Clinical trial NCT03463161
Conditions: Head and Neck Squamous Cell Carcinoma Head and Neck Cancer
Sponsor: University of Chicago
Start date: 2018-03-23; Completion date: 2018-12-04
Enrollment: 2 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study to determine response rate of the combination of pembrolizumab plus epacadostat in patients with head and neck cancers that have received prior immunotherapy.

Detailed description:

Arms: arm 1: Participants that have benefited from prior treatment with immunotherapy. Defined as response to prior treatment and/or stable disease lasting at least 5 months and disease worsening seen on most recent imaging.

Participants will receive Pembrolizumab and Epacadostat. arm 2: Participants that have not benefited from prior treatment with immunotherapy. Defined as stable disease lasting at least 5 months or suboptimal response (11-49% shrinkage of tumors). Disease continues to be stable on most recent imaging.

Participants will receive Pembrolizumab and Epacadostat.
Interventions: intervention 1: Pembrolizumab intervention 2: Epacadostat
Intervention descriptions: intervention 1: Pembrolizumab (200mg/kg) given by intravenous infusion every 3 weeks. intervention 2: Epacadostat (100mg) taken by mouth twice a day.

Protocol documents:
Prot_SAP_000.pdf: 
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SPONSOR: The University of Chicago  
 
TITLE: A Phase II study of Epacadostat + Pembrolizumab in Head and 
Neck Cancer patients, who failed prior PD-1/PD-L1 therapy. 
 
 
IND NUMBER: 133050 
 
 
University of Chicago IRB#: IRB17-1539 
 
 
Principal Investigator:  
 
Alexander Pearson, MD 
Coordinating Site: 
The University of Chicago  
Co-Investigators: 
 
Everett Vokes, MD  
Alexander Pearson, MD 
Nishant Agrawal, MD 
Gooi Zhen, MD 
Elizabeth Blair, MD 
Louis Portugal, MD 
 
 
Protocol Nurse: 
Allison Dekker, RN 
Study Coordinator: 
Sara Kochanny   
Statistician: 
Theodore Karrison, PhD 
 
PI Contact Information:  
Alexander Pearson, MD 
University of Chicago Medical Center 
5841 S. Maryland Avenue, MC2115 
Chicago, IL 60637 
Tel: 773- 834-1604 /  Fax: 773-702-3163 
apearson@medicine.bsd.uchicago.edu  
  
 
 
Version Date:  
  PI-Ship change dated:04/24/2019


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Table of Contents 
 
1.0 
TRIAL SUMMARY .................................................................................................... 7 
2.0 
TRIAL DESIGN .......................................................................................................... 7 
2.1 
Trial Design .............................................................................................................. 7 
2.2 
Trial Diagram .......................................................................................................... 8 
3.0 
OBJECTIVE(S) & HYPOTHESIS(ES) .................................................................... 8 
3.1 
Primary Objective(s) & Hypothesis ....................................................................... 8 
3.2 
Secondary Objective(s) & Hypothesis ................................................................... 8 
3.3 
Exploratory/Translational Objectives ................................................................... 9 
4.0 
BACKGROUND & RATIONALE .......................................................................... 10 
4.1 
Background ............................................................................................................ 10 
4.1.1 Squamous Cell Carcinoma of the Head and Neck (HNSCC).............................. 10 
4.1.2 Immune Surveillance ........................................................................................... 10 
4.1.3 Pharmaceutical and Therapeutic Background ..................................................... 11 
4.1.4 Inhibition of PD-1 as a Target for Cancer ........................................................... 12 
4.1.5 Inhibition of Indoleamine 2,3–Dioxygenase as a Target for Cancer ................... 13 
4.1.6 Combined Immune Checkpoint Inhibition .......................................................... 15 
4.1.7 PD-1 blockade in Head and Neck cancer (HNSCC) ........................................... 16 
4.1.8 Preclinical and Clinical Study Data ..................................................................... 17 
4.1.9 Ongoing Clinical Studies ..................................................................................... 17 
4.2 
Rationale ................................................................................................................. 18 
4.2.1 Rationale for combining PD-1 blockade with IDO inhibition in HNSCC. ......... 18 
4.2.2 Rationale for Dose Selection/Regimen/Modification .......................................... 18 


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4.2.3 Translational Rationale ........................................................................................ 21 
4.2.4 Rationale for Endpoints ....................................................................................... 22 
4.3 
Benefit/Risk ............................................................................................................ 22 
5.0 
METHODOLOGY .................................................................................................... 25 
5.1 
Entry Criteria /   Eligibility .................................................................................. 25 
5.1.1 Diagnosis/Condition for Entry into the Trial ....................................................... 25 
5.1.2 Subject Inclusion Criteria .................................................................................... 25 
5.1.3 Subject Exclusion Criteria ................................................................................... 27 
5.2 
Trial Treatments .................................................................................................... 31 
5.2.1 Dose Selection ..................................................................................................... 31 
5.3 
Dose Modifications ................................................................................................ 31 
5.3.1 Criteria and Procedures for Treatment Interruption ............................................ 32 
5.3.2 Procedures for Subjects Exhibiting Immune-Related Adverse Events ............... 33 
5.3.3 Timing of Dose Administration of Epacadostat. ................................................. 34 
5.3.4 Supply, Packaging, and Labeling of Epacadostat ................................................ 34 
5.3.5 Storage and Dispensing of Epacadostat ............................................................... 35 
5.3.6 Timing of Dose Administration of Pembrolizumab. ........................................... 35 
5.3.7 Trial Blinding/Masking ....................................................................................... 35 
5.4 
Treatment Allocation ............................................................................................ 35 
5.5 
Stratification .......................................................................................................... 35 
5.6 
Concomitant Medications/Vaccinations (allowed & prohibited) ...................... 36 
5.6.1 Acceptable Concomitant Medications ................................................................. 36 
5.6.2 Restricted Medications and Measures ................................................................. 36 


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5.6.3 Prohibited Concomitant Medications .................................................................. 36 
5.7 
Rescue Medications & Supportive Care .............................................................. 37 
5.7.1 Supportive Care Guidelines ................................................................................. 37 
5.7.2 Procedures for Subjects Exhibiting Serotonin Syndrome ................................... 41 
5.7.3 Treatment After Initial Evidence of Radiologic Evidence of Disease Progression41 
5.8 
Diet/Activity/Other Considerations ..................................................................... 43 
5.8.1 Diet ...................................................................................................................... 43 
5.8.2 Contraception ....................................................................................................... 43 
5.8.3 Use in Pregnancy ................................................................................................. 43 
5.8.4 Use in Nursing Women ....................................................................................... 44 
5.9 
Subject Withdrawal/Discontinuation Criteria .................................................... 44 
5.9.1 Discontinuation of Study Therapy after CR ........................................................ 45 
5.10 
Subject Replacement Strategy .............................................................................. 45 
5.11 
Clinical Criteria for Early Trial Termination .................................................... 45 
6.0 
TRIAL FLOW CHART ............................................................................................ 47 
6.1 
Study Flow Chart .................................................................................................. 47 
7.0 
TRIAL PROCEDURES ............................................................................................ 51 
7.1 
Trial Procedures .................................................................................................... 51 
7.1.1 Administrative Procedures................................................................................... 51 
7.1.2 Clinical Procedures/Assessments ........................................................................ 53 
7.2 
Research Tests ....................................................................................................... 54 
7.2.1 Sample Shipping .................................................................................................. 55 
7.2.2 IHC staining ......................................................................................................... 55 


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7.2.3 Nanostring Analysis............................................................................................. 55 
7.2.4 Tumor DNA Analysis .......................................................................................... 55 
7.2.5 Germline DNA analysis ....................................................................................... 56 
7.2.6 RNA analysis from blood .................................................................................... 56 
7.2.7 Other Procedures ................................................................................................. 58 
7.2.8 Visit Requirements .............................................................................................. 58 
7.3 
Assessing and Recording Adverse Events ........................................................... 61 
7.3.1 Definition of an Overdose for This Protocol and Reporting ............................... 62 
7.3.2 Reporting of Pregnancy and Lactation ................................................................ 63 
7.3.3 Immediate Reporting of Adverse Events to Incyte and Merck ........................... 63 
7.3.4 Evaluating Adverse Events .................................................................................. 65 
7.3.5 Definition of an Overdose for This Protocol and Reporting of Overdose ........... 65 
7.3.6 Sponsor Responsibility for Reporting Adverse Events ....................................... 69 
7.4 
Efficacy assessment ............................................................................................... 69 
8.0 
STATISTICAL ANALYSIS PLAN ......................................................................... 70 
8.1 
Statistical Analysis Plan ........................................................................................ 70 
8.2 
Sample Size ............................................................................................................. 71 
9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES .................................................................................................................. 71 
9.1 
Investigational Product ......................................................................................... 71 
9.2 
Packaging and Labeling Information .................................................................. 71 
9.3 
Clinical Supplies Disclosure .................................................................................. 71 
9.4 
Storage and Handling Requirements ................................................................... 71 


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9.5 
Returns and Reconciliation .................................................................................. 72 
10.0 
ADMINISTRATIVE AND REGULATORY DETAILS ....................................... 72 
10.1 
Food and Drug Administration (FDA) Approval ............................................... 72 
10.2 
New Protocol Distribution and IRB Submission ................................................ 72 
10.3 
Amendment Distribution and IRB Submission .................................................. 73 
10.4 
Annual IRB Renewals, Continuing Review and Final Reports ........................ 73 
10.5 
Departure from the Protocol ................................................................................ 73 
10.6 
Registration ............................................................................................................ 74 
10.7 
Reporting of Adverse Events to the Coordinating Center ................................. 75 
10.8 
Reporting of Adverse Events by the Coordinating Center ................................ 76 
10.9 
Data Management ................................................................................................. 76 
10.10 Data and Safety Monitoring ................................................................................. 77 
10.11 Auditing .................................................................................................................. 78 
10.12 Record Retention ................................................................................................... 78 
10.13 Obligations of Study Site Investigators ............................................................... 78 
11.0 
APPENDICES ............................................................................................................ 80 
11.1 
ECOG Performance Status .................................................................................. 80 
11.2 
Common Terminology Criteria for Adverse Events V4.0 (CTCAE) ............... 80 
11.3 
RECIST 1.1 reference ........................................................................................... 80 
11.4 
References .............................................................................................................. 81 
 


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1.0 TRIAL SUMMARY 
Abbreviated Title 
Pembrolizumab and Epacadostat in HNC 
Trial Phase 
II 
Clinical Indication 
Head and Neck Cancer (HNC) 
Trial Type 
Parallel single arm 
Route of administration 
Intravenously and oral 
Trial Blinding 
None, open label 
Treatment Groups  
Acquired Resistance Cohort / Suboptimal Benefit 
Number of trial subjects 
30 
Estimated enrollment period 
18 months 
Estimated duration of trial 
24 months 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
Phase II, 2-cohort, single arm trial treated with the combination of the following two agents: 
1. Pembrolizumab (MK3475) 200mg, every three weeks, iv 
2. Epacadostat (INCB24360) 100mg, po BID 
 
 


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2.2 
Trial Diagram 
 
3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1 
Primary Objective(s) & Hypothesis 
(1) Objective:  Response Rate 
Hypotheses:   
Cohort 1: In patient with prior response to anti-PD-1/PD-L1+ therapy and subsequent 
(acquired) resistance combined IDO1 and PD-1 inhibition will re-induce responses. 
Cohort 2: In patients with suboptimal benefit from prior anti-PD-1/PD-L1 therapy combined 
IDO1 and PD-1 inhibition will induce clinically meaningful responses.  
 
3.2 
Secondary Objective(s) & Hypothesis 
(1) Objective:  1-year Progression-free (PFS) and Overall (OS) survival 
Hypothesis:  Combined PD-1 blockade with pembrolizumab + epacadostat in HNSCC patients 
will lead to improved 1-year survival in patients who a) progress on prior anti-PD-1/PD/L1 
therapy on, and/or b) compared to patients who progress on 2nd line chemotherapy. 
(2) Safety 
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Hypothesis:  Combined treatment with pembrolizumab and epacadostat will be safe and 
tolerable in HNSCC patients. 
 
3.3 
Exploratory/Translational Objectives 
(1) 
Interferon-gamma Gene Expression Profile (GEP) (Seiwert ASCO 2015, Ribas ASCO 2015) 
and evaluation of RR, PFS, and OS in GEP positive and GEP negative patients. 
(2) 
Determine the micro-environment that underlies resistance/suboptimal treatment  
a) underlying degree of tumor inflammation  
b) Baseline PD-L1 expression 
d) Determine underlying Interferon Gamma signature  
(3) 
Assess underlying mutational burden (Snyder 2014)) 
Preclinical hypothesis: IDO1 inhibition will alter the micro-environment to a be “more T-cell 
inflamed” and make tumors amenable to benefit from anti-PD-1 treatment (when given concurrently 
with IDO1 inhibition). Hence we will evaluate tumors, with prior response exhibiting acquired 
resistance as well as tumors with minor/suboptimal benefit from prior PD-1/PD-L1 therapy for 
evidence (at baseline) of suboptimal immune microenvironmental conditions. 
 
 
 


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4.0 BACKGROUND & RATIONALE 
4.1 
Background 
Refer to the respective Investigator’s Brochure (IB) for detailed background information 
on pembrolizumab and epacadostat. 
4.1.1 Squamous Cell Carcinoma of the Head and Neck (HNSCC) 
     Squamous cell carcinoma of the head and neck (HNSCC) is the fifth most common malignancy 
worldwide and is comprised of 1) HPV-negative HNSCC (genetically closely resembling Lung SCC, 
triple negative breast cancer, bladder cancer), and 2) HPV-positive HNSCC (resembling other virus 
associated tumors, e.g. cervical cancer, anal cancer, but also EBV-associated NPC, Merkel cell 
etc.)(HNC-TCGA, Nature 2015; Seiwert 2015).  
      While HPV-positive tumors have a favorable outcome in the curative intent setting, once 
metastatic, prognosis remains poor. The incidence of HPV-positive HNSCC is increasing rapidly 
(Chaturvedi 2011). 
 
