Pembrolizumab (MK-3475) and Epacadostat (INCB024360) in Thymic Carcinomas
Phase: PHASE2
Conditions: Thymic Carcinoma, Thymus Neoplasms, Thymus Cancer
Sponsor: Georgetown University

 
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Protocol Version 6.0 Dated February 15, 2018 
 
 
 
SPONSOR:  Georgetown University Medical Center 
 
 
Georgetown Lombardi Comprehensive Cancer Center 
 
 
TITLE: A phase II study of MK-3475 in patients with thymic carcinoma 
 
   Pembrolizumab (MK-3475) and Epacadostat (INCB024360) in thymic carcinomas 
 
IND NUMBER: 125098/136867 
 
 
 
Principal Investigator: Giuseppe Giaccone, MD PhD 
 
Sub-investigators: Deepa Subramanian, MD, Stephen Liu, MD, Jillian Thompson NP 
 
Pathology: Bhaskar Kallakury, MD, Jeoffrey Chahine, PhD 
 
Statistician: Ming Tan, PhD 
 
Biomarker Research: Yuwen Zhang, PhD 
 
Affiliation: Georgetown University, Lombardi Comprehensive Cancer Center, Washington 
DC 
 
 
Additional Institutions: 
 
Co-Investigator (Affiliated Institution): Martin Gutierrez, MD 
 
Affiliation: Hackensack University Medical Center, Hackensack N.J. 
 
 
Co-Investigator: Gregory Riely 
 
Affiliation: Memorial Sloan Kettering Cancer Center, New York 
 
 
Drugs and Support provided by Merck and Incyte 
 

 
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Protocol Version 6.0 Dated February 15, 2018 
 
 
1.0 TRIAL SUMMARY 
Abbreviated Title 
MK-3475 in thymic carcinomas 
Trial Phase 
II 
Clinical Indication 
Thymic carcinoma 
Trial Type 
Non-randomized 
Type of control 
Historical  
Route of administration 
IV 
Trial Blinding 
No 
Treatment Groups  
One treatment group only 
Number of trial subjects 
21-41 
Estimated duration of trial 
24 months 
Duration of Participation 
24 months 
 
 
 
AMENDED TRIAL SUMMARY 
Abbreviated Title 
Pembrolizumab (MK-3475) and Epacadostat (INCB024360) in thymic 
carcinomas 
Trial Phase 
II 
Clinical Indication 
Thymic carcinoma 
Trial Type 
Non-randomized 
Type of control 
Historical  
Route of administration 
IV and PO 
Trial Blinding 
No 
Treatment Groups  
One treatment group only 
Number of trial subjects 
26 
Estimated duration of trial 
24 months 
Duration of Participation 
24 months 
 
 
 
 
2.0 TRIAL DESIGN 
2.1 Trial Design 
This is a phase II non-randomized clinical trial in patients with thymic carcinomas who failed prior 
systemic therapy. 
 
 

 
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REASON FOR AMENDMENT  
The results from 40 eligible patients treated with pembrolizumab showed enough evidence of 
activity to warrant further study in thymic carcinoma. The combination of pembrolizumab and 
epacadostat (an IDO1) inhibitor appears to have additive if not synergistic activity in preclinical 
models and very promising activity in advanced melanoma where sufficient information is 
available. A combination of pembrolizumab and epacadostat will be tested in an expansion cohort 
of this study in thymic carcinoma. Patients treated with pembrolizumab single agent will not be 
allowed. 
2.2 Trial Diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AMENDED TRIAL DIAGRAM 
 
Continuous 
Pembrolizumab 
Treatment: 200mg 
every 3 weeks 
Epacadostat 
100mg BID p.o. ** 
Advanced 
(inoperable) 
thymic 
carcinoma 
At least 1 prior line of 
chemotherapy  
Measureable disease by 
RECIST v1.1 criteria 
ECOG PS 0-1 
Adequate organ and marrow 
function 
Unacceptable  
Toxicity 
Stop 
Treatment 
PD 
Restage by modified 
RECIST: Tumor 
measurements are 
repeated every 6 weeks 
for patients on treatment 
< 1 year; every 12 weeks 
thereafter. 
CR, PR, SD 
**Subjects will continue treatment 
until unacceptable toxicity, death, PD, 
or 
withdrawal 
of 
Pembrolizumab/Epacadostat 
study 
treatment: 24 months (35 cycles) 
Continuous MK-
3475 Treatment: 
200mg every 3 
weeks** 
Advanced 
(inoperable) 
thymic 
carcinoma 
At least 1 prior line of 
chemotherapy  
Measureable disease by 
RECIST v1.1 criteria 
ECOG PS 0-2 
Adequate organ and marrow 
function 
Unacceptable  
Toxicity 
Stop 
Treatment 
PD 
Restage by modified 
RECIST: Tumor 
measurements are 
repeated every 6 weeks 
for patients on treatment 
< 1 year; every 12 weeks 
thereafter. 
CR, PR, SD 
**Subjects will continue treatment 
until unacceptable toxicity, death, PD, 
or withdrawal of MK-3475 study 
treatment: 24 months 

 
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3.0 
OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1 
Primary Objective(s) & Hypothesis(es) 
(1) 
Objective: Response Rate 
Hypothesis:  MK-3475 will determine a response rate of at least 20% in this rare tumor type 
3.2 
Secondary Objective(s) & Hypothesis(es) 
(1) 
Objective:  Progression-free survival, overall survival, tolerability 
Hypothesis:  MK-3475 will increase progression-free survival and overall survival compared to 
historical controls, and will be well tolerated. 
3.3 
Exploratory Objectives 
(1) 
Correlate PDL-1 expression in tumor samples and outcome to treatment 
(2) 
Develop conditionally reprogrammed cell from tumors whenever possible, in order to 
genetically characterize the tumor of origin 
(3) 
Perform Next-generation sequencing on tumors and correlate the molecular profile with 
treatment outcome 
3.0 AMENDED OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1 Primary Objective(s) & Hypothesis(es) 
(2) Objective: Response Rate 
Hypothesis:  Pembrolizumab (MK-3475) and Epacadostat (INCB024360) will determine a 
response rate of at least 45% in this rare tumor type 
3.2 Secondary Objective(s) & Hypothesis(es) 
(1) Objective:  Progression-free survival, overall survival, tolerability 
Hypothesis:  Pembrolizumab (MK-3475) and Epacadostat (INCB024360) will increase 
progression-free survival and overall survival compared to historical controls (sunitinib or 
pembrolizumab single agent, see below), and will be well tolerated. 
3.3 Exploratory Objectives 
(1) Correlate PDL-1 expression in tumor samples and outcome to treatment 
(2) Develop conditionally reprogrammed cell from tumors whenever possible, in order to 
genetically characterize the tumor of origin 

 
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(3) Perform Next-generation sequencing on tumors and correlate the molecular profile with 
treatment outcome 
(4) Assess IDO1 expression in tumor samples and correlate it to treatment outcome 
(5) Explore kynurein/tryptophan blood levels before and during treatment. 
 
4.0 BACKGROUND & RATIONALE 
4.1 Background 
4.1.1 Pharmaceutical and Therapeutic Background for Pembrolizumab (MK-3475) 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [1].  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in various 
solid tumors.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-cells / 
FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-term survival in 
many solid tumors. Tumor-infiltrating lymphocytes can be expanded ex vivo and re-infused, 
inducing durable objective tumor responses in cancers such as melanoma [2; 3]. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.  The normal function of PD-1, expressed on the cell surface of activated T-cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related to 
CD28 and CTLA-4, which has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or PD-L2) [4; 5].  The structure of murine PD-1 has been 
resolved [6].  PD-1 and family members are type I transmembrane glycoproteins containing an Ig 
Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail which is 
responsible for the binding of signaling molecules.  The cytoplasmic tail of PD-1 contains 2 
tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and 
an immunoreceptor tyrosine-based switch motif (ITSM).  Following T-cell stimulation, PD-1 
recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, 
leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70, which 
are involved in the CD3 T-cell signaling cascade [5; 7; 8; 9]. The mechanism by which PD-1 down 
modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both molecules 
regulate an overlapping set of signaling proteins [10; 11].  PD-1 was shown to be expressed on 
activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural 
Killer cells [12; 13].  Expression has also been shown during thymic development on CD4-CD8- 
(double negative) T-cells as well as subsets of macrophages and dendritic cells [14].  The ligands 
for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell 
types, including non-hematopoietic tissues as well as in various tumors [11; 15; 16; 17].  Both 
ligands are type I transmembrane receptors containing both IgV- and IgC-like domains in the 
extracellular region and contain short cytoplasmic regions with no known signaling motifs.  

 
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Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell 
receptor.  PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably on 
vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting 
cells found in lymphoid tissue or chronic inflammatory environments.  PD-L2 is thought to control 
immune T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-
cell function in peripheral tissues [11].  Although healthy organs express little (if any) PD-L1, a 
variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor.  High 
expression of PD-L1 on tumor cells (and to a lesser extent of PD-L2) has been found to correlate 
with poor prognosis and survival in various cancer types, including renal cell cancer [18], 
pancreatic carcinoma [19], hepatocellular carcinoma [20], and ovarian carcinoma [21].  PD-1 has 
been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma [22].  This 
suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and should 
be considered as an attractive target for therapeutic intervention. 
MK-3475 (previously known as SCH 900475) is a potent and highly selective humanized 
monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction 
between PD-1 and its ligands, PD-L1 and PD-L2.   
It is clear that whereas there are tumors that are very sensitive to PD-1 blockade, the majority of 
tumors are not and combinations with other strategies are warranted in order to increase efficacy. 
Combinations with other immunological agents is of particular interest. The CTLA4 and PD1 
combination has been shown to be superior to PD1 and CTLA4 single agents in metastatic 
melanoma, however the combination has higher rates of severe toxicities. 
4.1.2 IDO1 and Epacadostat (INCB024360), preclinical and clinical developmentIndoleamine 
2,3-dioxygenase (IDO1) is a heme-containing 
monomeric oxidoreductase, which is expressed in 
tumor cells and antigen-presenting cells. IDO1 
mediates catabolism of tryptophan (Trp) to 
kynurenine (Kyn) within immune cells and within 
a subset of tumor cells and increases local levels of 
cytotoxic tryptophan metabolites. See Figure 
below. 
Tryptophan catabolism results in the inhibition of 
antitumor, 
cell-mediated 
immune 
responses 
through reduced cytotoxic and helper T-cell 
activities and increased regulatory (suppressor) T-
cell activities. 
IDO1 is highly expressed in multiple tumor types, 
including melanoma, NSCLC, ovarian cancer, 
pancreatic cancer, colorectal cancer, glioblastoma, 
squamous cell carcinoma of the head and neck, 
endometrial carcinoma, DLBCL, renal cell cancer 

 
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and triple negative breast cancer.  Accumulation of IDO1 expression in lymphnodes of melanoma 
patients was associated with decreased survival. 
Epacadostat (INCB024360) is a potent, highly selective and orally available small molecule IDO1 
inhibitor. In tumor-bearing mice, decreased Kyn levels (78%–87%) were observed in plasma, 
tumors, and lymph nodes.  
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.  
The chemical name of epacadostat is (Z)-N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-(2-
(sulfamoylamino)ethylamino)-1,2,5-oxadiazole-3-carboximidamide and the structural formula is 
presented in the Figure below. Epacadostat has a molecular formula of C11H13BrFN7O4S and a 
molecular weight of 438.23. 
In preclinical models, IDO1-expressing tumors were 
sensitive to epacadostat monotherapy. IDO1 inhibition 
leads to increased number of TILs and decreased 
suppressor cells in tumors and enhanced IFN-γ 
secretion from TILs was observed following IDO1 
inhibitor treatment. 
A second gene, IDO2, was discovered that shares 
structural similarity (43% identity) to IDO1. Whereas human IDO1 can efficiently convert Trp to 
Kyn, human IDO2 does not do so effectively; therefore, the precise biological function of IDO2 is 
unclear. 
Epacadostat did not produce any adverse effects after a single oral dose to rats (1000 mg/kg) in 
central nervous system (CNS) or respiratory safety pharmacology studies, and no adverse effects 
were noted in a cardiovascular study in telemeterized dogs. In repeat oral dose studies in mice, no 
adverse epacadostat-related effects were observed in any parameter evaluated. Clinical 
observations associated with epacadostat administration in the 3-month dog study included thin 
appearance and increased incidence of emesis and diarrhea (≥ 250 mg/kg per day) and lower food 
consumption and body weight loss (1000 mg/kg per day). Microscopic findings included 
lymphangiectasia in the small intestine (≥ 250 mg/kg per day), hepatocellular hypertrophy, 
lymphoid depletion of the thymus, and chronic inflammation with fibrosis and subacute 
inflammation in the large intestine (1000 mg/kg per day). 
Combinations of epacadostat and checkpoint inhibition (both CTLA4 and PD-1 antibodies) were 
associated with enhanced T-cell proliferation and cytokine secretion in vivo. The combination of 
epacadostat and either an anti-mouse CTLA4 or an anti-mouse PDL1 antibody was also shown to 
act synergistically in significantly reducing tumor growth in a melanoma xenograft model. 
Several clinical studies have been completed or are ongoing with epacadostat as single agent or in 
combination. 

 
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Study INCB 24360-101 was a completed Phase 1 with 52 patients. Subjects were administered 
doses of epacadostat ranging from 50 mg once daily (QD) to 700 mg BID. Fatigue was the most 
frequently reported TEAE (36 subjects, 69.2%). Two dose-limiting toxicities (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 (MTD) was not determined. Epacadostat plasma 
concentrations attained the peak values (Cmax) typically at 2 hours (median Tmax) postdose; the 
t½ was 2.9 hours. A high-fat meal did not cause a statistically significant change in epacadostat 
plasma exposures. 
The clinical study ECHO-201 in untreated metastatic melanoma showed a response rate of 31% 
(vs 11% of historical control of ipilimumab) with the combination of ipilimumab and epacadostat. 
A large phase I followed by expansion cohorts (ECHO-202) in several tumor types has been 
performed with the combination of epacadostat and pembrolizumab. Out of 62 patients assessed 
in the phase I part, no excess toxicity was observed and no autoimmune disorders were noted. Out 
of 19 patients with melanoma 11 responded (58%). Based on these data a phase III study of this 
combination is ongoing in untreated melanoma (Gangadhar et al. ESMO 2016). In 12 advanced 
NSCLC there were 5 responders. 
Five patients (8%) experienced treatment-related AEs that led to discontinuation, including 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. There were no treatment-related deaths. 
Table 1 below summarizes the treatment-related AEs. 
Table1.  Related TEAEs ≥ 5% or Grade 3/4 TEAEs in ≥ 1 Subject in the Phase 1 Population in 
Study INCB 24360202 
 
* All-grade AEs ≥5% or grade 3/4 AEs in ≥1 patient in total phase 1 population. † Rash includes 
the following MedDRA preferred terms: rash, rash erythematous, rash generalized, rash maculo-
papular, rash pruritic, and rash follicular. ‡ Pruritus includes the following MedDRA preferred 
terms: pruritus and pruritus generalized. 
 

