Clinical trial NCT03361228
Conditions: Solid Tumors
Keywords: Non-small cell lung cancer (NSCLC) melanoma urothelial carcinoma squamous cell carcinoma of the head and neck (SCCHN) small cell lung cancer (SCLC) colorectal cancer (CRC) arginase 1 inhibitor indoleamine 2,3-dioxygenase 1 inhibitor programmed death-1 receptor (PD-1) inhibitor
Sponsor: Incyte Corporation
Start date: 2018-03-01; Completion date: 2019-03-30
Enrollment: 5 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the safety and antitumor activity of INCB001158 plus epacadostat, with or without pembrolizumab, in participants with advanced or metastatic solid tumors.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: INCB001158 intervention 2: Epacadostat intervention 3: Pembrolizumab
Intervention descriptions: intervention 1: Phase 1: INCB001158 administered orally twice daily at the protocol-defined dose. Phase 2: INCB001158 administered orally twice daily at the recommended dose from Phase 1. intervention 2: Epacadostat at the protocol-defined dose administered orally twice daily. intervention 3: Pembrolizumab at the protocol-defined dose administered intravenously every 3 weeks.

Protocol documents:
Prot_SAP_000.pdf: 
Incyte Corporation 
Page 1 of 146 
Protocol INCB 01158-202 Am 2 
Version 2 
01 JUN 2018 
 
Clinical Study Protocol 
 
INCB 01158-202 
An Open-Label, Multicenter, Nonrandomized, Dose-Escalation, and 
Tumor-Expansion Phase 1/2 Study to Evaluate the Safety, 
Tolerability, and Antitumor Activity of INCB001158 Plus 
Epacadostat (INCB024360), With or Without Pembrolizumab, in 
Subjects With Advanced Solid Tumors 
 
 
 
Product: 
INCB001158 
IND Number: 
136,524 
EudraCT Number: 
2017-002716-13 
Phase of Study: 
1/2 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
Original Protocol (Version 0): 
02 OCT 2017 
Date of Amendment (Version) 1: 
27 OCT 2017 
Date of Amendment (Version) 2: 
01 JUN 2018 
 
 
This study will be performed in accordance with ethical principles that have their origin in the Declaration of 
Helsinki and conducted in adherence to the study Protocol, Good Clinical Practices as defined in Title 21 of the 
US Code of Federal Regulations Parts 11, 50, 54, 56, and 312, as well as ICH GCP consolidated guidelines (E6) and 
applicable regulatory requirements. 
 
The information in this document is confidential.  No part of this information may be duplicated, referenced, or 
transmitted in any form or by any means (electronic, mechanical, photocopy, recording, or otherwise) without the prior 
written consent of Incyte Corporation. 
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Protocol INCB 01158-202 Am 2 
Version 2 
01 JUN 2018 
INVESTIGATOR'S AGREEMENT 
I have read the INCB 01158-202 Protocol Amendment 2 (Version 2 dated 01 JUN 2018) and 
agree to conduct the study as outlined.  I agree to maintain the confidentiality of all information 
received or developed in connection with this Protocol. 
 
 
 
 
 
(Printed Name of Investigator) 
 
 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 
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Protocol INCB 01158-202 Am 2 
Version 2 
01 JUN 2018 
SYNOPSIS 
Name of Investigational Product:  INCB001158 (formerly known as CB-1158) 
Title of Study:  An Open-Label, Multicenter, Nonrandomized, Dose-Escalation and Tumor-Expansion 
Phase 1/2 Study to Evaluate the Safety, Tolerability, and Anti-Tumor Activity of INCB001158 plus 
Epacadostat (INCB024360), with or without Pembrolizumab, in Subjects With Advanced or Metastatic 
Solid Tumors 
Protocol Number:  INCB 01158-202 
Study Phase:  1/2 
Indication:  Any advanced or metastatic solid tumors in Phase 1 Dose Escalation and selected, 
advanced or metastatic solid tumors in Phase 2 Parts A and B Tumor Expansion cohorts. 
As of this Protocol Amendment (Version) 2, enrollment of subjects into any part of Study 
INCB 01158-202 is halted.  This is based on the results from the ECHO-301/KEYNOTE-252 
melanoma clinical study.  In an interim analysis, the study did not meet the prespecified 
endpoint of improvement in progression-free survival (PFS) for the combination of 
pembrolizumab and epacadostat compared with pembrolizumab and placebo.  The overall 
survival endpoint was also not expected to reach statistical significance.  There were no safety 
concerns with the treatment (pembrolizumab + epacadostat) arm compared with the control 
(pembrolizumab + placebo) arm. 
Given the outcome of study ECHO-301/KEYNOTE-252, the changes to the INCB 01158-202 
study design are summarized below: 
• The ongoing Phase 1 portion (dose escalation and safety evaluation of INCB001158 in
combination with epacadostat and pembrolizumab) will stop further enrollment, except for 
subjects who have consented and are in screening as of 08 MAY 2018.  These subjects will be 
permitted to enroll if eligibility is determined as outlined per the Protocol. 
• The Phase 1 backfill cohorts and the Phase 2 portion of the study (Part A – tumor expansion
of INCB001158 + epacadostat + pembrolizumab and Part B – tumor expansion of 
INCB001158 + epacadostat) will not be opened. 
• Phase 1 subjects may continue treatment with INCB001158 + epacadostat + pembrolizumab
as long as, per the Protocol, they are deriving clinical benefit, tolerating the treatment, and do 
not meet any withdrawal criteria. 
Sections of the Protocol relating to the parts of the study that will no longer be conducted are 
now not applicable and should be ignored. 
Objectives and Endpoints:  
Primary Objectives 
Primary Endpoints 
Phase 1 only:  To assess the safety and 
tolerability, and to determine the recommended 
Phase 2 dose (RP2D) of INCB001158 in 
combination with epacadostat ± pembrolizumab. 
Safety, tolerability, dose-limiting toxicities (DLTs), and 
RP2D of INCB001158 in combination with epacadostat 
± pembrolizumab, as assessed by adverse events (AEs), 
clinical laboratory assessments, physical examination 
results, and 12-lead electrocardiogram (ECG) results. 
Phase 2 only:  To evaluate the objective response 
rate (ORR) of INCB001158 in combination with 
epacadostat ± pembrolizumab. 
ORR, defined as the percentage of subjects having a 
complete response (CR) or partial response (PR), as 
determined by investigator assessment of radiographic 
disease as per RECIST v1.1. 
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Protocol INCB 01158-202 Am 2 
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Secondary Objectives 
Secondary Endpoints 
Phase 2 only:  To assess the safety, tolerability, 
and RP2D of INCB001158 in combination with 
epacadostat ± pembrolizumab. 
Safety, tolerability, and RP2D of INCB001158 in 
combination with epacadostat ± pembrolizumab, as 
assessed by AEs, clinical laboratory assessments, 
physical examination results, and 12-lead ECG results. 
To evaluate the antitumor effect of INCB001158 
in combination with epacadostat ± pembrolizumab 
by RECIST v1.1. 
• ORR, defined as the percentage of subjects having a 
CR or PR, as determined by investigator assessment of 
radiographic disease as per RECIST v1.1 (Phase 1 
only). 
• Disease control rate (DCR), defined as the percentage 
of subjects having CR, PR, or stable disease (SD) for 
at least 56 days, as determined by investigator 
assessment of radiographic disease as per RECIST 
v1.1. 
• Duration of response (DoR), determined by 
radiographic disease assessment, defined as the time 
from earliest date of disease response until the earliest 
date of disease progression per RECIST v1.1, or death 
due to any cause, if occurring sooner than progression. 
• PFS, defined as the time from date of first dose of 
study treatment until the earliest date of disease 
progression, as determined by investigator assessment 
of objective radiographic disease assessments per 
RECIST v1.1, or death due to any cause, if occurring 
sooner than progression. 
To determine the pharmacokinetics (PK) of each 
of INCB001158 and epacadostat in subjects 
treated with INCB001158 in combination with 
epacadostat ± pembrolizumab. 
The PK of INCB001158 and epacadostat will be 
assessed by summarizing Cmin, Cmax, tmax, AUC0-t, and 
AUC0-τ. 
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Protocol INCB 01158-202 Am 2 
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Overall Study Design:  This is a Phase 1/2 study, with Phase 1 being a dose-escalation of the triplet 
combination of INCB001158 plus epacadostat and pembrolizumab, and with Phase 2 consisting of 
tumor expansion cohorts to study the RP2D of the triplet combination of INCB001158 plus 
epacadostat and pembrolizumab in Part A and the RP2D of the doublet combination of INCB001158 
plus epacadostat in Part B.  The figure below shows a schematic of the study design. 
Subjects with advanced or metastatic solid tumors will be enrolled in Phase 1.  Subjects with select 
advanced or metastatic solid tumors will be enrolled in Phase 2 Parts A (non–small cell lung cancer 
[NSCLC], melanoma, urothelial carcinoma, squamous cell carcinoma of the head and neck [SCCHN], 
and small cell lung cancer [SCLC]) and B (urothelial carcinoma, SCCHN, and colorectal cancer 
[CRC]). 
Phase 1:  Dose Escalation:   
In this study, the RP2D of both the triplet (INCB001158 + epacadostat + pembrolizumab) and doublet 
(INCB001158 + epacadostat) will be determined from the dose escalation of the triplet combination in 
Phase 1.  The INCB001158 dose will be escalated while keeping the epacadostat (100 mg twice 
daily [BID]) and pembrolizumab (200 mg once every 3 weeks [Q3W]) doses fixed at the levels used to 
study this doublet in Phase 3.  INCB001158 is not expected to have overlapping toxicity with either of 
these molecules, based on their respective mechanisms and on the available safety data from the 
first-in-human study, INCB 01158-101 and the epacadostat + pembrolizumab INCB 24360-202 
Phase 2 study.  In the ongoing INCB 01158-101 study, INCB001158 doses have been identified that 
are pharmacologically active and well-tolerated.  Thus, it is hypothesized that when INCB001158 is 
escalated with the Phase 3 doses of epacadostat plus pembrolizumab, an RP2D will be identified based 
on an INCB001158 pharmacologically active dose (PAD) and before a maximum tolerated dose 
(MTD) is reached.  In that case, the INCB001158 and epacadostat doses in the triplet RP2D would be 
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Protocol INCB 01158-202 Am 2 
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appropriate to also use as the RP2D for the INCB001158 + epacadostat doublet in Phase 2 Part B.  
Hence, no separate dose escalation of INCB001158 with epacadostat 100 mg BID will be conducted in 
this study. 
An open-label, Bayesian Optimal Interval (BOIN) design will be used to determine the RP2D of the 
triplet combination of INCB001158, epacadostat, and pembrolizumab in 21-day treatment cycles in 
subjects with advanced or metastatic solid tumors.  Given the target DLT rate of 33% for the 
INCB001158 plus epacadostat and pembrolizumab combination, the dose escalation and de-escalation 
rules are shown in the table below.  The BOIN design also includes an elimination rule.  When 
≥ 3 subjects have been treated, if the probability that the estimated toxicity rate that is above the target 
DLT rate is > 95% at a certain dose level, then this dose level and higher dose levels are assumed too 
toxic and will be eliminated.  If the lowest dose level is eliminated, the whole dose escalation will be 
terminated.  The table below (in the bottom row) provides the elimination rules.  Based on this 
algorithm, a minimum of 3 evaluable subjects and a maximum of 9 evaluable subjects will be enrolled 
at each tested dose level.  The dose escalation will continue, based on the rules in the table, until the 
rules require at least 1 of the following: 
• Enrollment of additional subjects in a cohort that already has 9 evaluable subjects, or 
• Dose escalation to a dose level that has already been eliminated, or 
• Dose escalation above the maximum allowable dose level identified in the INCB 01158-101 study.   
At that point, the dose escalation will be stopped. 
Dose Escalation, De-Escalation, and Elimination Boundaries for Target DLT Rate = 33% in 
Phase 1 
Action 
 