HNSCC shows some of the highest levels of a T-cell inflammation/tumor infiltrating 
lymphocytes. Based on TCGA data the top three tumor entities are melanoma, Head and Neck 
Cancer, and Lung Cancer (HNC-TCGA 2015; Keck 2015).  Our group showed data defining this T-
cell inflamed phenotype for HNSCC (Saloura ASCO 2014). Furthermore, there is widespread 
expression of multiple immune escape markers and PD-L1 expression is present in 70% of tumors 
(Seiwert Lancet Oncology 2016; Saloura ASCO 2014) 
4.1.2 Immune Surveillance  
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades (Disis et al 2010). Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis 
in various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-term 
survival in many solid tumors. 
The inability of the immune system to control tumor growth does not appear to result from 
an inability to recognize the tumor as foreign.  Tumor cells have been shown to evade immune 
destruction despite displaying recognizable antigens on their surface and despite the presence of 
high-avidity T cells that are specific for these antigens (Boon and van der Bruggen 1996, Ercolini et 
al 2005).  Histologic evaluation of many human cancers shows extensive infiltration by 
inflammatory and immune cells (Galon et al 2006), suggesting that the immune system responds to 
malignancy, albeit less effectively than needed to eradicate the tumors.  These observations have led 
to the hypothesis that failure of the immune system to generate an effective response to malignancy 


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could be the result of inadequate stimulation or exaggerated negative regulation.  A combination of 
immunotherapy agents that stimulate an immune response targeted to tumor cells combined with the 
relief of negative regulation should synergize in allowing the immune system to generate a response 
leading to enhanced tumor rejection. 
4.1.3 Pharmaceutical and Therapeutic Background  
Epacadostat (formerly INCB024360) represents a novel, potent, and selective inhibitor of 
the enzyme indoleamine 2,3 dioxygenase-1 (IDO1) in both human tumor cells and human dendritic 
cells (DCs).  Pembrolizumab is a potent and highly selective humanized mo noclonal antibody of the 
immunoglobulin (Ig)G4/kappa isotype directed against programmed death receptor 1 (PD -1). For a 
thorough discussion of the pharmacology of pembrolizumab and epacadostat, refer to the 
pembrolizumab Investigator's Brochure and the epacadostat Investigator's Brochure. 
 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades (Disis et al 2010).  The inability of the immune 
system to control tumor growth does not appear to result from an inability to recognize the 
tumor as foreign. Tumor cells have been shown to evade immune destruction despite displaying 
recognizable antigens on their surface and despite the presence of high avidity T cells that are 
specific for these antigens  (Boon et al 1996, Ercolini et al 2005)    Histologic  evaluation  of  
many  human  cancers  show s  extensive infiltration by inflammatory and immune cells (Galon et 
al 2006), suggesting that the immune system responds less effectively to malignancy.   These 
observations have led to the hypothesis that dominant mechanisms of immune  tolerance  or  
immune  suppression are  responsible for  the  immune system's inability to effectively respond in a 
way that consistently results in rejection. 
 
There are a number of  inhibitory mechanisms that have been identified to  be involved 
in tumor-mediated immune suppression and include expression of the programmed death ligand 1 
(PD-L1), which can engage the inhibitory receptor PD -1 on activated T cells; the presence of the 
tryptophan-catabolizing enzyme IDO1, which exposes the exquisi te sensitivity of T cells to 
tryptophan depletion and tryptophan metabolites; and infiltration with FoxP3 + regulatory T cells 
(Treg), which can mediate extrinsic suppression of effector T -cell function. Therefore, agents 
that target these negative regulatory pathways and thereby allow the expansion of effector T cells 
present in the tumor may be beneficial in the clinic. 
 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on pembrolizumab. 
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).  The structure of murine PD-1 has been resolved.  


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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.  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.  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.  Expression has also been shown during thymic development 
on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells.  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.  Both ligands are type I 
transmembrane receptors containing both IgV- and IgC-like domains in the extracellular region and 
contain short cytoplasmic regions with no known signaling motifs.  Binding of either PD-1 ligand to 
PD-1 inhibits T-cell activation triggered through the T-cell receptor.  PD-L1 is expressed at low 
levels on various 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.  
Although healthy organs express little (if any) PD-L1, a variety of cancers were demonstrated to 
express abundant levels of this T-cell inhibitor.  PD-1 has been suggested to regulate tumor-specific 
T-cell expansion.  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. 
Pembrolizumab 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.  KeytrudaTM (pembrolizumab) has recently been approved in the United States for 
the treatment of patients with platinum refractory head and neck squamous cell carcinoma on 
8/5/2016) based on the Keynote 12 study data (Seiwert et al 2016) 
4.1.4 Inhibition of PD-1 as a Target for Cancer 
 
The PD-1 receptor-ligand interaction is a major pathway stimulated 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 immunoglobulin (Ig) superfamily 
member related to CD28 and cytotoxic T -lymphocyte-associated  antigen-4 (CTLA-4),  which  
has  been  shown  to  negatively  regulate  antigen  receptor  signaling  upon 


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engagement of its ligands (PD-L1 and/or PD-L2) (Talmadge et al 2007, Usubutun et al 
1998).  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 (Hiraoka et al 2010, Nobili et al 2008).  PD-1 has been shown to be expressed on 
activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, Tregs, and 
natural killer cells (Hodi et al 2010, Kloor et al 2009).   Expression has also been shown 
during thymic development on CD4-CD8- (double negative) T cells as well as subsets of 
macrophages and dendritic cells (Hillen et al 2008). The ligands for PD-1 (PD-L1 and PD-
L2) are constitutively expressed or can be induced in a variety of cell types, including 
nonhematopoietic tissues as well as in various tumors (Nobiliy et al 2008, Lee et al 2008 
Leffers et al 2009, Nishimura et al 2000).  Binding of either PD-1 ligand to PD-1 inhibits T-
cell activation triggered through the T-cell receptor.  PD-L1 is expressed at low levels on 
various nonhematopoietic tissues, most notably on vascular endothelium,  whereas  PD-L2  
protein  is  only  detectably  expressed  on antigen-presenting cells found in lymphoid tissue 
or chronic inflammatory environments.  PD-L2 is thought to control immune T-cell activation 
in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in 
peripheral tissues (Hodi et al 2010).  Although healthy organs express little (if any) PD-L1, 
a variety of cancers were demonstrated to express abundant levels of this T- cell inhibitor.  
PD-1 has been suggested to regulate tumor-specific T-cell expansion in subjects with 
melanoma (Liotta et al 2010) and other cancers like head and neck cancer (Seiwert et al 
2016).  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. 
 
 
4.1.5 Inhibition of Indoleamine 2,3–Dioxygenase as a Target for Cancer  
 
Recent interest has focused on the role of indoleamine 2,3–dioxygenase (IDO1) as a 
mechanism of induction of tolerance to malignancy (Godin-Ethier et al 2011).   IDO1 is a 
heme-containing, monomeric oxidoreductase that catalyzes the degradation of the  essential  
amino acid  tryptophan to N- formyl-kynurenine. Kynurenine can be subsequently 
metabolized through a series of enzymatic steps to nicotinamide adenine dinucleotide.  IDO1 
is the first rate-limiting enzyme in one of the breakdown pathways of tryptophan.  In another 
pathway, tryptophan hydroxylase catalysis of tryptophan leads to the formation of serotonin 
and melatonin. 
 
The expression and activity profiles of IDO1 are distinct from those of tryptophan 
dioxygenase, an enzyme predominantly expressed in liver that catalyzes the same enzymatic 
reaction as IDO1 and maintains proper tryptophan balance in response to dietary uptake.  In 
contrast to tryptophan dioxygenase, IDO1 is expressed in a variety of tissues, with 
particularly high levels found in areas of contact with potential sources of immune 
challenge (e.g., gut, respiratory tract, placenta, spleen), consistent with a role for regulating 
tryptophan metabolism in a local microenvironment (Mellor et al 2004).  Within the immune 
system, IDO1 activity is specifically induced in cells such as DCs and macrophages at 
localized sites of inflammation (Munn et al 2007). 
 


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IDO1 driven oxidation of tryptophan results in a strong inhibitory effect on the 
development of T-cellmediated  responses by blocking T-cell activation and inducing T-
cell apoptosis (Mellor et al 2003). Both the reduction in local tryptophan levels and the 
production of tryptophan catabolites that are inhibitory to cell proliferation contribute to the 
immunosuppressive effects (Frumento et al 2002).  IDO1 activity also promotes the 
differentiation of naive T cells to cells with a regulatory phenotype (Treg) (Fallarino et 
al 2006).  Since increased Treg activity has been shown to promote tumor growth and Treg 
depletion has been shown to allow an otherwise ineffectual antitumor immune response 
to occur (Zou et al 2006), IDO1 expansion of Tregs may provide an additional mechanism 
whereby IDO1 could promote an immunosuppressive environment. 
 
The biological relevance of IDO1 inhibition to immune tolerance was first 
demonstrated when it was shown that treating mice with a small molecule inhibitor of the 
IDO1 pathway, 1-methyl- tryptophan, could break the tolerogenic state that protects 
allogeneic concepti from the maternal immune system (Munn et al 1998).  A critical role for 
IDO1 in immunomodulation has been confirmed in numerous animal models, including 
models of allograft tolerance, inflammation, and cancer (Mellor et al 2004. While IDO1 
inhibition can exacerbate disease in models of autoimmune disorders (Mellor et al 2004), 
IDO1 null mice show no evidence of susceptibility to developing spontaneous autoimmunity 
or alterations in immune system development (Mellor et al 2003), suggesting that IDO1 
inhibition, in a therapeutic setting, may produce  minimal  side  effects  in  subjects  
without  pre-existing  autoimmune conditions. 
 
Within the context of cancer, there are several lines of evidence to suggest that IDO1 
is a key regulator of the immunosuppressive mechanisms responsible for tumor escape from 
immune surveillance.  Several groups have demonstrated that blockade of IDO1 activity can 
directly influence the ability of tumor-bearing animals to reject tumors (Uyttenhove et al 
2003, Muller et al 2005).  In addition, studies with 1-methyl-tryptophan, demonstrate that 
IDO1 inhibition dramatically increases the efficacy of various chemotherapeutic agents (e.g., 
platinum compounds, taxane derivatives, cyclophosphamide) without increased toxicity 
(Muller et al 2005).   Although the specific mechanisms responsible for this potentiation 
remain to be fully elucidated, the effects were not observed in T- celldeficient animals, 
suggesting that the results may be the consequence of the disablement of immunosuppressive 
mechanisms that exist within the tumor microenvironment. 
 
Based on studies examining serum levels of tryptophan and kynurenine, IDO1 
appears to be chronically activated in subjects with cancer, and IDO1 activation correlates 
with more extensive disease (Huang et al 2010, Weinlich et al 2007).  IDO1 has 
subsequently been found to be overexpressed by a wide variety of human tumor cell types as 
well as by the DCs that localize to the tumor draining lymph nodes (Uyttenhove et al 2003).   
Increased expression of IDO1 in tumor cells has been shown to be an independent prognostic 
variable for reduced overall survival (OS) in subjects with melanoma, ovarian, colorectal, and 
pancreatic cancers (Okamoto et al 2005, Brandacher et al 2006, Ino et al 2006, Nakamura et 
al 2007, Witkiewicz et al 2008).  Together, these results suggest that the IDO1 pathway is a 
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tolerance.   Small molecule inhibitors of IDO1 may provide an innovative and tractable 
method to treat advanced malignancies either alone or in combination with 
chemotherapeutics and/or immunotherapy-based strategies. 
 
4.1.6 Combined Immune Checkpoint Inhibition  
Blockade of immune inhibitory pathways is emerging as an important therapeutic 
modality for the treatment of cancer as evidenced by the clinical responses observed 
with antibodies to CTLA-4 and PD-1/PD-L1.  Ipilimumab, a fully human, IgG1 
monoclonal antibody blocking CTLA-4, improved OS in patients with advanced 
melanoma (Hodi et l 2010, Robert et l 2011).   Nivolumab, a fully human IgG4 antibody 
blocking PD-1, produced durable overall responses in patients with melanoma, renal cell 
cancer, and NSCLC (Topalian et al 2012, Hmid et al 2013, Wolchok et al 2013).  
Although these single agents have antitumor activity, multiple immune inhibitory 
mechanisms are present concurrently within the tumor microenvironment, suggesting that 
combination therapies may be required for optimal therapeutic effect (Quezada et al 2013). 
 
For example, CTLA-4 and PD-1 appear to play complementary roles in regulating 
adaptive immunity.  Whereas PD-1 contributes to T-cell exhaustion in peripheral tissues, 
CTLA-4 inhibits at earlier points in T-cell activation.  In preclinical models, combined 
blockade of PD-1 and CTLA-4 achieved more pronounced antitumor activity than 
blockade of either pathway alone (Curran et al 2010, Selby et al 2013). 
 
On the basis of these observations, a Phase 3 study was conducted to investigate the 
safety and efficacy of combined CTLA-4 and PD-1 blockade (with the use of ipilimumab 
and nivolumab, respectively) in patients with advanced melanoma.  The objective response 
rate (ORR; according to modified World Health Organization criteria) for all patients in the 
concurrent-regimen group was 61% among subjects with BRAF wild-type tumors versus 
11% in the ipilimumab alone group. Median duration of response had not been reached in 
either group. Median PFS had not been reached with the combination therapy and was 
4.4 months for ipilimumab monotherapy. Grade 3 or 4 AEs occurred in 54% of subjects in 
the concurrent-regimen group and were 24% in the ipilimumab monotherapy group 
(Postow et al 2015).   Common Grade 3 or 4 selected AEs that were related to the 
combination therapy included colitis (17%), diarrhea (11%), and an elevated alanine 
aminotransferase level (11%).  Diarrhea (11%) was the most frequently reported Grade 3 
or 4 
 
AE associated with ipilimumab monotherapy, followed by colitis (7%).  In both 
regimen groups, treatment-related AEs were manageable and generally reversible with the 
use of immunosuppressants (or hormone-replacement therapy for endocrinopathies) 
according to previously established algorithms (Postow et al 2015). 
 
As described previously, IDO1 is another negative regulatory mechanism that 
contributes to tumor-derived immune suppression.  In preclinical models, IDO1 inhibition 
has been shown to synergize with blockade of either antiCTLA-4 or antiPD-1/PD-L1 in 
delaying tumor growth and increasing OS (Holmgaard et al 2013, Spranger 2013).  This 


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effect was shown to be T-cell dependent, leading to enhanced T-cell proliferation and 
interleukin-2 production within the tumor and to a marked increase in the effector-to-
regulatory T cell ratios in the tumors. 
 