 
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Table 2: Summary of Treatment-Related Potential Immune-Related Adverse Events at 100 mg 
BID (Data Cutoff 28 MAR 2016) 
Variable, n (%) 
Epacadostat 
100 mg BID (Phase 1)a 
(n = 18) 
Epacadostat 
100 mg BID (Phase 2)b 
(n = 99) 
Rashc  
0 
13 (13.1) 
Pruritus  
0 
4 (4.0) 
Diarrhea  
4 (22.2) 
3 (3.0) 
Arthralgia  
4 (22.2) 
3 (3.0) 
Hypothyroidism  
1 (5.6) 
0 
Adrenal insufficiency  
0 
0 
Colitis  
0 
0 
Pneumonitis  
0 
0 
aIn combination with pembrolizumab 2 mg/kg IV Q3W or 200 mg IV Q3W.  
bIn combination with pembrolizumab 200 mg IV Q3W.  
cRash includes the following terms: rash, rash generalized, rash macular, rash maculo-papular. 
4.1.3 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochures for Preclinical and Clinical data for both agents. 
4.2 
Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
Thymic epithelial tumors (TET) are rare tumors of the thymic gland. There are approximately 400-
600 new cases each year in the United States. Thymic carcinomas represent approximately 10% 
of the thymic malignancies, which are grossly divided into thymomas (WHO A – B) and thymic 
carcinoma (WHO C) [23]. Thymic carcinomas represent the most aggressive histological type 
among thymic malignancies. Survival depends on stage at presentation, histological features and 
completeness of resection when resectable. Many thymic carcinomas are unresectable and develop 
distant metastases. This is different from thymomas, especially the A subtype, which have about 
100% survival at 10 years. The survival of thymic carcinomas is about 40% at 5 years. Another 
difference between thymomas and thymic carcinomas is that autoimmune syndromes, of which 
myasthenia gravis represents the most common one (30-40% in thymomas) are exclusively seen 
in thymomas but not in thymic carcinomas [24; 25; 26]. Of 17 patients tested for anti-cytokine 
autoantibodies, the majority of thymomas had one or more autoantibody present even if not 
associated to any autoimmune syndrome. In contrast, of 4 thymic carcinomas tested, only 1 had 
autoantibodies detectable in the blood [27]. In patients treated with cixutumumab (an antibody 
against IGF1R) 9/37 patients with thymoma developed an autoimmune syndrome but none (0/12) 
of the patients with thymic carcinomas, and patients with autoimmune syndromes had a worse 
survival [26]. Patient selection based on histology appears therefore very important. 
Systemic treatment of patients with thymic epithelial tumors in advanced stage is chemotherapy. 
However chemotherapy induces responses in less than 50% of patients with thymic carcinomas. 
The classical PAC regimen (cisplatin, doxorubicin, cyclophosphamide) and more recently reported 
carboplatin and paclitaxel are among the more commonly utilized regimens [23; 28]. There is no 
standard treatment after failure of initial chemotherapy. I have conducted several phase II studies 

 
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in patients with TETs over the years and more recently with the use of targeted agents [29; 30; 31; 
26; 32]. The most promising anticancer agent tested has been sunitinib, with a response rate of 
26% (6/23) in patients with thymic carcinomas [32]. However tolerance has been suboptimal in 
this patient population. 
Response rate in several phase II studies in thymic carcinomas ranged from 0% (several studies) 
to 26% with sunitinib (the highest response reported to date) [32]. Progression-free survival ranged 
from 1.7 [26] to 7.2 months [32]. 
There is an urgent need to develop active and well tolerated treatments for these patients. 
Molecularly, thymic carcinomas are the most frequently mutated tumors among TETs with p53 
mutations found in 26% of 47 cases that we analyzed using next generation sequencing [33]. The 
presence of frequent somatic mutations may make tumors more sensitive to blockade of immune 
check-points. 
Expression of PDL-1 and PDL-2 has been demonstrated in normal cortical and medullary 
epithelial cells of the thymus from which thymic epithelial tumors derive. Importantly, 100% of 
invasive thymoma and 88% of thymic carcinomas were found positive for PD-L1 expression [15]. 
It is conceivable that presence of PDL-1 expression on thymic carcinoma cells might inhibit the 
immune system, similarly to what has been observed in several epithelial tumors. 
PDL-1 is expressed on thymic stromal cells  [34], and given the cellular relationship of normal 
thymus and thymic carcinoma, it is highly likely that thymic carcinoma is a prototypic disease for 
expression of PDL-1 and consequent limited success of therapy.  We have a tissue bank and a 
tissue microarray of clinically annotated specimens from over 200 patients from which we can 
determine the incidence of PDL-1 expression.  Approximately 100 are from thymic carcinomas. 
We intend to confirm the high level of expression as described before [15]. 
Recently a TMA study was presented [35] where 69 TETs and 17 normal thymic controls were 
included. Immunohistochemistry used a monoclonal antibody (clone 15, Sino Biological, Beijing, 
China) to human PD-L1 using human placenta for staining titration. To distinguish PD-L1 
expression on epithelial cells from that on lymphocytes, a CK5/6 cytokeratin stain was used. The 
epithelial cells of both TETs and normal controls stained positive for PD-L1. All TETs had some 
level of positivity, however, PD-L1 staining intensity was significantly higher in TETs than 
controls. PD-L1 high TETs are more frequently of WHO subtype B2, B3, & C. PD-L1 high TETs 
was also associated with a worse prognosis (adjusted age/gender: OS, HR 5.4, p=0.035 and RFS 
HR 2.94, p=0.064). Three out of 4 tested thymic carcinomas displayed high PDL-1 expression. 
The PD-1 pathway functions to limit unwanted or excessive immune responses, including 
autoimmune reactions. PD-L1 is typically expressed at low levels on various non-hematopoietic 
tissues, and PDL-2 is only detectably-expressed on antigen-presenting cells in the lymphoid tissue 
or chronic inflammatory environments. PDL-1 is also expressed in the tumor microenvironment 
of various cancers and activation of the PD-1 pathway may be a critical mechanism to evade T-
cell mediated tumor rejection.  

 
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So far reports of autoimmune disease in patients treated with PD-1 or PDL-1 antibodies have been 
rare, however, given the propensity for some subtypes of thymomas to be associated with a broad 
range of auto-immune syndromes (myasthenia gravis being the most frequent), this study will only 
include patients with thymic carcinomas, which are not known to be associated with autoimmune 
syndromes. 
Initial studies with PD-1 and PDL-1 antibodies have produced dramatic responses of significant 
duration in solid tumors traditionally known to be sensitive to immunotherapeutic approaches, 
such as renal cell carcinoma and melanoma, as well as epithelial tumors that are typically known 
to be refractory, such as non-small cell lung cancer. Pembrolizumab (MK-3475), a PD-1 antibody, 
has shown response rate of approximately 38% in patients with melanoma [36] and ~20% in 
patients with NSCLC. Pembrolizumab is presently approved for several solid tumors. Given the 
potential important role of the PD-1/PDL-1 axis in TETs, and the reportedly high level of 
expression of PDL-1 in these tumors, we completed a phase II study in thymic carcinoma using 
Pembrolizumab. 
RATIONALE FOR THE AMENDMENT 
The initial study of pembrolizumab alone recruited 41 patients with thymic carcinoma from March 
2015 to December 2016 as a single institution at Georgetown University Medical Cancer. One 
patient was ineligible because of increased liver enzymes and received only one course of 
treatment. All the other patients are eligible. None had autoimmune disorders in their history or at 
start of treatment. Patient characteristics of the 40 eligible patients are listed in Table 3 below: 
Table 3. 
Patient characteristic 
# 
Gender: M/F 
29/12 
Median age (range), yrs 
57 (25-80) 
Race: Caucasian/African American/Latino/ Asian 
33/2/1/4 
Histology: squamous / thymic carcinoma unspecified / 
neuroendocrine / Castle 
14/19/6/1 
Stage: IVA/IVB 
6/34 
Performance status: 0/1/2 
19/19/2 
 
The treatment was in general well tolerated, and in line with the toxicity profile of pembrolizumab. 
However 
6 
patients 
developed 
autoimmune 
disorders: 
(1 
myositis/myocarditis; 
1 
myositis/myocarditis/hepatitis/MG; 1 myositis/hepatitis; 1 bullous pemphigoid, 1 hepatitis; 1 
hepatitis/pancreatitis/diabetes mellitus type 1). All autoimmune disorders were successfully 
treated with steroids, except the patient who developed diabetes. The two patients who developed 
myocarditis required pacemaker placing. Five patients developed hypothyroidism and one 
hyperthyroidism. The only factor that was significantly associated with risk of developing a severe 
autoimmune disorder was female gender (4/6; p=.026).  

 
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As of January 2017, all 40 eligible patients had at least one restaging assessment and the response 
rate is 22.5%: 1 complete response, 8 partial responses (plus 1 unconfirmed), 20 patients with 
stable disease and 11 progressions. Two partial responses show minimal residual disease and 
negative PET scans. Two responders have progressed and 5 responses are beyond 12 months 
duration. 
Of 29 cases where PD-L1 staining was tested (Dako 22C3), high PD-L1 (>50% tumor cells 
positive) was found in 8 cases (28%); of the 9 responders 6 had high PD-L1 expression. Targeted 
next generation sequencing performed so far in 15 cases did not show correlation between 
mutational burden and response. 
Further assessment of PD-L1 and completion of NGS are underway, as well as Nanostring. 
Given the relatively high response rate, similar to other tumors where pembrolizumab is active 
(e.g. lung cancer), and the long duration of responses, despite the onset of newly diagnosed 
autoimmune disorders, it is felt that an attempt should be made to try and increase the response 
rate even further by combining pembrolizumab with the IDO inhibitor Epacadostat 
(INCB024360).  The addition of Epacadostat to pembrolizumab has led to an increase in the 
response rate in melanoma and non-small cell lung cancer (ASCO 2017) and an attempt to increase 
the response rate in patients with thymic carcinoma beyond that of pembrolizumab single agent is 
warranted.  
 
4.2.2 Rationale for Dose Selection/Regimen/Modification  
Pembrolizumab 
An open-label Phase I trial (Protocol 001) was conducted to evaluate the safety and clinical activity 
of single agent Pembrolizumab.  The dose escalation portion of this trial evaluated three dose 
levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with 
advanced solid tumors.  All three dose levels were well tolerated and no dose-limiting toxicities 
were observed.  This first in human study of Pembrolizumab showed evidence of target 
engagement and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg 
and 10 mg/kg Q2W).  No MTD has been identified to date.  10.0 mg/kg Q2W, the highest dose 
tested in PN001, will be the dose and schedule utilized in Cohorts A, B, C and D of this protocol 
to test for initial tumor activity.  Recent data from other clinical studies within the Pembrolizumab 
program has shown that a lower dose of Pembrolizumab and a less frequent schedule may be 
sufficient for target engagement and clinical activity. 
PK data analysis of Pembrolizumab administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic data (IL-2 
release assay) suggested that peripheral target engagement is durable (>21 days).  This early PK 
and pharmacodynamic data provides scientific rationale for testing a Q2W and Q3W dosing 
schedule.   

 
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A population pharmacokinetic analysis has been performed using serum concentration time data 
from 476 patients. Within the resulting population PK model, clearance and volume parameters of 
Pembrolizumab were found to be dependent on body weight. The relationship between clearance 
and body weight, with an allometric exponent of 0.59, is within the range observed for other 
antibodies and would support both body weight normalized dosing or a fixed dose across all body 
weights.  Pembrolizumab has been found to have a wide therapeutic range based on the melanoma 
indication.  The differences in exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg 
Q3W body weight based regimen are anticipated to remain well within the established exposure 
margins of 0.5 – 5.0 for Pembrolizumab in the melanoma indication. The exposure margins are 
based on the notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed 
dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population PK 
evaluation revealed that there was no significant impact of tumor burden on exposure. In addition, 
exposure was similar between the NSCLC and melanoma indications. Therefore, there are no 
anticipated changes in exposure between different indication settings. 
Pembrolizumab in combination with epacadostat 
The safety profile for the 300mg bid dose of epacadostat in combination with pembrolizumab in 
the Phase I/II study (INCB24360-202) did not exceed the MTD.  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.  The dose of 300mg epacadostat in combination with 
pembrolizumab is currently under study in most of current protocols of this combination. 
The dose combination of 100 mg bid epacadostat plus pembrolizumab for the ongoing Phase III 
melanoma study (INCB24360-301) is based upon a benefit/risk assessment made specifically in 
melanoma in collaboration with Merck.  In INCB24360-202, there was evidence of improved 
efficacy in melanoma subjects at all doses of epacadostat of from 50 to 300mg bid.  Given that 
melanoma is an immunotherapy responsive tumor, and lower doses of epacadostat appeared to 
have similar activity, the decision was made to take the 100mg bid dose combination forward 
because of the lower incidence of dose interruptions and dose reductions compared to the 300mg 
bid dose. 
However, in other tumor types, which appear to demonstrate more resistance to known 
immunotherapies, greater target coverage for inhibition of IDO1 may be necessary. PK/PD 
modelling suggests that doses of 100mg bid epacadostat achieve an average IC50 at trough in most 
patients.  At 300mg bid, epacadostat achieves target inhibition above the IC90 at trough. Greater 
target inhibition may be necessary in more resistant tumors, and potentially balances benefit/risk 
in favor of the higher epacadostat dose combination given that the dose does not exceed the MTD. 
In the present study a dose of epacadostat of 100mg BID has been selected, based on the fact that 
pembrolizumab had activity in our previous cohort of pembrolizumab as single agent, and based 
on a potentially lower side effect profile. 

 
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4.2.3 Rationale for Endpoints 
Given the rarity of the disease, and the relatively indolent natural course, response rate will be the 
primary endpoint of this study.  
4.2.3.1 Efficacy Endpoints 
Response rate is the primary endpoint. 
Secondary endpoints: progression-free survival, overall survival and tolerability. 
4.2.3.2 Biomarker Research 
Archival tissue or a new biopsy will be used to perform immunohistochemistry for PDL-1 staining. 
PDL-1 expression and response to treatment will be correlated. 
Whenever feasible fresh tissue will be obtained to establish new cell lines, using the recently 
established method of “conditionally reprogrammed cells” [37].  Cells will be characterized with 
several immunohistochemistry markers and a genetic level (see below).  
Tumor tissues (either fresh and paraffin embedded) will be submitted to Next-Generation 
sequencing for a selected number of genes [33; 38]. Correlation between number and type of 
mutations and response to treatment will be studied. Results obtained in new biopsies will be 
compared to those obtained before systemic treatment, since potentially this could increase or 
change the mutational spectrum of the tumor. 
In patients where a new biopsy will be available, PDL-1 expression will be performed and 
compared to the archival material, since potentially exposure to systemic treatment might change 
the expression of this immune check-point. Expression of IDO1 will also be assessed as an 
exploratory study in tumor samples. 
1. Correlation between PD-L1 expression in thymic carcinomas and response to anti-
PD-1 antibody therapy. Immunohistochemistry Procedure: The anti-PD-L1, 22C3 
antibody which is an FDA approved Ready-to-Use Kit (SK006), will be used for PD-L1 
staining, The expected staining pattern (based on literature) is membranous staining. 
Specimen preparation: The antibody can be used for labeling formalin-fixed, paraffin-
embedded tissue sections and cytology cell blocks. Tissue specimens should be cut into 
sections of approximately 4 µm. Pre-treatment of formalin-fixed, paraffin-embedded tissue 
sections with heat-induced epitope retrieval (HIER) is required. Optimal results are 
obtained by pretreating tissues with HIER using diluted Envision FLEX Target Retrieval 
Solution, Low pH (50x) (K8004). Deparaffinization, rehydration and epitope retrieval are 
performed in DAKO PT Link (PT100/PT101). The following parameters are used for PT 
Link: Pre-Heat temperature: 65ºC, epitope retrieval temperature and time: 97ºC for 
20 minutes, cool down to 65ºC. Racks are placed in diluted Envision Flex Wash Buffer 
(20x) (code K8007) for 5 minutes. The slides are first incubated with Envision Flex 
Peroxidase-Blocking reagent (Cat# K8002-SM801), followed by the primary antibody 
Anti-PD-L1. Then an incubation with a secondary antibody Envision Flex Rabbit Linker 