The Number of Subjects Treated at the Current Dose 
1 
2 
3 
4 
5 
6 
7 
8 
9a 
Escalate if # of 
DLTs ≤ 
NA 
NA 
0 
1 
1 
1 
1 
2 
2 
De-escalate if # 
of DLTs ≥ 
1 
1 
2 
2 
2 
3 
3 
4 
4 
Elimination if # 
of DLTs ≥ 
NA 
NA 
3 
3 
4 
4 
5 
5 
6 
DLT = dose-limiting toxicity; NA = not applicable. 
a If 9 evaluable subjects are enrolled in a cohort and 3 of those subjects experience a DLT, the medical monitor and the 
investigators will review the entirety of the data and decide whether to dose-escalate, dose de-escalate, or to stop at that 
dose level. 
Dose escalation will begin with starting doses of INCB001158 at least 2 dose levels below the 
maximum tolerated and tested dose from the INCB 01158-101 study (likely to be 50 mg BID or 75 mg 
BID – see tables below) and epacadostat 100 mg orally (PO) BID continuous dose administration, and 
pembrolizumab 200 mg IV Q3W.  Epacadostat 100 mg BID was selected as the starting dose because 
it has been shown to be active and tolerable in several epacadostat combination clinical studies, 
including with pembrolizumab.  The starting dose of pembrolizumab is the standard, approved dose 
and schedule and also the dose used in combination with epacadostat in Phase 3.   
If the starting doses of the triplet combination of INCB001158, epacadostat, and pembrolizumab are 
tolerable (eg, none of the first 3 evaluable subjects experiences a DLT), the INCB001158 dose will be 
escalated in subsequent cohorts, while keeping the epacadostat and pembrolizumab doses constant, 
until one of the stopping rules, described above, is met. 
If the starting doses of INCB001158, epacadostat 100 mg BID, and pembrolizumab 200 mg Q3W are 
not tolerable, then an additional cohort will be enrolled at a reduced dose of either INCB001158 or 
epacadostat, depending on which one is deemed most likely to have caused the intolerability, upon 
agreement between the medical monitor and the study investigators (ie, Dose Level -1A or -1B). 
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01 JUN 2018 
• For Phase 2 Part A Cohort A1 – Anti-PD-1/PD-L1–naive NSCLC:   
- Subjects with histologically or cytologically confirmed NSCLC, who have received no more than 
2 prior systemic chemotherapy regimens for Stage IV disease (not including neoadjuvant and/or 
adjuvant therapy except as described below). 
- For subjects who have received 1 or 2 lines of prior systemic chemotherapy for Stage IV disease, 
1 of the prior systemic regimens must include a platinum-based therapy.  Subjects who have only 
received non–platinum-based regimens may be enrolled with medical monitor approval. 
- Tumors with driver mutations (epidermal growth factor receptor [EGFR] mutation–positive, 
anaplastic lymphoma kinase fusion oncogene–positive, proto-oncogene tyrosine-protein kinase 
ROS1–positive, or BRAF V600 mutant–positive) treated with a tyrosine kinase inhibitor are 
permitted and will not be considered a systemic chemotherapy regimen.  However, subjects should 
have progressed on or be intolerant to the targeted therapy. 
- Maintenance or switch maintenance therapy after first- or second-line chemotherapy will be 
considered part of the prior systemic chemotherapy regimen and is acceptable. 
- Subjects who completed and progressed on a platinum-containing regimen as adjuvant, 
neoadjuvant, or part of a course of chemoradiation therapy within the 6 months before screening 
would be counted as 1 prior platinum-containing regimen and therefore would not require 
re-treatment with a platinum-containing regimen for Stage IV disease. 
• For Phase 2 Part A Cohort A2 – Primary anti-PD-1/PD-L1–refractory NSCLC (primary refractory 
cohort):   
- Subjects with histologically or cytologically confirmed locally advanced unresectable or metastatic 
NSCLC. 
- Subjects with tumors with driver mutations (EGFR mutation–positive, anaplastic lymphoma kinase 
fusion oncogene–positive, proto-oncogene tyrosine-protein kinase ROS–positive, or BRAF V600 
mutant–positive) should have progressed on or be intolerant to the targeted therapy. 
- Subjects must have received prior treatment with anti–PD-1 or anti–PD-L1 therapy (alone or as 
part of a combination) in the advanced or metastatic setting and have PD as their best response to 
treatment that is confirmed at least 4 weeks later (no less than 28 days). 
o Subjects must have received at least 2 doses of a prior anti–PD-1 or anti–PD-L1 agent. 
- Progressive disease must also be at least 12 weeks from first dose of anti–PD-1 or anti–PD-L1 
therapy and confirmed 4 weeks (no less than 28 days) later. 
• For Phase 2 Part A Cohort A3 – Anti-PD-1/PD-L1–relapsed NSCLC (relapsed cohort): 
- Subjects must have received prior anti–PD-1 or anti–PD-L1 therapy (alone or as part of a 
combination) in the advanced or metastatic setting and achieved either SD for at least 24 weeks or 
PR/CR, but later have confirmed PD (PD confirmed at least 4 weeks [no less than 28 days] later). 
• For Phase 2 Part A Cohort B1 – Anti-PD-1/PD-L1–naive melanoma:   
- Subjects with histologically or cytologically confirmed unresectable Stage III or Stage IV 
melanoma, as per American Joint Committee on Cancer (AJCC) staging system, not amenable to 
local therapy. 
- Have documentation of V600-activating BRAF mutation status or consent to BRAF V600 
mutation testing during the screening period. 
- Subjects must not have received more than 2 prior lines of systemic therapy for unresectable 
Stage III or Stage IV melanoma. 
- Ocular melanoma is excluded. 
• For Phase 2 Part A Cohort B2 – Primary anti-PD-1/PD-L1–refractory melanoma (primary refractory 
cohort): 
- Subjects with histologically or cytologically confirmed unresectable Stage III or Stage IV 
melanoma, as per AJCC staging system, not amenable to local therapy. 
- Have documentation of V600-activating BRAF mutation status or consent to BRAF V600 
mutation testing during the screening period. 
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- Subjects must have received prior treatment with anti–PD-1 or anti–PD-L1 therapy (alone or as 
part of a combination) in the advanced or metastatic setting and have PD as their best response to 
treatment that is confirmed at least 4 weeks later (no less than 28 days). 
o Subjects must have received at least 2 doses of a prior anti–PD-1 or anti–PD-L1 agent. 
o Progressive disease must also be at least 12 weeks from first dose of anti–PD-1 or anti–PD-L1 
therapy and confirmed 4 weeks (no less than 28 days) later. 
- Ocular melanoma is excluded. 
• For Phase 2 Part A Cohort B3 – Anti-PD-1/PD-L1–relapsed melanoma (relapsed cohort): 
- Subjects must have received prior anti–PD-1 or anti–PD-L1 therapy (alone or as part of a 
combination) in the advanced or metastatic setting and achieved either SD for at least 24 weeks or 
PR/CR, but later have confirmed PD (PD confirmed at least 4 weeks [no less than 28 days] later). 
• For Phase 2 Part A Cohort C – Anti-PD-1/PD-L1–naive urothelial carcinoma:   
- Subjects with histologically or cytologically confirmed, metastatic or inoperable locally advanced 
urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra that is transitional cell or mixed 
transitional/nontransitional (predominantly transitional) cell type. 
- Subjects must not have received more than 2 prior lines of systemic therapy for metastatic or 
inoperable locally advanced urothelial carcinoma. 
- For subjects who have received 1 or 2 lines of prior systemic therapy for metastatic or inoperable 
locally advanced urothelial carcinoma, 1 of the prior systemic regimens must include a 
platinum-based therapy.  Subjects who have only received non–platinum-based regimens may be 
enrolled with medical monitor approval.  
• For Phase 2 Part A Cohort D – Anti-PD-1/PD-L1–naive SCCHN:   
- Subjects with histologically or cytologically confirmed SCCHN not amenable to local therapy with 
curative intent (surgery or radiation with or without chemotherapy). 
- Carcinoma of the nasopharynx, salivary gland, or nonsquamous histologies are excluded. 
- Subjects must have received at least 1 prior platinum-based systemic chemotherapy regimen, and 
no more than 2 prior systemic chemotherapy regimens, including neoadjuvant and/or adjuvant 
therapy.  Subjects who relapsed within 6 months of adjuvant therapy, including a platinum-
containing regimen, may enroll. 
• For Phase 2 Part A Cohort E – Anti-PD-1/PD-L1–naive SCLC: 
- Subjects with histologically or cytologically confirmed, advanced or metastatic SCLC with PD 
after at least 1 line of therapy that includes a platinum-based regimen in the first-line setting, and 
after no more than 2 prior lines of chemotherapy, and regardless of tumor PD-L1 status. 
• For Phase 2 Part B Cohort A – Urothelial carcinoma:   
- Subjects with histologically or cytologically confirmed urothelial carcinoma of the renal pelvis, 
ureter, bladder, or urethra that is transitional cell or mixed transitional/nontransitional 
(predominantly transitional) cell type. 
- Metastatic or inoperable locally advanced urothelial carcinoma that has progressed on prior 
standard therapy with a platinum-based regimen and a checkpoint inhibitor. 
• For Phase 2 Part B Cohort B – SCCHN: 
- Subjects with histologically confirmed metastatic or recurrent SCCHN not amenable to local 
therapy with curative intent (surgery or radiation with or without chemotherapy). 
- Must have had disease progression on prior treatment with a platinum-based therapy and an 
anti−PD-1 therapy.  Subjects who relapsed within 6 months of adjuvant therapy, including a 
platinum-containing regimen, may enroll. 
- Must have documented human papilloma virus status. 
- Carcinoma of the nasopharynx, salivary gland, or nonsquamous histologies are excluded. 
 