The IDO1 inhibitor epacadostat has completed a Phase 1 study and has several 
ongoing Phase 1 and Phase 2 studies in combination with immune-targeted agents, such 
as anti–PD-1, anti– PD-L1, and anti–CTLA-4 antibodies.  In a study combining 
epacadostat and ipilimumab (INCB24360-201) subjects received ipilimumab (3 mg/kg IV 
every 3 weeks for 4 cycles) with epacadostat at doses of 25 mg BID, 50 mg BID continuous, 
50 mg BID intermittent (2 wks on, 1 wk off), and 75 mg (50 mg q AM/25 mg q PM). A total 
of 42 subjects were enrolled: 25 mg BID (n=8), 50 mg BID (continuous) (n=18), 50 mg BID 
(intermittent) (n=9), and 75 mg (n=7). DLTs were: 25 mg BID, Grade 3 increased AST 
(n=1); 50 mg BID (continuous), Grade 3 diarrhea, Grade 3 increased ALT/AST grade 3 
colitis and grade 3 pneumonitis (n=1 each); 50 mg BID(intermittent), Grade 3 colitis (n=1); 
75 mg, Grade 3 rash (n=1). The most common all Grade immune-related adverse events 
(irAEs) were rash (52%), pruritus (38%), diarrhea (33%), increased ALT (21%), increased 
AST (16%) hypothyroidism (12%) and colitis (10%). Grade ≥3 irAEs occurred in 23% of 
subjects. Grade ≥ 3 irAEs occurring in more than 1 subjects were increased AST and colitis 
(n=4 [9.5%] each). Among 32 immunotherapy-naïve subjects, ORR was 31% (10/32) per 
irRC and 28% (9/32) per RECIST and the CR rate per both criteria was 9.4%. At data 
cutoff, responses were ongoing in 6 subjects. The disease control rate (DCR; CR+PR+SD) 
was 62.5% per irRC and 53% per RECIST. Median PFS was 8.2 months by irRC and 5.3 
months by RECIST. Among 10 subjects previously treated with immunotherapy, the 
DCR by both criteria was 30% (all SDs).  In a study combining pembrolizumab and 
epacadostat (INCB 24360-202/ECHO-202) reported at ESMO 2016 (Ghangadhar et al), 
epacadostat combined with pembrolizumab showed a favorable objective response rate 
(58%), CR rate (26%), and disease control rate (74%), roughly on par with efficacy seen with 
nivolumab/ipilimumab in this early and small number dataset with a favorable side effect 
profile.  
 
 
In summary, both IDO1 and PD-1 have been shown to suppress T-cell-mediated 
antitumor immunity, and IDO1 and the PD-1 ligand PD-L1 have been shown to be 
coexpressed in multiple cancer types and to correlate with poor prognosis.  Combined 
inhibition of both pathways may therefore lead to greater suppression of  antitumor  
immunity  and  to  increased  efficacy. Preclinical and early clinical data indicate that 
these pathways are important in melanoma as well as in other cancers, including NSCLC, 
HNSCC, and other tumor types. 
 
4.1.7 PD-1 blockade in Head and Neck cancer (HNSCC) 
      
PD-1 blockade was shown to be effective in HNSCC with a response rate of 16-18% 
as reported recent in the Keynote 12 study (Seiwert Lancet Oncology 2016, Chow et al JCO 
2016), with an estimated median overall survival of ~10-12months despite a heavily 
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median overall survival of 10.1 months using the EXTREME regimen (platinum/5-
FU/cetuximab) in first-line recurrent/metastatic HNSCC in a much more favorable first line 
population (Vermorken NEJM 2008).  
 
Based on the Keynote 12 data Pembrolizumab received accelerated FDA approval as 
of August 5th 2016 by the FDA in the US. 
Furthermore, evidence of long-term survival is seen in ~40% of patients (Chow et al 
ESMO 2014). However, a number of patients were also observed to eventually develop 
acquired resistance and some of those tumors with acquired resistance were biopsied and 
analysis is ongoing. 
    Despite the prominent inflamed phenotype with widespread TIL infiltration and PD-
L1 expression, HNSCC shows a lower rate of benefit from PD-1 blockade than melanoma, 
and acquired resistance/suboptimal benefit/treatment responses are prominent problems.  
Please refer to the Investigator’s Brochure for additional Preclinical and Clinical data. 
 
4.1.8 Preclinical and Clinical Study Data 
Refer to the current Investigator's Brochures for additional details regarding pembrolizumab 
and epacadostat (iIB) for preclinical and clinical study data.   
 
4.1.9 Ongoing Clinical Studies 
Refer to the Investigator's Brochures (IB s) for pembrolizumab and epacadostat for 
preclinical and clinical study data. 
 
 


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4.2 
Rationale 
4.2.1 Rationale for combining PD-1 blockade with IDO inhibition in HNSCC. 
 
IDO1 is a negative regulatory mechanism that contributes to tumor-derived immune 
suppression. In preclinical models, IDO1 inhibition has been shown to synergize with 
blockade of anti−PD-1/PD-L1 in delaying tumor growth and increasing OS (Holmgaard 
2013, Spranger 2013). This effect was shown to be T-cell dependent, leading to enhanced T-
cell proliferation and interleukin-2 production within the tumor and to a marked increase in 
the effector-to-regulatory T cell ratios in the tumors. 
Epacadostat represents a novel, potent, and selective inhibitor of the enzyme 
indoleamine 2,3 dioxygenase 1 (IDO1) in both human tumor cells and human dendritic cells 
(DCs).  For a thorough discussion of the pharmacology of epacadostat, refer to the 
epacadostat Investigator's Brochure (iIB). 
While the majority of such patients with HNC can be treated with curative intent 
using multimodality approaches, a significant fraction of patients will fail therapy (typically 
within 12-18 months), especially those patients with high risk features such as 
advanced/bulky nodal stage, non-response to induction chemotherapy, residual disease on 
salvage surgery, and HPV-negative status. 
HNSCC shows some of the highest levels of a CD3+/8+ lymphocyte infiltration 
(TILs), and T-cell inflammation, and multiple immune escape mechanisms are present 
(Saloura/Seiwert, ASCO 2014, Lyford-Pike 2013). PD-L1 expression is prominent in up to 
70% of tumors, and similarly to other cancer type (Powderly 2013) correlates with response 
in the Keynote 12 study (Seiwert, ASCO 2014/2015) as well as a smaller cohort using the 
anti-PD-L1 antibody MEDI4636 (Gibson ASCO 2015). 
Since pembrolizumab has shown significant single agent activity in HNC with a 
response rate of 16-18% (Seiwert Lancer Oncology 2016; Chow JCO 2016), excellent 
tolerability, and potentially affords long-term survival in a fraction of patients, further study 
of pembrolizumab, in particular combination aimed at overcoming acquired resistance or 
suboptimal benefit are indicated and clinically relevant.  
4.2.2 Rationale for Dose Selection/Regimen/Modification  
4.2.2.1 Justification of Treatment Regimen 
The dose selected for epacadostat for the current study was formed on the basis of 
having a well - tolerated safety profile as monotherapy and in combination with  
pembrolizumab, a  robust objective response rate, durable disease control rates, as well as 
providing optimal target inhibition of IDO1 based on nonclinical models.   Doses of 
epacadostat of up to 700 mg BID as monotherapy have been well tolerated and doses of 25 
mg BID to 300 mg BID in combination with pembrolizumab, nivolumab, durvalumab and 
atezolizumab are currently being evaluated in several ongoing Phase 2 studies. Doses of 
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study of pembrolizumab in combination with epacadostat. Reductions in tumor burden were 
seen in 15 of 19 evaluable subjects across doses of 25 mg BID to 100 mg BID in 
combination with pembrolizumab 2 mg/kg and 200 mg flat dosi ng. Objective responses 
were observed in all tumor types and all are ongoing and this combination has been well 
tolerated. 
 
Based on a pharmacokinetic-pharmacodynamic model for epacadostat, nearly all 
patients’ C avg exceeded the IC50, the range of active drug exposure seen in non-clinical 
models; further dose of 100 mg BID and above exceeded the IC50 at trough in nearly all 
patients [52]. 
The safety profile for the 300mg bid dose of epacadostat in combination with 
pembrolizumab in our Phase I/II study (INCB24360-202) did not exceed the MTD in that 
study.  While there was a higher incidence of grade 3 rash in the 300mg bid cohort compared 
to the 100mg bid cohort, these did not qualify as protocol-specified DLTs.  The dose of 
300mg epacadostat in combination with pembrolizumab is currently under study in all of 
Incyte’s  current protocols. 
The dose combination of 100mg bid epacadostat plus pembrolizumab for our 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, Incyte believes that greater target coverage for inhibition of IDO1 
may be necessary.  Our 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.  Incyte believes that 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. 
 
Based on observed systemic exposures and  a  pharmacokinetic-pharmacodynamic 
model for epacadostat, all patients who received 100 mg BID epacadostat in combination 
with pembrolizumab had time-averaged inhibition of IDO1 activity exceeding 50%, a 
level of PD activity associated with inhibition of tumor growth seen in non-clinical models.  
Dosing of 100 mg BID and above exceeded the IC50 at trough in nearly all patients [52]; 
further, the majority of patients had trough epacadostat exposures that were above the IC50 
of IDO1 inhibition. Therefore, 100 mg BID was selected as the recommended Phase 2 dose 
for epacadostat in study INCB 24360-202 because this regimen had better tolerability as 
demonstrated by the Phase 1 safety data including fewer dose modifications (suspension 
and reductions) and resulted in consistent inhibition of IDO1. The overall experience of 
the epacadostat 1 00 mg BID dose in combination with pembrolizumab in study INCB 
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4.2.2.2 Rationale for a fixed dose of Pembrolizumab  
The dose of pembrolizumab planned to be studied in this study is 200 mg e very 3 
weeks (Q3W). The dose recently approved in the United States for treatment of melanoma 
subjects is 2 mg/kg Q3W. Information on the rationale for selecting 200 mg Q3W is 
summarized below. 
 
An open-label Phase I study (Keynote 001) is being conducted to evaluate the safety 
and clinical activity of single agent pembrolizumab. The dose escalation portion of this study 
evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks 
(Q2W) and dose expansion cohort evaluated 2 mg/kg Q3W and 10 mg/kg Q3W in subjects 
with advanced solid tumors.  All 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.  No 
MTD has been identified. 
 
In Keynote 001, two randomized cohort evaluations (Cohorts B2 and D) of melanoma 
subjects receiving pembrolizumab at  a  dose  of  2  mg/kg  Q3W  versus  10  mg/kg  Q3W  
have  been completed, and one randomized Cohort (Cohort B3) evaluating 10 mg/kg Q3W 
versus 10 mg/kg Q2W has also been completed.  The clinical efficacy and safety data 
demonstrate a lack of clinically important differences in efficacy or safety profile at these 
doses.   For example, in Cohort B2, advanced melanoma subjects who had received prior 
ipilimumab therapy were randomized to receive pembrolizumab at 2 mg/kg Q3W versus 10 
mg/kg Q3W, and the objective response rate (ORR) was 28% (22/79) in the 2 mg/kg Q3W 
group and 28% (21/76) in the 10 mg/kg Q3W group (per RECIST 1.1 by independent 
central review).  The proportion of subjects with drug-related adverse events (AEs), Grade 3-
5 drug-related AEs, serious drug-related AEs, death or discontinuation due to an AE was 
comparable between groups.  Cohort D which compared 2 mg/kg Q3W versus 10 mg/kg 
Q3W in advanced melanoma subjects naïve to ipilimumab also demonstrated overall 
similarity in efficacy and safety profile between two doses. In Cohort B3, advanced 
melanoma subjects (irrespective of prior ipilimumab therapy) were randomized to receive 
pembrolizumab at 10 mg/kg Q2W versus 10 mg/kg Q3W.   The results demonstrate that 
the ORR was 35.0% (41/117) in the 10mg/kg Q2W group and 30.8% (33/107) in the 10 
mg/kg Q3W group (per RECIST 1.1 by independent central review) (cut-off date of 18-
April-2014).  The proportion of subjects with drug-related AEs, Grade 3-5 drug- related 
AEs, serious drug related AEs, death or discontinuation due to an AE was comparable 
between groups. 
 
An integrated body of evidence suggests that 200 mg every 3 weeks (Q3W) is 
expected to provide similar response to 2 mg/kg Q3W, 10 mg/kg Q3W and 10 mg/kg every 
2 weeks (Q2W). Previously, a flat pembrolizumab exposure-response relationship for 
efficacy and safety has been found in subjects with melanoma in the range of doses between 
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will be close to those obtained with 2 mg/kg Q3W dose.  2 mg/kg Q3W is the approved dose 
for metastatic melanoma in the US. 
 
A population PK model, which characterized the influence of body weight and other 
patient covariates on exposure, has been developed using available data from 1139 subjects 
from Keynote 001 (cut-off date of 18-April-2014) and Keynote 002 (cut-off date of 12-May-
2014), of which the majority (94.6% (N=1077)) were patients with advanced melanoma.  
The PK profile of pembrolizumab is consistent with that of other humanized monoclonal 
antibodies, which typically have a low clearance and a limited volume of distribution. The 
distribution of exposures from the 200 mg fixed dose are predicted to considerably overlap 
those obtained with the 2 mg/kg dose and importantly will maintain individual patient 
exposures within the exposure range established in melanoma as associated with maximal 
clinical response.  The slight increase in PK variability predicted for the fixed dose relative 
to weight-based dosing is not expected to be clinically important given that the range of 
individual exposures is well contained within the range of exposures shown in the melanoma 
studies of 2 and 10 mg/kg to provide similar efficacy and safety. 
efficacy and safety as observed in subjects with melanoma can be expected, as the 
anti -tumor effect of pembrolizumab is driven through immune system activation rather than 
through a direct interaction with tumor cells, rendering it independent of the specific tumor 
type.   In addition, available pharmacokinetic (PK) results in subjects with melanoma, 
NSCLC, and other solid tumor types support a lack of meaningful difference in 
pharmacokinetic exposures obtained at tested doses among tumor types.  Thus the 200 mg 
Q3W fixed dose regimen is considered an appropriate fixed dose for other solid tumor 
indications as well. 
 
4.2.3 Translational Rationale  
 
The micro-environmental changes responsible for resistance to PD-1/PD-L1 blockade 
are incompletely understood. We will evaluate baseline tissue (archival or freshly obtained) 
for evidence of factors that may correlate with acquired resistance/suboptimal benefit as 
related to the immune microenvironment/tumor inflammation/IDO. 
 
HNSCC is a disease with oftentimes biopsy accessible tumors, and baseline biopsies 
are optional (if archival tissue is available) or mandatory if no archival tissue is available. 
Core biopsies (3-5 cores) will be obtained at baseline as indicated (see 
above/eligibility). An on treatment biopsy at 2-4 weeks on treatment will considered / is 
optional and dependent on ability to safely biopsy the tumor. Also in patients who have 
benefit and subsequently progress (acquired resistance) a biopsy may be considered. 
 