 
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(Cat# K8002-SM805) is followed by the HRP (labeled polymer) (Cat#K8002-SM802), and 
the staining procedure is finalized with the addition of Envision Flex DAB+ chromogen + 
substrate buffer solution (Cat# K8002-SM803). The stained slides are evaluated by a 
pathologist to confirm staining specificity as well as tumor cells positive percentage and 
intensity. Tumor cells percentage positive and intensity will be retrospectively correlated 
to response to treatment. 
2. Correlation between the type/number of genetic mutations of thymic carcinomas and 
PD-L1 expression as well as response to anti-PD-1 antibody therapy: Our whole exome 
and targeted cancer-associated gene sequencing studies [33; 38] revealed that thymic 
carcinomas exhibit higher incidence of somatic non-synonymous mutations than 
thymomas. In addition to the previously reported TP53 and KIT mutations, epigenetic 
regulatory genes were also found recurrently mutated in thymic carcinomas but not in 
thymomas. Preliminary data have suggested that heavy smokers who accumulate many 
somatic mutations in NSCLCs may be more sensitive to PD-L1 and PD-1 antibody 
therapies (Soria JC, ECC, 2013, Amsterdam). We hypothesize that additional mutations 
may appear after chemotherapy that could potentially lead to PD-L1 upregulation in thymic 
carcinomas and therefore induce sensitivity to PD-1 antibody therapy. Thus we plan to 
explore whether specific genetic mutations and the number of mutations are associated 
with PD-L1 expression in thymic carcinomas and patients’ response to PD-1 therapy. 
Attempts will be made to obtain tumor material before enrolling onto this study. Samples 
(fresh or FFPE samples) collected post chemotherapy and their normal blood pairs as well 
as 10 fresh or archived FFPE tumor materials derived from the same patients before 
systemic chemotherapy will be sequenced using NEXTGEN technology on our recently 
acquired Miseq sequencer in the lab. A custom-designed cancer-associated gene (~220) 
panel which includes all the identified recurrent mutations in thymic carcinomas [33; 38], 
published 
cancer 
driver 
genes 
[39] 
and 
COSMIC 
cancer 
gene 
census 
(http://cancer.sanger.ac.uk/cosmic/census) has been used for targeted sequencing. 
Comparative sequencing analysis of the tumor/blood pairs allows us to identify specific 
somatic mutations and the number of somatic mutations in a given tumor. Moreover, 
comparative analysis of tumor samples from the same patient before and after systemic 
treatment can uncover whether the tumor may acquire additional mutations after 
chemotherapy. The data will be employed to evaluate the correlation between the 
type/number of mutations and PD-L1 expression in the tumors and patients’ response to 
PD-1 antibody therapy. So far we have analyzed 15 samples from the Pembrolizumab 
phase II study, and there does not seem to be a direct relation between tumor burden or 
specific mutations and response. Further analysis will be performed on the rest of the 
samples. 
There is new data suggesting that mutational burden and the use of whole exome 
sequencing may allow the identification of neoepitopes (Rizvi et al. Science 2015). In the 
next cohort of pembrolizumab and Epacadostat, we will perform whole exome sequencing. 
This will be done by contracting an outside sequencing facility (to be determined). 
3. The impact of genetic heterogeneity of thymic carcinomas on the response to anti-PD-
1 antibody therapy: Whenever the fresh tumors are available, we plan to establish cell 

 
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lines or grow the primary tumor cells in culture using the  “Conditional Cell Programming” 
technology recently described by Dr. D. Schlegel of our institute [37]. This new technology 
has allowed us to establish several cell lines from thymic epithelial tumors. During the 
course of this study, we observed that some thymic carcinomas of the same patients formed 
morphologically distinguishable colonies in vitro and some didn’t. It is possible that the 
morphologically distinguishable colonies may be derived from subclones of an individual 
tumor. Tumor heterogeneity is thought to be a significant challenge to single-agent targeted 
therapy and to be an inevitable resistant mechanism to targeted therapy. Whether tumor 
heterogeneity may have an impact on PD-1 antibody therapy remains unclear. Fresh tumor 
specimens will be propagated in culture. Morphologically distinguishable or similar 
colonies derived from individual tumors will be expanded and isolated for NEXTGEN 
sequencing as described above. Somatic mutations will be compared among the same 
tumor-derived colonies and tumor heterogeneity will be determined based on the genomic 
mutation information. Individual tumor-derived colonies will be examined for PD-L1 
expression and thymic carcinoma-related immunological markers (cytokeratins, C-Kit, E-
Cad, EpCam, P63 etc) by immunofluorescence analysis. The results will be compared with 
PD-L1 expression of primary tumors and patients’ response to PD-1 antibody therapy. The 
study will enable us to determine the effectiveness of PD-1 antibody therapy on thymic 
carcinomas in relation to their tumor heterogeneity status.  
Fresh material and archival material should be sent to: 
Yuwen Zhang, PhD in Giaccone’s Laboratory, 
Lombardi Comprehensive Cancer Center, Georgetown University, Research Bldg., 
room E212, 3970 Reservoir Rd., Washington DC 20007, tel 202 6874738. 
 
5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
Patients with advanced thymic carcinoma, for whom no radical treatment exists, who have failed 
at least one line of prior chemotherapy. 
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Histologic confirmation of thymic carcinoma (WHO Classification, See Appendix 12.1) 
 
2. Advanced disease (Masaoka staging, See Appendix 12.2) not amenable to curative 
treatment.  
 
3. At least 1 prior line of chemotherapy.  

 
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4. Progression of disease must be documented prior to study entry. 
 
5. Absence of any autoimmune syndrome typically associated with thymomas but not 
thymic carcinomas (myasthenia gravis, pure red cell aplasia, etc.). 
 
6. Be willing and able to provide written informed consent/assent for the trial. 
7. Be  18 years of age on day of signing informed consent. 
8. Have measurable disease based on RECIST 1.1.   
9. Have provided tissue from an archival tissue sample or newly obtained core or excisional 
biopsy of a tumor lesion. 
10. Have a performance status of 0 or 1 on the ECOG Performance Scale (See Appendix 12.3). 
11. Demonstrate adequate organ function as defined in Table 4, all screening labs should be 
performed within 10 days of treatment initiation.   
Table 4.  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L  
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 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 ≤ ULN for subjects with total bilirubin levels > 
1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for subjects with liver metastases 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
≤1.5 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. 
 
12. Female subject of childbearing potential should have a negative urine or serum pregnancy 
within 72 hours prior to receiving the first dose of study medication.  If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required.   

 
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13. Female subjects of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of the 
study through 120 days after the last dose of study medication (Reference Section 5.7.2).  
Subjects of childbearing potential are those who have not been surgically sterilized or have 
not been free from menses for > 1 year.  
14. Male subjects should agree to use an adequate method of contraception starting with the 
first dose of study therapy through 120 days after the last dose of study therapy. 
5.1.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Has disease which is amenable to radical treatment with surgery or radiation or a 
combination of treatments. 
2. Is currently participating in or has participated in a study of an investigational agent or 
using an investigational device within 4 weeks of the first dose of treatment. 
3. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other 
form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
 
 
4. Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not 
recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered 
more than 4 weeks earlier.  
5. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 
2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from 
adverse events due to a previously administered agent. 
- 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and 
may qualify for the study. 
- 
Note:  If subject received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting therapy.   
6. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, 
or in situ cervical cancer that has undergone potentially curative therapy.   
7. 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.   

 
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8. Has an active automimmune disease requiring systemic treatment within the past 3 months 
or a documented history of clinically severe autoimmune disease, or a syndrome that 
requires systemic steroids or immunosuppressive agents.  Subjects with vitiligo or resolved 
childhood asthma/atopy would be an exception to this rule.  Subjects that require 
intermittent use of bronchodilators or local steroid injections would not be excluded from 
the study.  Subjects with hypothyroidism stable on hormone replacement or Sjorgen’s 
syndrome will not be excluded from the study. 
9. Has evidence of interstitial lung disease  
10. Has a history of non-infectious pneumonitis that required steroids, or has a history of active 
pneumonitis. 
11. Has an active infection requiring systemic therapy. 
12. Has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the trial, interfere with the subject’s participation for the full 
duration of the trial, or is not in the best interest of the subject to participate, in the opinion 
of the treating investigator.   
13. Has known hypersensitivity to pembrolizumab (MK-3475) or its formulation. 
14. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
15. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit through 
120 days after the last dose of trial treatment. 
16. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or 
anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including 
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or 
checkpoint pathways). 
17. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
18. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
19. Has received a live vaccine within 30 days prior to the first dose of trial treatment.   
20. Inability to swallow food or any condition of the upper gastrointestinal tract that precludes 
administration of oral medications. 
21. Screening ECG with QTc interval > 480 milliseconds (corrected by Fridericia). In the event 
that a single QTc is >480 msec, the subject may enroll if the average QTc for 3 ECGs is < 
480 msec. 

 
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22. Prior receipt of an IDO inhibitor. 
23. Receipt of MAOIs within 21 days before first dose of study treatment.  
24. History of serotonergic syndrome. 
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 5  
Table 5.  Trial Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 
200 mg flat 
dose 
Every 3 
weeks 
IV infusion 
3 weeks 
Experimental 
Epacadostat 
100 mg BID 
Daily 
PO 
3 weeks 
Experimental 
Dose and interval modifications of Epacadostat can be found  in Section 5.2.1.2. 
 
Trial treatment should begin within a week from registration into the trial.  
5.2.1 Dose Selection/Modification 
5.2.1.1 Pembrolizumab 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – Background 
and Rationale.   
Dose Modifications  
Pembrolizumab will be withheld for drug-related Grade 4 hematologic toxicities, non-
hematological toxicity ≥ Grade 3 including laboratory abnormalities, and severe or life-threatening 
AEs as per Table 6. There are no dose modifications for pembrolizumab. 
 

 
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Table 6. Dose modification guidelines for drug-related adverse events. 
Toxicity 
Grade 
Hold Treatment 
(Y/N) 
Timing for 
restarting 
treatment 
Dose/Schedule for restarting treatment 
 
Discontinue Subject (after 
consultation with PI) 
Epacadostat 
Pembrolizumab 
Hematological Toxicity 
 
1, 2 
No 
N/A 
N/A 
N/A  
N/A 
3 
Yes 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
N/A 
 
Toxicity does not resolve 
within 6 weeks of last 
infusion 
Permanent discontinuation 
should be considered for 
any severe or life-
threatening event 
4 
Yes 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
Reduce dose by 
one dose level 
. Restart for following events: 
grade 4 neutropenia for < 7 days, 
grade 4 lymphopenia or 
leukopenia; for all other Grade 4 
hematological toxicity 
pembrolizumab may not be 
restarted 
Non-hematological toxicity 
 
Note:  Exception to be treated 
similar to grade 1 toxicity  
• Grade 2 alopecia 
• Grade 2 fatigue 
 
For additional information 
regarding Adverse Events 
with a potential Immune-
Etiology reference Section 
5.6.1.1. 
1 
No 
N/A 
N/A 
N/A 
N/A 
2 
Consider 
withholding for 
persistent 
symptoms 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
Restart at the 
same dose 
Clinical AE resolves within 4 
weeks:  Same dose and schedule 
Clinical AE does not resolve 
within 4 weeks:   
Toxicity does not resolve 
within 12 weeks of last 
infusion 
3 
 
Yes 
Toxicity 
resolves to 
Grade 0-1 or 
baseline  
Restart at 1 
dose level 
lower 
 
Toxicity does not resolve 
within 6 weeks of last 
infusion; Permanent 
discontinuation should be 
considered for any severe 
or life-threatening event 
4 
Yes 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
Restart at 1 
dose level 
lower 
Restart only permitted as noted 
b. For all other Grade 4 non-
hematological toxicities, 
pembrolizumab may not be 
restarted 
Toxicity does not resolve 
within 6 weeks of last 
infusion; Permanent 
discontinuation should be 
considered for any severe 
or life-threatening event 
 
 

 
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Note: Subjects who experience a recurrence of the same severe or life-threatening AE at the same grade or greater treatment should be 
discontinued from study treatment.  
a) The following exceptions for asymptomatic amylase or lipase do not require a dose delay:  Grade 3 amylase or lipase abnormalities 
that are not associated with symptoms or clinical manifestations of pancreatitis.  It is recommended to consult with the medical monitor 
for Grade 3 amylase or lipase abnormalities.  
b) Isolated Grade 4 lipase or amylase abnormalities not associated with symptoms or clinical manifestations of pancreatitis.  Medical 
monitor should be consulted for any Grade 4 amylase or lipase abnormality.

 
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In case toxicity does not resolve to Grade 0-1 within 6 weeks after last infusion, treatment should 
be discontinued after consultation with the PI. With treating investigator and PI agreement, 
subjects with a laboratory adverse event still at Grade 2 after 12 weeks may continue treatment in 
the trial only if asymptomatic and controlled.  For information on the management of adverse 
events, see Section 5.6.1.   
Subjects who experience a recurrence of the same severe or life-threatening event at the same 
grade or greater with re-challenge of Pembrolizumab should be discontinued from trial treatment. 
5.2.1.2 Epacadostat 
Description and Administration 
Epacadostat will be available as 25 or 100 mg tablets to be administered in a BID administration 
schedule.  All BID doses of epacadostat will be taken PO in the morning and evening, 
approximately 12 hours apart without regard to food.  If the morning or evening dose is missed 
by more than 4 hours, then that dose should be skipped, and the next scheduled dose should be 
taken at the usual time.  Doses of epacadostat will be self-administered except on the days 
scheduled to be given at the study clinic. 
Subjects should be counseled by the investigator to maintain strict adherence to the study 
regimen as prescribed and to keep a record of any missed doses.  The subject will be instructed 
to bring all unopened, empty, and opened/partially used bottles of study drug at Day 1 study 
visits, at which time compliance will be assessed. 
Supply, Packaging, and Labeling 
Study drug tablets are packaged in high-density polyethylene bottles; no preparation is required.   
Storage 
Bottles should be stored at room temperature, 15°C to 30°C (59°F to 86°F) and closed tightly to 
protect the tablets from humidity. 
Instruction to Subjects for Handling Epacadostat 
The subject must be instructed in the handling of study drug as follows: 
• To store the study drug at room temperature. 
• To only remove from the study drug bottle/kit the number of tablets needed at the 
time of administration. 
• Not to remove doses in advance of the next scheduled administration. 
• To make every effort to take doses on schedule. 
• To report any missed doses. 
• If the subject vomits after taking study drug, the subject should not take another dose. 

 
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• If the morning or evening dose of epacadostat is missed by more than 4 hours, then 
that dose should be skipped, and the next scheduled dose should be taken at the usual 
time. 
• To keep study drug in a safe place and out of reach and sight of children. 
• To bring all used and unused study drug kits to the site at each visit. 
Epacadostat Dose Modifications 
Table 7 describes epacadostat dose reductions that may occur due to any related AEs.  Dose 
reductions should occur in a step-wise fashion from the initial starting dose of the cohort, and a 
maximum of 1 dose reduction of epacadostat is allowed for the management of an AE, regardless 
of the initial starting dose.  If an AE recurs/does not return to baseline after the second dose 
reduction of epacadostat, then the subject must permanently discontinue epacadostat.  If a subject 
does not tolerate 50 mg BID, then the subject must permanently discontinue epacadostat. 
Table 7: 
Epacadostat Dose Reductions 
Dose Level 
Dose 
0 
100 mg BID 
-1 
50 mg BID 
 
5.2.2 Timing of Dose Administration 
Pembrolizumab treatment should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 6.0).  
Trial treatment may be administered up to 3 days before or after the scheduled Day 1 of each cycle 
due to administrative reasons. 
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab will be administered as a 30 minute IV infusion   Sites 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 minutes and +10 minutes is permitted (i.e., 
infusion time is 30 minutes: -5 min/+10 min). 
5.2.3 Timing of Dose Administration (Epacadostat) 
Epacadostat will be administered orally BID every 12 hours without regard to food at the dose 
identified in this study.  If a dose is missed by more than 4 hours, then that dose should be skipped, 
and the next dose should be taken at the next scheduled time point.  All BID doses will be taken 
in the morning and evening, approximately 12 hours apart. 
Subjects will begin treatment with epacadostat on Day 1 of the study, with the first dose 
administered in the evening and will continue administration through the evening prior to the 
scheduled date of the subject's post-treatment visit.  Subjects should plan to take the AM dose of 
epacadostat on Day 1 of each cycle in the clinic.  There is no priority to the order of administration 

 
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of epacadostat and pembrolizumab when administered in combination; however, the dose of 
epacadostat should be taken as close to the regularly scheduled 12-hour dosing interval as possible.   
5.2.4 Trial Blinding/Masking 
This is an open-label trial; therefore, there will be no blinding or masking.  
5.3 
Randomization or Treatment Allocation 
This is a single arm non-randomized phase II study. 
5.4 
Stratification 
There is no stratification for this study. 
5.5 
Concomitant Medications/Vaccinations (allowed & prohibited) 
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 treating investigator should discuss any questions regarding this 
with the PI.  The final decision on any supportive therapy or vaccination rests with the investigator 
and/or the subject's primary physician.  However, the decision to continue the subject on trial 
therapy or vaccination schedule requires the mutual agreement of the treating Investigator, the PI, 
and the subject.  
5.5.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be administered 
at the discretion of the investigator in keeping with the community standards of medical care.  All 
concomitant medication will be recorded on the case report form (CRF) including all prescription, 
over-the-counter (OTC), herbal supplements, and IV medications and fluids.  If changes occur 
during the trial period, documentation of drug dosage, frequency, route, and date may also be 
included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs and 
ECIs as defined in Section 7.2. 
5.5.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and Treatment 
Phase (including retreatment for post-complete response relapse) of this trial, unless otherwise 
noted below: 
• Anti-cancer systemic chemotherapy or biological therapy  

 
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• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• 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  
• Investigational agents other than Pembrolizumab and Epacadostat 
• 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; however, intranasal influenza vaccines (eg, FluMist®) are 
live attenuated vaccines and are not allowed. 
• Any chronic immunological-suppressive treatment for any reason.  (Note:  Inhaled or 
topical steroids are allowed, and systemic steroids at doses ≤10 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) 
• 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 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. 