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Key Exclusion Criteria:  A subject who meets any of the following criteria will be excluded from the 
study: 
• Participation in any other study in which receipt of an investigational study drug or device occurred 
within 2 weeks or 5 half-lives (whichever is longer) before first dose.  For investigational agents with 
long half-lives (eg, 5 days), enrollment before the fifth half-life requires medical monitor approval. 
• Has received a prior monoclonal antibody within 4 weeks or 5 half-lives (whichever is shorter) 
before administration of study drug.   
- EXCEPTION:  No time off anti–PD-1 or anti–PD-L1 therapy is required. 
- EXCEPTION:  Denosumab may be used. 
• Phase 2 Part A Cohorts A1, B1, C, D, and E only:  Has had prior therapy with an anti–PD-1, 
anti–PD-L1, anti–PD-L2, anti–CTLA-4, anti-CD137, or any other antibody or drug specifically 
targeting checkpoint pathways. 
- EXCEPTION:  Prior therapy with an anti–cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) 
in the adjuvant setting is permitted. 
• Phase 2 Part A Cohorts A2, A3, B2, and B3 only:  Had any Grade 3/4 or any ocular toxicity while 
receiving prior anti–PD-1 therapy. 
• Has had prior chemotherapy or targeted small molecule therapy within 2 weeks before 
administration of study treatment. 
• Has had prior therapy with an IDO1 or arginase 1 inhibitor. 
• Has received prior radiotherapy within 2 weeks of enrollment (except for radiation to central nervous 
system [CNS], which requires ≥ 4-week washout).  Subjects must have recovered from all 
radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. 
• Has had major surgery within 4 weeks before enrollment (C1D1). 
• Has a known additional malignancy that is progressing or requires active treatment, or history of 
other malignancy within 2 years of study entry with the exception of cured basal cell or squamous 
cell carcinoma of the skin, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in 
situ of the cervix, or other noninvasive or indolent malignancy, or cancers from which the subject has 
been disease-free for > 1 year, after treatment with curative intent. 
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dose 
regimens exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive 
therapy within 7 days before the first dose of study treatment. 
• Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, 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. 
• Has a known history of human immunodeficiency virus (HIV) infection.  HIV testing is not required 
unless mandated by the local health authority. 
• Has known history of or is positive for hepatitis B (hepatitis B virus surface antigen [HBsAg] 
reactive) or hepatitis C (HCV RNA).  Note:  Testing must be performed to determine eligibility.  
- Hepatitis B virus DNA must be undetectable and HBsAg negative at screening visit. 
- Hepatitis C antibody testing is allowed for screening purposes in countries where HCV RNA is not 
part of standard of care.  In these cases, HCV antibody positive patients will be excluded. 
- Subjects who have had definitive treatment for HCV are permitted if HCV RNA is undetectable at 
screening visit. 
• Phase 1 and Phase 2 Part A only:  Has a history of (noninfectious) pneumonitis that required steroids 
or has current pneumonitis. 
• Has known active CNS metastases and/or carcinomatous meningitis.  Subjects with previously 
treated brain metastases may participate provided that they are stable (without evidence of 
progression by imaging for at least 4 weeks before the first dose of study treatment, and any 
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neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain 
metastases confirmed by repeat imaging (note that the repeat imaging should be performed during 
study screening), and have not required steroids for at least 14 days before study treatment. 
• Subjects with evidence of cerebral edema will be excluded from participation.  In addition, subjects 
will be excluded from participation in the study if it has been < 4 weeks since radiation therapy was 
delivered to the CNS. 
• Has had a significant cardiac event within 6 months before Cycle 1 Day 1, including myocardial 
infarction (including severe/unstable angina), coronary/peripheral artery bypass graft, symptomatic 
congestive heart failure, cerebrovascular accident or transient ischemic attack, or pulmonary 
embolism.  Medically controlled arrhythmia is permitted. 
• Has a history or presence of an abnormal ECG that, in the investigator's opinion, is clinically 
meaningful.  Screening QTc interval > 480 milliseconds is excluded (corrected by Fridericia or 
Bazett formula).  In the event that a single QTc is > 480 milliseconds, the screening ECG may be 
repeated in triplicate, and the subject may enroll if the average QTc is < 480 milliseconds. 
• Has received live vaccine within 30 days before the first dose of study treatment.  Examples of live 
vaccines include, but are not limited to, the following:  measles, mumps, rubella, chicken pox, 
yellow fever, rabies, Bacillus Calmette–Guérin, and typhoid vaccine.  Seasonal influenza vaccines 
for injection are generally killed virus vaccines and are allowed; however, intranasal influenza 
vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed. 
• Has any history of serotonin syndrome after receiving serotonergic drugs. 
• Concomitant therapy with valproic acid/valproate-containing therapies. 
• Concomitant therapy with allopurinol and other xanthine oxidase inhibitors. 
• Has received therapy with a monoamine oxidase inhibitor or UGT1A9 inhibitor within 21 days 
before starting treatment, or anticipates requiring one of these prohibited medications during the 
treatment phase.  
• Has a known or suspected defect in the function of the urea cycle, including a known deficiency of 
carbamoyl phosphate synthetase I, ornithine transcarbamylase, argininosuccinate synthetase, 
argininosuccinate lyase, N-acetyl glutamate synthetase, or arginase. 
• Has a history of gastrointestinal condition (eg, inflammatory bowel disease, Crohn's disease, 
ulcerative colitis) that may affect drug absorption. 
INCB001158, Epacadostat, and Pembrolizumab Dosage, and Mode of Administration:   
Drug 
Dose 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment Period 
INCB001158 
25-150 mg 
BID 
Oral 
Phase 1 and Phase 2 Part A:  Daily until 
meets discontinuation criteria or for 
35 cyclesa, whichever is sooner  
Phase 2 Part B:  Daily until meets 
discontinuation criteria 
Epacadostat 
50-100 mg 
BID 
Oral 
Phase 1 and Phase 2 Part A:  Daily until 
meets discontinuation criteria or for 
35 cyclesa, whichever is sooner  
Phase 2 Part B:  Daily until meets 
discontinuation criteria 
Pembrolizumab 
200 mg 
Every 
3 weeks 
IV infusion 
Phase 1 and Phase 2 Part A:  Day 1 of 
each cycle until meets discontinuation 
criteria or for up to 35 cyclesa, whichever 
is sooner 
a A cycle length of 21 days. 
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with advanced or metastatic solid tumors.  The RP2D will then be further assessed in triplet tumor 
expansion cohorts in Phase 2 Part A.  The equivalent INCB001158 + epacadostat doublet RP2D will 
be further assessed in doublet tumor expansion cohorts in Phase 2 Part B. 
Each Simon 2-stage design will have a stopping rule to allow early termination of a particular tumor 
type within a treatment group at the end of Stage 1 if there is insufficient response observed, while 
enrolling enough subjects to predict possible target responses worthy of cohort expansion and potential 
further evaluation in future studies. 
The proposed designs for each tumor type will be used for any planned Simon 2-stage design.  Each 
Simon 2-stage design is set up to have a 1-sided Type I error of 0.1 and power of 80%.  The response 
rates for each tumor type will be estimated with 95% confidence intervals.   
Phase 2 Part A:  Simon 2-Stage Design 
Cohort 
Background 
ORR 
Target 
ORR 
Alpha 
Power 
N for 
Stage 1 
ORR to 
Proceed 
≥ (r1 + 1) 
/ n1a 
N for 
Stage 2 
ORR for 
Positive 
Cohort 
≥ (r + 1) 
/ na 
A1 
30% 
50% 
0.1 
80% 
15 
6/15 
17 
13/32 
A2 
2% 
15% 
0.1 
80% 
11 
1/11 
15 
2/26 
A3 
15% 
35% 
0.1 
80% 
9 
2/9 
14 
6/23 
B1 
56% 
76% 
0.1 
80% 
12 
8/12 
19 
21/31 
B2 
2% 
15% 
0.1 
80% 
11 
1/11 
15 
2/26 
B3 
15% 
35% 
0.1 
80% 
9 
2/9 
14 
6/23 
C 
30% 
50% 
0.1 
80% 
15 
6/15 
17 
13/32 
D 
39% 
59% 
0.1 
80% 
15 
7/15 
16 
16/31 
E 
25% 
45% 
0.1 
80% 
15 
5/15 
12 
10/27 
a r1 = response rate at the end of Stage 1; n1 = sample size for Stage 1 only; r = overall response rate for combined Stage 1 
and 2; n = sample size for combined Stage 1 and 2. 
Phase 2 Part B:  Simon 2-Stage Design 
Cohort 
Background 
ORR 
Target 
ORR 
Alpha 
Power 
N for 
Stage 1 
ORR to 
Proceed 
≥ (r1 + 1) 
/ n1a 
N for 
Stage 2 
ORR for 
Positive 
Cohort 
≥ (r + 1) 
/ na 
A 
2% 
15% 
0.1 
80% 
11 
1/11 
15 
2/26 
B 
2% 
15% 
0.1 
80% 
11 
1/11 
15 
2/26 
C 
2% 
15% 
0.1 
80% 
11 
1/11 
15 
2/26 
a r1 = response rate at the end of Stage 1; n1 = sample size for Stage 1 only; r = overall response rate for combined Stage 1 
and 2; n = sample size for combined Stage 1 and 2. 
Primary Analysis:  
Objective response rate, defined as the percentage of subjects enrolled in Phase 2 Part A (plus subjects 
enrolled in Phase 1 who meet all of the inclusion and exclusion criteria for Phase 2 Part A) or Phase 2 
Part B having a CR or PR, as determined by investigator assessment of radiographic disease as per 
RECIST v1.1 will be summarized by treatment cohort. 
 
 
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Secondary Analysis:  
The following efficacy analyses will be assessed for all subjects in each treatment combination: 
• ORR defined as the percentage of subjects having a CR or PR, as determined by investigator 
assessment of radiographic disease as per RECIST v1.1 (Phase 1 only). 
• DCR, defined as the percentage of subjects having CR, PR, or SD for at least 56 days, as determined 
by investigator assessment of radiographic disease as per RECIST v1.1. 
• DoR, determined by radiographic disease assessment, defined as the time from earliest date of 
disease response until the earliest date of disease progression per RECIST v1.1, or death due to any 
cause, if occurring sooner than progression. 
• PFS, defined as the time from date of first dose of study treatment until the earliest date of disease 
progression, as determined by investigator assessment of objective radiographic disease assessments 
per RECIST v1.1, or death due to any cause, if occurring sooner than progression. 
The PK of INCB001158, epacadostat, and pembrolizumab, and the 
 will be 
summarized. 
Interim Analysis: 
In Phase 1, the BOIN design will be used to determine the RP2D of the combination of INCB001158, 
epacadostat, and pembrolizumab.  Based on the algorithm of the BOIN design, a minimum of 
3 evaluable subjects will be enrolled in each dose level with a maximum of 9 evaluable subjects in 
each dose level.   
In Phase 2, the Simon 2-stage design will be applied for each tumor within a given treatment group.  
During Stage 1, n1 evaluable subjects treated at the recommended dose and schedule will be enrolled, 
and if r1 or fewer responses are observed, then the cohort will be discontinued.   
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TABLE OF CONTENTS 
SYNOPSIS ......................................................................................................................................3 
LIST OF ABBREVIATIONS ........................................................................................................25 
1. 
INTRODUCTION ......................................................................................................28 
1.1. 
Background .................................................................................................................28 
1.1.1. 
The Role of the Immune System in Cancer ................................................................28 
1.1.2. 
Inhibition of Arginase as a Target for Cancer ............................................................28 
1.1.2.1. 
Activity of the Arginase 1 Inhibitor INCB001158 in Solid Tumors ..........................29 
1.1.3. 
Inhibition of PD-1 as a Target for Cancer ..................................................................30 
1.1.3.1. 
Activity of PD-1/PD-L1 Inhibitors in Solid Tumors ..................................................31 
1.1.4. 
Inhibition of Indoleamine 2,3-Dioxygenase as a Target for Cancer ..........................31 
1.1.5. 
Combinations of Immunotherapies for Cancer ...........................................................33 
1.1.5.1. 
Combined Inhibition of PD-1 and IDO1 as a Target for Cancer ................................33 
1.1.5.2. 
Combined Inhibition of PD-1, IDO1, and Arginase 1 as a Target for Cancer ...........34 
1.2. 
Study Rationale ...........................................................................................................34 
1.2.1. 
Rationale for Combining INCB001158 With Epacadostat in Solid Tumors .............34 
1.2.2. 
Rationale for Combining INCB001158 With Epacadostat and 
Pembrolizumab in Solid Tumors ................................................................................35 
1.2.3. 
Rationale for the Study Population .............................................................................35 
1.2.3.1. 
Phase 1:  Dose Escalation of INCB001158 + Epacadostat + Pembrolizumab ...........35 
1.2.3.2. 
Phase 2 Part A:  Tumor Expansion of INCB001158 + Epacadostat + 
Pembrolizumab ...........................................................................................................35 
1.2.3.3. 
Phase 2 Part B:  Tumor Expansion of INCB001158 + Epacadostat...........................36 
1.2.4. 
Rationale for the Dose and Schedule of INCB001158 ...............................................36 
1.2.5. 
Rationale for the Dose of Epacadostat ........................................................................37 
1.2.6. 
Rationale for the Dose of Pembrolizumab ..................................................................37 
1.2.7. 
Rationale for the Study Endpoints ..............................................................................37 
1.2.7.1. 
Primary Endpoints ......................................................................................................37 
1.2.7.2. 
Secondary Endpoints ..................................................................................................38 
 