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4.2.4 Rationale for Endpoints 
4.2.4.1 Efficacy Endpoints 
Primary Endpoint: Response Rate is a widely used and accepted marker of activity, 
and especially in a setting of prior PD-1/PD-L1 treatment failure is expected to be a robust 
outcome measure. For immunotherapy agents generally speaking response rate may 
underestimate the benefit (namely survival) as many patients with stable disease still achieve 
improved or prolonged survival. 
Secondary Endpoint: Overall Survival (e.g. 1-year overall survival is an acceptable 
early outcome measure to estimate survival in a poor prognosis patient population with an 
estimate median overall survival of ≤6 months and ~30% of patients alive at one year 
(Stewart 2009)). 
4.2.4.2 Biomarker Research 
In an effort to identify those patients who may be more likely to respond to 
pembrolizumab, baseline tumor samples will be evaluated for PD-L1 expression as well as 
other markers using an IHC or IF assay. This work will be done retrospectively.  
Furthermore, patient samples will be analyzed retrospectively for GEP scoring using the 
Nanostring platform.  
Based on data from hundreds of patients in numerous pembrolizumab studies in multiple 
cancer types, these biomarkers may potentially be predictive of patient benefiting from 
adjuvant pembrolizumab.  The purpose of this trial is to assess whether potential benefit from 
adjuvant therapy is also related to PD-L1 and/or GEP biomarkers.   
A key question of this study is whether IDO inhibition combined with PD-1 inhibition 
is more effective in PD-L1 expressing / GEP positive tumors or whether this combination is 
able to overcomes the less inflamed phenotype and lead to a response in PD-L1 
negative/GEP low patients. 
 
4.3 
Benefit/Risk 
4.3.1.1 Risk from Epacadostat  
In 28-day toxicology studies, Cmax values have exceeded the IC50 for the IDO1 
enzyme in cells (7 nM) by up to 370-fold, and the IC50 for the vasopressin 1a receptor by up 
to 40 -fold (130-fold in single dose studies) in the absence of any toxicity, so the risk of 
unintended pharmacological activity is expected to be low.   In the Phase 1 clinical study 
in subjects with refractory solid tumors (INCB 24360-101) doses up to 700 mg BID were 
given without an MTD determined. Epacadostat was well tolerated with a single SAE of 
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report of asymptomatic and reversible hypopituitarism despite continued administration of 
epacadostat, and 1 event of Grade 3 fatigue determined by the investigator to be related to 
study drug and considered a DLT in the 400 mg BID dose group. 
 
Theoretically, inhibition of IDO1 could cause an increase in serotonin levels that 
could precipitate a cluster of AEs termed serotonin syndrome (SS) when administered in 
combination with other serotonergic agents.  This rare syndrome has been associated with 
some monoamine oxidase inhibitors (MAOIs) and combinations of serotonergic drugs [53].   
The clinical manifestations of SS range from barely perceptible to lethal; onset is rapid 
(within 12 hours of drug(s) administration). Based on preliminary studies in the rat, 
concentrations of epacadostat in the cerebrospinal fluid were below the quantifiable limit of 
detection (2 nM) after IV dosing, and total brain homogenate concentrations were 
approximately 15% of corresponding plasma concentrations.  Therefore, epacadostat 
exhibits apparent limited penetration across the blood- brain barrier and is likely not 
associated with significant effects on tryptophan metabolism in the brain that might impact 
brain serotonin levels.  This represents a hypothetical risk only and has not been observed in 
any clinical studies of epacadostat with over 600 subjects treated to date. Twelve subjects in 
the INCB 24360-201 combination study with ipilimumab were receiving concomitant 
treatment with an SSRI without any consequences. Although the risk is theoretical, use of 
MAOIs will be prohibited during the study and all 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 are observed. 
4.3.1.2 Risk from Pembrolizumab  
An open-label Phase I study (Protocol 001) is being conducted to evaluate the safety 
and clinical activity of single agent pembrolizumab.  The dose -escalation portion of this 
study evaluated 3 dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 
weeks in subjects with advanced solid tumors.   All 3 dose levels were well tolerated and 
no DLTs were observed. Based on pharmacokinetic (PK) data showing a half-life of 21 
days, the Protocol was amended to include a dosing frequency of every 3 weeks in 
expansion cohorts.  Of a total of 479 subjects, who have  received  pembrolizumab  in  
Protocol  001,  466  (97.3%)  experienced  treatment - emergent AEs, of which 368 (76.8%) 
were considered drug -related.  Serious AEs were reported in 30.1% of subjects, but SAEs 
that were attributed as potentially (possibly, probably, or definitely) drug-related by 
investigators were reported in 6.7% of subjects overall.   Potential irAEs have been 
observed, including pneumonitis in both melanoma and NSCLC cohorts.  The most 
commonly reported treatment-emergent AEs experienced have been fatigue, nausea, cough, 
pruritus, diarrhea, and rash. Most subjects continued treatment despite of AEs, and only 
4.2% of subjects discontinued study treatment becaus e of an AE that was considered 
related to study treatment by investigators.  Thus, the overall AE summary suggests that 
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4.3.1.3 Risk from combined Pembrolizumab and Epacadostat  
The combination of pembrolizumab and epacadostat has the potential to cause 
more frequent, more severe, and/or new immune-related toxicities as compared with each 
individually. 
 
In the ongoing Phase 1/2 study combi ning pembrolizumab and epacadostat, 
preliminary data suggest that doses up to 300 mg BID of epacadostat are well tolerated with 
200 mg IV of pembrolizumab. While 300 mg bid did not exceed the MTD, there were 
higher rates of dose holds and reductions compared to 100 mg bid supporting 100 mg bid as 
the Phase 2 dose (as is detailed later in this section).  In the Phase 1 portion of the study, a 
DLT of Grade 3 rash and Grade 3 arthralgia were seen in 2/19 evaluable subjects with 
epacadostat 50 mg BID; 2 DLTs out of 15 evaluable subjects were seen with epacadostat 
100 mg BID cohort (Grade 3 AST and Grade 2 nervous system disorder, other - ataxia), 
and 4 DLTs out of 19 evaluable subjects were seen at 300 mg BID (Grade 1 erythema, 2 
Grade 3 rashes and 1 nervous system disorder – other – vomiting without nausea). 
 
The most frequently reported (≥ 15%) adverse events (AEs) of any grade for the combined 
Phase 1 and Phase 2 treatment groups (n=117) treated with epacadostat 100 mg BID were 
fatigue (35.0%), constipation (24.8%), diarrhea (20.5%), nausea (20 .5%), vomiting 
(18.8%), pyrexia (16.2%) and dyspnea (15.4%).  Fatigue (13.7%) and rash (11.1%) 
(including the preferred terms rash, rash maculopapular, rash generalized, and rash macular) 
were the only treatment -related AE reported in > 10% of subjects. Treatment-related AEs of 
rash were only reported in the Phase 2 group. 
 
Any Grade 3/4 AEs occurring in more than 1 subjects in the combined Phase 1 
and Phase 2 epacadostat 100 mg BID group include: rash (n=5, 4.3%), dehydration (n=4 
3.4%), nausea, vomiting and AST increased,  (n= 3 each, 2.6%), diarrhea, small intestine 
obstruction, fatigue, lipase increased, hypercalcemia, hyponatremia, tumour pain, and 
pneumonia aspiration (n=2 each, 1.7%).  Treatment-related AEs ≥ Grade 3 occurring in 
more than one subject included rash (5 subjects, 4.3%) and dehydration, lipase increased, 
AST increased and nausea (2 subjects [1.7%] each). 
 
In subjects receiving epacadostat 300 mg  BID, there was an observable trend in 
increased adverse events of rash (total events as wel l as severity) and the number of 
required dose holds and dose reductions for epacadostat, compared to subjects receiving 100 
mg BID. 
 
Although the rashes observed at the 300 mg BID dose level were reversible with dose 
interruptions and medical treatment, total dose interruptions were higher in the 300 mg 
BID group with 5/19 interrupting epacadostat and 3 requiring dose reductions due to adverse 
events compared to 1 subject in 100 mg BID requiring a dose interruption, 2 subjects in 50 
mg BID and 1 subject in 25 mg BID. Based on the risk for early progression during dose 
interruptions and dose reductions associated with epacadostat 300 mg BID in combination 
with pembrolizumab 200 mg IV Q3 weeks, 100 mg BID was selected as the dose for use 
in a proposed Phase 3 study. 
 


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Additional details regarding specific benefits and risks for subjects participating in 
this clinical trial may be found in the accompanying pembrolizumab and epacadostat 
Investigators Brochures (IBs) and Informed Consent documents. 
 
5.0 METHODOLOGY 
5.1 
Entry Criteria /   Eligibility 
5.1.1 Diagnosis/Condition for Entry into the Trial 
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must fulfill the following entry 
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1. Patients must have histologically confirmed squamous cell carcinoma of the head and 
neck (unresectable and not amenable to curative intent therapy) 
2. Meet criteria for either the Acquired Resistance OR the Suboptimal Benefit Cohort 
a. Acquired Resistance is defined as (i and ii must both be met): 
i. Prior benefit from anti-PD-1/PD-L1 therapy defined as a) prior 
response, and/or b) ≥5 months of stable disease (SD). Intervening 
therapies are allowed. 
ii. Progressive Disease (PD) on recent scans 
b. Suboptimal Benefit is defined as (i  and ii must both be met): 
i. Prolonged stable disease ≥5 months OR Suboptimal response 
(>10% & <50% shrinkage per RECIST at any evaluation 
timepoint)  
ii. Ongoing stable disease on recent scans 
iii. Last treatment with an anti-PD-1/PD-L1 agent within 6 weeks 
prior to starting protocol treatment 
3. Archival tissue for PD-L1 staining (alternatively a new biopsy (core) at baseline can 
be used). A minimum of 10 slides is required (unless approval from the PI is 
obtained) 
4. Measurable disease per RECIST 1.1. 
5. Known HPV status 
6. ECOG performance status 0 or 1 
 
7. Be willing and able to provide written informed consent/assent for the trial. 
8. Be  18 years of age on day of signing informed consent. 
9. Demonstrate reasonable organ function as defined in  
10. Table 1, all screening labs should be performed within 10 days of treatment initiation.   
 
Table 1  Adequate Organ Function Laboratory Values 


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System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency 
(within 7 days of assessment) 
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 
 
≥40 mL/min for subject with creatinine levels > 2.0 X 
institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.2 X ULN OR in case of Gilbert’s disease an elevated total 
Bilirubin is allowed if direct Bilirubin is ≤40% of total 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  
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. 
 
11. Female subject of childbearing potential should have a negative urine or serum 
pregnancy test 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.   
12. 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.  
13. 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. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
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2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment. 
 
3. Has a known history of active TB   (Bacillus Tuberculosis) 
 
4. Has hypersensitivity to pembrolizumab, epacadostat or any of its excipients. 
5. Has had a prior anti-cancer monoclonal antibody (mAb) within 3 weeks prior to study 
Day 1, or targeted small molecule 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 
agents administered more than 4 weeks earlier. 
6. Has not recovered from prior surgery, chemotherapy or radiation therapy from 
adverse events due to a previous treatment/ administered agent (i.e., ≤ Grade 1 or 
return to baseline prior to treatment). 
- 
Note:  Subjects with ≤ Grade 2 neuropathy, any grade hearing loss or tinnitus, 
or typical side effects from radiotherapy 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.   
7. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of 
the skin that has undergone potentially curative therapy or in situ cervical cancer or 
any tumors that are not likely to influence live expectancy in the subsequent 3 years 
without active treatment (e.g. low grade prostate cancer in absence of therapy). 
8. Has known active (=growing) central nervous system (CNS) metastases and/or 
carcinomatous meningitis. Radiation or resected brain metastasis are acceptable if 
clinically stable. 
9. Has active autoimmune disease that has required systemic treatment in the past 2 
years 
(i.e. 
with 
use 
of 
disease 
modifying 
agents, 
corticosteroids 
or 
immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, 
etc.) is not considered a form of systemic treatment.  
10. Has known history of, or any evidence of active, non-infectious pneumonitis. 
11. Warfarin use, even if low dose warfarin is not acceptable. However, other anti-
coargulants (e.g. aspirin, enoxaparin and heparin derivatives, thrombin inhibitors, etc) 
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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 psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
14. 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. 
15. Has received prior therapy with an IDO inhibiting agent. 
16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
18. Has received a live vaccine within 30 days of planned start of study therapy. 
19. Subjects receiving MAO-inhibitors (MAOI) or drug which has significant MAOI 
activity (meperidine, linezolid, methylene blue) within the 21 days before screening. 
20. Any history of Serotonin Syndrome after receiving serotonergic drugs. 
21. History or presence of an abnormal electrocardiogram (ECG) that, in the 
investigator's opinion, is clinically meaningful. Screening QTc interval > 470 
milliseconds is excluded. In the event that a single QTc is > 470 milliseconds, the 
subject may enroll if the average QTc for the 3 ECGs is < 470 milliseconds. For 
subjects with an intraventricular conduction delay (QRS interval > 120 milliseconds), 
the JTc interval may be used in place of the QTc with sponsor approval. The JTc 
must be < 340 milliseconds if JTc is used in place of the QTc. Subjects with left 
bundle branch block are excluded. 
Note: QTc prolongation due to pacemaker may enroll if the JTc is normal. 
22. Use of any UGT1A9 inhibitor from screening through follow-up period, including the 
following:  diclofenac, imipramine, ketoconazole, mefenamic acid, and probenecid. 
See Section 5.11 for more details. 
23. History of organ transplant that requires use of immunosuppressives. 
24. Any condition that would jeopardize the safety of the subject or compliance with the 
Protocol. 
25. Clinically significant cardiac disease, including unstable angina, acute myocardial 
infarction within 6 months from Day 1 of study drug administration, New York Heart 
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Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed within 30 days prior to initiation of 
treatment. 
 
