criteria using 
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20.0 
APPENDICES 
List appendices here. Appendices will be stored in a separate file and will be submitted in 
electronic and/or paper format. If electronic format, please submit on file per appendix. 
 
 
Appendix A. Procedure for Research Blood and Biopsy Collection 
Research Biopsy Collection 
Given the requirement for fresh and frozen tissue, FFPE archival samples cannot be substituted for 
the baseline or subsequent biopsies. 
The same metastatic tumor site should be biopsied at each time point if feasible. Cores will be 
representative of tumor and obtained with 18-gauge needles where appropriate and be of at least 
1cm in length. Cores will be representative of tumor, and targeted to the de-differentiated 
component in the case of de-differentiated liposarcoma. 
The quality, viability and tumor content of biopsies will be confirmed by the on-call clinical 
pathologist at the time of retrieval. 
A goal of 6 cores should be obtained with a minimum of one formalin-fixed, one fresh and one flash 
frozen in liquid nitrogen. 
 
 
1 FFPE (path core) 
2 Fresh (Immune monitoring facility (IMF)) 
3 Flash frozen (IMF) 
4 Fresh (IMF) 

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5 Flash frozen (IMF) 
 
6 FFPE (path core) 
 
 
 
FFPE cores should be placed in formaldehyde solution and sent to the central pathology lab. 
 
Fresh core should be placed in RPMI media in a falcon tube and transported on ice (RPMI media 
should be kept in a fridge and should not be kept longer than two weeks, fresh bottle are available 
from the IMF lab) 
Flash frozen cores should be placed in a clean cryovial (nunc tube) then placed in liquid nitrogen 
for at least 2 minutes, transported in preferably a dewar flask of liquid nitrogen or in dry ice. 
If any extra cores are obtained they should be flash frozen with liquid nitrogen as above. 
 
Samples will be labeled using an adherent, liquid nitrogen proof label with the following 
information: 
 
 
1) Procurement date 
2) Study IRB number 
3) Study patient number 
4) Time point (baseline or on-treatment) 
5) Anatomical biopsy site 
 
Research blood collection 
 
Please schedule research blood draws for the morning and have them batched and sent to 
the lab by 2pm (they can take up to 2 hours to be delivered by STAT messenger) Bloods 
cannot be processed on the same day if they arrive after 4pm. 
At each research blood collection time point the following samples will be collected: 
 
4x8ml of peripheral venous blood will be collected in green/red speckled top CPT vacutainer tubes. 
The tubes will be inverted 8-10 times to mix the sodium heparin solution. Specimens will be placed 
in a biohazard bag and kept at room temperature. 
 
 
Samples will be labeled with the following information: 
 
 
 
1) Procurement date 
2) Study IRB number 
3) Study patient number 
4) Time point (baseline or week-X) 

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Laboratory Contact Details 
 
Research blood samples and tumor biopsy samples, along with completed requisition forms, are to 
be transported to the Immune Monitoring Facility in the Zuckerman Research Bldg, Room Z- 
1513. At least 24 hr advanced notification prior to biopsy or blood collection must be provided by 
email to the IMF contacts below or entered in the IMF shared calendar 
(zzCAL_LAB_Clinical_Trials/Shared Calendar), with clinical site location and contact information 
from which samples are arriving indicated. Samples must be delivered between the hours of 9 am- 
4 pm to a member of the lab. 
 
 
Rosemarie Ramsawak <ramsawar@mskcc.org> 646-888-3106 
Zhenyu Mu <muz@mskcc.org> 646-888-2114 
Kevin Crawford <crawfork@mskcc.org> 646-888-3106 
Luisa Caro <carol@mskcc.org> 646-888-3106 
 
 
 
 
Appendix B. 
Supportive care guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by 
the treating investigator. Suggested supportive care measures for the management of 
adverse events with potential immunologic etiology are outlined below. Where appropriate, 
these guidelines include the use of oral or intravenous treatment with corticosteroids as 
well as additional anti-inflammatory agents if symptoms do not improve with administration 
of corticosteroids. Note that several courses of steroid tapering may be necessary as 
symptoms may worsen when the steroid dose is decreased. For each disorder, attempts 
should be made to rule out other causes such as metastatic disease or bacterial or viral 
infection, which might require additional supportive care. The treatment guidelines are 
intended to be applied when the investigator determines the events to be related to 
pembrolizumab. 
A2.1 Pneumonitis 
 