38 
1.3. 
Potential Risks and Benefits of the Treatment Regimen ............................................39 
1.3.1. 
Risks for INCB001158 ...............................................................................................39 
1.3.1.1. 
Potential Urea Cycle Toxicity ....................................................................................39 
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1.3.1.2. 
Immune-Related Adverse Events ...............................................................................40 
1.3.1.3. 
Alterations in Hemodynamic Status ...........................................................................41 
1.3.1.4. 
Clinical Experience .....................................................................................................41 
1.3.2. 
Risks for Epacadostat .................................................................................................41 
1.3.3. 
Risks for Pembrolizumab ...........................................................................................42 
1.3.4. 
Risks for the Combination of INCB001158, Epacadostat, and 
Pembrolizumab ...........................................................................................................42 
1.3.5. 
Benefits for the Combination of INCB001158, Epacadostat, and 
Pembrolizumab ...........................................................................................................43 
1.3.6. 
Risks for the Combination of INCB001158 and Epacadostat ....................................43 
1.3.7. 
Benefits for the Combination of INCB001158 and Epacadostat ................................43 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................44 
3. 
SUBJECT ELIGIBILITY ...........................................................................................46 
3.1. 
Subject Inclusion Criteria ...........................................................................................46 
3.2. 
Subject Exclusion Criteria ..........................................................................................51 
4. 
INVESTIGATIONAL PLAN .....................................................................................54 
4.1. 
Overall Study Design ..................................................................................................54 
4.1.1. 
Phase 1:  Dose Escalation of INCB001158 + Epacadostat + Pembrolizumab ...........55 
4.1.2. 
Phase 2 Part A:  Tumor Expansion of INCB001158 + Epacadostat + 
Pembrolizumab ...........................................................................................................59 
4.1.3. 
Phase 2 Part B:  Tumor Expansion of INCB001158 + Epacadostat...........................61 
4.2. 
Measures Taken to Avoid Bias ...................................................................................62 
4.3. 
Number of Subjects ....................................................................................................63 
4.3.1. 
Planned Number of Subjects ......................................................................................63 
4.3.2. 
Replacement of Subjects .............................................................................................63 
4.4. 
Duration of Treatment and Subject Participation .......................................................63 
4.5. 
Overall Study Duration ...............................................................................................63 
4.6. 
Study Termination ......................................................................................................63 
4.6.1. 
Protocol Amendment (Version) 2 ...............................................................................64 
5. 
TREATMENT ............................................................................................................65 
5.1. 
Treatment Assignment ................................................................................................65 
5.1.1. 
Subject Numbering and Treatment Assignment .........................................................65 
5.1.2. 
Randomization and Blinding ......................................................................................65 
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5.2. 
Study Drugs and Other Study Treatments ..................................................................65 
5.2.1. 
INCB001158 ...............................................................................................................66 
5.2.1.1. 
Description and Administration ..................................................................................66 
5.2.1.2. 
Supply, Packaging, and Labeling ...............................................................................66 
5.2.1.3. 
Storage ........................................................................................................................66 
5.2.1.4. 
Instruction to Subjects for Handling Study Drug (INCB001158) ..............................66 
5.2.2. 
Epacadostat .................................................................................................................67 
5.2.2.1. 
Description and Administration ..................................................................................67 
5.2.2.2. 
Supply, Packaging, and Labeling ...............................................................................68 
5.2.2.3. 
Storage ........................................................................................................................68 
5.2.2.4. 
Instruction to Subjects for Handling Epacadostat ......................................................68 
5.2.3. 
Pembrolizumab ...........................................................................................................68 
5.2.3.1. 
Description and Administration ..................................................................................68 
5.2.3.2. 
Supply, Packaging, and Labeling ...............................................................................69 
5.2.3.3. 
Storage ........................................................................................................................69 
5.3. 
Treatment Compliance ................................................................................................69 
5.4. 
Treatment Interruptions and Adjustments ..................................................................69 
5.4.1. 
Dose Modifications .....................................................................................................69 
5.4.1.1. 
INCB001158 ...............................................................................................................69 
5.4.1.2. 
Epacadostat .................................................................................................................70 
5.4.1.3. 
Pembrolizumab ...........................................................................................................70 
5.4.2. 
Dose-Limiting Toxicity and Determination of Maximum Tolerated Dose in 
Phase 1 ........................................................................................................................70 
5.4.3. 
Management of Dose-Limiting Toxicities or Other Urgent Situations ......................71 
5.4.4. 
Follow-Up of Dose-Limiting Toxicities .....................................................................71 
5.4.5. 
Procedures for Cohort Review and Dose Escalation ..................................................72 
5.4.6. 
Dose Modifications for Immune-Related AEs and AEs Related to 
Urea-Cycle Inhibition .................................................................................................72 
5.4.7. 
Procedures for Subjects Exhibiting Serotonin Syndrome ..........................................84 
5.4.8. 
Supportive Care Guidelines for Management of Hyperammonemia .........................85 
5.4.9. 
Infusion Reaction Dose Modifications .......................................................................86 
5.4.10. 
Criteria for Permanent Discontinuation of Study Treatment ......................................87 
5.5. 
Withdrawal of Subjects From Study Treatment .........................................................88 
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5.5.1. 
Withdrawal Criteria ....................................................................................................88 
5.5.2. 
Withdrawal Procedures ...............................................................................................88 
5.6. 
Concomitant Medications ...........................................................................................89 
5.6.1. 
Permitted Medications ................................................................................................89 
5.6.2. 
Restricted Medications and Measures ........................................................................90 
5.6.3. 
Prohibited Medications ...............................................................................................90 
6. 
STUDY ASSESSMENTS ..........................................................................................92 
6.1. 
Screening ..................................................................................................................100 
6.2. 
Treatment ..................................................................................................................100 
6.3. 
End of Treatment ......................................................................................................100 
6.4. 
Follow-Up .................................................................................................................101 
6.4.1. 
Safety Follow-Up ......................................................................................................101 
6.4.2. 
Disease Status Follow-Up .........................................................................................101 
 
 ..................................................................................................101 
6.5. 
End of Study .............................................................................................................101 
6.6. 
Unscheduled Visits ...................................................................................................102 
7. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES .........................102 
7.1. 
Administration of Informed Consent Form ..............................................................102 
7.2. 
Interactive Response Technology Procedure ............................................................102 
7.3. 
Demography and Medical History ............................................................................103 
7.3.1. 
Demographics and General Medical History ...........................................................103 
7.3.2. 
Disease Characteristics and Treatment History ........................................................103 
7.4. 
Prior and Concomitant Medications and Procedures ................................................103 
7.5. 
Post-Treatment Anticancer Therapy Status ..............................................................103 
7.6. 
Safety Assessments ...................................................................................................103 
7.6.1. 
Adverse Events .........................................................................................................103 
7.6.2. 
Physical Examinations ..............................................................................................104 
7.6.2.1. 
Comprehensive Physical Examination .....................................................................104 
7.6.2.2. 
Targeted Physical Examination ................................................................................104 
7.6.3. 
Vital Signs ................................................................................................................104 
7.6.4. 
Electrocardiograms ...................................................................................................104 
7.6.5. 
Laboratory Assessments ...........................................................................................104 
7.6.5.1. 
Chemistries ...............................................................................................................105 
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7.6.5.2. 
Urinalysis ..................................................................................................................105 
7.6.5.3. 
Plasma Ammonia ......................................................................................................106 
7.6.5.4. 
Pregnancy Testing ....................................................................................................106 
7.6.5.5. 
Hepatitis and HIV Screening Tests ...........................................................................106 
7.7. 
Efficacy Assessments ...............................................................................................106 
7.7.1. 
Tumor Imaging and Assessment of Disease .............................................................106 
7.7.1.1. 
Initial Tumor Imaging ...............................................................................................107 
7.7.1.2. 
Tumor Imaging During the Study.............................................................................107 
7.7.1.3. 
End of Treatment and Follow-Up Imaging ..............................................................108 
7.7.1.4. 
RECIST v1.1 Assessment of Disease .......................................................................108 
 
 ..............................................................................108 
7.8. 
Performance and Quality-of-Life Assessments ........................................................113 
7.8.1. 
Eastern Cooperative Oncology Group Performance Status ......................................113 
7.9. 
Pharmacokinetic Assessments ..................................................................................113 
7.9.1. 
Blood Sample Collection ..........................................................................................113 
7.9.2. 
Bioanalytical Methodology and Analysis .................................................................114 
 
 ................................................................................................114 
 
 .............................................................................................114 
 
 .............................................................115 
 
...............................................................115 
 
 .........................................................................115 
 
 ........................................................................................................115 
 