 


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5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2 
Table 2  Trial Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 
200 mg mg/kg 
Q3W 
IV infusion 
Day 1 of each 3 
week cycle 
Experimental 
Epacadostat 
100mg 
Daily, 
BID 
PO 
continuous 
Experimental 
Treatment Period: Both Epacadostat and Pembrolizumab are given concurrently. 
Trial treatment should initiate as soon as PD-L1 status and cohort allocation are known 
5.2.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale.   
Details on preparation and administration of pembrolizumab (MK-3475) and Epacadostat are 
provided in the respective Pharmacy Manuals.   
5.3 
Dose Modifications 
Adverse events (both non-serious and serious) associated with pembrolizumab and 
epacadostat exposure may represent an immunologic etiology.  These adverse events may 
occur shortly after the first dose or several months after the last dose of treatment. 
Pembrolizumab must be withheld for drug-related toxicities and severe or life-threatening 
AEs as per Table 3 below. See below for supportive care guidelines, including use of 
corticosteroids. 
Table 3: Dose Modification Guidelines for Drug-Related Adverse Events for 
Pembrolizumab and Epacadostat 
Toxicity 
Hold 
Treatment 
For Grade 
Agent 
Timing for Restarting 
Treatment 
Dose Level 
for 
Treatment Discontinuation 
Diarrhea/Colitis 2-3 
Pembrolizu 
mab 
Toxicity   resolves   to 
Grade 0-1 
n/a 
Toxicity does not resolve within 12 
weeks of 
last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day 
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Dosing interruptions are permitted in the case of medical / surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, patient 
vacation, and/or holidays). Subjects should be placed back on study therapy within 3 weeks 
of the scheduled interruption, unless otherwise discussed with the PI. The reason for 
interruption should be documented in the patient's study record. 
5.3.1 Criteria and Procedures for Treatment Interruption 
 
In some circumstances, it may be necessary to temporarily interrupt both study treatments as a 
result of AEs that may have an unclear relationship to study drug.  Any interruptions of > 2 
weeks or for LFT abnormalities must be discussed with the medical monitor before resuming 
Epacadostat  
Toxicity   resolves   to 
Grade 0-1 
Related: Reduce 
by 1 dose level 
Not Related: Same
dose level 
Toxicity does not resolve within 12 
weeks of 
last dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day 
within 12 weeks 
4 
Pembrolizu 
mab 
Permanently 
discontinue 
n/a 
Permanently discontinue 
Epacadostat 
 
Permanently 
discontinue 
n/a 
Permanently discontinue 
AST,    ALT,    
or Increased 
Bilirubin 
2 
Pembrolizu 
mab 
Toxicity   resolves   to 
Grade 0-1 
n/a 
Toxicity does not resolve within 12 
weeks of 
Epacadostat 
 
Toxicity   resolves   to 
Grade 0-1 
Related: Reduce 
by 1 dose level 
Not Related: Same
dose level 
Toxicity does not resolve within 12 
weeks of last dose 
3-4 
Pembrolizu 
mab 
Permanently 
discontinue 
n/a 
Permanently discontinue 
Epacadostat 
 
Permanently 
discontinue 
n/a 
Permanently discontinue 
Type  1  
diabetes 
mellitus  (if  
new onset)          
or Hyper-
glycemia 
T1DM or 
3-4 
Pembrolizu 
mab 
Hold    pembrolizumab 
for new onset Type 1 
diabetes    mellitus    or 
Grade                      3-4 
hyperglycemia 
associated              with 
evidence  of  beta  cell 
failure 
n/a 
Resume pembrolizumab when 
subjects are clinically and 
metabolically stable 
Epacadostat 
 
Toxicity   resolves   to 
Grade 0-1 
Related: Reduce 
by 1 dose level 
Not Related: Same
dose level 
Resume   epacadostat   when   subjects 
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treatment.  Treatment with both study drugs should be withheld for drug-related Grade 4 
hematologic toxicities, nonhematological toxicity ≥ Grade 3 (including laboratory 
abnormalities), and severe or life-threatening AEs (see Table 3).  Table 3 summarizes the 
dosing actions for MK-3475 and INCB024360 that must be implemented with the indicated 
related AEs. Additional information related to dose changes for INCB024360 and MK-3475 
can be found in subsequent Sections. 
 
Except in cases of emergency, it is recommended that the investigator consult with the 
sponsor's medical monitor (or other representative of the sponsor) before temporarily 
interrupting therapy for reasons other than Protocol-mandated medication hold.  Additionally, 
the investigator must notify the sponsor's medical monitor and study project manager via 
email before restarting study drug that was temporarily interrupted because of an AE. 
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study therapy (e.g, elective surgery, unrelated medical events, subject vacation, 
and/or holidays).  Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the sponsor.  The reason for 
interruption should be documented in the subject's study record. 
In case toxicity does not resolve to Grade 0 to 1 within 12 weeks after last infusion of MK-
3475, study treatment should be discontinued after consultation with the sponsor.  With 
investigator and sponsor agreement, subjects with a laboratory AE still at Grade 2 after 12 
weeks may continue treatment in the study only if asymptomatic and controlled.  For 
information on the management of irAEs, see below/next sections. 
 
5.3.2 Procedures for Subjects Exhibiting Immune-Related Adverse Events 
 
This section is meant to apply to suspected irAEs or events of clinical interest (ECIs) of 
a potential immunologic etiology from INCB024360, MK-3475 or the combination.   
 
Events of clinical interest of a potential immunologic etiology or irAEs may be defined as 
an AE of unknown etiology, associated with drug exposure and consistent with an immune 
phenomenon. irAEs may be predicted based on the nature of the MK-3475 or INCB024360 
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.  Of note, the requirement for reporting ECIs applies 
to all groups, including comparators, of MK-3475. 
 
If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, 
toxin or other etiologic causes before labeling an AE as an irAE.  Information on how to 
identify and evaluate irAEs has been developed and is included in the Event of Clinical 
Interest and Immune-Related Adverse Event Guidance Document.  Subjects who develop a 
≥ Grade 2 irAE should be discussed immediately with the PI. 
 
Recommendations for management of specific immune-mediated AEs such as 
pneumonitis enterocolitis, and hepatitis are detailed in the sections below. 
 
Table 4:         General Approach to Handling Immune-Related Adverse Events 


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irAE 
Withhold/Discontinue 
Pembrolizumab (MK-3475) 
and Epacadostat 
Supportive Care 
Grade 1 
No action. 
Provide symptomatic treatment. 
Grade 2 
May withhold MK-3475 and INCB024360. 
Subjects with intolerable or persistent Grade 2 
drug-related AE may hold study medication at 
physician's discretion. Permanently 
discontinue study drug for persistent Grade 2 
AEs for which treatment with study drug has 
been held, that do not recover to Grade 0 to 1 
within 12 weeks of the last dose. 
Consider systemic corticosteroids in addition to 
appropriate symptomatic treatment. 
Grade 3 or 
severe 
Withhold MK-3475 and INCB024360. 
Discontinue if unable to reduce corticosteroid 
dose to < 10 mg/day prednisone equivalent 
within 12 weeks of toxicity or permanently 
discontinue for any severe or ≥ Grade 3 drug- 
related AE that recurs or any life-threatening 
event. 
 
For grade 3 rash, dose interruption and topical 
treatment (see next column) until resolution 
are recommended  Resume at same dose 
although dose reduction in cases of persistent 
rash can be considered 
Systemic corticosteroids are indicated in 
addition to appropriate symptomatic treatment. 
 
 
 
 
 
Topical steroids per physician choice (e.g. 
hydrocortisone, or stronger). Typically oral 
steroids are not required. 
Grade 4 
Permanently discontinue 
Systemic corticosteroids are indicated in 
addition to appropriate symptomatic treatment. 
 
5.3.3 Timing of Dose Administration of 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, that dose should 
be skipped and the next dose should be taken at the next scheduled timepoint.  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 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 clinic days also 
at the same time.  There is no priority to the order of administration 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.   
5.3.4 Supply, Packaging, and Labeling of Epacadostat 
Epacadostat will be available as 25, or 100 mg tablets packaged in high-density 
polyethylene bottles. All tablet excipients comply with the requirements of the applicable 
compendial monographs (Ph. Eur., USP/NF) (refer to the iIB).  All Incyte investigational 


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product labels will be in the local language and will comply with the legal requirements of 
each country. 
5.3.5 Storage and Dispensing of Epacadostat 
Clinical supplies must be stored as described in the iIB. 
An initial bulk supply of epacadostat will be provided to investigative sites prior to 
enrollment of the first subject.  When dispensing to subjects, the investigator or designee will 
remove the appropriate quantity of epacadostat from their stock, dispense the medication, and 
enter the amount dispensed into the CRF and drug accountability log.   
 
5.3.6 Timing of Dose Administration of Pembrolizumab. 
Combination treatment (during treatment period) 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 200 mg will be administered as a 30-minute IV infusion every 3 
weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without 
disease progression.  .  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). 
The Pharmacy Manual contains specific instructions for the preparation of the 
pembrolizumab infusion fluid and administration of infusion solution. 
5.3.7 Trial Blinding/Masking 
This is an open label trial without randomization. 
  
 
5.4 
Treatment Allocation 
Please see eligibility / Inclusion criteria for allocation to one of the two cohorts.  
5.5 
Stratification 
There will be no stratification 
 


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5.6 
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 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.  
5.6.1 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.   
5.6.2 Restricted Medications and Measures 
None, see 5.6.3 prohibited concomitant medications 
 
 
5.6.3 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: 
 Antineoplastic systemic chemotherapy or biological therapy  
 Immunotherapy not specified in this protocol 
 Chemotherapy not specified in this protocol 
 Investigational agents other than pembrolizumab 
 Use of coumarin-based anticoagulants (eg, Coumadin®) is not allowed. Alternatives 
to coumarin-based anticoagulants should be considered and are acceptable. 
 Radiation therapy  
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may 
be allowed at the investigator’s discretion.   
 Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  
 Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  The use of physiologic 
doses of corticosteroids may be approved after consultation with the PI (typically 
≤10mg of Prednisone or equivalent). 


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 Any melatonin supplements.  
 Any MAOI or drug associated with significant MAO inhibitory activity agents is 
prohibited from 21 days before Day 1 through 2 weeks after the final dose of 
epacadostat has been taken (see Appendix C).  
 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, mefenamic acid, mycophenolic acid, niflumic acid, 
nilotinib, phenobarbital, phenylbutazone, phenytoin, probenecid, propofol, quinidine, 
ritonavir, Sorafenib, sulfinpyrazone, valproic acid, and verapamil.  
 NOTE: Propofol, when used for short-term sedation during surgical/biopsy 
procedures, is allowed after consultation with the medical monitor. The epacadostat 
dose may be taken on the morning of the procedure, and the evening dose held 
following the procedure. Epacadostat may be resumed the next day. 
 
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 may describe other medications, which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.7 
Rescue Medications & Supportive Care 
5.7.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by 
the treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below and in greater detail in the 
ECI guidance document. Where appropriate, these guidelines include the use of oral or 
intravenous treatment with corticosteroids as well as additional anti-inflammatory agents if 
symptoms do not improve with administration of corticosteroids.   Note that several courses 
of steroid tapering may be necessary as symptoms may worsen when the steroid dose is 
decreased. For each disorder, attempts should be made to rule out other causes such as 
metastatic disease or bacterial or viral infection, which might require additional supportive 
care. The treatment guidelines are intended to be applied when the investigator determines 
the events to be related to pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the investigator is 
instructed to follow the ECI reporting guidance but does not need to follow the treatment 


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guidance (as outlined in the ECI guidance document). Refer to Section 5.2.1 for dose 
modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. Suggested conditional procedures, as 
appropriate, can be found in the ECI guidance document. 
 Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
 
 Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus).   
 
o All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid 
and electrolytes should be substituted via IV infusion.  For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out 
colitis. 
o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with 
intravenous steroids followed by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
 
 
 Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
 
o For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria.  
 Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
 


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 Hypophysitis: 
 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
 
 
 Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during treatment, 
and as indicated based on clinical evaluation) and for clinical signs and symptoms of 
thyroid disorders. 
 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
 
 Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until 
returned to baseline values (consider weekly). 
 Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 
hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks. 
 
 Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  


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 Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion.  
 
Table 5 below shows treatment guidelines for subjects who experience an 
infusion reaction associated with administration of pembrolizumab (MK-3475). 
Table 5 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 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the 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 (MK-3475) 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. 
 


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5.7.2 Procedures for Subjects Exhibiting Serotonin Syndrome 
 
As noted in the background, there is a theoretical chance that Epacadostat/INCB024360 
could cause an increase in serotonin levels in the brain that might trigger SS (Boyer and 
Shannon 2005) 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, 
including tremor; hyperreflexia; spontaneous, ocular, or inducible clonus; together with 
agitation, fever, diaphoresis, or muscle rigidity: 
 
•   
Immediately 
interrupt 
Epacadostat/INCB024360 
administration.  
Administration of Pembrolizumab/MK-3475 may continue. 
 
•   Immediately interrupt any SSRI or SNRI 
administration. 
 
•   Provide appropriate medical management of the subject until all 
signs/symptoms are resolved (eg, IV fluids and/or sympathomimetic amines 
for hypotension, benzodiazepines for agitation, administration of 5-
hydroxytryptamine antagonists such as cyproheptadine). 
 
•   If subject chooses to remain in the study, restart treatment with 
INCB024360 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. 
 
•   If subject chooses to withdraw from the study, or must restart treatment 
with SSRI or SNRI, the subject should be scheduled for a follow-up visit.  
Treatment with SSRI or SNRI may be initiated 2 weeks after resolution of 
signs and symptoms of SS. 
 
 
5.7.3 Treatment After Initial Evidence of Radiologic Evidence of Disease Progression 
 
Immunotherapeutic agents such as Pembrolizumab (MK-3475) and Epacadostat 
(INCB024360) 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. 
 


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If radiologic imaging shows PD, tumor assessment should be repeated ≥ 4 weeks later to 
confirm PD, with the option of continuing treatment per below while awaiting radiologic 
confirmation of progression.  If repeat imaging shows a reduction in the tumor burden 
compared to the initial scan demonstrating PD, treatment may be continued as per 
treatment calendar.  If repeat imaging confirms PD, 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 non-target 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 as 
described in Table 6. 
 
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 (e.g., cord 
compression) requiring urgent alternative medical intervention. 
 
 
Table 6:       Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
First radiologic 
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 
confirms PD 
No additional 
imaging required 
Discontinue 
treatment 
No additional 
imaging required 
N/A 
Repeat scan 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 
 
 
 


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5.8 
Diet/Activity/Other Considerations 
5.8.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
5.8.2 Contraception 
Pembrolizumab and epacadostat may have adverse effects on a fetus in utero.  Furthermore, 
it is not known if pembrolizumab has transient adverse effects on the composition of sperm.  
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.  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. 
 
5.8.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, 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/Incyte without delay and within 24 hours to the Sponsor and within 2 working days to 
Merck/Incyte, as described in section 10.7,  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).   


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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/Incyte and followed as 
described above and in Section 7.2.2. 
5.8.4 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
5.9 
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 investigator or the Sponsor 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. 
 Confirmed radiographic disease progression (=2nd scan within 4-8 weeks) 
Note: For unconfirmed radiographic disease progression, please see Section 5.7.3 
Note: A subject may be granted an exception to continue on treatment with 
confirmed radiographic progression if clinically stable or clinically improved, 
please see Section 5.7.3 
 Unacceptable adverse experiences as described in Section 5.2.1.2 
 Intercurrent illness that prevents further administration of treatment 
 Investigator’s decision to withdraw the subject 
 The subject has a confirmed positive serum pregnancy test 
 Noncompliance with trial treatment or procedure requirements 
 The subject is lost to follow-up 
 Completed 12 months of uninterrupted treatment with pembrolizumab or 18 
administrations of study medication, whichever is later. 