All attempts should be made to rule out other causes such as metastatic disease, bacterial 
or viral infection. It is important that patients with a suspected diagnosis of pneumonitis be 
managed as per the guidance below until treatment-related pneumonitis is excluded. 
Treatment of both a potential infectious etiology and pneumonitis in parallel may be 

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warranted. Management of the treatment of suspected pneumonitis with steroid treatment 
should not be delayed for a therapeutic trial of antibiotics. 
 
If an alternative diagnosis is established, the patient does not require management as below. 
Course of Action 
Grade 2 events: 
• 
Hold pembrolizumab. 
• 
Consider pulmonary consultation with bronchoscopy and biopsy/BAL. 
• 
Consider ID consult 
• 
Conduct an in person evaluation approximately twice per week 
• 
Consider frequent Chest X-ray as part of monitoring 
• 
 Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or 
equivalent. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. 
• 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less 
of prednisone or equivalent per day within 12 weeks. 
• 
Second episode of pneumonitis - discontinue pembrolizumab if upon re-challenge 
the patient develops a second episode of Grade 2 or higher pneumonitis. 
 
Grade 3 and 4 events: 
• 
Discontinue pembrolizumab. 
• 
Hospitalize patient 
• 
Bronchoscopy with biopsy and/or BAL is recommended. 
• 
Immediately treat with intravenous steroids (methylprednisolone 125 mg IV). When 
symptoms improve to Grade 1 or less, a high dose oral steroid (prednisone 1 to 2 
mg/kg once per day or dexamethasone 4 mg every 4 hours) taper should be started 
and continued over no less than 4 weeks. 
• 
If IV steroids followed by high dose oral steroids does not reduce initial symptoms 
within 48 to 72 hours, treat with additional anti-inflammatory measures. Discontinue 
additional antiinflammatory measures upon symptom relief and initiate a prolonged 
steroid taper over 45 to 60 days. If symptoms worsen during steroid reduction, initiate 
a re-tapering of steroids starting at a higher dose of 80 or 100 mg followed by a more 
prolonged taper and administer additional antiinflammatory measures, as needed 
• 
Add prophylactic antibiotics for opportunistic infections. 
A2.2 Colitis 
 
All attempts should be made to rule out other causes such as metastatic disease, bacterial 
or parasitic infection, viral gastroenteritis, or the first manifestation of an inflammatory bowel 

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disease by examination for stool leukocytes, stool cultures, a Clostridium difficile titer and 
endoscopy. 
 
Course of Action 
 
Grade 2 Diarrhea/Colitis (4-6 stools/day over baseline, dehydration requiring IV fluids< 24 
hours, abdominal pain, mucus or blood in stool): 
• 
Hold pembrolizumab. 
• 
Symptomatic Treatment 
• 
For Grade 2 diarrhea that persists >1 week, and for diarrhea with blood and/or mucus, 
o Consider GI consultation and endoscopy to confirm or rule out colitis 
o 
Administer oral corticosteroids (prednisone 1-2 mg/kg QD or equivalent) 
• 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
• 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less 
of prednisone or equivalent per day within 12 weeks. 
• 
If symptoms worsen or persist > 3 days treat as Grade 3 
 
Grade 3 Diarrhea/Colitis (or Grade 2 diarrhea that persist for greater than 3 days): 
• 
Hold pembrolizumab. 
• 
Rule out bowel perforation. Imaging with plain films or CT can be useful. 
• 
Recommend consultation with Gastroenterologist and confirmation biopsy with 
endoscopy. 
• 
 Treat with intravenous steroids (methylprednisolone 125 mg) followed by high dose 
oral steroids (prednisone 1 to 2 mg/kg once per day or dexamethasone 4 mg every 4 
hours) When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. Taper over 6 to 8 weeks in patients with 
diffuse and severe ulceration and/or bleeding. 
• 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less 
of prednisone or equivalent per day within 12 weeks. 
• 
If IV steroids followed by high dose oral steroids does not reduce initial symptoms 
within 48 to 72 hours, consider treatment with additional anti-inflammatory measures 
as described in the literature. Discontinue additional anti-inflammatory measures 
upon symptom relief and initiate a prolonged steroid taper over 45 to 60 days. If 
symptoms worsen during steroid reduction, initiate a re-tapering of steroids starting 
at a higher dose of 80 or 100 mg followed by a more prolonged taper and administer 
additional anti-inflammatory measures as needed. 
 