 
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There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.6 
Rescue Medications & Supportive Care 
5.6.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the treating 
investigator including but not limited to the items outlined below: 
• Nausea/vomiting: Nausea and vomiting should be treated aggressively, and consideration 
should be given in subsequent cycles to the administration of prophylactic antiemetic 
therapy according to standard institutional practice.  Subjects should be strongly 
encouraged to maintain liberal oral fluid intake. 
• Anti-infectives: Subjects with a documented infectious complication should receive oral or 
IV antibiotics or other anti-infective agents as considered appropriate by the treating 
investigator for a given infectious condition, according to standard institutional practice. 
• Immune-related adverse events: Please see Section 5.6.1.1 below and the separate guidance 
document in the administrative binder regarding diagnosis and management of adverse 
experiences of a potential immunologic etiology.   
• Management of Infusion Reactions:  Acute infusion reactions (which can include cytokine 
release syndrome, angioedema, or anaphylaxis) are different from allergic/hypersensitive 
reactions, although some of the manifestations are common to both AEs.  Signs and 
symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion. Signs/symptoms may include: 
Allergic reaction/hypersensitivity (including drug fever); Arthralgia (joint pain); 
Bronchospasm; Cough; Dizziness; Dyspnea (shortness of breath); Fatigue (asthenia, 
lethargy, malaise); Headache; Hypertension; Hypotension; Myalgia (muscle pain); 
Nausea; Pruritis/itching; Rash/desquamation; Rigors/chills; Sweating (diaphoresis); 
Tachycardia; Tumor pain (onset or exacerbation of tumor pain due to treatment); Urticaria 
(hives, welts, wheals); Vomiting. 
Table 8 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of Pembrolizumab. 
 
Table 8.  Infusion Reaction Treatment Guidelines 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
 
None 
Grade 2 
 
Stop Infusion and monitor symptoms. 
 

 
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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Requires infusion interruption but 
responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); prophylactic 
medications indicated for < =24 
hrs 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(e.g. from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until 
symptoms resolve and the subject should be 
premedicated for the next scheduled dose. 
Subjects who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from 
further trial treatment administration. 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of Pembrolizumab 
with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms following 
initial improvement; 
hospitalization indicated for other 
clinical sequelae (e.g., renal 
impairment, pulmonary infiltrates) 
 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued 
from further trial treatment 
administration. 
 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration. 
For Further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov and Appendix 
 
5.6.1.1 Supportive Care Guidelines for Events of Clinical Interest and Immune-related 
Adverse Events (irAEs) 
Events of clinical interest of a potential immunologic etiology (irECIs) may be defined as an 
adverse event of unknown etiology, associated with drug exposure and is consistent with an 
immune phenomenon.   

 
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This section is meant to apply to suspected irAEs from epacadostat, pembrolizumab, or the 
combination. Immune-related AEs may be predicted based on the nature of the pembrolizumab or 
epacadostat 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 be suggestive of potential irAEs.  An irAE can occur shortly after the first dose or several 
months after the last dose of treatment. 
General recommendations to managing irAEs not detailed elsewhere in the Protocol are detailed 
in Table 9  Recommendations for management of specific immune-mediated AEs such as 
pneumonitis, enterocolitis, hepatitis, dermatitis, neuropathies, endocrinopathies, and other 
immune-mediated AEs are detailed in the sections below. 
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 adverse event as an irAE. Subjects who develop a Grade 
2 or higher irAE should be discussed immediately with the PI.  Recommendations to managing 
irAEs not detailed elsewhere in the protocol are detailed in Table 9.  
 
 

 
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Table 9. General Approach to Handling Immune-Related Adverse Events 
irAE 
Withhold/Discontinue 
Pembrolizumab 
and 
Epacadostat 
Guidance for Restarting Study Treatment 
Supportive Care 
Grade 1 
No action. 
Not applicable. 
Provide symptomatic 
treatment. 
Grade 2 
May withhold 
pembrolizumab and 
epacadostat per 
investigator's discretion. 
May return to treatment if improves to Grade 
1 or resolves within 6 weeks.  If AE resolves 
within 4 weeks, subject may restart at the 
same 
dose 
and 
schedule 
for 
both 
pembrolizumab and epacadostat.   
For an AE that does not resolve within 
4 weeks, epacadostat should be reduced 
1 dose level, but pembrolizumab may be 
restarted at the same dose and schedule.  If 
AE does not resolve within 6 weeks, study 
treatment with both study drugs should be 
discontinued or discussed with medical 
monitor. 
Consider systemic 
corticosteroids in addition 
to appropriate 
symptomatic treatment. 
Grade 3  
Withhold or discontinue 
pembrolizumab and 
epacadostat. 
Discontinue if unable to 
reduce corticosteroid 
dose to < 10 mg/day of 
prednisone or equivalent 
within 6 weeks of 
toxicity. 
Any restart of study treatment must be 
discussed with medical monitor before 
restarting treatment. 
Systemic corticosteroids 
are indicated in addition 
to appropriate 
symptomatic treatment.  
May use 1 to 2 mg/kg of 
prednisone or equivalent 
per day. 
Steroid taper should be 
considered once 
symptoms improve to 
≤ Grade 1 and tapered 
over at least 4 weeks in 
most cases. 
Grade 4 
Discontinue 
pembrolizumab and 
epacadostat. 
Not applicable.  Any exceptions require 
medical monitor approval. 
Systemic corticosteroids 
are indicated in addition 
to appropriate 
symptomatic treatment.  
May use 1 to 2 mg/kg of 
prednisone or equivalent 
per day. 
 
5.6.1.2 Supportive Care Guidelines for Pneumonitis 
Subjects with symptomatic pneumonitis should immediately stop receiving Pembrolizumab and 
Eapacadostat and have an evaluation.  The evaluation may include bronchoscopy and pulmonary 

 
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function tests to rule out other causes such as infection.  If the subject is determined to have study 
drug associated pneumonitis, the suggested treatment plan is detailed in Table 10. 
Table 10. Recommended Approach for Handling Noninfectious Pneumonitis 
Study Drug(s) 
Associated 
Pneumonitis 
Withhold/Discontinue 
Pembrolizumab and 
Epacadostat 
Guidance for Restarting Study 
Treatment 
Supportive Care 
Grade 1 
(asymptomatic) 
No action. 
Not applicable. 
Intervention not 
indicated. 
Grade 2 
Withhold 
pembrolizumab and 
epacadostat. 
First episode of pneumonitis: 
If improves to near baseline:   
Decrease the dose of epacadostat by 
1 dose level, and for pembrolizumab, 
restart at same dose and schedule 
subsequent cycles. 
If not improved after 2 weeks or 
worsening, permanently discontinue 
pembrolizumab.  Discuss with medical 
monitor if restart with epacadostat is 
permitted. 
Second episode of pneumonitis: 
Permanently discontinue 
pembrolizumab and epacadostat if 
upon rechallenge subject develops 
pneumonitis ≥ Grade 2. 
Systemic 
corticosteroids 
are indicated.  
Taper if 
necessary. 
Grades 3 and 4 
Discontinue 
pembrolizumab and 
epacadostat. 
Not applicable.  Any exceptions 
require medical monitor approval. 
Systemic 
corticosteroids 
are indicated.  
The use of 
infliximab may 
be indicated as 
appropriate.   
 
5.6.1.3 
Procedures and Guidance for Enterocolitis 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such 
as peritoneal signs and ileus).  In symptomatic subjects, infectious etiologies should be ruled out, 
and endoscopic evaluation should be considered for persistent or severe symptoms.  
Recommendations for management of enterocolitis are shown in Table 11. 
 
 

 
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Table 11. Recommended Approach for Handling Enterocolitis 
Study 
Drug(s) 
Associated 
Enterocolitis 
Withhold/Discontinue  
Pembrolizumab and 
Epacadostat 
Guidance for Restarting Study 
Treatment 
Supportive Care 
Grade 1 
No action. 
Not applicable. 
All subjects who experience 
diarrhea should be advised to 
drink liberal quantities of 
clear fluids.  If sufficient oral 
fluid intake is not feasible, 
fluid and electrolytes should 
be substituted via IV 
infusion.  An antidiarrheal 
can be started. 
Grade 2 
Withhold 
pembrolizumab and 
epacadostat. 
 
May return to treatment if improves 
to Grade 1.  If AE resolves within 4 
weeks, subject may restart at the 
same dose and schedule for both 
pembrolizumab and epacadostat.   
For an AE that does not resolve 
within 4 weeks, epacadostat should 
be reduced 1 dose level, but 
pembrolizumab may be restarted at 
the same dose and schedule.  If AE 
does not resolve within 6 weeks, 
study treatment with both study 
drugs should be discontinued or 
discussed with medical monitor. 
An antidiarrheal should be 
started.  If symptoms are 
persistent for > 1 week, 
systemic corticosteroids 
should be initiated (eg, 0.5-1 
mg/kg per day of prednisone 
or equivalent).  When 
symptoms improve to 
≤ Grade 1, corticosteroid 
taper should be started and 
continued over at least 
1 month. 
Grades 3 
and 4 
Discontinue 
pembrolizumab and 
epacadostat. 
Not applicable.  Any exceptions 
require medical monitor approval. 
Treatment with systemic 
corticosteroids should be 
initiated at a dose of 1 to 
2 mg/kg per day of 
prednisone or equivalent.  
Systemic corticosteroids are 
indicated.  The use of 
infliximab may be indicated 
as appropriate.  When 
symptoms improve to 
≤ Grade 1, corticosteroid 
taper should be started and 
continued over at least 
1 month. 
 
5.6.1.4 Procedures and Guidance for Hepatitis 
Liver chemistry tests (hepatic transaminase and bilirubin levels) should be monitored and signs 
and symptoms of hepatotoxicity should be assessed before each dose of pembrolizumab and 
epacadostat.  In subjects with hepatotoxicity, infectious or malignant causes should be ruled out, 

 
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and frequency of LFT monitoring should be increased until resolution.  Recommendations for 
managing hepatitis are shown in Table 12. 
Table 12: 
Recommended Approach for Handling Hepatitis 
Study 
Drug(s) 
Associated 
Hepatitis 
Withhold/Discontinue 
Pembrolizumab and 
Epacadostat 
Guidance for Restarting 
Study Treatment 
Supportive Care 
Grade 1 
No action. 
Not applicable. 
Increase frequency of LFT 
monitoring to twice per 
week until LFTs return to 
baseline. 
Grade 2 
Withhold 
pembrolizumab and 
epacadostat. 
If AE resolves to ≤ Grade 1 or 
baseline within 4 weeks, 
subject may restart at the same 
dose and schedule for both 
pembrolizumab and 
epacadostat.  For an AE that 
does not resolve within 
4 weeks, epacadostat should be 
reduced 1 dose level but 
pembrolizumab may be 
restarted at the same dose and 
schedule.  If AE does not 
resolve within 6 weeks, study 
treatment with both study 
drugs should be discontinued. 
Increase frequency of LFT 
monitoring to twice per 
week until LFTs return to 
baseline.  If elevation 
persists for > 1 week, 
systemic corticosteroids 
should be initiated (eg, 
0.5 mg/kg per day of 
prednisone or equivalent).  
When symptoms improve 
to ≤ Grade 1, corticosteroid 
taper should be started and 
continued over at least 
1 month. 
Grades 3 
and 4 
Discontinue 
pembrolizumab and 
epacadostat. 
Not applicable.  Any 
exceptions require medical 
monitor approval. 
Increase frequency of LFT 
monitoring to every 
1-2 days.  Treatment with 
systemic corticosteroids 
should be initiated at a dose 
of 1 to 2 mg/kg per day of 
prednisone or equivalent.  
When symptoms improve 
to ≤ Grade 1, corticosteroid 
taper should be started and 
continued over at least 
1 month. 
 
5.6.1.5 Procedures for Immune-Mediated Dermatitis 
Monitor subjects for signs and symptoms of dermatitis such as rash and pruritus.  Unless an 
alternate etiology has been identified, signs or symptoms of dermatitis should be considered 
immune-mediated.  Recommendations for management of dermatitis are shown in Table 13 

 
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Table 13: 
Recommended Approach for Handling Dermatitis 
irAE 
Withhold/Discontinue 
Pembrolizumab and Epacadostat 
Guidance for Restarting 
Study Treatment 
Supportive Care 
Grade 1 
No action. 
Not applicable. 
For mild to moderate 
dermatitis, such as 
localized rash and 
pruritus, treat 
symptomatically.  
Administer topical or 
systemic corticosteroids 
if there is no 
improvement of 
symptoms within 
1 week. 
Grade 2 
No action. 
Not applicable. 
For mild to moderate 
dermatitis, such as 
localized rash and 
pruritus, treat 
symptomatically.  
Administer topical or 
systemic corticosteroids 
if there is no 
improvement of 
symptoms within 
1 week. 
Grades 3 and 
4 
Withhold epacadostat and 
pembrolizumab in subjects with 
moderate to severe signs and 
symptoms of rash.   
Permanently discontinue 
epacadostat and pembrolizumab in 
subjects with Stevens-Johnson 
syndrome, toxic epidermal 
necrolysis, or rash complicated by 
full thickness dermal ulceration or 
by necrotic, bullous, or 
hemorrhagic manifestations. 
If AE resolves to baseline 
within 4 weeks, subject may 
restart at the same dose and 
schedule for both 
pembrolizumab and 
epacadostat.  For an AE that 
does not resolve within 
4 weeks, epacadostat should 
be reduced 1 dose level, but 
pembrolizumab may be 
restarted at the same dose 
and schedule.  If AE does 
not resolve within 6 weeks, 
study treatment with both 
study drugs should be 
discontinued or discussed 
with medical monitor. 
Administer systemic 
corticosteroids at a dose 
of 1 to 2 mg/kg per day 
of prednisone or 
equivalent.  When 
dermatitis is controlled, 
corticosteroid tapering 
should occur over a 
period of at least 
1 month. 
 
5.6.1.6 Procedures for Immune-Mediated Neuropathies 
Subjects should be monitored for symptoms of motor or sensory neuropathy such as unilateral or 
bilateral weakness, sensory alterations, or paresthesia.  Recommendations for management of 
neuropathies are shown in Table 14.  