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 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, the end of the study, or 2 years beyond the last administration of study drug, 
whichever occurs first. 
5.9.1 Discontinuation of Study Therapy after CR  
For subjects who have overt disease at any point during study treatment, discontinuation of 
treatment may be considered if they attain a confirmed CR AND have been treated for at 
least 24 weeks with pembrolizumab and had at least two treatments with pembrolizumab 
beyond the date when the initial CR was declared.  Subjects who then experience 
radiographic disease progression may be eligible for up to one year of additional treatment 
with pembrolizumab via the Second Course Phase at the discretion of the investigator if no 
cancer treatment was administered since the last dose of pembrolizumab, the subject meets 
the safety parameters listed in the Inclusion/Exclusion criteria, and the trial is open.  Subjects 
will resume therapy at the same dose and schedule at the time of initial discontinuation.  
Additional details are provided in Section 7.1.5.5. 
5.10 Subject Replacement Strategy 
Patients who receive 0, or only 1 dose only will be replaced due to inadequate treatment 
exposure. An intention to treat analysis will be performed as a secondary analysis, but for the 
primary analysis only patients with adequate treatment exposure to 2 or more doses of 
pembrolizumab will be included. 
5.11 Clinical Criteria for Early Trial Termination 
Early trial termination at a participating site 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 


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In the event of Merck/Incyte 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: 
Screening Phase 
 
Treatment Cycles* 
End of 
Treat-
ment 
Post-Treatment 
Treatment Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main Study 
Screening 
(Visit 2) 
 
1 
2  
3 
4 
To be repeated beyond 8 
cycles ** 
Discontin
uation 
(D/C) 
Safety 
Follow-
up 
Follow 
Up Visits  
Survival 
Follow-Up 
5 
6 
7 
8 
 
Scheduling Window (Days): 
 
-28 to -1 
 
 
± 3 
± 3 ± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
D/C 
30 days 
post 
D/C 
Every 8 
weeks 
post D/C 
Every 12 
weeks  
Administrative Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication Review 
X 
X 
 
X 
X 
X  
X 
X 
X 
X 
X 
X 
 
 
 
Trial Treatment Administration 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Clinical Procedures/Assessments 
Epacadostat administration (daily po) 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Pembrolizumab administration (iv q3 weeks) 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Review Adverse Events 
 
 
 
X 
X 
X 
X 
X 
X** 
X 
X** 
X 
 
 
 
Full Physical Examination 
 
X 
 
X 
 
X 
 
X 
X** 
 
X** 
X 
X 
X 
 
Vital Signs and Weight 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG Performance Status 
 
X 
 
X 
X 
X 
X 
X 
X** 
X 
X** 
X 
X 
X 
 


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Trial Period: 
Screening Phase 
 
Treatment Cycles* 
End of 
Treat-
ment 
Post-Treatment 
Treatment Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main Study 
Screening 
(Visit 2) 
 
1 
2  
3 
4 
To be repeated beyond 8 
cycles ** 
Discontin
uation 
(D/C) 
Safety 
Follow-
up 
Follow 
Up Visits  
Survival 
Follow-Up 
5 
6 
7 
8 
 
Scheduling Window (Days): 
 
-28 to -1 
 
 
± 3 
± 3 ± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
D/C 
30 days 
post 
D/C 
Every 8 
weeks 
post D/C 
Every 12 
weeks  
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
For Women of childbearing potential - 
Pregnancy Test – (continued) 
Urine or Serum -HCG  
(also see Table 9, page 37) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
 
Comprehensive Serum Chemistry Panel 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
T3, FT4 and TSH 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
Efficacy Measurements 
Tumor Imaging (every 8 weeks) 
 
 
X 
 
Every 8 weeks 
 
 
 
 
X 
 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Archival (or Newly Obtained) Tissue 
Collection (typically FFPE, ≥10 tumor 
containing 5-micron slides to be collected) 
If NOT available will require a new biopsy (not 
FNA) unless biopsy is not safe/technically 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Trial Period: 
Screening Phase 
 
Treatment Cycles* 
End of 
Treat-
ment 
Post-Treatment 
Treatment Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main Study 
Screening 
(Visit 2) 
 
1 
2  
3 
4 
To be repeated beyond 8 
cycles ** 
Discontin
uation 
(D/C) 
Safety 
Follow-
up 
Follow 
Up Visits  
Survival 
Follow-Up 
5 
6 
7 
8 
 
Scheduling Window (Days): 
 
-28 to -1 
 
 
± 3 
± 3 ± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
D/C 
30 days 
post 
D/C 
Every 8 
weeks 
post D/C 
Every 12 
weeks  
feasible 
Correlative Studies Blood Collection including 
a) germline DNA collection and b) PAXgene 
tube for RNA 
 
 
X2,3 
 
 
 
 
X3 
 
 
 
 
 
 
 
 
 
 
 
1. The fresh biopsy/FNA requirement can be waived under extenuating circumstances after approval by the PI (Dr. Pearson) e.g 
such a procedure is not safe or technically feasible. 
 If clinically indicated tissue from a biopsy will also be banked using the UCCCC# 8980 banking protocol.  
2. -- 2  Purple top tubes, blood volume, processing etc will follow HTRC SOPs 
3. – PAXgene tube, blood volume, processing etc will follow HTRC SOPs 
* Treatment cycle length = 21 days 
** After cycle 8, as clinically appropriate ECOG performance status, physical exam, and adverse event recording interval may be 
increased to every other cycle (=every 6 weeks). 
End of Treatment = end of 2 years of treatment OR progressive disease as outlined in prior section. 


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Survival follow-up can be done via phone if patient is not coming in for additional care 
Laboratory tests for screening or potentially a Second Treatment Course should be performed within 14 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.    
 
 


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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 Sponsor and/or 
Merck/Incyte 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’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 that captures the subject’s dated signature or by the subject’s legally acceptable 
representative’s dated signature. 
The informed consent will adhere to IRB requirements and applicable laws and regulations. 
 


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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 Randomization Number 
Not applicable, this is an open label, non-randomized trial 
7.1.1.7 Trial Compliance (Medication/Diet/Activity/Other) 
Patients are expected to follow the outlined treatment schedule, and violation of trial 
procedures may lead to trial discontinuation (see Section 5.8) if compliance is felt to impact 
treatment in a meaningful way or interpretability of data (consultation with the PI 
recommended). 
 
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.  Toxicities will be characterized 
in terms regarding seriousness, causality, toxicity grading, and action taken with regard to 
trial treatment.  
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.   
Safety assessments will consist of monitoring and recording all adverse events and serious 
adverse events, the regular monitoring of hematology, blood chemistry and urine values, 
regular measurement of vital signs and the performance of physical examinations. 
 
These assessments should be performed within ±7 days of the scheduled day of assessment 
except for adverse events that will be evaluated continuously through the study. Safety and 
tolerability 
will 
be 
assessed 
according 
to 
the 
NIH/NCI 
CTC 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
 
Patients whose treatment is interrupted or permanently discontinued due to an adverse 
event or abnormal laboratory value suspected to be related to treatment must be followed at 
least weekly until the adverse event or abnormal laboratory resolves or returns to grade 1. If 
a patient requires a dose delay of >16 weeks from the intended day of the next scheduled 
dose, then the patient must be discontinued from the study. 
 
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,  


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7.1.2.3 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 (Section 6.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 
7.1.2.4 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 11.1) at 
screening, prior to the administration of each dose of trial treatment and discontinuation of 
trial treatment as specified in the Trial Flow Chart.   
7.1.2.5 Tumor Imaging and Assessment of Disease 
Tumor imaging will be performed as outline in the flowchart under Section 6, typically every 
8-16 weeks or as clinically indicated. 
Radiologic recurrence/progression of disease should be confirmed 4-8 weeks after the initial 
scan and patients can continued treatment until confirmation if clinically stable and no other 
immediate reason for discontinuation is present. 
Whenever possible clinical progression should be confirmed radiologically.  
7.1.2.6 Tumor Tissue Collection and Correlative Studies Blood Sampling 
A minimum of 10 slides (from the original tumor prior to initiation of curative intent therapy) 
will be collected. 
Blood will be obtained at baseline and at the time of the second treatment. Please see 
tissue/blood collection SOP provided separately. 
 
7.2 
Research Tests 
 
Tissue 
obtained 
(PRIOR 
to 
curative 
intent 
therapy) 
from 
the 
diagnostic 
biopsy/panendoscopy and/or during surgical resection, and whole blood samples (in 
PAXGene tubes). 
 
The correlative work will be performed/coordinated at the University of Chicago, and 
may be done with collaborators e.g. at Incyte or Merck. 
 
 
 
 


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7.2.1 Sample Shipping 
 
All the tissue, whole blood and serum samples will be collected in the HTRC and 
additional details will be provided in a brief Tissue/Blood SOP that will be continually 
updated. 
 
 
7.2.2 IHC staining 
 
 Multicolor immunohistochemistry will be performed and results will be descriptive and 
presented in tabular with a focus on highlighting changes from pre- treatment samples.    
Markers will include PD-L1 (research), and CD8. 
Initial PD-L1 for allocation to a sample group will be done using the DAKO 22C3 CLIA 
assay for PD-L1 staining. 
Additional staining for FOXP3, CD163, IDO, CD206, CD11a, CD163, and related markers if 
appropriate based on assay availability may be added. 
 
7.2.3 Nanostring Analysis 
From 3-5 FFPE slides RNA will be extracted using the Qiagen RNA/DNA FFPE kit and 
protocol. A Nanostring probeset including ca 20-800 immune and other marker related 
probes will be used using the Nanostring (Seattle) standard ordering and analysis process. 
The Nanostring nCounter available in the White lab at the University of Chicago will be 
used. Alternatively FFPE based RNAseq libraries may be constructed using the Illumina 
FFPE RNA access protocol. The lab is experienced with both the Nanostring and FFPE 
RNAseq process and additional details are available on request. These are exploratory 
analyses. Specific processing information will be made available in a continually updated 
SOP for tissue collection and processing.  
7.2.4 Tumor DNA Analysis 
Exome sequencing from tumor and normal blood white cells will be performed on the tumor 
samples for an exploratory analysis of correlation of genetic aberrations, immune phenotype 
and tumor response. In addition tumor RNAseq analysis will be performed from tumor 
tissue. Specific processing information will be made available in a continually updated SOP 
for tissue collection and processing.  


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7.2.5 Germline DNA analysis 
Blood will be obtained from all patients for exome sequencing of normal DNA (see above). 
Specific processing information will be made available in a continually updated SOP for 
tissue collection and processing.  
7.2.6 RNA analysis from blood 
Blood samples will be obtained at baseline and after 3 weeks (administration of cycle 2 
dose). Samples will be processed for RNA expraction (e.g. using thje PAXgene RNA 
kit/tubes). RNA will be analyses by Nanostring (see above) or RNAseq) in an exploratory 
fashion comparing baseline with on-treatment inflammatory markers. Specific processing 
information will be made available in a continually updated SOP for tissue collection and 
processing. 
 
7.2.7  Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below under Laboratory Safety Evaluations (Hematology, Chemistry and 
Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 7.   


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Table 7  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal)  
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Free tyroxine (T4) 
Absolute Lymphocyte Count 
  (CO2 or biocarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Uric Acid 
 
PK 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies 
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
‡ If considered standard of care in your region. 
 
 
 


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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.  
7.2.6.1 Pharmacodynamic Evaluations 
7.2.6.1.1 Blood Collection for RNA 
Blood will be collected at baseline, and at the time of 2nd administration of pembrolizumab. 
Details are provided in the Flow Chart and a brief SOP for tissue will be available and 
updated continually during the study period containing specific details (tube color, numbers, 
HTRC contact info etc). 
No Pharmacokinetic evaluations will be done. 
7.2.7 Other Procedures 
7.2.7.1 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 may discontinue treatment with the option of restarting 
treatment if they meet the criteria specified in Section 7.1.5.5.  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). 
7.2.7.2 Blinding/Unblinding 
There is no blinding in this study. 
 
7.2.8 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. 
7.2.8.1 Screening period 
Screening period is 30 days prior to initiation of study drug. See flow chart under Section 6 
for specific items. 
 


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x   All patients must have completed curative intent therapy for locally advanced 
HNSCC within 24 weeks prior to enrollment. 
 
x   Tissue must have been collected PRIOR to starting curative intent therapy on all 
patients (see eligibility criteria) 
 
 
7.2.8.2 Treatment Assignment  
 
 
Cohort assignment will be based presence of acquired resistance versus suboptimal 
benefit as defined under study entry/inclusion criteria. 
 
 
7.2.8.3 Treatment Period 
Treatment period is 2 years or until progression.  
 
7.2.8.4 Post-Treatment Visits 
7.1.5.4.1  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.  Subjects who are eligible for retreatment 
with pembrolizumab (as described in Section 7.1.5.5) may have up to two safety follow-up 
visits, one after the Treatment Period and one after the Second Course Phase. 
7.2.8.5 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 8-12 weeks (± 7 days) by 
radiologic imaging to monitor disease status.  After 1 year, the imaging time point will occur 
every 12-16 weeks (± 7 days). 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 as detailed in Section 
7.1.5.5.  Information regarding post-study anti-neoplastic treatment will be collected if new 
treatment is initiated. 