Grade 4 events: 
• 
Permanently discontinue pembrolizumab. 
• 
Manage as per Grade 3. 

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A2.3  Endocrine 
 
All attempts should be made to rule out other causes such as brain metastases, sepsis 
and/or infection. 
 
Hypophysitis or other symptomatic endocrinopathy other than hypo- or 
hyperthyroidism 
 
Grade 2 events: 
• 
Hold pembrolizumab 
• 
Monitor thyroid function or other hormonal level tests and serum chemistries more 
frequently until returned to baseline values. 
• 
Pituitary gland imaging should be considered (MRls with gadolinium and selective 
cuts of the pituitary can show enlargement or heterogeneity and confirm the 
diagnosis). 
• 
Treat with prednisone 40 mg p.o. or equivalent per day. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. Replacement of appropriate hormones may be required as the steroid dose 
is tapered. 
• 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less 
of prednisone or equivalent per day within 12 weeks. 
• 
Consultation with an endocrinologist may be considered. 
 
Grade 3 events: 
• 
Hold pembrolizumab. 
• 
Endocrine consultation is recommended. 
• 
Rule out infection and sepsis with appropriate cultures and imaging. 
• 
Treat with an initial dose of methylprednisolone 1 to 2 mg/kg intravenously followed 
by oral prednisone 1 to 2 mg/kg per day. When symptoms improve to Grade 1 or less, 
steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is 
tapered. 
• 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less 
of prednisone or equivalent per day within 12 weeks. 
• 
Hypophysitis with clinically significant adrenal insufficiency and hypotension, 
dehydration, and electrolyte abnormalities (such as hyponatremia and hyperkalemia) 
constitutes adrenal crisis. 
• 
Hospitalization and endocrine consultation should be considered. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 17-508 A(8) 
Approval date: 07-May-2024 
Page 106 of 112 
 
 
 
 
Grade 4 events: 
• 
Discontinue pembrolizumab. 
• 
Manage as per Grade 3 
 
 
Thyroid disorders can occur at any time during treatment. Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during treatment, 
and as indicated based on clinical evaluation) and for clinical signs and symptoms of 
thyroid disorders. 
 
Grade 2 events (and Grade 3-4 hypothyroidism): 
• 
Monitor thyroid function or other hormonal level tests and serum chemistries more 
frequently until returned to baseline values. 
• 
Thyroid hormone and/or steroid replacement therapy to manage adrenal 
insufficiency. 
• 
 Therapy with pembrolizumab can be continued while treatment for the thyroid 
disorder is instituted. 
• 
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested as 
initial therapy. 
• 
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care. 
• 
Consultation with an endocrinologist may be considered. 
 
Grade 3 hyperthyroidism events: 
• 
Hold pembrolizumab. 
• 
Rule out infection and sepsis with appropriate cultures and imaging. 
• 
Treat with an initial dose of methylprednisolone 1 to 2 mg/kg intravenously followed 
by oral prednisone 1 to 2 mg/kg per day. When symptoms improve to Grade 1 or less, 
steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is 
tapered. 
• 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less 
of prednisone or equivalent per day within 12 weeks. 
 
Grade 4 events: 
• 
Discontinue pembrolizumab. 
• 
Manage as per Grade 3 
 
 
A2.4 Hematologic 

Memorial Sloan Kettering Cancer Center 
IRB Number: 17-508 A(8) 
Approval date: 07-May-2024 
Page 107 of 112 
 
 
 
 
All attempts should be made to rule out other causes such as metastases, sepsis and/or 
infection. Relevant diagnostic studies such as peripheral blood smear, reticulocyte count, 
LOH, haptoglobin, bone marrow biopsy or Coomb's test, etc., should be considered to 
confirm the diagnosis. 
 