 ...................................................115 
7.11. 
Other Study Procedures ............................................................................................116 
7.11.1. 
Distribution of Subject Reminder Cards and Subject Diaries ..................................116 
7.11.2. 
Data Collection for Survival Follow-Up ..................................................................116 
8. 
SAFETY MONITORING AND REPORTING .......................................................117 
8.1. 
Adverse Events .........................................................................................................117 
8.1.1. 
Definitions ................................................................................................................117 
8.1.2. 
Reporting ..................................................................................................................117 
8.2. 
Laboratory Test Abnormalities .................................................................................119 
8.3. 
Serious Adverse Events ............................................................................................119 
8.3.1. 
Definitions ................................................................................................................119 
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8.3.2. 
Reporting ..................................................................................................................120 
8.4. 
Emergency Unblinding of Treatment Assignment ...................................................121 
8.5. 
Pregnancy .................................................................................................................121 
8.6. 
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor ...............................................................................................................122 
8.7. 
Warnings and Precautions ........................................................................................122 
8.8. 
Data Monitoring Committee .....................................................................................122 
8.9. 
Events of Clinical Interest ........................................................................................123 
8.10. 
Product Complaints ..................................................................................................123 
9. 
STATISTICS ............................................................................................................124 
9.1. 
Study Populations .....................................................................................................124 
9.2. 
Selection of Sample Size ..........................................................................................124 
9.2.1. 
Sample Size for Phase 1 ...........................................................................................124 
9.2.2. 
Sample Size for Phase 2 ...........................................................................................124 
9.3. 
Level of Significance ................................................................................................125 
9.4. 
Statistical Analyses ...................................................................................................125 
9.4.1. 
Efficacy Analyses .....................................................................................................125 
9.4.1.1. 
Primary Efficacy Analyses .......................................................................................125 
9.4.1.2. 
Secondary Efficacy Analyses ...................................................................................125 
 
 ...........................................................................................126 
9.4.2. 
Safety Analyses ........................................................................................................126 
9.4.2.1. 
Adverse Events .........................................................................................................126 
9.4.2.2. 
Clinical Laboratory Tests .........................................................................................126 
9.4.2.3. 
Vital Signs ................................................................................................................127 
9.4.2.4. 
Electrocardiograms ...................................................................................................127 
9.4.3. 
Pharmacokinetic Analysis ........................................................................................127 
 
.128 
9.5. 
Interim Analysis ........................................................................................................128 
9.5.1. 
Interim Analysis for the BOIN Design .....................................................................128 
9.5.2. 
Interim Analysis for the Simon 2-Stage Design .......................................................128 
10. 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES ........................................................................................................130 
10.1. 
Investigator Responsibilities .....................................................................................130 
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10.2. 
Accountability, Handling, and Disposal of Study Treatments .................................131 
10.3. 
Data Management .....................................................................................................132 
10.4. 
Data Privacy and Confidentiality of Study Records .................................................132 
10.5. 
Financial Disclosure .................................................................................................133 
10.6. 
Publication Policy .....................................................................................................133 
11. 
REFERENCES .........................................................................................................134 
APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS .............................................................................139 
APPENDIX B. PHARMACOKINETIC ANALYTICAL PARAMETERS ............................140 
APPENDIX C. PROHIBITED MONOAMINE OXIDASE INHIBITORS .............................141 
APPENDIX D. PROTOCOL AMENDMENT SUMMARY OF CHANGES .........................142 
 
LIST OF TABLES 
Table 1: 
Study Objectives and Endpoints .................................................................................44 
Table 2: 
Dose Escalation, De-Escalation, and Elimination Boundaries for Target DLT 
Rate = 33% in Phase 1 ................................................................................................56 
Table 3: 
Dose Levels for Phase 1:  INCB001158 + Epacadostat + Pembrolizumab, 
Based on INCB001158 Starting Dose of 50 mg BID .................................................58 
Table 4: 
Dose Levels for Phase 1:  INCB001158 + Epacadostat + Pembrolizumab, 
Based on INCB001158 Starting Dose of 75 mg BID .................................................58 
Table 5: 
Phase 2 Part A:  Simon 2-Stage Design......................................................................61 
Table 6: 
Phase 2 Part B:  Simon 2-Stage Design ......................................................................62 
Table 7: 
Study Drug and Other Study Treatments ....................................................................65 
Table 8: 
Definition of Dose-Limiting Toxicity ........................................................................71 
Table 9: 
Dose Modification and Toxicity Management Guidelines for Adverse Events 
in Subjects Receiving INCB001158 and Epacadostat ± Pembrolizumab ..................73 
Table 10: Dose Level Adjustments of Epacadostat ....................................................................84 
Table 11: Signs and Symptoms of Serotonin Syndrome ............................................................85 
Table 12: Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines ...................................................................................................................86 
Table 13: Warfarin Dose Adjustment Recommendation When Initiating Concurrent 
Epacadostat Treatment ................................................................................................90 
Table 14: Schedule of Clinical Assessments ..............................................................................93 
Table 15: Schedule of Laboratory Assessments .........................................................................96 
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Table 16: Laboratory Tests:  Required Analytes ........................................................................99 
Table 17: Sample Collection Times for Urine Assessments of Orotic Acid ............................105 
Table 18: Imaging and Treatment After First Radiologic Evidence of PD ..............................112 
Table 19: Eastern Cooperative Group Performance Status Scoring .........................................113 
Table 20: Extensive Sample Collection Time Windows for Pharmacokinetic 
Assessments for INCB001158 and Epacadostat in First 12 Subjects Enrolled 
in Phase 2 Part B .......................................................................................................114 
Table 21: Sparse Sample Collection Time Windows for Pharmacokinetic Assessments 
for INCB001158 and Epacadostat in Phase 1 and Phase 2 Part A and the 
Thirteenth Subject Onwards Enrolled in Phase 2 Part B ..........................................114 
Table 22: Sample Collection Time Windows for Pharmacokinetic and 
 
 in Phase 1 and Phase 2 Part A .............114 
Table 23: Criteria for Clinically Notable Vital Sign Abnormalities .........................................127 
Table 24: Criteria for Clinically Notable Electrocardiogram Abnormalities ...........................127 
Table 25: Probability of Early Termination for Simon 2-Stage Design in Phase 2 ..................129 
 
LIST OF FIGURES 
Figure 1: 
Arginase and Arginine in Cancer Patients ..................................................................29 
Figure 2: 
Study Design ...............................................................................................................55 
 
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LIST OF ABBREVIATIONS 
The following abbreviations and special terms are used in this clinical study Protocol. 
Abbreviation 
Definition 
 
 
AE 
adverse event 
AJCC 
American Joint Committee on Cancer 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
BCG 
Bacillus Calmette–Guérin 
BID 
twice daily 
BOIN 
Bayesian Optimal Interval 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
CNS 
central nervous system 
CR 
complete response 
CRC 
colorectal cancer 
CrCl 
creatinine clearance  
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T-lymphocyte-associated protein 4 
DC 
dendritic cell 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DoR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EGFR 
epidermal growth factor receptor 
EMA 
European Medicines Agency 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GM-CSF 
granulocyte macrophage colony-stimulating factor 
HBsAg 
hepatitis B virus surface antigen 
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Abbreviation 
Definition 
ORR 
objective response rate 
 
 
PAD 
pharmacologically active dose 
PD 
progressive disease  
PD-1 
programmed death-1 receptor 
PD-L1 
programmed death-1 receptor ligand 
PFS 
progression-free survival 
PI 
package insert 
PK 
pharmacokinetic 
PO 
per os (ie, orally administered) 
PR 
partial response 
PT 
prothrombin time 
Q3W 
once every 3 weeks 
QD 
once daily 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors version 1.1 
RNA 
ribonucleic acid 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SCCHN 
squamous cell carcinoma of the head and neck 
SCLC 
small cell lung cancer 
SD 
stable disease 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic-pyruvic transaminase 
SNRI 
selective serotonin/norepinephrine reuptake inhibitor 
SPC 
summary of product characteristics 
SS 
serotonin syndrome 
SSRI 
selective serotonin reuptake inhibitor 
SUSAR 
suspected unexpected serious adverse reaction 
T1DM 
Type 1 diabetes mellitus 
Treg 
regulatory T cells 
ULN 
upper limit of normal 
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1. 
INTRODUCTION 
1.1. 
Background 
1.1.1. 
The Role of the Immune System in Cancer 
The immune system is composed of diverse sets of cells designed to protect a host from 
pathogens while distinguishing from host and foreign antigens.  This immune response is 
controlled by a series of checks and balances to allow for robust immune responses to pathogens 
while preventing either an excessive inflammatory event or an autoimmune response.  Through 
immune surveillance, the immune system has been shown to recognize, attack, and destroy 
tumor cells (Wolchok and Saenger 2008).  Detailed analysis of CD8+ T cells and the ratio of 
CD8+ Teffs/FoxP3+ Tregs seem to correlate with improved prognosis and long-term survival in 
many solid tumors (Nosho et al 2010, Chang et al 2014, Preston et al 2013).  Although the 
immune system has been shown to recognize and reject a tumor, many tumors persist in evading 
immune surveillance or develop mechanisms of resistance.  
These include expression of 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 exquisite 
sensitivity of T cells to tryptophan depletion and tryptophan metabolites; infiltration with 
FoxP3+ Treg, which can mediate extrinsic suppression of effector T-cell function; and the 
depletion of arginine in the tumor microenvironment by arginase-expressing MDSCs and 
neutrophils, which inhibits the proliferation and activation of cytotoxic T cells and NK cells. 
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. 
Targeting the immune system is a proven and effective approach for cancer therapies.  FDA- and 
EMA-approved checkpoint inhibitors, including inhibitors of PD-1, pembrolizumab and 
nivolumab, allow for the immune response to continue proliferating in spite of inhibitory signals.  
Epacadostat is being developed in combination with PD-1 and PD-L1 inhibitors (see 
Section 1.2.2).  Targeting arginase is another promising treatment approach and is the focus of 
this clinical study, in combination with IDO1 and PD-1 inhibition. 
1.1.2. 
Inhibition of Arginase as a Target for Cancer 
Two isoforms of arginase are found in the body.  Arginase 1 (gene symbol:  ARG1) is a 
cytoplasmic enzyme that is highly expressed in the liver and is a critical enzyme in the urea 
cycle.  Arginase 1 is also expressed by granulocytic myeloid cells (MDSCs and neutrophils) and 
is localized in secretory granules within these cell types.  A separate gene encodes arginase 2 
(gene symbol:  ARG2), a mitochondrial enzyme that is more widely expressed across cell types. 
In cancer patients, arginase 1 in the tumor microenvironment is expressed by myeloid cells 
which release arginase from intracellular granules into the extracellular milieu following 
stimulation.  Arginase is released from fully differentiated neutrophils/polymorphonuclear cells 
and/or from granulocytic MDSCs, which are immature neutrophils.  These granulocytic cells 
degranulate and release arginase into the extracellular space when stimulated by factors produced 
by the tumor (eg, IL-8 and TNF-α), resulting in substantial depletion of the amino acid arginine, 
itself a critical factor in the proliferation and activation of cytotoxic T cells and NK cells.  
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Antitumor activity has been reported in mice when arginase is knocked out in the myeloid 
lineage in mice (Colegio et al 2014). 
Immunohistochemical staining of tumor microarrays from multiple histotypes revealed that 
tumor cells themselves generally did not stain positive for arginase 1.  Instead, large numbers of 
infiltrating polymorphonuclear cells containing arginase 1 were found across many histotypes 
with the greatest frequency in lung, colorectal, gastric, and bladder cancers (Figure 1 [A]).  The 
positive arginase 1 IHC staining in tumor microarrays in this study was largely confined to 
polymorphonuclear cells based on morphology. 
In addition to the high arginase 1 observed by IHC in tumor-infiltrating granulocytic myeloid 
cells, analysis of plasma from cancer patients across multiple histotypes demonstrated elevated 
arginase 1 protein levels and lower arginine levels compared with normal healthy control 
subjects (Figure 1 [B,C]).  It has been hypothesized that arginase released from myeloid cells in 
the tumor microenvironment can be recovered in plasma, which may account for the elevated 
arginase 1 protein levels and lower arginine levels measured systemically. 
Figure 1: 
Arginase and Arginine in Cancer Patients 
 