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Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria 
in Section 7.1.5.5 will move from the follow-up phase to the Second Course Phase when they 
experience disease progression.  
7.2.8.5.1 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 approximately every 12 to 16 weeks to assess for survival status until death, 
withdrawal of consent, or the end of the study, whichever occurs first OR at most 2 years out 
from the last patient receiving pembrolizumab.  
7.2.8.6 Second Course Phase (Retreatment Period) 
Subjects who stop pembrolizumab/epacadostat with SD or better may be eligible for up to 
one year of additional therapy with pembrolizumab + epacadostat if they progress after 
stopping study treatment.  This retreatment is termed the Second Course Phase of this study 
and is only available if the study remains open and the subject meets the following 
conditions: 
 Either  
o Stopped initial treatment with pembrolizumab + epacadostat after attaining an 
investigator-determined confirmed CR according to RECIST 1.1, and 
 Were treated for at least 24 weeks with pembrolizumab + epacadostat before 
discontinuing therapy 
 Received at least two treatments with pembrolizumab and concurrent 
epacadostat (during that timeframe) beyond the date when the initial CR was 
declared 
 
 
OR 
o Had SD, PR or CR and stopped pembrolizumab/epacadostat treatment after 24 
months of study therapy for reasons other than disease progression or 
intolerability 
AND 
 Experienced an investigator-determined confirmed radiographic disease progression 
after stopping their initial treatment with pembrolizumab/epacadostat 
 Did 
not 
receive 
any 
anti-cancer 
treatment 
since 
the 
last 
dose 
of 
pembrolizumab/epacadostat 


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 Has a performance status of 0 or 1 on the ECOG Performance Scale 
 Demonstrates adequate organ function as detailed in Section 5.1.2 
 Female subject of childbearing potential should have a negative serum or urine 
pregnancy test within 72 hours prior to receiving retreatment with study medication.   
 Female subject of childbearing potential should be willing to use one of the following 
methods of contraception (Intrauterine device (IUD), Vasectomy of a female subject’s 
male partner, Contraceptive rod implanted into the skin),  2 other methods of birth 
control (as listed in below footnote) 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 child bearing potential are 
those who have not been surgically sterilized or have been free from menses for > 1 
year.  
 Male subject 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.   
 Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might 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. 
Subjects who restart treatment will be retreated at the same dose and dose interval as when 
they last received pembrolizumab.  Treatment will be administered for up to one additional 
year. 
Footnote: two of the following contraception methods are acceptable when used in 
combination: 
The two birth control methods can be 2 barrier methods or 1 barrier method plus 1 hormonal method to prevent pregnancy.  
The following birth control methods are allowed during the study: 
 
Barrier methods:  
o 
Diaphragm with spermicide (cannot be used with cervical cap 
o 
Cervical cap with spermicide (cannot be used with diaphragm) 
o 
Condom (male or female cannot be used together) 
o 
Copper intrauterine device (IUD) 
o 
Contraceptive sponge 
 
Hormonal methods: 
o 
Hormonal contraceptives (such as the birth control pill, skin patch, vaginal ring, or subcutaneous injection) 
 
7.3 
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), 


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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/Incyte 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. 
Merck/Incyte product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by Merck/Incyte for human use. 
Adverse events may occur during the course of treatment 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.  
Progression of the cancer under study is not considered an adverse event unless it is 
considered to be drug related by the investigator. 
All adverse events will be recorded from the time of first study drug administration through 
90 days following cessation of treatment or if a subject initiates new anticancer therapy, 
whichever is earlier 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. 
7.3.1 Definition of an Overdose for This Protocol and Reporting  
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose).  No specific information is available on the 
treatment of overdose of pembrolizumab. Appropriate supportive treatment should be 
provided if clinically indicated. In the event of overdose, the subject should be observed 
closely for signs of toxicity.  Appropriate supportive treatment should be provided if 
clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck/Incyte 
product, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met. 
If a dose of Merck/Incyte products meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.” 


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All reports of overdose with and without an adverse event must be reported within 24 hours 
to the Sponsor and within 2 working days hours to Incyte / Merck Global Safety as described 
below / in section 10.7.  
7.3.2 Reporting of Pregnancy and Lactation 
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 hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events).  If the pregnancy continues to term, the outcome (health of 
infant) must also be reported. 
All Serious Adverse Events (“SAE”), including pregnancy and lactation exposure, 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 any additional reports agreed upon by Institution or Principal Investigator and 
Incyte.  SAE Reports will be sent to IncytePhVOpsIST@incyte.com.  By sending to this e-
mail address, the Incyte Pharmacovigilance group will receive copies of the reports.   This 
process will be tested and established before the first patient is enrolled in the Study. 
Notwithstanding anything to the contrary herein, Institution will have the primary 
responsibility of reporting adverse events (“AE”) to regulatory authorities.” 
Also see Section 10.7 for reporting to Merck Global Safety.  
 
7.3.3 Immediate Reporting of Adverse Events to Incyte and Merck 
7.3.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck/Incyte products 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); 


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 Is associated with an overdose; 
 Is an other important medical event  
Refer to Table 8 for additional details regarding each of the above criteria. 
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 of first dose of study drug through 90 days following cessation of treatment, or the 
initiation of new anti-cancer therapy, whichever is earlier, whether or not related to 
Merck/Incyte products, must be reported within 24 hours to the Sponsor and within 2 
working days to Inctyte/Merck Global Safety as described in section 10.7.  
Non-serious Events of Clinical Interest will be forwarded to Incyte / Merck Global Safety 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/Incyte products 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 /Incyte as described in sectin 
10.7. 
This study will be conducted under an IND held by Dr. Alexander Pearson at the University 
of Chicago.  Annual Progress Reports will be submitted as required by FDA. Additionally 
the IND holder will submit a copy of these reports to Incyte/Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. 
All subjects with serious adverse events must be followed up for outcome. 
 
The investigator must assess and record the relationship of each SAE to the specific study 
drug, and report this as described in section 10.7. The original copy of the SAE Report 
and the fax confirmation sheet must be kept at the study site. 
 
Follow-up information is sent to the same person to whom the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original report. Each re-occurrence, complication, 
or progression of the original event should be reported as a follow-up to that event 
regardless of when it occurs. The follow-up information should describe whether the event 
has resolved or continues, if and how it was treated, whether the blind was broken or not (if 
applicable), and whether the patient continued or withdrew from study participation.  
 
 
7.3.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical 
Interest 
(ECI) and must be reported within 24 hours to the PI as well as Incyte/Merck. 


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For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours if it causes the subject to be excluded from the trial, or is the 
result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure. 
 
For the time period beginning at treatment allocation through 30 days following cessation of 
treatment, any ECI, or follow up to an ECI, whether or not related to study products, must be 
reported within 24 hours. 
 
Events of clinical interest for this trial include: 
 
1. 
an overdose of one of the investigational products, as defined below under 
Definition of an Overdose for This Protocol and Reporting of Overdose, that is not 
associated with clinical symptoms or abnormal laboratory results. 
2. 
an elevated AST or ALT lab value that is greater than or equal to 3X the upper 
limit of normal and an elevated total bilirubin lab value that is greater than or 
equal to 2X the upper limit of normal and, at the same time, an alkaline phosphatase 
lab value that is less than 2X the upper limit of normal, as determined by way of 
protocol-specified laboratory testing or unscheduled laboratory testing.* 
 
*Note: 
These criteria are based upon available regulatory guidance documents. 
The purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology.  
 
 
7.3.4 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. 
 
7.3.5 Definition of an Overdose for This Protocol and Reporting of Overdose 
In this trial, an overdose is any dose higher than ≥1000 mg (5 times the dose) of 
pembrolizumab or ≥1000 mg of epacadostat.   No specific information is available on the 
treatment of overdose of pembrolizumab or epacadostat. In the event of overdose, 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. 
 


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If a dose meeting the protocol definition of overdose is taken without any associated 
clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
 
All  reports  of  overdose  with  and  without  an  adverse  event  must  be  reported  by  the 
investigator within 24 hours to Incyte/Merck.  


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Table 8  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 Merck/Incyte 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 the Merck/Incyte product to be discontinued? 
Relationship to 
test drug  
Did the Merck / Incyte product cause the adverse event? The determination of the likelihood that the Merck /Incyte product 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/Incyte product and the AE; the greater the correlation with the 
components and their respective elements (in number and/or intensity), the more likely the Merck /Incyte product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to the Merck/Incyte products such as: reliable history, acceptable compliance assessment 
(pill count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 


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Time Course 
Did the AE follow in a reasonable temporal sequence from administration of the Merck/Incyte products?  
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 
 
 
Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to 
investigational 
product 
(continued)  
Dechallenge 
Was the Merck/Incyte products 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 the Merck/Incyte products; or (3) the trial is a single-dose drug trial); or (4) Merck/Incyte products(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to the Merck/Incyte products 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/Incyte products(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 THE STUDY DRUG, APPROVAL FROM THE PI IS REQUIRED 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Merck/Incyte products 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 a Merck/Incyte products relationship). 
Yes, there is a reasonable 
possibility of Merck/Incyte 
products relationship. 
There is evidence of exposure to the Merck/Incyte products.  The temporal sequence of the AE onset relative to the administration of the 
Merck/Incyte products is reasonable.  The AE is more likely explained by the Merck/Incyte products than by another cause. 
No, there is not a reasonable 
possibility Merck/Incyte products 
relationship 
Subject did not receive the Merck/Incyte products OR temporal sequence of the AE onset relative to administration of the Merck/Incyte 
products 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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7.3.6 Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable laws and regulations.  
 
7.4 
Efficacy assessment 
 
The primary study endpoint is Response Rate assessed per RECIST 1.1.   
 
Disease progression (PD) will be evaluated by clinical and radiographic methods and date of 
progression will be recorded. Radiographic progression should be confirmed with a second scan 
4-8 weeks after initial scan and treatment can continue until then.  
 
If in question, disease progression should be confirmed pathologically. Site of disease 
progression will be classified as local (progression at primary tumor site), regional (progression 
in cervical lymph nodes), and/or distant (metastatic disease). 
 
 
A diagnosis of second primary tumor must be confirmed pathologically. Deaths on study should 
be classified as disease (HNSCC), non-disease, or study treatment related. 
 
 


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8.0 STATISTICAL ANALYSIS PLAN 
8.1 
Statistical Analysis Plan  
This study includes two cohorts. These will be handled as parallel cohorts/trials with the 
same statistical assumptions for both cohorts: 
Primary Outcome: Response rate 
    Clinical and pathologic response rates will be determined and 90% confidence 
intervals obtained using the exact binomial distribution.   
 
A Simon's two-stage design (Simon, 1989) will be used – using the Minimax variant - for 
both cohorts. The null hypothesis that the true response rate is 3% [p0] (assuming poor efficacy 
of e.g. pembrolizumab treatment in patients, who have failed prior PD-1/PD-L1 therapy) will be 
tested against a one-sided alternative. In the first stage, 10 [n1] patients will be accrued. If there 
are no responses [r1] in these 10 [n1] patients, the study will be stopped.  
    Otherwise, 5 additional patients will be accrued for a total of 15 [n] patients. The null 
hypothesis will be rejected if 2 or more responses are observed in 15 patients. This design yields 
a type I error rate of 0.0667 and 80% power when the true response rate is 20%. 
A response rate of 20% would be considered clinically meaningful for HNC in the 
absence of alternative treatment options in the 2nd/3rd line setting (after PD-1/PD-L1 failure) and 
further development of pembrolizumab + epacadostat would proceed.  
 
Secondary Outcome: Overall and Progression free survival / Safety 
     
Survival: Assuming full enrollment of 30 patients, both cohorts will be combined for 
assessment of secondary outcome of one-year overall survival. Kaplan-Meier (1958) curves will 
be generated for overall (OS) and progression free survival (PFS); the latter endpoint will be 
defined as the time from enrollment until disease progression or death from any cause.  Median 
OS and PFS will be estimated along with 90% confidence intervals using the method of 
Brookmeyer and Crowley (1982). Duration of response will be determined as the time from 
response until disease progression or death among the subset of patients who respond, and 
estimated by Kaplan-Meier.  The disease control rate (CR+PR+SD) and 90% confidence interval 
will also be determined.  
 
Toxicity: Toxicities will be summarized in tabular form by type and severity and 
incidence rates generated.  
 


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8.2 
Sample Size 
Sample size for each cohort is up to 15 patients (total of up to 30 patients). 
 
 
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 and are summarized in Table 9. 
Table 9  Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
Epacadostat tablets 
25mg, 100mg 
 
 
 
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. 


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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 Incyte 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 Food and Drug Administration (FDA) Approval 
This study will be conducted under an IND held by Dr. Alexander Pearson at the University of 
Chicago.  The University of Chicago CCTO will be responsible for facilitating all 
communications with the FDA on behalf of the IND holder.   Participating sites should not 
communicate directly with the FDA. 
10.2 New Protocol Distribution and IRB Submission 
 
Once final Merck, Incyte, and University of Chicago  (U  of C)  IRB  approval  is  received,  
the protocol and consent form will be distributed via the Cancer Center website. This study is 
intended as a single center study to be run at the University of Chicago. 
 
Before the study can be initiated the following documentation must be provided to the Cancer 
Clinical Trials Office (CCTO) at the University of Chicago Comprehensive Cancer Center. 
 A copy of the official local IRB approval letter for the protocol and informed consent 
 IRB membership list 
 CVs and medical licensure for the principal investigator and any sub-investigators who 
will be involved in the study. 
 Form FDA 1572 appropriately filled out and signed with appropriate documentation  
 CAP and CLIA Laboratory certification numbers and institution lab normal values 
 Investigational drug accountability standard operating procedures 
 Additionally, before the study can be initiated at any site, the required executed research 
contract/subcontract must be on file with the University of Chicago. 


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10.3 Amendment Distribution and IRB Submission 
 
All modifications to the protocol, consent form, and/or questionnaires will be submitted to the 
University of Chicago IRB for review and approval. A list of the proposed modifications or 
amendments to the protocol and/or an explanation of the need of these modifications will be 
submitted, along with a revised protocol incorporating the modifications. Only the Study Lead 
PI can authorize any modifications, amendments, or termination of the protocol. Once a 
protocol amendment has been approved by the University of Chicago IRB, the Regulatory 
Manager will send the amended protocol and consent form (if applicable) to the affiliate 
institutions electronically. Upon receipt of the packet the affiliate institution is expected to do 
the following: 
 The affiliate must reply to the email from the Regulatory Manager indicating that the 
amendment was received by the institution and that it will be submitted to the local IRB.  
 The amendment should be submitted to the affiliate institution’s IRB as soon as 
possible after receipt. The amendment must be IRB approved by the institution within 
3 months from the date that it was received.  
 The  University  of  Chicago  version  date  and/or  amendment  number  must  
appear  on  the  affiliate consent form and on the affiliate IRB approval letter.  The 
version dates can be found on the footer of every page of the protocol and consent form.  
The amendment number can be found on the University of Chicago IRB amendment 
approval letter that is sent with the protocol/amendment mailing.  
 The IRB approval for the amendment and the amended consent form (if amended 
consent is necessary) for the affiliate institution must be sent to the designated UC 
Regulatory Manager as soon as it is received. 
 
10.4 Annual IRB Renewals, Continuing Review and Final Reports 
 
A continuing review of the protocol will be completed by the University of Chicago IRB and 
the affiliates’ IRBs at least once a year for the duration of the study. The annual IRB renewals 
for the affiliate institution should be emailed promptly to the Regulatory Affairs 
Administrator. If the institution’s IRB requires a new version of the consent form with the 
annual renewal the consent form should be included with the renewal letter. 
 
 
10.5 Departure from the Protocol 
 
An investigator cannot modify the  protocol  without  satisfying  procedures  in  this protocol 
as outlined in the study calendar.    Any changes in research activity, except those necessary to 
remove an apparent, immediate hazard to the study subject, must be reviewed and approved 


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by the local IRB.  When a variation from the protocol is deemed necessary for an individual 
subject, the principal investigator or study chair must be contacted by phone or email 
(Alexander Pearson , 773-834-1604 / 312-823-7990, apearson@medicine.bsd.uchicago.edu  ).  
Such contact must be made as soon as possible to permit a decision as to whether or not the 
subject is to continue in the study. 
 