Course of Action 
Grade 2 events: 
• 
Hold pembrolizumab 
• 
Prednisone 1-2 mg/kg daily may be indicated 
• 
Consider Hematology consultation. 
• 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less 
of prednisone or equivalent per day within 12 weeks. 
 
Grade 3 events: 
• 
Hematology consultation. 
• 
Hold pembrolizumab Discontinuation should be considered as per specific protocol 
guidance. 
• 
 Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg p.o. (or equivalent) 
as 
• 
appropriate 
• 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less 
of prednisone or equivalent per day within 12 weeks. 
 
Grade 4 events: 
• 
Hematology consultation 
• 
Discontinue pembrolizumab for all solid tumor indications; refer to protocol for 
hematologic 
• 
malignancies. 
• 
Treat with methylprednisolone 
 
3.5 Hepatic 
Course of Action 
Grade 2 events: 
• 
Hold pembrolizumab 
• 
Monitor liver function tests more frequently until returned to baseline values (consider 
weekly). 

Memorial Sloan Kettering Cancer Center 
IRB Number: 17-508 A(8) 
Approval date: 07-May-2024 
Page 108 of 112 
 
 
 
 
• 
Treat with 0.5-1 mg/kg/day methylprednisolone or oral equivalent and when LFT 
returns 
• 
to grade 1 or baseline, taper steroids over at least 1 month, consider prophylactic 
• 
antibiotics for opportunistic infections, and resume pembrolizumab per protocol 
• 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less 
of prednisone or equivalent per day within 12 weeks. 
• 
Permanently discontinue pembrolizumab for patients with liver metastasis who begin 
treatment with Grade 2 elevation of AST or ALT, and AST or ALT increases 50% 
relative to baseline and lasts 1 week. 
 
Grade 3 events: 
• 
Discontinue pembrolizumab when AST or ALT >5.0 times ULN and/or total bilirubin 
>3.0 times ULN. 
• 
Consider appropriate consultation and liver biopsy to establish etiology of hepatic 
injury, if necessary 
• 
Treat with high-dose intravenous glucocorticosteroids for 24 to 48 hours. 
o 
When symptoms improve to Grade 1 or less, a steroid taper with 
dexamethasone 4 mg every 4 hours or prednisone at 1 to 2 mg/kg should be 
started and continued over no less than 4 weeks. 
• 
 If serum transaminase levels do not decrease 48 hours after initiation of systemic 
steroids, oral mycophenolate mofetil 500 mg every 12 hours may be given. lnfliximab 
is not recommended due to its potential for hepatotoxicity. 
• 
Several courses of steroid tapering may be necessary as symptoms may worsen 
when the steroid dose is decreased. 
• 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less 
of prednisone or equivalent per day within 12 weeks. 
 
Grade 4 events: 
• 
Permanently discontinue pembrolizumab 
• 
Manage patient as per Grade 3 above 
 
 
A2.6 Neurologic 
 
All attempts should be made to rule out other causes such as metastatic disease, other 
medications or infectious causes. 
Course of Action 
Grade 2 events: 
• 
Moderate (Grade 2) - consider withholding pembrolizumab. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 17-508 A(8) 
Approval date: 07-May-2024 
Page 109 of 112 
 
 
 
 
• 
Consider treatment with prednisone 1-2 mg/kg p.a. daily as appropriate 
• 
Consider Neurology consultation. Consider biopsy for confirmation of diagnosis. 
• 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less 
of prednisone or equivalent per day within 12 weeks. 
 