[A] Frequency of arginase 1 expressing myeloid cells infiltrating human solid tumors.  Arginase 1 protein was 
detected using a specific rabbit monoclonal antibody to human arginase 1.  Digital quantification of arginase 
expression in myeloid cells was performed and the number of arginase 1–positive cells per mm2 is plotted.  
[B] Arginase protein and [C] arginine levels in plasma of cancer patients versus healthy subjects.  Plasma from 
cancer patients and healthy normal volunteers were assayed for arginase 1 levels by ELISA and arginine levels by 
LC/MS-MS. 
1.1.2.1. 
Activity of the Arginase 1 Inhibitor INCB001158 in Solid Tumors 
INCB001158 (formerly known as CB-1158) is a potent, selective, and reversible inhibitor of 
human recombinant arginase 1 and arginase 2 (IC50 of 100 and 275 nM, respectively). 
In cell-based assays, INCB001158 reversed the growth-suppressive effects of human neutrophils 
on human T cells when co-cultured ex vivo with an EC50 of 162 nM.  Similarly, INCB001158 
reversed inhibition of T-cell growth by patient-derived MDSCs with similar potency.  In both 
cases, INCB001158 was able to antagonize the depletion of arginine mediated by neutrophils or 
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MDSCs in a dose-dependent manner.  INCB001158 has no direct growth inhibitory or cytotoxic 
activity on tumor cells or on immune effector cells. 
INCB001158 has single agent and combination activity in syngeneic tumor models.  Oral BID 
administration of single agent INCB001158 produced a dose-dependent reduction in the growth 
of subcutaneously implanted LLC (lung) tumors.  The efficacy of INCB001158 in LLC tumors is 
immune-mediated.  When LLC tumors were grown in immunocompromised scid mice, there was 
no antitumor activity of INCB001158.  The combinations of INCB001158 with anti–PD-L1 in 
the CT26 (colon) model and with epacadostat in the B16F10 (melanoma) model resulted in 
enhanced antitumor activity. 
The safety and tolerability of INCB001158 in patients with advanced or metastatic solid tumors 
is being evaluated in the ongoing first-in-human Phase 1 study, INCB 01158-101 (formerly 
CX-1158-101).  Early data from monotherapy dose-escalation cohorts (data cutoff: 
24 APR 2017) showed that oral dosing of INCB001158 was well-tolerated at the first 3 doses 
tested (50, 100, and 150 mg BID); the steady-state trough levels of INCB001158 were above the 
IC90 for arginase inhibition at all dose levels, with 90% to 95% arginase inhibition and increases 
in plasma arginine, and there was preliminary evidence of peripheral immune modulation 
(Papadopoulos et al 2017). 
Refer to the Investigator's Brochure for additional details of the INCB001158 preclinical 
experiments and updated data from the INCB 01158-101 clinical study (iIB). 
1.1.3. 
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 
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; 
Talmadge et al 2007, Usubütün 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 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 and Dranoff 2010, Kloor 2009).  Expression has also been 
shown during thymic development on CD4-CD8- (double negative) T cells as well as subsets of 
macrophages and DCs (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 (Lee et al 2008, Leffers et al 2009, Nishimura et al 2000, 
Nobili et al 2008).  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. 
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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 (Nobili et al 2008).  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).  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. 
1.1.3.1. 
Activity of PD-1/PD-L1 Inhibitors in Solid Tumors 
A number of PD-1/PD-L1 checkpoint inhibitors have demonstrated activity in a variety of solid 
and liquid tumors: 
• Pembrolizumab (Keytruda®) is a humanized IgG4-kappa monoclonal antibody that 
binds to PD-1 and is approved for certain patients with melanoma, NSCLC, SCCHN, 
urothelial carcinoma, classical Hodgkin lymphoma, and microsatellite instability-high 
cancer (Keytruda PI 2017, Keytruda SPC 2017).  
• Nivolumab (Opdivo®) is a fully human IgG4 monoclonal antibody that also binds to 
PD-1 and is approved for certain patients with melanoma, NSCLC (both as 
monotherapy and in combination with ipilimumab), renal cell carcinoma, SCCHN, 
classical Hodgkin lymphoma, and urothelial carcinoma (Opdivo PI 2017, 
Opdivo SPC 2017). 
• Atezolizumab (Tecentriq®) is an Fc-engineered, humanized, monoclonal antibody 
that binds to PD-L1 and is approved for certain patients with urothelial carcinoma and 
NSCLC (Tecentriq PI 2017). 
• Durvalumab (Imfinzi®) is a human monoclonal antibody against PD-L1 and is 
approved for certain patients with urothelial carcinoma (Imfinzi PI 2017). 
• Avelumab (Bavencio®) is a human monoclonal antibody against PD-L1 and is 
approved for certain patients with Merkel cell carcinoma (Bavencio PI 2017).   
These data support the use of PD-1/PD-L1 inhibitors in a variety of solid tumors.  However, the 
majority of patients do not derive a benefit as evidenced by the relatively low response rates, and 
there remains a high unmet medical need for more efficacious therapies.  One approach being 
tried is to combine PD-1/PD-L1 inhibitors with other molecules, including those that can affect 
the tumor microenvironment.  This is discussed in Section 1.1.5. 
1.1.4. 
Inhibition of Indoleamine 2,3-Dioxygenase as a Target for Cancer 
Recent interest has focused on the role of 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.   
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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 (eg, gut, respiratory tract, placenta, 
spleen), consistent with a role for regulating tryptophan metabolism in a local microenvironment  
(Mellor and Munn 2004).  Within the immune system, IDO1 activity is specifically induced in 
cells such as DCs and macrophages at localized sites of inflammation (Mellor and Munn 2004). 
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).  
Because 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 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 and Munn 2004).  While IDO1 inhibition can exacerbate 
disease in models of autoimmune disorders (Mellor and Munn 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 (eg, 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 
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with 2 key modifications.  Firstly, in Cohort E, subjects may have had no more than 2 prior lines 
of systemic therapy for metastatic or advanced disease, whereas approximately a third of SCLC 
patients in KEYNOTE-028 had received ≥ 3 previous lines of therapy.  Secondly, while 
KEYNOTE-028 enrolled only PD-L1–positive patients (≥1%), Cohort E will not select based on 
tumor PD-L1 status.  This is based on the results from the CheckMate 032 study in an unselected 
population of patients with recurrent SCLC, where responses with nivolumab were observed 
regardless of PD-L1 status (Hellman et al 2017).  Therefore, the KEYNOTE-028 data will only 
provide a rough baseline to assess the effect of adding INCB001158 and epacadostat to 
pembrolizumab. 
In Cohorts A2 and A3 (NSCLC) and B2 and B3 (melanoma), subjects will not be naive to 
anti–PD-1 or anti–PD-L1 therapy or any other drug targeting the checkpoint pathways.  Instead 
they will have had documented radiological disease progression while receiving an anti–PD-1 or 
anti–PD-L1 agent in a previous line of therapy.  In Cohorts A2 and B2, the subjects will be 
primary refractory to anti–PD-1 or anti–PD-L1 therapy; in Cohorts A3 and B3, the subjects will 
be anti–PD-1/anti–PD-L1 relapsed.  This will allow an evaluation of whether INCB001158, in 
combination with epacadostat, can make these tumors responsive to anti–PD-1 therapy again and 
is based on the high arginase 1 expression observed in a distinct 'immunologically cold' subset of 
tumors (low IFN-γ signature expression; see Section 1.1.5.2), plus the 
 dual inhibition of 
G-MDSCs and M-MDSCs by INCB001158 and epacadostat, respectively. 
1.2.3.3. 
Phase 2 Part B:  Tumor Expansion of INCB001158 + Epacadostat 
In Phase 2 Part B, 3 tumor types (urothelial carcinoma, SCCHN, and CRC) were selected that 
have high infiltration with arginase 1–positive cells (see Section 1.1.2), such that treatment with 
an arginase 1 inhibitor may be effective.  In addition, the 
 dual inhibition of G-MDSCs 
and M-MDSCs by INCB001158 and epacadostat, respectively, may fully abrogate the myeloid 
immunosuppressive tumor microenvironment (see Section 1.1.5.2). 
Because it is unknown whether INCB001158 in combination with epacadostat will be active, 
only subjects with metastatic disease or advanced disease that is not amenable to local therapy 
will be enrolled.  Further, only subjects for whom there are no available therapies that have been 
shown to provide clinical benefit (eg, OS benefit) will be enrolled. 
1.2.4. 
Rationale for the Dose and Schedule of INCB001158  
The starting dose of INCB001158 in the Phase 1 dose-escalation portion of the proposed study 
will be at least 2 dose levels below the highest dose of INCB001158 that is shown to be tolerable 
as a monotherapy in the INCB 01158-101 study, but no lower than 50 mg BID. 
As described in Section 1.3.1, INCB001158 has the potential to disrupt the hepatic urea cycle via 
inhibition of its constituent arginase.  This can be measured via urinary orotic acid, which is used 
as a sensitive assay to identify defects in the urea cycle.  Elevations of urinary orotic acid are not 
necessarily associated with toxicity, and in this study, dose-limiting events of urea cycle 
inhibition (eg, an increase in fasted urinary orotic acid to > 10 × ULN or any urinary orotic acid 
value to > 40 × ULN, or symptomatic hyperammonemia) are included in the assessment of 
tolerability in this study (see also Section 5.4.2 for definitions of DLTs and dose-limiting 
events). 
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In Study INCB 01158-101, as of the 21 JUL 2017 data cutoff, there were no DLTs or 
dose-limiting events at the 50 mg BID (n = 8), 75 mg BID (n = 7), and 100 mg BID (n = 8) dose 
levels, and there were no DLTs but 2 asymptomatic dose-limiting events of elevated urinary 
orotic acid ≥ 5 × ULN at the 150 mg BID (n = 3) dose level.  Given that such elevations of 
urinary orotic acid are an indication of inhibition of the urea cycle, albeit asymptomatically, and 
given that relatively small increases in INCB001158 doses in rats resulted in dramatic increases 
in urinary orotic acid levels (> 1000-fold) and toxicity (refer to the iIB), it was decided a cautious 
approach was warranted and the starting dose was set at least 2 dose levels below the maximum 
tolerated and tested dose from Study INCB 01158-101. 
In addition, dose escalation of INCB001158 in this study may go no higher than the maximum 
tolerated and tested monotherapy dose identified in the INCB 01158-101 study. 
The criteria for the selection of the RP2D of INCB001158 plus epacadostat and pembrolizumab, 
and the RP2D of INCB001158 plus epacadostat are described in Section 4.1.1. 
1.2.5. 
Rationale for the Dose of Epacadostat 
In the Phase 1 dose escalation, the epacadostat dose will be kept constant at 100 mg BID, 
because it has been shown to be active and tolerable in several epacadostat combination clinical 