 
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Table 14: 
Recommended Approach for Handling Neuropathies 
irAE 
Withhold/Discontinue 
Pembrolizumab and 
Epacadostat 
Guidance for Restarting 
Study Treatment 
Supportive Care 
Grade 1 
No action. 
Not applicable. 
Provide symptomatic 
treatment. 
Grade 2 
May withhold 
pembrolizumab and 
epacadostat. 
If AE resolves to ≤ Grade 1 
or baseline within 4 weeks, 
subject may restart at the 
same dose and schedule for 
both pembrolizumab and 
epacadostat.  For an AE 
that does not resolve within 
4 weeks, epacadostat 
should be reduced 1 dose 
level but pembrolizumab 
may be restarted at the 
same dose and schedule.  If 
AE does not resolve within 
6 weeks, study treatment 
with both study drugs 
should be discontinued or 
discussed with medical 
monitor. 
Consider systemic 
corticosteroids in addition 
to appropriate symptomatic 
treatment. 
Grades 3 
and 4 
Discontinue 
pembrolizumab and 
epacadostat. 
Not applicable.  Any 
exceptions require medical 
monitor approval. 
Consider initiation of 
systemic corticosteroids at 
a dose of 1 to 2 mg/kg per 
day prednisone or 
equivalent for severe 
neuropathies.   
Institute medical 
intervention as appropriate 
for management of severe 
neuropathy. 
 
5.6.1.7 
Procedures for Immune-Mediated Endocrinopathies 
Subjects should be monitored for clinical signs and symptoms of hypophysitis, adrenal 
insufficiency (including adrenal crisis), and hyper- or hypothyroidism.  Subjects may have fatigue, 
headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension or have 
nonspecific symptoms that may resemble other causes such as brain metastasis or underlying 
disease.  Unless an alternate etiology has been identified, signs or symptoms of endocrinopathies 
should be considered immune-mediated. 

 
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Thyroid function tests and clinical chemistries should be monitored at the start of treatment, before 
each dose and as clinically indicated based on symptoms.  In a limited number of subjects, 
hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland.  
Recommendations for management of endocrinopathies are shown in Table 15.   
Table 15: 
Recommended Approach for Handling Endocrinopathies 
irAE 
Withhold/Discontinue 
Pembrolizumab and 
Epacadostat 
Guidance for Restarting Study 
Treatment 
Supportive Care 
Grade 1 
No action. 
Not applicable. 
Provide symptomatic 
treatment. 
Grade 2 
May withhold 
pembrolizumab and 
epacadostat. 
If AE resolves within 4 weeks, subject 
may restart at the same dose and 
schedule for both pembrolizumab and 
epacadostat.  For an AE that does not 
resolve within 4 weeks, epacadostat 
should be reduced 1 dose level, but 
pembrolizumab may be restarted at the 
same dose and schedule.  If AE does not 
resolve within 6 weeks, study treatment 
with both study drugs should be 
discontinued. 
Initiate systemic 
corticosteroids treatment at a 
dose of 1 to 2 mg/kg per day 
of prednisone or equivalent, 
and initiate appropriate 
hormone replacement therapy. 
Grade 3  
Withhold or discontinue 
both pembrolizumab 
and epacadostat.  
 
 
If AE resolves or is controlled within 
4 weeks, subject may restart at the same 
dose and schedule for both 
pembrolizumab and epacadostat.  For an 
AE that does not resolve within 4 weeks, 
epacadostat should be reduced 1 dose 
level, but pembrolizumab may be 
restarted at the same dose and schedule.  
If AE does not resolve within 6 weeks, 
study treatment with both study drugs 
should be discontinued or discussed with 
medical monitor 
Consider initiating systemic 
corticosteroids treatment at a 
dose of 1 to 2 mg/kg per day 
of prednisone or equivalent, 
and initiate appropriate 
hormone replacement therapy. 
Grade 4  
Discontinue both 
pembrolizumab and 
epacadostat. 
Not applicable.  Any exceptions require 
medical monitor approval. 
Consider initiation of systemic 
corticosteroids at a dose of 
1 to 2 mg/kg per day of 
prednisone or equivalent, and 
initiate appropriate hormone 
replacement therapy.   
 
5.6.1.8 Procedures for Other Immune-Mediated Adverse Reactions, Including Ocular 
Manifestations 
Epacadostat and pembrolizumab should be permanently discontinued for severe immune-mediated 
adverse reactions.  Systemic corticosteroids treatment should be initiated at a dose of 1 to 2 mg/kg 
per day of prednisone or equivalent for severe immune-mediated adverse reactions. 

 
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Corticosteroid eye drops should be administered to subjects who develop uveitis, iritis, or 
episcleritis.  Epacadostat and pembrolizumab should be permanently discontinued for 
immune-mediated ocular disease that is unresponsive to local immunosuppressive therapy.   
5.7 
Treatment After Initial Evidence of Radiographic Disease Progression 
Immunotherapeutic agents such as pembrolizumab and epacadostat may produce antitumor effects 
by potentiating endogenous cancer-specific immune responses.  The response patterns seen with 
such as approach may extend beyond the typical time course of responses seen with cytotoxic 
agents and can manifest as a clinical response after an initial increase in tumor burden or even the 
appearance of new lesions. 
If radiographic imaging shows PD, tumor assessment should be repeated ≥ 4 weeks later to confirm 
PD, with the option of continuing treatment as outlined below, while awaiting radiographic 
confirmation of progression.  If repeat imaging shows a reduction in the tumor burden compared 
to the initial scan demonstrating PD, treatment may be continued as per treatment calendar.  If 
repeat imaging confirms PD, subjects will be discontinued from study therapy.  In determining 
whether the tumor burden has increased or decreased, investigators should consider all target 
lesions as well as nontarget lesions. 
When feasible, subjects should not be discontinued until progression is confirmed; however, the 
decision to continue study treatment after the first evidence of disease progression is at the 
investigator's discretion based on the clinical status of the subject.   
Subjects may receive study treatment while waiting for confirmation of PD if they are clinically 
stable as defined by the following criteria: 
• Absence of signs and symptoms (including worsening of laboratory values) indicating 
disease progression. 
• No decline in ECOG performance status. 
• Absence of rapid progression of disease. 
• Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention.  
 

 
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Table 16. Imaging and Treatment After First Radiographic Evidence of Progressive Disease 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
First radiographic 
evidence of PD 
Repeat imaging at 
≥ 4 weeks to 
confirm PD 
May continue 
study treatment at 
the investigator's 
discretion while 
awaiting 
confirmatory scan 
Repeat imaging at 
≥ 4 weeks to 
confirm PD if 
possible 
Discontinue 
treatment 
Repeat scan at 
≥ 4 weeks 
confirms PD 
No additional 
imaging required 
Discontinue 
treatment 
No additional 
imaging required 
N/A 
Repeat scan at 
≥ 4 weeks shows 
SD, PR, or CR 
Continue 
regularly 
scheduled 
imaging 
assessments every 
9 weeks 
Continue study 
treatment at the 
investigator's 
discretion 
Continue 
regularly 
scheduled 
imaging 
assessments every 
9 weeks 
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable 
per investigator's 
discretion 
 
5.8 
Procedures for Subjects Exhibiting Serotonin Syndrome (SS) 
There is a possibility that epacadostat could cause an increase in serotonin levels in the brain that 
might trigger Serotonin Syndrome (SS), when administered in combination with other serotonergic 
agents.  This syndrome has been most closely associated with use of MAOIs, Demerol®, linezolid, 
or methylene blue; all of these agents are prohibited during the study. 
Serotonin reuptake inhibitors (SSRIs) and serotonin/norepinephrine reuptake inhibitors (SNRIs) 
are permitted in the study. The following procedures will be implemented if subjects exhibit the 
signs/symptoms of SS described in Table 17, including tremor; hyperreflexia; spontaneous, ocular, 
or inducible clonus; together with agitation, fever, diaphoresis, or muscle rigidity: 
• Immediately interrupt epacadostat administration. 
• 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 the 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 dosing MAY NOT be restarted. 

 
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If the subject chooses to discontinue the study or must restart treatment with SSRI or SNRI, the 
subject should be scheduled for a follow-up visit.  Selective serotonin reuptake inhibitor or SNRI 
treatment may be initiated 2 weeks after resolution of signs and symptoms of SS. 
Table 17.  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 
 
Study INCB 24360-101 was a Phase 1, multicenter, open-label, dose-escalation study in subjects 
with refractory solid tumors that used a 3 + 3 design to determine the safety and tolerability, PK, 
and pharmacodynamics of escalating oral doses of epacadostat.  Subjects were administered doses 
of epacadostat ranging from 50 mg QD to 700 mg BID.  Of the 52 subjects treated, 8 subjects 
(15.4%) had an AE leading to death.  Of these 8 subjects, the cause of death was disease 
progression in 7 subjects and hypoxia in the remaining subject.  During the study 25 subjects 
(48.1%) had a serious adverse event (SAE).  The most frequently reported SAEs were disease 
progression (4 subjects, 7.7%), abdominal pain, nausea, and hypoxia (3 subjects each, 5.8%).  
Treatment-emergent AEs (TEAEs) were reported in all subjects.  Fatigue was the most frequently 
reported TEAE (36 subjects, 69.2%).  Two dose-limiting toxicities (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 (MTD) was not determined. 
An uncommon risk of IDO1 inhibition is 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 (MAOIs) and combinations of serotonergic drugs (Boyer and Shannon 2005). 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. In another preclinical study in rats, the effect of epacadostat on the brain 
extracellular fluid concentration of serotonin was evaluated either alone or when co-administrated 
with the MOA inhibitor linezolid with or without the SSRI fluoxetine.  Both control conditions 
resulted in 2-6-fold increases in serotonin. In contrast, neither epacadostat alone or in combination 
with linezolid had an effect on the brain extracellular serotonin levels.  These preclinical data 
suggest that SS is unlikely following treatment with either epacadostat alone or with combination 
with MAO inhibitors such as linezolid (Zhang, Li, Diamond et al 2016).  Therefore, taken together, 
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.  

 
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As of 27 February 2017, 2 subjects across the epacadostat program (958 subjects treated) have 
reported serotonin syndrome or symptoms of serotonin syndrome and both were mild in their 
severity and resolved.  One subject from study INCB 24360-202 reported chills, increased blood 
pressure, and temperature (CTC Grade 1) on Cycle 1 day 1 and resolved within one week while 
dosing was stopped.  The subject was taking an SSRI and while he experienced mild symptoms the 
full constellation of SS was not observed nor could it be ruled out.  The SSRI was discontinued and 
subject was able to restart epacadostat about one week later at the same dose level of 100 mg BID 
without further incidents.  The other subject from study INCB 24360-203 reported CTC Grade 1 
tremors and CTC Grade 2 agitation on Cycle 4 day 5 and assessed for SS on Cycle 5 day 1.  The 
subject was not on an SSRI but on a medication for anxiety (alprazolam). The events resolved and 
the dosing with epacadostat was interrupted for one week.  Retreatment started with a lower dose 
of epacadostat of 50 mg BID PO from 75 mg BID on Cycle 5 day 3. Although this incidence is 
uncommon, use of MAOIs will be prohibited during the study, and all subjects should be assessed 
for SS symptoms at an appropriate timeframe after dosing.  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. 
5.9 
Diet/Activity/Other Considerations 
5.9.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting. 
5.9.2 Contraception 
Pembrolizumab and Epacadostat may have adverse effects on a fetus in utero.  Furthermore, it is 
not known if they have transient adverse effects on the composition of sperm.  Non-pregnant, non-
breast-feeding women may be enrolled if they are willing to use 2 methods of birth control or are 
considered highly unlikely to conceive.  Highly unlikely to conceive is defined as 1) surgically 
sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had menses for 
greater than 1 year will be considered postmenopausal), or 3) not heterosexually active for the 
duration of the study.  The two birth control methods can be either two barrier methods or a barrier 
method plus a hormonal method to prevent pregnancy. Subjects should start using birth control 
from study Visit 1 throughout the study period up to 120 days after the last dose of study therapy.  
The following are considered adequate barrier methods of contraception: diaphragm, condom (by 
the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or intramuscular 
agents). 
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, they must adhere to the contraception requirement (described above) for the duration of the 
study and during the follow-up period defined in section 7.2.2-Reporting of Pregnancy and 

 
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Lactation to the Sponsor, to Merck and Incyte.  If there is any question that a subject will not 
reliably comply with the requirements for contraception, that subject should not be entered into 
the study. 
5.9.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment, the subject will immediately be 
removed from the study.  The site will contact the subject at least monthly and document the 
subject’s status until the pregnancy has been completed or terminated.  The outcome of the 
pregnancy will be reported to the Sponsor and to Merck and Incyte without delay and within 24 
hours if the outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, 
or other disabling or life-threatening complication to the mother or newborn).  The study 
investigator will make every effort to obtain permission to follow the outcome of the pregnancy 
and report the condition of the fetus or newborn to the Sponsor.   If a male subject impregnates 
his female partner the study personnel at the site must be informed immediately and the 
pregnancy reported to the Sponsor and to Merck and Incyte and followed as described above and 
in Section 7.2.2.  
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that study drug may 
have interfered with the effectiveness of a contraceptive medication or method.  When a 
pregnancy has been confirmed in a subject during maternal or paternal exposure to study drug, 
the following procedures should be followed in order to ensure subject safety: 
• The study drug must be discontinued immediately (female subjects only). 
• The investigator must complete and submit the Incyte Clinical Trial Pregnancy form 
to the sponsor or its designee within 24 hours of learning of the pregnancy. 
Data on fetal outcome and breastfeeding are collected for regulatory reporting and drug safety 
evaluation.  Follow-up should be conducted for each pregnancy to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence of any 
birth defects, congenital abnormalities, or maternal and/or newborn complications, by following 
until the first well-baby visit.  Pregnancy should be recorded on a Clinical Trial Pregnancy form 
and reported by the investigator to the sponsor or its designee.  Pregnancy follow-up information 
should be recorded on the same form and should include an assessment of the possible causal 
relationship to the sponsor's study drug to any pregnancy outcome, as well as follow-up to the 
first well-baby visit or the duration specified in local regulations, whichever is later.  Refer to the 
Incyte Reference Guide for Completing the Clinical Trial Pregnancy Form. 
Any SAE occurring during pregnancy must be recorded on the SAE report form and 
submitted to the sponsor or designee. 
 
5.9.4 Use in Nursing Women 
It is unknown whether Pembrolizumab and Epacadostat are excreted in human milk.  Since many 
drugs are excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 

 
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5.10 Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the treating investigator or the PI if enrollment into the trial is inappropriate, the trial 
plan is violated, or for administrative and/or other safety reasons.  Specific details regarding 
discontinuation or withdrawal are provided in Section 7.1.4 – Other Procedures. 
A subject must be discontinued from the trial for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) withdraws consent. 
• The subject becomes pregnant 
• Confirmed radiographic disease progression 
Note: For unconfirmed radiographic disease progression, please see Section 5.7 
Note: A subject may be granted an exception to continue on treatment with confirmed 
radiographic progression if clinically stable or clinically improved,  
• Unacceptable adverse experiences  
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Completed 24 months of treatment  
• Note: 24 months of study medication is calculated from the date of first dose. Subjects who 
stop Pembrolizumab after 24 months (35 cycles) may be eligible for up to one year of 
additional study treatment if they progress after stopping study treatment. 
• Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow Chart) 
and Section 7.1.5 (Visit Requirements).  After the end of treatment, each subject will be followed 
for 30 days for adverse event monitoring (serious adverse events will be collected for 90 days after 
the end of treatment as described in Section 7.2.3.1).  Subjects who discontinue for reasons other 
than progressive disease will have post-treatment follow-up for disease status until disease 
progression, initiating a non-study cancer treatment, withdrawing consent or becoming lost to 
follow-up.  After documented disease progression each subject will be followed by telephone for 
overall survival until death, withdrawal of consent, or the end of the study, whichever occurs first. 

 
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5.11 Subject Replacement Strategy 
Patients who receive at least one treatment will not be replaced. 
5.12 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential health 
hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be provided 
so that appropriate adjustments to subject treatment can be made. 