Grade 3 and 4 events: 
• 
Discontinue pembrolizumab 
• 
Obtain neurology consultation. Consider biopsy for confirmation of diagnosis 
• 
Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent 
once per day. If condition worsens consider IVIG or other immunosuppressive 
therapies as per local guidelines 
• 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
A2.7 Ocular 
 
All attempts should be made to rule out other causes such as metastatic disease, infection 
or other ocular disease (e.g. glaucoma or cataracts). However the AE should be reported 
regardless of etiology. 
Course of Action 
Grade 2 events: 
• 
Evaluation by an ophthalmologist is strongly recommended. 
• 
Treat with topical steroids such as 1% prednisolone acetate suspension and 
iridocyclitics. 
• 
Discontinue pembrolizumab as per protocol if symptoms persist despite treatment 
with topical immunosuppressive therapy. 
 
Grade 3 events: 
• 
Evaluation by an ophthalmologist is strongly recommended 
• 
Hold pembrolizumab and consider permanent discontinuation as per specific protocol 
guidance. 
• 
 Treat with systemic corticosteroids such as prednisone at a dose of 1 to 2 mg/kg per 
day. 
o When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
• 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less 
of prednisone or equivalent per day within 12 weeks. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 17-508 A(8) 
Approval date: 07-May-2024 
Page 110 of 112 
 
 
 
 
Grade 4 events: 
• 
Evaluation by an ophthalmologist is strongly recommended 
• 
Permanently discontinue pembrolizumab. 
• 
Treat with corticosteroids as per Grade 3 above 
A2.8 Renal 
 
All attempts should be made to rule out other causes such as obstructive uropathy, 
progression of disease, or injury due to other chemotherapy agents. A renal consultation is 
recommended. However the AE should be reported regardless of etiology. 
Course of Action 
Grade 2 events: 
• 
Hold pembrolizumab 
• 
Treatment with prednisone 1-2 mg/kg p.o. daily. 
• 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less 
of prednisone or equivalent per day within 12 weeks. 
 
Grade 3-4 events: 
• 
Discontinue pembrolizumab 
• 
Renal consultation with consideration of ultrasound and/or biopsy as appropriate 
• 
 Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone IV or 
equivalent once per day. 
o When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
 
A2.9 Skin - Rash and Pruritus 
Course of Action 
Grade 2 events: 
• 
Symptomatic treatment should be given such as topical glucocorticosteroids (e.g., 
betamethasone 0.1% cream or hydrocortisone 1%) or urea-containing creams in 
combination with oral antipruritics (e.g., diphenhydramine HCI or hydroxyzine HCI). 
• 
Treatment with oral steroids is at physician's discretion for Grade 2 events. 
 
Grade 3 events: 
• 
Hold pembrolizumab. 
• 
Consider Dermatology Consultation and biopsy for confirmation of diagnosis. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 17-508 A(8) 
Approval date: 07-May-2024 
Page 111 of 112 
 
 
 
 
• 
 Treatment with oral steroids is recommended, starting with 1 mg/kg prednisone or 
equivalent once per day or dexamethasone 4 mg four times orally daily. 
o When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
• 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less 
of prednisone or equivalent per day within 12 weeks. 
 
Grade 4 events: 
• 
Permanently discontinue pembrolizumab. 
• 
Dermatology consultation and consideration of biopsy and clinical dermatology 
photograph. 
• 
Initiate steroids at 1 to 2 mg/kg prednisone or equivalent. 
o When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
 
A2.10 Other 
 
All attempts should be made to rule out other causes. Therapeutic specialists should be 
consulted as appropriate. 
 
Course of Action 
 
Grade 2 events or Grade 1 events that do not improve with symptomatic treatment: 
• 
Withhold pembrolizumab. 
• 
Systemic corticosteroids may be indicated. 
• 
Consider biopsy for confirmation of diagnosis. 
• 
If pembrolizumab held and corticosteroid required, manage as per grade 3 below. 
 
Grade 3 events: 
• 
Hold pembrolizumab 
• 
Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent 
once per day. 
• 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
• 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less 
of prednisone or equivalent per day within 12 weeks. Otherwise, pembrolizumab 
treatment may be restarted and the dose modified as specified in the protocol 
 
Grade 4 events: 

Memorial Sloan Kettering Cancer Center 
IRB Number: 17-508 A(8) 
Approval date: 07-May-2024 
Page 112 of 112 
 
 
 
 
• 
 Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent 
once per day. 
• 
Discontinue pembrolizumab