studies, including with pembrolizumab (eIB, Gangadhar et al 2017, Hamid et al 2017a, 
Hamid et al 2017b, Smith et al 2017), and it is the dose selected or use in combination with 
pembrolizumab in Phase 3 (eg, NCT02752074). 
If unacceptable toxicity is observed at Dose Level 1 and is deemed to be due to epacadostat, a 
lower dose of epacadostat (50 mg BID) may be tested (see Section 4.1.1). 
The selection of the RP2D of INCB001158 plus epacadostat and pembrolizumab, and the RP2D 
of INCB001158 plus epacadostat is described in Section 4.1.1. 
1.2.6. 
Rationale for the Dose of Pembrolizumab 
In the Phase 1 dose escalation, the dose of pembrolizumab will be kept constant at 200 mg Q3W, 
which is the approved dose and schedule (Keytruda PI 2017, Keytruda SPC 2017) and also the 
dose being used in combination with epacadostat in Phase 3 studies, such as INCB 24360-301 in 
metastatic melanoma (NCT02752074). 
The criteria for the selection of the RP2D of INCB001158 plus epacadostat and pembrolizumab 
are described in Section 4.1.1. 
1.2.7. 
Rationale for the Study Endpoints 
1.2.7.1. 
Primary Endpoints 
The primary safety endpoint will assess AEs, clinical laboratory assessments, physical 
examination results, and 12-lead ECG results to determine the RP2D of INCB001158 in 
combination with epacadostat ± pembrolizumab in Phase 1. 
The primary efficacy endpoint will evaluate the ORR of INCB001158 in combination with 
epacadostat ± pembrolizumab by RECIST v1.1 in Phase 2.  This is a standard endpoint for 
assessing the antitumor activity of immunotherapies and has been used for epacadostat and 
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1.3. 
Potential Risks and Benefits of the Treatment Regimen 
1.3.1. 
Risks for INCB001158 
INCB001158 is a potent and selective inhibitor of arginase 1 and arginase 2.  Arginase 1 is 
primarily expressed in granulocytic myeloid cell granules, where it is excreted extracellularly 
and depletes extracellular arginine levels, and in liver hepatocytes, where it functions 
intracellularly as part of the urea cycle.  It has been shown that INCB001158 is approximately 
1000-fold more potent at inhibition of extracellular arginase 1 than intracellular arginase 1 that is 
engaged in the urea cycle.  This is primarily due to poor penetration of INCB001158 across cell 
membranes and the "enzymatic channeling" phenomenon, whereby the enzymes of the urea 
cycle are grouped within the cell to transfer intermediates efficiently between themselves and 
restrict access of exogenous arginine or INCB001158 to urea cycle enzymes 
(Cheung et al 1989).  Arginase 2 is primarily expressed in the mitochondria of many other 
tissues, including the gut and kidney.  The functions of arginase 2 in these tissues include 
regulation of systemic arginine concentration, regulation of the production of downstream 
products (eg, proline, polyamines), and regulation of arginine availability for NO synthesis.  
Inhibition of arginase 2 is thought to result in elevations in systemic arginine levels, which may 
contribute to the therapeutic effect.  Elevated arginine (up to ~100-fold above baseline) has been 
well-tolerated in humans following intravenous administration.  Ten-fold elevations in plasma 
arginine (to a mean concentration of 822 μM) was associated with no change in systolic or 
diastolic blood pressure, and a 100-fold increase in arginine was associated with mild reductions 
in systolic and diastolic blood pressure (~9 mmHg for each; Mehta et al 1996, 
Bode-Böger et al 1998). 
The results of the GLP-compliant rat and monkey toxicity studies are described in the 
INCB001158 IB (iIB).  The low- and mid-dose levels were well-tolerated, with no adverse 
findings and the mid-dose being considered the no-observed-adverse-effect level in both species.  
INCB001158 exposures at the mid-dose level were > 16-fold above the projected human 
efficacious exposure and were associated with robust pharmacodynamic effects (eg, elevated 
plasma arginine) with no significant toxicities noted. 
1.3.1.1. 
Potential Urea Cycle Toxicity 
As detailed in the INCB001158 IB (iIB), high doses of INCB001158 that resulted in significant 
morbidity and mortality in mice, rats, and monkeys achieved exposures over 19-fold above the 
projected human efficacious exposure.  In the nonclinical animal studies, the toxicity at the high 
doses was associated with evidence of hepatic urea cycle inhibition, including an elevation in 
liver arginine concentration, an increase in plasma ammonia concentration, a decrease in BUN 
concentration, and an increase in urinary orotic acid levels.  Of particular interest, urinary orotic 
acid was elevated by > 1000-fold in rats at the high dose following a single dose, before any 
signs of toxicity.  Smaller elevations in urinary orotic acid were also measured in some animals 
at the well-tolerated mid-dose level.  Elevations of urinary orotic acid have also been observed in 
cancer patients administered at the highest tested dose of 150 mg BID in the first-in-human 
INCB 01158-101 study.  Refer to the INCB001158 IB (iIB) and Section 1.2.4 for the latest 
INCB 01158-101 data plus the rationale for the thresholds of orotic acid (Section 5.4.2) to be 
used in this study. 
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Several measures of potential toxicity related to urea cycle inhibition will be evaluated in this 
study (see Table 14, Table 15, and Table 16).  In particular, urinary orotic acid, plasma (venous) 
ammonia, and BUN will be measured on Day 1 and at regular intervals in the dose escalation 
portion of the study (Phase 1). 
• Orotic acid – When the urea cycle is disrupted, the urea cycle substrate carbamoyl 
phosphate accumulates and is diverted into the pyrimidine synthesis pathway, 
producing substantial quantities of the pyrimidine precursor orotic acid.  The elevated 
orotic acid is rapidly cleared in the urine and is used as a sensitive assay to identify 
defects in the urea cycle either due to inborn errors or toxic or therapeutic inhibition. 
• Ammonia – Urea cycle inhibition can result in large elevations in ammonia, which 
can lead to CNS toxicity.  Inhibition of arginase, the last step in the urea cycle, does 
not tend to cause dramatic elevations in ammonia, but they are possible and will be 
evaluated as ammonia is the primary mechanism of acute toxicity associated with 
urea cycle inhibition.  Because plasma ammonia can be quite variable, elevations in 
plasma ammonia should be confirmed, particularly in asymptomatic patients. 
• BUN – Blood urea nitrogen is a measure of plasma urea and can be reduced in the 
setting of urea cycle inhibition.  Because BUN is also affected by other factors 
(eg, protein consumption, fluid status/dehydration), it is not an ideal biomarker of 
urea cycle function.  However, clear evidence of significant reduction in plasma BUN 
would be consistent with sustained inhibition of the hepatic urea cycle and should be 
avoided. 
1.3.1.2. 
Immune-Related Adverse Events 
It is not known to what extent arginine depletion is operative in normal tissues or in noncancer 
inflammatory states.  However, because arginase-mediated depletion of arginine is an 
immunosuppressive mechanism, irAEs may be associated with the restoration of local arginine 
by INCB001158 treatment.  Although preclinical toxicity studies have not demonstrated any 
evidence of increased inflammation or autoimmunity, these models tend to be poor predictors of 
the safety profile of immune-oncology agents in humans.  Experience with other 
immuno-oncology agents that target endogenous immunosuppressive mechanisms has 
demonstrated that irAEs can affect any organ or tissue, but most frequently occur in the skin 
(rash), gastrointestinal system (diarrhea/colitis), liver (hepatitis), lungs (pneumonitis), endocrine 
system (endocrinopathies due to inflammation of the pituitary, thyroid, and adrenals), and 
kidneys (nephritis).   
Documentation of the immune-mediated nature of toxicities (eg, through demonstration of 
immune infiltration in biopsy tissue) will be of great value, and an effort should be made in cases 
of severe or prolonged potential irAEs to provide evidence of the role of the immune system.  
Management of irAEs will follow the general approach that has been used for other 
immuno-oncology agents, including 1) withholding study drug for events of moderate or worse 
severity (Grade ≥ 2) and 2) the use of immunosuppressive corticosteroids for more severe irAEs 
(Grade ≥ 3) or prolonged irAEs (lasting > 2 weeks with minimal or no improvement despite 
withholding study drug).  High-dose steroids may be used for particularly severe irAEs or irAEs 
that fail to respond to initial oral steroids within 3 to 4 days.  Nonsteroid immunosuppressive 
agents may also be employed for steroid-refractory irAEs. 
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1.3.1.3. 
Alterations in Hemodynamic Status 
Although preclinical toxicity studies have not identified this as a toxicity signal, reductions in 
blood pressure leading to orthostatic hypotension, presyncope, or syncope are possible due to 
increased production of NO in response to the increased availability of circulating arginine, a key 
substrate for the NO-producing NOS enzymes.  This is considered an unlikely toxicity for 
INCB001158 based on the absence of preclinical evidence of hypotension and the tolerability of 
very high levels of arginine when administered intravenously to humans, including the absence 
of an effect on blood pressure in individuals with a 10-fold mean increase of plasma arginine 
(Mehta et al 1996, Bode-Böger et al 1998).  There has been no preclinical evidence of altered 
hemodynamic status in any preclinical studies of INCB001158, and no clinical evidence to date 
in the INCB 01158-101 study (iIB).  In order to identify modest changes in hemodynamic status, 
blood pressure will be monitored in this study as part of the standard vital signs. 
1.3.1.4. 
Clinical Experience 
The INCB 01158-101 first-in-human study is ongoing.  See Section 1.1.2.1 for early data from 
this study and the INCB001158 IB (iIB) and Section 1.2.4 for more recent data.  Urinary orotic 
acid will continue to be studied in all clinical studies, to understand the role of food and the 
effects of extended exposure to INCB001158 and to combinations of INCB001158 with other 
molecules.   
1.3.2. 
Risks for Epacadostat 
Study INCB 24360-101 was a Phase 1, multicenter, open-label, dose-escalation study in subjects 
with refractory solid tumors that used a 3 + 3 design to determine the safety and tolerability, PK, 
and pharmacodynamics of escalating oral doses of epacadostat.  Subjects were administered 
doses of epacadostat ranging from 50 mg QD to 700 mg BID.  Of the 52 subjects treated, 
8 subjects (15.4%) had an AE leading to death.  Of these 8 subjects, the cause of death was 
disease progression in 7 subjects and hypoxia in the remaining subject.  During the study, 
25 subjects (48.1%) had an SAE.  The most frequently reported SAEs were disease progression 
(4 subjects, 7.7%), abdominal pain, nausea, and hypoxia (3 subjects each, 5.8%).  
Treatment-emergent AEs were reported in all subjects.  Fatigue was the most frequently reported 
TEAE (36 subjects, 69.2%).  Two DLTs occurred:  1 DLT of radiation pneumonitis at the 
300 mg BID dose level and 1 DLT of fatigue at the 400 mg BID dose level.  An MTD was not 
determined. 