 
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6.0 TRIAL FLOW CHART 
6.1 
Study Flow Chart 
Trial Period: 
Treatment Cycles 
End of Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Main 
Study 
Screening 
(Visit 1) 
1 
2  
3 
4 etc. 
Discon 
Safety 
Follow-
up 
Follow Up 
Visitsa 
Survival 
Follow-
Upb 
Scheduling Window (Days): 
-28 to -1 
 
± 3 
± 3 
± 3 
At time of Discon 
30 days 
post 
discon 
Every 12 
weeks post 
discon 
Every 12 
weeks  
Informed Consent 
x 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
x 
 
 
 
 
 
 
 
 
Demographics and Medical History 
x 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication Review 
x 
 
x 
x 
x 
x 
x 
 
 
Trial Treatment Administration 
 
x 
x 
x 
x 
 
 
 
 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
x 
x 
Survival Status 
 
 
 
 
 
x 
 
 
x 
Review Adverse Events 
 
 
x 
x 
x 
x 
x 
 
 
Full Physical Examination 
x 
x 
x 
x 
x 
x 
x 
 
 
Directed Physical Examination 
 
 
 
 
 
 
 
x 
x 
Vital Signs and Weight 
 
x 
x 
x 
x 
x 
x 
x 
x 
ECOG Performance Status 
x 
x 
x 
x 
x 
x 
x 
x 
x 
12-lead ECG 
x# 
x## 
x### 
 
x 
x 
 
 
 
Pregnancy Test – Urine or Serum -HCG* 
x 
 
 
 
 
 
 
 
 
PT/INR and aPTT** 
x 
 
 
 
 
 
 
 
 
CBC with Differential** 
x 
 
x 
x 
x 
x 
x 
 
 
Comprehensive Serum Chemistry Panel** 
x 
 
x 
x 
x 
x 
x 
 
 
Hepatitis panel*** 
 
 
 
 
 
 
 
 
 
Urinalysis** 
x 
 
x 
x 
x 
x 
x 
 
 
Endocrine Panel** 
x 
 
x 
x 
x 
x 
x 
 
 

 
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Trial Period: 
Treatment Cycles 
End of Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Main 
Study 
Screening 
(Visit 1) 
1 
2  
3 
4 etc. 
Discon 
Safety 
Follow-
up 
Follow Up 
Visitsa 
Survival 
Follow-
Upb 
Scheduling Window (Days): 
-28 to -1 
 
± 3 
± 3 
± 3 
At time of Discon 
30 days 
post 
discon 
Every 12 
weeks post 
discon 
Every 12 
weeks  
Tumor Imaging**** 
x 
 
x 
 
 
x 
 
x 
 
Archival or Newly Obtained Tissue 
Collection 
x 
 
 
 
 
 
 
 
 
Correlative Studies Blood Collection 
(Kynurenine/Trypotophan) 
x 
xc 
xc 
 
 
x 
 
 
 
 
*pregnancy test to be done within 72 hours of starting treatment  
**the rest of the blood tests are to be done within 10 days  
***for hepatitis panel see table 16 for details  
****FDG-PET to be performed if indicated in order to clarify sites of activity, before starting treatment and potentially to assess 
response. CT scans are performed at the end of the cycle indicated in the chart. 
a. follow-up visits until progression for up to 1 year in patients not progressing. b. for one year after last treatment. c. on day 15 of 
cycle 1 and cycle 2 
# Triplicate ECG at baseline.  
## Timed triplicate ECGs (separated by 5 min ± 2 min) at predose and at 2 and 4 hours (± 15 min) postdose.  
### ECG will be performed on D1 of every other cycle after C2 (eg, C4, C6, C8).  

 
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^ ECGs only need to be performed in triplicate if there has been a QT prolongation on study or the ECG shows a clinically significant 
abnormality not present at baseline. 
 

 
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7.0 TRIAL PROCEDURES 
7.1 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each visit.  
Individual trial procedures are described in detail below.  It may be necessary to perform these 
procedures at unscheduled time points if deemed clinically necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the PI and/or Merck for 
reasons related to subject safety. In some cases, such evaluation/testing may be potentially 
sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may require that 
additional informed consent be obtained from the subject.  In these cases, such evaluations/testing 
will be performed in accordance with those regulations. 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to participating 
in a clinical trial. 
7.1.1.1.1 General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally acceptable 
representative’s dated signature on a consent form along with the dated signature of the person 
conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before participation in 
the trial. 
The initial informed consent form, any subsequent revised written informed consent form and any 
written information provided to the subject must receive the IRB/ERC’s approval/favorable 
opinion in advance of use.  The subject or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to the 
subject’s willingness to continue participation in the trial.  The communication of this information 
will be provided and documented via a revised consent form or addendum to the original consent 
form that captures the subject’s dated signature or by the subject’s legally acceptable 
representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at the 
protocol level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations and 
Sponsor requirements. 

 
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7.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to 
ensure that the subject qualifies for the trial.  
7.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history will 
include all active conditions, and any condition diagnosed within the prior 10 years that are 
considered to be clinically significant by the Investigator.  Details regarding the disease for which 
the subject has enrolled in this study will be recorded separately and not listed as medical history.   
7.1.1.4 Prior and Concomitant Medications Review 
7.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any protocol-
specified washout requirement, and record prior medication taken by the subject within 28 days 
before starting the trial.  Treatment for the disease for which the subject has enrolled in this study 
will be recorded separately and not listed as a prior medication.  
7.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject during 
the trial.  All medications related to reportable SAEs and ECIs should be recorded as defined in 
Section 7.2. 
7.1.1.5 Disease Details and Treatments 
7.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease status.  
7.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including systemic 
treatments, radiation and surgeries. 
7.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days after 
the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the first dose 
of the new therapy.  Once new anti-cancer therapy has been initiated the subject will move into 
survival follow-up.  

 
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7.1.1.6 Assignment of Screening Number 
Patients who will be screened will receive a Screening Number 
7.1.1.7 Assignment of Randomization Number 
There will be no randomization in this study. 
7.1.1.8 Trial Compliance (Medication/Diet/Activity/Other) 
Trial compliance will be assessed regularly before every cycle while on treatment. 
7.1.2 Clinical Procedures/Assessments 
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-up 
period according to NCI CTCAE Version 4.0 (see Section 12.2).  Toxicities will be characterized 
in terms regarding seriousness, causality, toxicity grading, and action taken with regard to trial 
treatment.  
All AEs of unknown etiology associated with Pembrolizumab or Epacadostat exposure should be 
evaluated to determine if it is possibly an event of clinical interest (ECI) of a potentially 
immunologic etiology (irAE).  See Section 5.6.1.1 and the separate guidance document in the 
administrative binder regarding the identification, evaluation and management of AEs of a 
potential immunological etiology.   
Please refer to section 7.2 for detailed information regarding the assessment and recording of AEs.   
7.1.2.2 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the screening 
period.  Clinically significant abnormal findings should be recorded as medical history.  A full 
physical exam should be performed during screening,  
7.1.2.3 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration.   
7.1.2.4 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the administration 
of each dose of trial treatment and at treatment discontinuation as specified in the Trial Flow Chart 

 
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Protocol Version 6.0 Dated February 15, 2018 
 
 
 
(Section 6.0).  Vital signs should include temperature, pulse, respiratory rate, weight and blood 
pressure.  Height will be measured at screening only. 
7.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Appendix 12.3) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial treatment as 
specified in the Trial Flow Chart.  After Cycle 8 assessment of ECOG status will be performed 
every other cycle in conjunction with the directed or full physical exam. 
7.1.2.6 Tumor Imaging and Assessment of Disease 
Adequate imaging to assess the disease stage and burden will be performed before starting 
treatment. An FDG-PET/CT scan with diagnostic CT scan is recommended as part of the staging 
procedures at screening. If the FDG-PET was positive, it will be repeated when indicated. 
7.1.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling 
Archival tumor material will be obtained for histological confirmation and will be used for 
immunohistochemistry for PDL-1 expression and for Next-Generation sequencing. Submssion of 
a tumor block or 20 unstained slides is acceptable. Whenever feasible a new biopsy will be 
obtained before starting treatment, and normal blood will be collected for Next-Generation 
Sequencing. 
7.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below.  
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 18.  
 

 
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Table 18: 
Local Laboratory Tests:  Required Analytes 
Serum Chemistries 
Hematology 
Urinalysis With 
Microscopic Examination 
Hepatitis Screening 
Coagulation 
Albumin 
Alkaline phosphatase 
ALT 
AST  
Bicarbonate 
Blood urea nitrogen  
Calcium 
Chloride  
Creatinine 
Glucose 
Lactate dehydrogenase 
Phosphate 
Potassium 
Sodium 
Total bilirubin 
Direct bilirubin (if total 
bilirubin is elevated above 
ULN) 
Total protein 
Uric acid 
Troponin 
Creatine Kinase (the MB 
fraction if total is elevated) 
Complete blood count, 
including: 
Hemoglobin 
Hematocrit 
Platelet count 
Red blood cell count 
White blood cell count 
 
Differential count, 
including: 
Basophils 
Eosinophils 
Lymphocytes 
Monocytes 
Neutrophils 
 
Absolute values must be 
provided for:  
WBC differential 
laboratory results: 
Lymphocytes 
Neutrophils 
Color and appearance 
pH and specific gravity 
Bilirubin 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Occult blood 
Protein 
Urobilinogen 
Hepatitis B surface 
antigen 
Hepatitis B core antibody 
HBV-DNA 
HCV antibody 
HCV-RNA 
PT 
PTT 
INR 
Endocrine Monitoring 
Tumor Markers 
Pregnancy Testing 
ACTH 
Serum cortisol  
Prolactin 
TSH 
Free thyroxine (T4) 
Total triiodothyronine 
(T3) 
Serum testosterone  
If elevated 
Female subjects of 
childbearing potential 
only require a serum 
test at screening (must 
be performed within 
72 hours before the 
first dose of study 
drug) and at safety 
follow-up.  
Pregnancy tests (serum 
or urine) should be 
repeated if required by 
local regulations. 
ACTH = adrenocorticotropic hormone. 
Note:  Additional tests may be required, as agreed by investigator and sponsor, based on emerging safety data. 
 

 
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Laboratory tests for screening or entry into the Second Course Phase should be performed within 
10 days prior to the first dose of treatment.  After Cycle 1, pre-dose laboratory procedures can be 
conducted up to 72 hours prior to dosing.  Results must be reviewed by the investigator or qualified 
designee and found to be acceptable prior to each dose of trial treatment.  
7.1.3.1 Pharmacokinetic/Pharmacodynamic Evaluations 
There will be no blood or urine taken for pharmacokinetic analysis.  
Levels of tryptophan and kynurenine will be evaluated by liquid chromatography with tandem 
mass spectrometry to monitor systemic activity in modulating the IDO1 enzyme. PI will request 
its measurement to Incyte Corporation (Wilmington, DE) or Incyte's designee. A total of 5mL of 
blood will be drawn. Blood samples will be collected for pharmacodynamics studies (Plasma 
Tryptophan/ Kynurenine Ratio) from all participating subjects at Baseline, C1D15, and C2D1 for 
PD analysis for epacadostat. Patients should be fasting prior to blood collection as food intake 
can affect Tryptophan levels and unfasted samples can make Tryptophan/Kynurenine ratios 
difficult to interpret. The procedures for specimen collection, handling and shipping are as 
follows: 
  
a.      A total of 5mL blood will be collected into a  sodium heparinized tube. 
 After obtaining sample, immediately invert collection tube several times gently to mix. 
b.     Within 1 hour of collection, centrifuge at 400 x g for 10 minutes to separate cells 
and plasma. 
c.      Transfer plasma equally into (1) 2 mL (Aliquot A) and (1) 2 mL (Aliquot B) 
cryovials with appropriate labeling using standard laboratory technique. 
d.     Freeze on dry ice or at - 20ºC to - 80ºC immediately. 
e.      Store aliquots in a freezer set to maintain a temperature of - 70°C or colder until 
ready for shipment. Samples must be maintained in the frozen state until assayed. 
f.      Ship frozen Plasma Aliquot A samples daily with a 2-day supply of dry ice to the 
designated lab for priority (next morning) overnight delivery using the insulated 
container and pre-printed air bill provided by study. If you are unable to ship the sample 
the same day, the next business day is acceptable. 
g.     Aliquot B samples will be shipped monthly with a 2-day supply of dry ice to the 
designated lab (A samples and B samples from the same individual at the same time point 
should not be shipped together). 
h.     Include a copy of the requisition with each shipment. 
  
7.1.3.1.1 Blood Collection for Serum Pembrolizumab or Epacadostat 
There will be no blood collection for pharmacokinetic analysis. 
7.1.3.1.2 Blood Collection for Anti-Pembrolizumab Antibodies  
There will be no sample collection for antibodies against Pembrolizumab. 

 
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7.1.4 Other Procedures 
7.1.4.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities scheduled 
for the final trial visit should be performed at the time of discontinuation.  Any adverse events 
which are present at the time of discontinuation/withdrawal should be followed in accordance with 
the safety requirements outlined in Section 7.2 - Assessing and Recording Adverse Events.  
Subjects who a) attain a CR or b) complete 24 months of treatment with Pembrolizumab and 
Epacadostat may discontinue treatment with the option of restarting treatment if they meet the 
criteria specified in Section 7.1.5.2.1.  After discontinuing treatment following assessment of CR, 
these subjects should return to the site for a Safety Follow-up Visit (described in Section 7.1.5.3.1) 
and then proceed to the Follow-Up Period of the study (described in Section 7.1.5.4). 
7.1.4.2 Blinding/Unblinding 
This is an open label study. 
7.1.5 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
7.1.5.1 Screening 
Once the subject has been identified, he/she will be subjected to screening procedures as identified 
in section 6.0. 
7.1.5.1.1 Screening Period 
Within 28 days from start of treatment. 
7.1.5.2 Treatment Period 
Patients will be treated within a week from registration, every 3 weeks (one cycle) and will 
continue treatment until there are signs of benefit, but not beyond progression unless they are 
deemed to be clinically stable or clinically improved (see 5.8). The maximum treatment duration 
is 24 months.  
7.1.5.2.1 Retreatment-Second Course Phase 
Subjects who have stable disease (SD), PR, or CR after receiving 35 pembrolizumab treatments 
may be eligible for up to an additional 17 cycles (approximately 1 year) of pembrolizumab 
treatment.  This retreatment is termed the Second Course Phase of this trial and will only be 
available if the trial remains open and the subject meets the following conditions: 

 
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• Had SD, PR, or CR and stopped treatment after completion of 35 administrations 
(approximately 2 years) of pembrolizumab either in the Initial Treatment Phase or in a 
combination of the Initial Treatment and the Continued Treatment Phase OR stopped trial 
treatment for reasons other than disease progression or intolerability AND 
• Experienced an investigator-determined radiographic disease progression by RECIST 1.1 
after stopping initial treatment, and 
• No new anticancer treatment was administered after the last dose of trial treatment, and 
• The subject meets all of the safety parameters listed in the inclusion criteria and none of 
the safety parameters listed in the exclusion criteria, and 
• The trial is ongoing. 
 