The principal investigator or study chair must be informed of all intentional or unintentional 
departures from the protocol and will decide whether or not the subject is to continue in the 
study 
(Alexander 
Pearson, 
773-834-1604 
/ 
312-823-7990, 
apearson@medicine.bsd.uchicago.edu).  All  departures  from  the  protocol, intentional and 
unintentional, along with the decision of the principal investigator will be submitted to the 
local and University of Chicago IRB per institutional guidelines. 
 
10.6 Registration 
 
Prior to registration and any study-specific evaluations being performed, all patients must have 
given written informed consent for the study and must have completed the pre-treatment 
evaluations.  Patients must meet all of the eligibility requirements listed above. Study co-
ordinators will register patients. This study is intended as a single center study performed at 
the University of Chicago. 
 
When registering a subject, the following must occur:  
 
 Confirm that a current IRB approval letter for the correct version of protocol/consent 
and has an annual update on file, if appropriate.  
 Submit all required materials (Eligibility Checklist, Source documentation, & signed 
consent form) to confirm eligibility and required pre-study procedures to the CRA a 
minimum of 48 hours prior to the subject’s scheduled therapy start date.  
 Source documentation includes copies of all original documents that support each 
inclusion/exclusion criteria.  The eligibility checklist does not serve as source 
documentation but rather as a checklist that original source documentation exists for 
each criterion. 
 Communicate with the CRA to ensure all necessary supporting source documents are 
received and the potential subject is eligible to start treatment on schedule. If there are 
questions about eligibility, the CRA will discuss it with the PI. PI may clarify, but not 
overturn, eligibility criteria.  
 Affiliate sites must confirm registration of subjects by obtaining a subject study ID 
number from the CRA via phone, fax or email.  
 If a subject does not start on the scheduled day 1 treatment date, promptly inform the 
CRA as the delay in start may deem the subject ineligible and/or require further or 
repeat testing to ensure eligibility.  
 


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10.7 Reporting of Adverse Events to the Coordinating Center 
 
Use the UC CCC protocol number and the protocol-specific patient ID assigned during 
trial registration on all reports. 
 
All serious adverse events (as defined above) and all adverse events that have been 
specified as Events of Special Interest occurring on this study require expedited reporting 
to the University of Chicago Comprehensive Cancer Center (UC CCC).  The responsible 
Research Nurse or other designated individual at the treating site should report the SAE to 
the Study Lead Investigator, the University of Chicago CRA and the CCTO by the end of 
the business day when s/he becomes aware of the event.  Events occurring after business 
hours should be reported to the CCTO by 12pm (noon) the next business day.  Reports 
should be made using the ‘Serious Event Report’ or MedWatch 3500A Form.  
 
 
UC CCC Cancer Clinical Trials Office Quality Assurance: 
qaccto@bsd.uchicago.edu 
 
Any serious adverse event, or follow up to a serious adverse event, whether or not related 
to Merck/Incyte products, must be reported within 2 working days of coordinating site 
awareness to Merck Global Safety.  The coordinating site, the University of Chicago, will 
take responsibility for reporting the SAE to Merck/Incyte.  Non-serious Events of Clinical 
Interest will be forwarded to Incyte/Merck Global Safety and will be handled in the same 
manner as SAEs.  
 
1) SAE reports and any other relevant safety information are to be forwarded to the 
Merck Global Safety facsimile number:  +1-215-993-1220. 
 
2) All Serious Adverse Events (“SAE”), including pregnancy and lactation exposure, 
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 any additional reports agreed upon by 
Institution or Principal Investigator and Incyte.  SAE Reports will be sent to 
IncytePhVOpsIST@incyte.com.  By sending to this e-mail address, the Incyte 
Pharmacovigilance group will receive copies of the reports.   This process will be 
tested and established before the first patient is enrolled in the Study. 
Notwithstanding anything to the contrary herein, Institution will have the 
primary responsibility of reporting adverse events (“AE”) to regulatory 
authorities. 
   
An unexpected adverse event is are those not listed at the observed specificity or severity 
in the protocol, informed consent or IB.  An unexpected adverse event is considered to be 
an unexpected adverse reaction if there evidence to suggest a causal relationship to the 
study agent.  This may include a single occurrence of an event strongly associated with 


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drug exposure (e.g. Stevens-Johnson Syndrome), one or more occurrence of an event 
otherwise uncommon is the study population, or an aggregate analysis of specific events 
occurring at greater than expected frequency. 
 
All unexpected adverse reactions must be reported to the IND holder so that the 
University of Chicago CCTO can inform the FDA.  The responsible Research Nurse or 
other designated individual at the treating site should provide a complete written report 
using the FDA MedWatch 3500A form.  The completed form should be sent to the CCTO 
at qaccto@bsd.uchicago.edu and to the Phase II CRA at 
PhaseIICRA@medicine.bsd.uchicago.edu within the specified timelines below regardless 
of whether all information regarding the event is available.  If applicable, a follow-up 
report should be provided to the CCTO if additional information on the event becomes 
available.   
 
Participating sites should not forward any adverse event reports directly to the FDA.  The 
CCTO will report all events to the FDA as per the current FDA guidelines.   
 
Fatal or Life-threatening Events: within 4 calendar days from treating investigator 
knowledge of the event 
 
All Other Reportable Events: within 10 calendar days of treating investigator knowledge 
of the event 
 
All serious adverse events should also be reported to the local IRB of record according to 
their policies and procedures. 
 
10.8 Reporting of Adverse Events by the Coordinating Center 
The designated UC CCC Regulatory Manager will notify all participating sites of all 
unexpected and serious adverse reactions that occur on this clinical trial and which are 
reported to the FDA and/or UC Institutional Review Board (IRB).  When reported to the 
FDA, a copy of the completed Form 3500A (MedWatch) will be provided to the responsible 
Regulatory Manager by the CCTO IND Coordinator for distribution to all participating sites. 
10.9 Data Management 
Data reporting will be performed utilizing the eVelos electronic data capture system.  The 
University of Chicago CRA will provide you with the applicable user registration 
information.  
All required data must be recorded in the eVelos database at the completion of each cycle.  
AEs are to be entered in real time. SAEs are to be entered on the Serious Event Form within 
24 hours of the site’s knowledge of the event and sent via email (preferred) 
(accto@bsd.uchicago.edu; Fax: 773-702-4889). All case report forms must be completed by 
designated study personnel. Each screened (consented) patient is to be entered into eVelos 
within 48 hours of patient registration. In addition to direct data entry, you may be required 


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to provide supporting source documentation. Source records are original documents, data, 
and records (e.g., medical records, raw data collection forms, pharmacy dispensing records, 
recorded data from automated instruments, laboratory data) that are relevant to the clinical 
trial. Each site will prepare and maintain adequate and accurate source documents. These 
documents are designed to record all observations and other pertinent data for each subject 
enrolled in this clinical trial. Source records must be adequate to reconstruct all data 
transcribed onto the case report form. 
10.10  Data and Safety Monitoring 
This study will be remotely monitored by the designated University of Chicago Clinical 
Research Associate (CRA) in accordance with the University of Chicago, Section of 
Hematology/Oncology standard operating procedure titled Monitoring of Multi-Institutional 
Investigator Initiated Clinical Trials. 
Prior to subject recruitment, and unless otherwise specified, a participating site will undergo 
a Site Initiation Teleconference to be conducted by the designated University of Chicago 
research team. The site’s principal investigator and his or her study staff must attend the site 
initiation meeting.  
Monitoring will be conducted to verify the following: 
• 
Adherence to the protocol 
• 
Completeness and accuracy of study data and samples collected 
• 
Compliance with regulations  
• 
Submission of required source documents  
Participating sites will also undergo a site close-out teleconference upon completion, 
termination or cancellation of a study to ensure fulfillment of study obligations during the 
conduct of the study, and to ensure that the site Investigator is aware of his/her ongoing 
responsibilities. 
Unless otherwise specified, this protocol will undergo weekly review at the multi-
institutional data and safety monitoring teleconference as per procedures specified by the UC 
CCC NCI-approved Data and Safety Monitoring Plan. The conference will review: 
• 
Enrollment rate relative to expectations, characteristics of participants 
• 
Safety of study participants (Serious Adverse Event & Adverse Event reporting) 
• 
Adherence to protocol (protocol deviations) 
• 
Completeness, validity and integrity of study data 


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• 
Retention of study participants 
Protocol deviations are to be documented using the Protocol Deviation. Deviations that are 
considered major because they impact subject safety or alter the risk/benefit ratio, 
compromise the integrity of the study data, and/or affect subjects’ willingness to participate 
in the study must be reported within 7 days. Please contact the PI if you have questions about 
how to report deviations.  All major protocol deviations should also be reported to the local 
IRB of record according to their policies and procedures 
10.11 Auditing 
A regulatory authority (e.g. FDA) may wish to conduct an inspection of the study, during its 
conduct or even after its completion. If an inspection has been requested by a regulatory 
authority, the site investigator must immediately inform the University of Chicago Cancer 
Clinical Trials Office and Regulatory Manager that such a request has been made. 
10.12 Record Retention 
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents 
(e.g., protocol and amendments, IRB correspondence and approval, signed patient consent 
forms). 
Source documents include all recordings of observations or notations of clinical activities and 
all reports and records necessary for the evaluation and reconstruction of the clinical research 
study. 
Government agency regulations and directives require that all study documentation 
pertaining to the conduct of a clinical trial must be retained by the study investigator.  In the 
case of a study with a drug seeking regulatory approval and marketing, these documents shall 
be retained for at least two years after the last approval of marketing application in an 
International Conference on Harmonization (ICH) region.  In all other cases, study 
documents should be kept on file until three years after the completion and final study report 
of this investigational study. 
10.13 Obligations of Study Site Investigators 
The Study Site Principal Investigator is responsible for the conduct of the clinical trial at the 
site in accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki.  The Study Site Principal Investigator is responsible for personally overseeing the 
treatment of all study patients.  He/she must assure that all study site personnel, including 
sub-investigators and other study staff members, adhere to the study protocol and all 
FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and after 
study completion. 
The Study Site Principal Investigator at each institution or site will be responsible for 
assuring that all the required data will be collected and entered into the CRFs. Periodically, 


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monitoring visits or audits will be conducted and he/she must provide access to original 
records to permit verification of proper entry of data. 
 


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11.0 APPENDICES 
11.1 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). 
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. 
 
11.2 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) 
11.3 RECIST 1.1 reference 
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 
 
 


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. 
11.4 References 
Boon T, van der Bruggen P. Human tumor antigens recognized by T lymphocytes. J 
Exp Med 1996;183:725-729. 
 
Brandacher G, Perathoner A, Ladurner R, et al. Prognostic value of indoleamine 2,3- 
dioxygenase expression in colorectal cancer: effect of tumor infiltrating T cells. Clin 
Cancer Res 2006;12:1144-1151. 
Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human papillomavirus and rising 
oropharyngeal cancer incidence in the United States. Journal of Clinical Oncology. 
2011 Nov 10;29(32):4294-301. 
 
Curran  MA,  Montalvo  W,  Yagita  H,  Allison  JP.  PD-1  and  CTLA-4  combination 
blockade expands infiltrating T cells and reduces regulatory T and myeloid cells 
within B16 melanoma tumors. Proc Natl Acad Sci U S A 2010;107:4275-4280. 
 
Disis ML. Immune regulation of cancer. J Clin Oncol 2010;28:4531-4538. 
 
 
Ercolini AM, Ladle BH, Manning EA, et al. Recruitment of latent pools of high avidity 
CD8(+) T cells to the antitumor immune response. J Exp Med 2005;201:1591-1602. 
 
 
Frumento  G,  Rotondo  R,  Tonetti  M,  et al.     Tryptophan-derived  catabolites  are 
responsible for inhibition of T and natural killer cell proliferation induced by 
indoleamine 2,3-dioxygenase. J Exp Med 2002;196:459-468. 
 
Fallarino F, Grohmann U, You S, et al. The combined effects of tryptophan starvation 
and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a 
regulatory phenotype in naive T cells. J Immunol 2006;176:6752-6761. 
 
Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells 
within human colorectal tumors predict clinical outcome. Science 2006;313:1960-
1964. 
 
Godin-Ethier   J,   Hanafi   LA,   Piccirillo   CA,   et al.   Indoleamine   2,3-dioxygenase 
expression in human cancers: clinical and immunologic perspectives. Clin Can 
Res 2011;17:6985-6991. 
 
Hamid O, Rober C, Daud A, et al. Safety and tumor responses with lambrolizumab 
(Anti-PD-1) in melanoma. N Engl J Med 2013;369:134-144. 
 
Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular 
biology. Int J Clin Oncol 2010;15:544-551. 


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Hillen F, Baeten CIM, van de Winkel A, et al. Leukocyte infiltration and tumor cell 
plasticity are parameters of aggressiveness in primary cutaneous melanoma. Cancer 
Immunol Immunother 2008;57:97-106. 
 
Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J 
Cutan Pathol 2010;37(suppl 1):48-53. 
 
Holmgaard RB, Zamarin D, Munn DH, Wolchok JD, Allison JP. Indoleamine 2,3- 
dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy 
targeting CTLA-4. J Exp Med 2013;210:1389-1402. 
 
Huang  L,  Baban  b,  Johnson  BA,  Mellor  AL.  Dendritic  cells,  indoleamine  2,3 
dioxygenase and acquired immune privilege. Int Rev Immunol 2010;29:133-155. 
 
Ino  K,  Yoshida  N,  Kajiyama  H,  et  al.  Indoleamine  2,3-dioxygenase  is  a  novel 
prognostic indicator for endometrial cancer. Br J Cancer 2006;95:1555-1561. 
 
Keck MK, Zuo Z, Khattri A, Stricker TP, Brown C, Imanguli M, Rieke D, Endhardt K, 
Fang P, Bragelmann J, DeBoer R, El Dinali M, Aktolga S, Lei Z, Tan P, Rozen 
SG, Salgia R, Weichselbaum RR, Lingen MW, Story MD, Ang KK, Cohen EE, 
White KP, Vokes EE, Seiwert TY. Integrative analysis of Head and Neck Cancer 
identifies two biologically distinct HPV and three non-HPV subtypes. Clinical 
Cancer Research 2015 Feb 15:21(4):870-81. 
 
Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. Lancet Oncol 
2009;10:840-841. 
Lee HE, Chae SW,  Lee YJ, et al. Prognostic  implications of type and density of 
tumour-infiltrating lymphocytes in gastric cancer. Br J Cancer 2008;99:1704-1711. 
 
Leffers  N,  Gooden  MJM,  de  Jong  RA,  et  al.  Prognostic  significance  of  tumor- 
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