7.1.5.3 Post-Treatment Visits 
7.1.5.3.1  Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last 
dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever comes 
first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  Subjects with an 
AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 or until the beginning 
of a new anti-neoplastic therapy, whichever occurs first.  SAEs that occur within 90 days of the 
end of treatment or before initiation of a new anti-cancer treatment should also be followed and 
recorded.   
7.1.5.4 Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will move into 
the Follow-Up Phase and should be assessed every 12weeks (84 ± 7 days) by radiologic imaging 
to monitor disease status.  Every effort should be made to collect information regarding disease 
status until the start of new anti-neoplastic therapy, disease progression, death, end of the study or 
if the subject begins retreatment with Pembrolizumab.  Information regarding post-study anti-
neoplastic treatment will be collected if new treatment is initiated. 
Subjects who are eligible to receive retreatment with Pembrolizumab will move from the follow-
up phase to the Second Course Phase (Section 7.1.5.2.1) when they experience disease 
progression.    
7.1.5.4.1 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, the 
subject moves into the survival follow-up phase and should be contacted by telephone every 12 

 
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weeks to assess for survival status until death, withdrawal of consent, or the end of the study, 
whichever occurs first.  
7.2 
Assessing and Recording Adverse Events   
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have 
to have a causal relationship with this treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease 
temporally associated with the use of a medicinal product or protocol-specified procedure, whether 
or not considered related to the medicinal product or protocol-specified procedure.  Any worsening 
(i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting 
condition that is temporally associated with the use of the Merck’s or Incyte’s products, is also an 
adverse event. 
Changes resulting from normal growth and development that do not vary significantly in frequency 
or severity from expected levels are not to be considered adverse events.  Examples of this may 
include, but are not limited to, teething, typical crying in infants and children and onset of menses 
or menopause occurring at a physiologically appropriate time. 
Adverse events may occur during the course of the use of Merck/Incyte products in clinical trials 
or within the follow-up period specified by the protocol, or prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal. 
Adverse events may also occur in screened subjects during any pre-allocation baseline period as a 
result of a protocol-specified intervention, including washout or discontinuation of usual therapy, 
diet, placebo treatment or a procedure. 
All adverse events will be recorded from the time the consent form is signed through 30 days 
following cessation of treatment and at each examination on the Adverse Event case report 
forms/worksheets. The reporting timeframe for adverse events meeting any serious criteria is 
described in section 7.2.3.1. 
Adverse events will not be collected for subjects during the pre-screening period (for determination 
of archival tissue status) as long as that subject has not undergone any protocol-specified procedure 
or intervention.  If the subject requires a blood draw, fresh tumor biopsy etc., the subject is first 
required to provide consent to the main study and AEs will be captured according to guidelines for 
standard AE reporting. 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck and Incyte 
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed dose 
for Pembrolizumab and/or Epacadostat by 20% over the prescribed dose. No specific information 
is available on the treatment of overdose of Pembrolizumab or Epacadostat. In the event of 

 
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overdose, drugs should be discontinued and the subject should be observed closely for signs of 
toxicity.  Appropriate supportive treatment should be provided if clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose, the adverse event(s) is 
reported as a serious adverse event, even if no other seriousness criteria are met. 
If the overdose occurs 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 (Attn: Multi-Site Coordinator FAX 202-687-3821) and within 2 working days hours to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) and Incyte (see 
below)  
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them), including the pregnancy of a male subject's female partner that occurs during 
the trial or within 120 days of completing the trial completing the trial, or 30 days following 
cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier.  All 
subjects and female partners of male subjects who become pregnant must be followed to the 
completion/termination of the pregnancy.  Pregnancy outcomes of spontaneous abortion, missed 
abortion, benign hydatiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and 
stillbirth must be reported as serious events (Important Medical Events).  If the pregnancy 
continues to term, the outcome (health of infant) must also be reported. 
Such events must be reported within 24 hours to the Sponsor (Attn: CRMO Office FAX 202-687-
3821; and within 2 working days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 
215 993-1220) and Incyte (see below). 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
7.2.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck’s 
product that: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is a new cancer (that is not a condition of the study); 
• Is associated with an overdose; 

 
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• Is an other important medical event  
Refer to Table 19 for additional details regarding each of the above criteria. 
Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death. 
Any serious adverse event, or follow up to a serious adverse event, including death due to any 
cause other than progression of the cancer under study that occurs to any subject from the time the 
consent is signed through 90 days following cessation of treatment, or the initiation of new anti-
cancer therapy, whichever is earlier, whether or not related to Merck or Incyte product, must be 
reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety and 
Incyte (see below).  
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and Incyte (see 
below) and will be handled in the same manner as SAEs.  
Additionally, any serious adverse event, considered by an investigator who is a qualified physician 
to be related to Merck or Incyte product that is brought to the attention of the investigator at any 
time outside of the time period specified in the previous paragraph also must be reported 
immediately to the Sponsor and to Merck and Incyte. 
SAE reports and any other relevant safety information are to be forwarded to the Merck Global 
Safety facsimile number:  +1-215-993-1220 and Incyte as per their reporting guidelines below. 
All Serious Adverse Events (“SAE”) required to be reported pursuant to the Protocol shall be provided 
to Incyte and its representatives by Institution or Principal Investigator within twenty-four (24) hours 
of learning of the event as well as provide any additional reports agreed upon by the Institution or 
Principal Investigator and Incyte’s contact  below.  SAE Reports will be sent to the email address 
provided below.  By sending to this e-mail address, the Incyte Pharmacovigilance group and the 
Incyte clinical operations project manager will receive copies of the reports. This process will be 
tested and established before the first patient is enrolled in the trial. Notwithstanding anything to the 
contrary herein, Institution or Principal Investigator will have the primary responsibility of reporting 
adverse events (“AE”) to regulatory authorities. 
Copies of IND safety reports submitted to the FDA by the Institution will be shared with the contact 
below so that these reports can be evaluated and included in investigator brochure or Incyte IND 
safety submissions as required to ensure safety of other patients who are receiving the product from 
Incyte for sponsored trials. 
Incyte Corporation: IncytePhVOpsIST@incyte.com for e-mail transmission of individual SAE 
reports; 
Safety Contacts: Kathy Lenard Roberts, Exec. Dir, Incyte Pharmacovigilance, Phone: 302-498-6727, 
Email: kroberts@incyte.com  
Incyte reporting requirements for pregnancy: 

 
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Data on fetal outcome are collected for regulatory reporting and drug safety evaluation.  Follow-up 
should be conducted for each pregnancy to determine outcome, including spontaneous or voluntary 
termination, details of the birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications. 
Within 30 days of learning of the pregnancy, the investigational site completes the Clinical Trial 
Pregnancy Form (sections I, II, and question 18 in section III) or equivalent, and e-mails the report to 
Incyte at IncytePhVOpsIST@incyte.com.  
Within 30 days of learning of the outcome of the pregnancy (delivery, termination, or miscarriage), 
the investigational site completes the Clinical Trial Pregnancy Form (sections II, III, IV, and V) or 
equivalent, and e-mails the report to Incyte at IncytePhVOpsIST@incyte.com. 
NOTE:  If a woman has a positive pregnancy test at Baseline, the investigational site completes 
Clinical Trial Pregnancy Form (sections I, II, and III (question 18)) or equivalent and e-mails the 
report to Incyte at IncytePhVOpsIST@incyte.com, as per established timelines.  
Any SAE occurring during pregnancy must be reported to Incyte as an SAE, in accordance with 
Section 3 of the Serious Adverse Event Reporting Plan, as provided by Incyte. 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to the 
Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) and Incyte (see above) at the time of submission 
to FDA.  
All subjects with serious adverse events must be followed up for outcome. 
7.2.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest (ECI) 
and must be recorded as such on the Adverse Event case report forms/worksheets and reported 
within 24 hours to the Sponsor and within 2 working days to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) and Incyte (see section above)  
Events of clinical interest for this trial include: 
1.  an overdose of Pembrolizumab and/or Epacadostat product, as defined in Section 7.2.1 - 
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 

 
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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.  The trial site guidance for assessment and follow up of 
these criteria can be found in the Investigator Trial File Binder (or equivalent). 
ECIs that occur in any subject from the date of first dose through 90 days following cessation of 
treatment, or the initiation of a new anticancer therapy, whichever is earlier, whether or not related 
to the Merck’s product, must be reported within 24 hours to the Sponsor and to Merck Global 
Safety and Incyte (see section above) within 2 working days. 
7.2.4 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the NCI 
Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event which 
changes CTCAE grade over the course of a given episode will have each change of grade recorded 
on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 

 
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Table 19.  Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 
CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Pembrolizumab and/or Epacadostat product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer; (that is not a condition of the study) or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. An overdose that is not 
associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause Pembrolizumab and/or Epacadostat to be discontinued? 
Relationship to 
test drug  
Did Pembrolizumab and/or Epacadostat cause the adverse event? The determination of the likelihood that Pembrolizumab and/or Epacadostat caused the adverse 
event will be provided by an investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the 
causality noted on the AE form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required 
regulatory time frame. The criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test 
drug and the adverse event based upon the available information.  
The following components are to be used to assess the relationship between the Merck product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely Pembrolizumab and/or Epacadostat caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to Pembrolizumab and/or Epacadostat such as: reliable history, acceptable compliance 
assessment (pill count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of Pembrolizumab and/or Epacadostat?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors 
 

 
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Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Merck 
product 
(continued)  
Dechallenge 
Were Pembrolizumab and/or Epacadostat discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation 
of Pembrolizumab and Epacadostat; or (3) the trial is a single-dose drug trial); or (4) Pembrolizumab and Epacadostat were only used one time.) 
 
Rechallenge 
Was the subject re-exposed to Pembrolizumab and Epacadostat in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Merck product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY Pembrolizumab and/or Epacadostat, OR IF REEXPOSURE TO THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL 
MONITOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding Pembrolizumab and/or Epacadostat or drug class 
pharmacology or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to Pembrolizumab and/or Epacadostat.  The temporal sequence of the AE onset relative to the administration of 
drugs is reasonable.  The AE is more likely explained by drug exposure than by another cause. 
No, there is not a reasonable 
possibility Merck product 
relationship 
Subject did not receive Pembrolizumab and/or Epacadostat OR temporal sequence of the AE onset relative to administration of drugs is not 
reasonable OR there is another obvious cause of the AE.  (Also entered for a subject with overdose without an associated AE.) 

 
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7.2.5 Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.  
8.0 STATISTICAL ANALYSIS PLAN 
8.1 
Statistical Analysis Plan Summary 
This is a phase II study of MK-3475 in thymic carcinoma patients who recurred after at least one 
prior chemotherapy regimen. The primary endpoint is response rate; secondary endpoints are 
Progression-Free Survival, Overall Survival and treatment tolerability. Responses will be assessed 
according to RECIST 1.1; progression-free survival is defined as time between start of treatment 
and tumor progression or death, whichever comes first; survival is the time between start of 
treatment and death or last follow-up. Furthermore exploratory studies will be performed on 
archival tumor material (PDL-1 expression, next-generation sequencing), and fresh biopsies 
(culturing; next-generation sequencing). 
8.2 
Statistical Analysis Plan 
Simon's two-stage optimal design is used. The null hypothesis that the true response rate is 5% 
will be tested against a one-sided alternative. In the first stage, 21 patients will be accrued. If there 
are 1 or fewer responses in these 21 patients, the study will be stopped. Otherwise, 20 additional 
patients will be accrued for a total of 41. The null hypothesis will be rejected if 5 or more responses 
are observed in 41 patients. This design yields a type I error rate of 5% and power of 90% when 
the true response rate is 20%.  Should a need for unplanned interim analysis arise, the significance 
of the response test will be evaluated based on the reverse curtailing SCRPT method (see, Tan M, 
Xiong X. A Flexible Multi-Stage Design for Phase II Oncology Trials. Pharmaceutical Statistics. 
2011;10:369-73). Should the first stage indicate futility, the SCPRT method will also be used to 
assess the chance for a trend reversal at the end second stage. Kaplan–Meier estimator will be used 
for progression free survival and overall survival analysis. The response rate, tolerability rate and 
PDL-1 expression incidence rate will be separately estimated as a binomial proportion with 95% 
exact Clopper-Pearson confidence interval using exact binomial calculation. 
The results of NextGen sequencing will be analyzed assessing the relation between response and 
presence of any mutation, and response (percentage of tumor change) and number of mutation per 
sample by regression analysis with proper control of false discovery rate, using the regularized 
statistical learning model with cross validation. 
The results of the conditionally reprogrammed cell cultures will be analyzed in a descriptive 
manner. We will define whether the tumors are heterogeneous (i.e. have different morphologies 
and/or somatic mutation spectra) and whether these are related to response, again with regularized 
statistical model. 

 
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AMENDED STATISTICAL CONSIDERATIONS FOR THE COMBINATION OF 
PEMBROLIZUMAB AND EPACADOSTAT 
8.3 
Statistical Analysis Plan Summary 
The amended phase II study of Pembrolizumab and Epacadostat is for thymic carcinoma patients 
who recurred after at least one prior chemotherapy regimen. The primary endpoint is response rate; 
secondary endpoints are Progression-Free Survival, Overall Survival and treatment tolerability. 
Responses will be assessed according to RECIST 1.1; progression-free survival is defined as time 
between start of treatment and tumor progression or death; survival is the time between start of 
treatment and death. Furthermore exploratory studies will be performed on archival tumor material 
(PDL-1 expression, next-generation sequencing), and fresh biopsies (culturing; next-generation 
sequencing). 
8.4 
Statistical Analysis Plan 
In the amended protocol a new cohort of patients with advanced thymic carcinoma will be treated 
with the combination of pembrolizumab and epacadostat. The response rate that is expected is 
45%, comparing to a constant of 25%, which is roughly the response rate with pembrolizumab and 
sunitinib as single agents, the sample size is 26, with a type I error rate of 10%, power 80%, and 
one sided test. 
Kaplan–Meier estimator will be used for progression free survival and overall survival analysis. 
The response rate, tolerability rate and PDL-1 expression incidence rate will be separately 
estimated as a binomial proportion with 95% exact Clopper-Pearson confidence interval using 
exact binomial calculation. 
The results of NextGen sequencing will be analyzed assessing the relation between response and 
presence of any mutation, and response (percentage of tumor change) and number of mutation per 
sample by regression analysis with proper control of false discovery rate, using the regularized 
statistical learning model with cross validation. 
The results of the conditionally reprogrammed cell cultures will be analyzed in a descriptive 
manner. We will define whether the tumors are heterogeneous (i.e. have different morphologies 
and/or somatic mutation spectra) and whether these are related to response, again with regularized 
statistical model. 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
9.1 
Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate records 
and ensure appropriate supply, storage, handling, distribution and usage of investigational product 
in accordance with the protocol and any applicable laws and regulations. 
Clinical Supplies will be provided by Merck and Incyte as summarized in Table 20. 

 
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Table 20.  Product Descriptions 
Product Name & Potency 
Dosage Form 
MK-3475 100 mg/ 4mL 
Solution for Injection 
Epacadostat 100 mg BID 
25 and 100 mg Tablets 
 
9.2 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
9.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or designee 
are not blinded to treatment. Drug identity (name, strength) is included in the label text; random 
code/disclosure envelopes or lists are not provided. 
9.4 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial 
site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
9.5 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received from 
Merck or designee, the amount dispensed to and returned by the subjects and the amount remaining 
at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s responsibility 
to arrange for disposal of all empty containers, provided that procedures for proper disposal 
have been established according to applicable federal, state, local and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept. 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 Confidentiality 
10.1.1 Confidentiality of Data 
The investigator affirms that information furnished to the investigator by the Sponsor will be 
maintained in confidence, and such information will be divulged to the institutional review board, 

 
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other expert committees (LCCC Clinical Research Committee and Data Safety Monitoring 
Committee), Food and Drug Administration; and employees working on this study, only under an 
appropriate understanding of confidentiality. Data generated by this trial will be considered 
confidential by the investigators, except to the extent that it is included in publications. 
10.1.2 Confidentiality of Subject Records 
The investigator agrees that the Sponsor, IRB, or regulatory authority representatives may consult 
and/or copy trial documents in order to verify case report form data. By signing the consent form, 
the subject agrees to this process. The subject will be identified by a unique code only on all case 
report forms and correlative science specimens. 
The investigator agrees to treat all subject data used and disclosed in connection with this trial in 
accordance with all applicable privacy laws, rules, and regulations.   
10.2 Compliance with Financial Disclosure Requirements 
Financial disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the Principal 
Investigator’s responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator’s/subinvestigator’s 
responsibility to comply with any such request. 
10.3 Compliance with Law, Audit and Debarment 
The investigator agrees to conduct the trial in an efficient and diligent manner and in conformance 
with the protocol; generally accepted standards of Good Clinical Practice; and all applicable 
federal, state, and local laws, rules and regulations relati8ng to the conduct of the clinical trial. 
The investigator agrees to allow monitoring, audits, IRB review and regulatory authority 
inspection of trial-related documents and procedures and provide for direct access to all trial-
related source data and documents. 
Persons debarred from conducting or working on clinical trials by any court or regulatory authority 
will not be allowed to conduct or work on this trial. The investigator will immediately notify the 
Sponsor in writing if any person involved in conducting the trial is debarred or if any proceeding 
for debarment is pending or, to the best of the investigator’s knowledge, threatened. 
10.4 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food 
and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely responsible 
for determining whether the trial and its results are subject to the requirements for submission to 
the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information posted will allow 
subjects to identify potentially appropriate trials for their disease conditions and pursue 
participation by calling a central contact number for further information on appropriate trial 
locations and trial site contact information.     

 
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10.5 Data Safety Monitoring Plan 
The Georgetown Lombardi Comprehensive Cancer Center will be responsible for the data and 
safety monitoring of this multi-site trial.  As this study is an investigator initiated study Phase II 
study utilizing a non-FDA approved drug for which the PI holds the IND it is considered a high 
risk study which requires real-time monitoring by the PI and study team and quarterly reviews by 
the LCCC Data and Safety Monitoring Committee (DSMC). 
The Principal Investigator and the Co-Investigators will review the data including safety 
monitoring at their weekly institution based disease group meetings and on monthly disease group 
teleconferences.   
All Severe Adverse Events (SAEs) are required to be reported to the IRB.  Based on SAEs, the 
IRB retains the authority to suspend further accrual pending more detailed reporting and/or 
modifications to further reduce risk and maximize the safety of participating patients. 
Progress on the trial and the toxicities experienced will be reviewed by the LCCC Data and Safety 
Monitoring Committee every 4 months from the time the first patient is enrolled on the study. 
Results of the DSMC meetings will be forwarded to the IRB with recommendations regarding 
need for study closure.  
DSMC recommendations should be based not only on results for the trial being monitored as well 
as on data available to the DSMC from other studies.  It is the responsibility of the PI to ensure 
that the DSMC is kept apprised of non-confidential results from related studies that become 
available.  It is the responsibility of the DSMC to determine the extent to which this information 
is relevant to its decisions related to the specific trial being monitored. 
A written copy of the DSMC recommendations will be given to the trial PI and the IRB.  If the 
DSMC recommends a study change for patient safety or efficacy reasons the trial PI must act to 
implement the change as expeditiously as possible.  In the unlikely event that the trial PI does not 
concur with the DSMC recommendations, then the LCCC Deputy Director must be informed of 
the reason for the disagreement.  The trial PI, DSMC Chair, and the LCCC Deputy Director will 
be responsible for reaching a mutually acceptable decision about the study and providing details 
of that decision to the IRB.  Confidentiality must be preserved during these discussions.  However, 
in some cases, relevant data may be shared with other selected trial investigators and staff to seek 
advice to assist in reaching a mutually acceptable decision. 
If a recommendation is made to change a trial for reasons other than patient safety or efficacy the 
DSMC will provide an adequate rationale for its decision. If the DSMC recommends that the trial 
be closed for any reason, the recommendation will be reviewed by the LCCC Deputy Director.  
Authority to close a trial for safety reasons lies with the IRB, with the above described input from 
DSMC and the LCCC Deputy Director.   

 
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10.6 Data Management 
Patient data will be entered into the on-line accessible Oracle Clinical database. This database is 
housed at Georgetown, but is accessible anywhere there is internet access. All research 
coordinators and data managers will attend an on-line training session to learn how to accurately 
enter any data into the Oracle data base. All screening data should be entered prior to starting 
therapy, and all ongoing patient data should be entered within one week of each patient visit. The 
LCCC QA Manager will be reviewing all online data on a regular basis to ensure compliance. 
10.7 Multi-Site Study Coordination 
The multi-site coordinator in the Georgetown Lombardi Comprehensive Cancer Center CRMO 
will have responsibility for coordination among participating sites. She will be the main point of 
contact for the investigators for any study related concerns and to double check eligibility for each 
patient considered for enrollment. She will be the point of contact for data managers for data entry 
questions.  She will play a major role in regulatory coordination of this study, specifically by: 
a) Reviewing and confirming all study-related adverse events 
b) Submitting all SAE reports to the Georgetown IRB, FDA, and Merck (The research 
coordinators at collaborating sites will prepare SAE reports for subjects treated at their 
individual site, and the multi-site coordinator will submit the final report to all 
necessary parties). 
c) Gathering and preparing all primary source data for review/audit. 
 
Contact: CRMO Office   Ph: 202-687-1569 Fax: 202-687-3821  
 
11.0 LIST OF REFERENCES 
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Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. Adoptive 
cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the 
treatment of patients with refractory metastatic melanoma. J Clin Oncol 2005;23(10):2346-
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Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment of 
metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med 
2008;358(25):2698-703.   
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Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisted. Annu Rev Immunol 
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cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine 
phosphatase 2 to phosphotyrosine. PNAS 2001;98(24):13866-71. 

 
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6. 
Zhang X, Schwartz JC, Guo X, Bhatia S, Cao E, Lorenz M, et al. Structural and functional 
analysis of the costimulatory receptor programmed death-1. Immunity 2004;20:337-47. 
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Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 associate with 
immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T 
cell stimulation, but only receptor ligation prevents T cell activation. J Immunol 
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receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream 
signaling to PKCtheta. FEBS Lett 2004;574:37-41. 
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Riley JL. PD-1 signaling in primary T cells. Immunol Rev 2009;229:114-25. 
10. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, et al. 
CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 
2005;25:9543-53. 
11. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. 
Immunol Rev 2010;236:219-42. 
12. Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, Yagita H, et al. Expression of the 
PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol 
1996;8(5):765-72. 
13. Vibhakar R, Juan G, Traganos F, Darzynkiewicz Z, Finger LR. Activation induced expression 
of human programmed death-1 gene in T-lymphocytes. Exp Cell Res 1997;232:25-8. 
14. Nishimura H, Honjo T, Minato N. Facilitation of β selection and modification of positive 
selection in the thymus of PD-1-deficient mice. J Exp Med 2000;191(5):891-7.   
15. Brown JA, Dorfman DM, Ma F-R, Sullivan EL, Munoz O, Wood CR, et al. Blockade of 
programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine 
production. J Immunol 2003;170:1257-66.   
16. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated 
B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 
2002;8(8):793-800.   
17. Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nature 2002;2:116-26. 
18. Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, et al. PD-1 
expressed by tumor-infiltrating immune cells and is associated with poor outcome for patients 
with renal cell carcinoma. Clin Caner Res 2007;13(6):1757-61.   

 
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19. Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro, H, et al. Clinical significance and 
therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in 
human pancreatic cancer. Clin Cancer Res 2007;13:2151-7. 
20. Gao Q, Wang XY, Qiu SJ, Yamato I, Sho M, Nakajima Y, et al. Overexpression of PD-L1 
significantly associates with tumor aggressiveness and postoperative recurrence in human 
hepatocellular carcinoma. Clin Cancer Res 2009;15: 971-9. 
21. Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, et al. Programmed 
cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of 
human ovarian cancer. Proc Natl Acad Sci USA 2007;104:3360-5. 
22. Fourcade J, Kudela P, Sun Z, Shen H, Lenzner D, Guillaume P, et al. PD-1 is a regulator of 
NY-ESO-1-specific CD8+ T cell expansion in melanoma patients. J Immunol 
2009;182:5240-9. 
23. Kelly, R. J., Petrini, I., Rajan, A., Wang, Y., & Giaccone, G. (2011). Thymic malignancies: 
From clinical management to targeted therapies. Journal of Clinical Oncology : Official 
Journal of the American Society of Clinical Oncology, 29(36), 4820-4827. 
24. Kelly, R. J., Browne, S. K., Rajan, A., & Giaccone, G. (2010). Thymoma-associated 
paraneoplastic polymyositis. Journal of Clinical Oncology : Official Journal of the American 
Society of Clinical Oncology, 28(22), e378. 
25. Rajan, A., Kotlyar, D., & Giaccone, G. (2013). Acute autoimmune hepatitis, myositis, and 
myasthenic crisis in a patient with thymoma. Journal of Thoracic Oncology : Official 
Publication of the International Association for the Study of Lung Cancer, 8(10), e87-8. 
26. Rajan, A., Carter, C. A., Berman, A., Cao, L., Kelly, R. J., Thomas, A., et al. (2014). 
Cixutumumab for patients with recurrent or refractory advanced thymic epithelial tumours: A 
multicentre, open-label, phase 2 trial. The Lancet Oncology, 15(2), 191-200. 
27. Burbelo, P. D., Browne, S. K., Sampaio, E. P., Giaccone, G., Zaman, R., Kristosturyan, E., et 
al. (2010). Anti-cytokine autoantibodies are associated with opportunistic infection in patients 
with thymic neoplasia. Blood, 116(23), 4848-4858. 
28. Lemma, G. L., Lee, J. W., Aisner, S. C., Langer, C. J., Tester, W. J., Johnson, D. H., et al. 
(2011). Phase II study of carboplatin and paclitaxel in advanced thymoma and thymic 
carcinoma. Journal of Clinical Oncology : Official Journal of the American Society of Clinical 
Oncology, 29(15), 2060-2065. 
29. Giaccone, G., Ardizzoni, A., Kirkpatrick, A., Clerico, M., Sahmoud, T., & van Zandwijk, N. 
(1996). Cisplatin and etoposide combination chemotherapy for locally advanced or metastatic 
thymoma. A phase II study of the European Organization for Research and Treatment of 
Cancer lung cancer cooperative group. Journal of Clinical Oncology : Official Journal of the 
American Society of Clinical Oncology, 14(3), 814-820. 

 
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30. Giaccone, G., Rajan, A., Ruijter, R., Smit, E., van Groeningen, C., & Hogendoorn, P. C. 
(2009). Imatinib mesylate in patients with WHO B3 thymomas and thymic carcinomas. 
Journal of Thoracic Oncology : Official Publication of the International Association for the 
Study of Lung Cancer, 4(10), 1270-1273. 
31. Giaccone, G., Rajan, A., Berman, A., Kelly, R. J., Szabo, E., Lopez-Chavez, A., et al. (2011). 
Phase II study of belinostat in patients with recurrent or refractory advanced thymic epithelial 
tumors. Journal of Clinical Oncology : Official Journal of the American Society of Clinical 
Oncology, 29(15), 2052-2059. 
32. Thomas, A., Rajan, A., Berman, A., Brzezniak, C.E., Splitter, A.J., Carter, C.A., Guha, U., 
Wang, Y., Szabo, E., Loehrer, P.J., Giaccone, G. Phase II trial of sunitinib in patients with 
thymic epithelial tumors (TET). J Clin Oncol 32:5s, 2014 (suppl; abstr 7525) 
33. Wang Y, Meltzer PS, Lau C, Thomas A, Rajan A, Giaccone G. Recurrence of epigenetic gene 
mutations in thymic epithelial carcinomas revealed by targeted exome sequencing of cancer-
associated genes. J Clin Oncol 32:5s, 2014 (suppl; abstr 7529). 
34. Liang, S. C., Latchman, Y. E., Buhlmann, J. E., Tomczak, M. F., Horwitz, B. H., Freeman, 
G. J., et al. (2003). Regulation of PD-1, PD-L1, and PD-L2 expression during normal and 
autoimmune responses. European Journal of Immunology, 33(10), 2706-2716. 
35. Padda, S.K., Riess, J., Schwartz, E.J., Tian, L., Kohrt, H.E., Neal, J.W., Natkunam, Y., West, 
R.B., Wakelee, H.A. Programmed death receptor ligand-1 (PD-L1) expression in a thymoma 
(T) tissue microarray (TMA). J Clin Oncol 32:5s, 2014 (suppl; abstr 7606) 
36. Hamid O, Robert C, Daud A, Hodi FS, Hwu FS, Hwu WJ, Kefford R, Wolchok JD, Hersey 
P, et al. Safety and tumor response with lambrolizumab (anti PD-1) in melanoma. NEJM 
2013, 369, 134-144. 
37. Suprynowicz FA, Upadhyay G, Krawczyk E, Kramer SC, Hebert JD, Liu X, Yuan H, 
Cheluvaraju C, Clapp PW, Boucher RC Jr, Kamonjoh CM, Randell SH, Schlegel R. 
Conditionally reprogrammed cells represent a stem-like state of adult epithelial cells. Proc 
Natl Acad Sci U S A. 2012 Dec 4;109(49):20035-40. 
38. Petrini I, Meltzer PS, Kim IK, Lucchi M, Park KS, Fontanini G, Gao J, Zucali PA, Calabrese 
F, Favaretto A, Rea F, Rodriguez-Canales J, Walker RL, Pineda M, Zhu YJ, Lau C, Killian 
KJ, Bilke S, Voeller D, Dakshanamurthy S, Wang Y, Giaccone G. A specific missense 
mutation in GTF2I occurs at high frequency in thymic epithelial tumors. Nat Genet. 2014 
Aug;46(8):844-9. 
39. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW. Cancer 
genome landscapes. Science. 2013 Mar 29;339(6127):1546-58. 
40. Boyer EW, Shannon M. The serotonin syndrome. New Eng J Med 2005;352:1112-1120. 

 
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41. Y. Zhang, Y. Li, S. Diamond, S. Yeleswaram (AAPS, abstract/poster 2016).  Effects of 
Epacadostat with Co-Administration of Linezolid on Brain Extracellular Fluid Concentrations 
of Serotonin: An Intracerebral Microdialysis Study in Sprague-Dawley Rats 

 
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12.0 APPENDICES 
12.1 WHO histological classification (Rosai J SL. Histological typing of tumours of the thymus. 
2nd edition ed. New York: Springer; 1999) 
Type 
Description 
A 
A tumor composed of a population of neoplastic thymic epithelial cells having spindle/oval shape, lacking 
nuclear atypia, and accompanied by few or no non-neoplastic lymphocytes. 
AB 
A tumor in which foci having the features of type A thymoma are admixed with foci rich in lymphocytes. 
B1 
A tumor that resembles the normal functional thymus in that it combines large expanses having an 
appearance practically indistinguishable from normal thymic cortex with areas resembling thymic medulla. 
B2 
A tumor in which the neoplastic epithelial component appears as scattered plump cells with vesicular nuclei 
and distinct nucleoli among a heavy population of lymphocytes. Perivascular spaces are common and 
sometimes very prominent. A perivascular arrangement of tumor cells resulting in a palisading effect may 
be seen. 
B3 
A type of thymoma predominantly composed of epithelial cells having a round or polygonal shape and 
exhibiting no or mild atypia. They are admixed with a minor component of lymphocytes, resulting in a sheet-
like growth of the neoplastic epithelial cells. 
C 
A thymic tumor exhibiting clear-cut cytologic atypia and a set of cytoarchitectural features no longer specific 
to the thymus, but rather analogous to those seen in carcinomas of other organs. Type C thymomas lack 
immature lymphocytes; whatever lymphocytes may be present are mature and usually admixed with plasma 
cells. 
 
12.2 Masaoka staging system (Masaoka A, Monden Y, Nakahara K, Tanioka T. Follow-up-
study of thymomas with special reference to their clinical stages. Cancer 1981; 48: 2485-
92). 
Stage 
Description 
I 
 
Tumor remains completely encapsulated 
II 
A 
Microscopic transcapsular invasion 
 
B 
Macroscopic invasion into surrounding fatty tissue or 
grossly adherent to (but not through) mediastinal 
pleural or pericardium 
III 
 
Macroscopic invasion into neighboring organs (i.e. 
pericardium, great vessels, lung) 
 
A 
Without invasion of great vessels 
 
B 
With invasion of great vessels 
IV 
A 
Pleural or pericardial dissemination 
 
B 
Lymphogenous or hematogenous metastasis 
 
12.3 ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., 
light housework, office work). 

 
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Grade 
Description 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but unable 
to carry out any work activities. Up and about more than 50% of waking 
hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed 
or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., 
Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern 
Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative 
Oncology Group, Robert Comis M.D., Group Chair. 
 
12.4 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
12.5 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for Evaluating 
Response in Solid Tumors 
RECIST version 1.1* will be used in this study for assessment of tumor response. While either CT 
or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this study. 
* As published in the European Journal of Cancer: 
 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, 
S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, 
J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST guideline (version 
1.1). Eur J Cancer. 2009 Jan;45(2):228-47.