A potential concern of IDO1 inhibition is an increase in serotonin levels that could precipitate a 
cluster of AEs termed SS when administered alone or in combination with other serotonergic 
agents.  This rare syndrome has been associated with some MAOIs and combinations of 
serotonergic drugs (Boyer and Shannon 2005).  The clinical manifestations of SS range from 
barely perceptible to lethal; onset is rapid (within 12 hours of drug[s] administration).  
Preclinical data suggest that SS is unlikely after treatment with either epacadostat alone or in 
combination with MAOIs such as linezolid (Zhang 2016).  As of 27 FEB 2017, 2 of 958 subjects 
treated across the epacadostat program have reported nonserious SS or symptoms of SS; both 
episodes were mild in severity and resolved. 
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1.3.3. 
Risks for Pembrolizumab  
Pembrolizumab (KEYTRUDA®) is a PD-1–blocking antibody indicated for the treatment of 
patients with unresectable or metastatic melanoma, metastatic NSCLC, recurrent or metastatic 
SCCHN, refractory classical Hodgkin lymphoma, locally advanced or metastatic urothelial 
carcinoma, and microsatellite instability-high cancer (Keytruda PI 2017, Keytruda SPC 2017). 
Due to the mechanism of action of pembrolizumab, immune adverse reactions have been seen 
when used as monotherapy.  Infusion-related reactions are also possible following administration 
of pembrolizumab.  Guidance for the management of immune-related AEs and infusion-related 
reactions is in the Protocol. 
Additional details regarding specific benefits and risks for subjects participating in this clinical 
study may be found in the accompanying Investigator's Brochure (pIB) and Informed Consent 
documents. 
1.3.4. 
Risks for the Combination of INCB001158, Epacadostat, and Pembrolizumab  
Prior to this study, the triplet combination of INCB001158 plus epacadostat and pembrolizumab 
had not been tested in humans.  However, the doublet combination of pembrolizumab and 
epacadostat is being assessed in an ongoing Phase 1/2 study (INCB 24360-202), and the doublet 
of INCB001158 and pembrolizumab is being assessed in the first-in-human INCB 01158-101 
study. 
In the Phase 2 cohort-expansion part of the epacadostat plus pembrolizumab combination study 
(INCB 24360-202), safety data are available on 294 cancer subjects, of whom 273 had solid 
tumors and 21 had diffuse large B-cell lymphoma (Hamid et al 2017a).  All subjects were dosed 
at epacadostat 100 mg BID and pembrolizumab 200 mg Q3W.  The most frequently reported 
(≥ 10%) treatment-related AEs of any grade were fatigue (29%), rash (17%; including the 
preferred terms rash, rash generalized, rash macular, rash maculopapular, and rash pruritic), 
nausea (11%), and pruritus (10%).  Treatment-related AEs ≥ Grade 3 occurring in more than 
3 subjects were lipase increased (12 subjects, 4%), rash (9 subjects, 3%), fatigue, diarrhea, and 
amylase increased (4 subjects [1%] each).  Treatment-related AEs leading to treatment 
discontinuations occurred in 11 subjects (4%); the most common were arthralgia and rash 
(2 subjects each).  From the INCB 24360-202 study, epacadostat 100 mg BID plus 
pembrolizumab 200 mg Q3W was selected as a well-tolerated combination dose for further 
assessment in Phase 3.  The same doses of epacadostat and pembrolizumab will also be used in 
the triplet combination in this INCB 01158-202 study. 
By adding INCB001158, with its additional mechanism of inhibiting immunosuppression in the 
tumor microenvironment, there is the potential to cause more frequent, more severe, and/or new 
immune-related toxicities as compared with the doublet of epacadostat plus pembrolizumab.  
However, no immune-related toxicities have been observed to date in the ongoing 
INCB 01158-101 study (see iIB). 
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1.3.5. 
Benefits for the Combination of INCB001158, Epacadostat, and Pembrolizumab 
As described in Section 1.2.2, inhibition of arginase 1, using INCB001158, could further 
increase ORR, DCR, and DoR observed in multiple solid tumors with epacadostat and 
pembrolizumab by providing broad inhibition of both immunosuppressive MDSC cell types and 
by potentially making "cold" tumors responsive to PD-1 inhibition.  It is hypothesized that this 
additional benefit will not come at the cost of additional toxicity (see Section 1.3.4). 
1.3.6. 
Risks for the Combination of INCB001158 and Epacadostat 
As described in Section 1.1.5.2, INCB001158 and epacadostat have nonoverlapping 
mechanisms, and to date, the toxicities of each monotherapy have also been nonoverlapping.  
However, as the combination of INCB001158 and epacadostat has the potential to fully abrogate 
the myeloid immunosuppressive tumor microenvironment, there is the potential to cause more 
frequent, more severe, and/or new immune-related toxicities than epacadostat alone. 
1.3.7. 
Benefits for the Combination of INCB001158 and Epacadostat 
.  As described in Section 1.2.1, 
combined inhibition of arginase 1 and IDO1 may be effective through dual inhibition of both 
types of MDSC found in tumors, to fully abrogate the myeloid immunosuppressive tumor 
microenvironment.  It is hypothesized that the potential benefit associated with combining 
INCB001158 with epacadostat will not come at the cost of additional toxicity (see Section 1.3.6). 
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2. 
STUDY OBJECTIVES AND ENDPOINTS 
The study objectives and endpoints are presented in Table 1. 
Table 1: 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
Phase 1 only:  To assess the safety and 
tolerability, and to determine the RP2D of 
INCB001158 in combination with epacadostat ± 
pembrolizumab. 
Safety, tolerability, DLTs, and RP2D of 
INCB001158 in combination with epacadostat ± 
pembrolizumab, as assessed by AEs, clinical 
laboratory assessments, physical examination 
results, and 12-lead ECG results. 
Phase 2 only:  To evaluate the ORR of 
INCB001158 in combination with epacadostat ± 
pembrolizumab. 
ORR, defined as the percentage of subjects having 
a CR or PR, as determined by investigator 
assessment of radiographic disease as per RECIST 
v1.1. 
Secondary 
Phase 2 only:  To assess the safety, tolerability, 
and RP2D of INCB001158 in combination with 
epacadostat ± pembrolizumab. 
Safety, tolerability, and RP2D of INCB001158 in 
combination with epacadostat ± pembrolizumab, 
as assessed by AEs, clinical laboratory 
assessments, physical examination results, and 
12-lead ECG results. 
To evaluate the antitumor effect of INCB001158 
in combination with epacadostat ± pembrolizumab 
by RECIST v1.1. 
• ORR, defined as the percentage of subjects 
having a CR or PR, as determined by 
investigator assessment of radiographic disease 
as per RECIST v1.1 (Phase 1 only). 
• DCR, defined as the percentage of subjects 
having CR, PR, or SD for at least 56 days, as 
determined by investigator assessment of 
radiographic disease as per RECIST v1.1. 
• DoR, determined by radiographic disease 
assessment, defined as the time from earliest 
date of disease response until the earliest date 
of disease progression per RECIST v1.1, or 
death due to any cause, if occurring sooner 
than progression. 
• PFS, defined as the time from date of first dose 
of study treatment until the earliest date of 
disease progression, as determined by 
investigator assessment of objective 
radiographic disease assessments per RECIST 
v1.1, or death due to any cause, if occurring 
sooner than progression. 
To determine the PK of each of INCB001158 and 
epacadostat in subjects treated with INCB001158 
in combination with epacadostat ± 
pembrolizumab. 
The PK of INCB001158 and epacadostat will be 
assessed by summarizing Cmax, tmax, Cmin, AUC0-t, 
and Cl/F. 
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Table 1: 
Study Objectives and Endpoints (Continued) 
Objectives 
Endpoints 
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3. 
SUBJECT ELIGIBILITY 
Deviations from eligibility criteria are not allowed because they can potentially jeopardize the 
scientific integrity of the study, regulatory acceptability, and/or subject safety.  Therefore, 
adherence to the criteria as specified in the Protocol is essential. 
3.1. 
Subject Inclusion Criteria 
A subject who meets all of the following criteria may be included in the study: 
1. Men and women, aged 18 or older. 
2. For Phase 1:  Subjects with histologically or cytologically confirmed advanced or 
metastatic solid tumors that have failed prior standard therapy (disease progression; 
subject intolerance is also allowable).  Note:  There is no limit to the number of prior 
treatment regimens. 
3. For Phase 2 Part A Cohort A1 – Anti-PD-1/PD-L1–naive NSCLC (see cohort numbering 
in Section 4): 
a. Subjects with histologically or cytologically confirmed NSCLC, who have received 
no more than 2 prior systemic chemotherapy regimens for Stage IV disease (not 
including neoadjuvant and/or adjuvant therapy except as described below). 
b. For subjects who have received 1 or 2 lines of prior systemic chemotherapy for 
Stage IV disease, 1 of the prior systemic regimens must include a platinum-based 
therapy.  Subjects who have only received non–platinum-based regimens may be 
enrolled with medical monitor approval. 
c. Tumors with driver mutations (EGFR mutation–positive, anaplastic lymphoma kinase 
fusion oncogene–positive, proto-oncogene tyrosine-protein kinase ROS1–positive, or 
BRAF V600 mutant–positive) treated with a tyrosine kinase inhibitor are permitted 
and will not be considered a systemic chemotherapy regimen.  However, subjects 
should have progressed on or be intolerant to the targeted therapy. 
d. Maintenance or switch maintenance therapy after first- or second-line chemotherapy 
will be considered part of the prior systemic chemotherapy regimen and is acceptable. 
e. Subjects who completed and progressed on a platinum-containing regimen as 
adjuvant, neoadjuvant, or part of a course of chemoradiation therapy within the 
6 months before screening would be counted as 1 prior platinum-containing regimen 
and therefore would not require re-treatment with a platinum-containing regimen for 
Stage IV disease. 
4. For Phase 2 Part A Cohort A2 – Primary anti-PD-1/PD-L1–refractory NSCLC (primary 
refractory cohort):   
a. Subjects with histologically or cytologically confirmed locally advanced unresectable 
or metastatic NSCLC. 
b. Subjects with tumors with driver mutations (EGFR mutation–positive, anaplastic 
lymphoma kinase fusion oncogene–positive, proto-oncogene tyrosine-protein kinase 
ROS–positive, or BRAF V600 mutant–positive) should have progressed on or be 
intolerant to the targeted therapy. 
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c. Subjects must have received prior treatment with anti–PD-1 or anti–PD-L1 therapy 
(alone or as part of a combination) in the advanced or metastatic setting and have PD 
as their best response to treatment that is confirmed at least 4 weeks later (no less than 
28 days). 
− Subjects must have received at least 2 doses of a prior anti–PD-1 or anti–PD-L1 
agent. 
− Progressive disease must also be at least 12 weeks from first dose of anti–PD-1 or 
anti–PD-L1 therapy and confirmed 4 weeks (no less than 28 days) later. 
5. For Phase 2 Part A Cohort A3 – Anti-PD-1/PD-L1–relapsed NSCLC (relapsed cohort): 
a. Subjects must have received prior anti–PD-1 or anti–PD-L1 therapy (alone or as part 
of a combination) in the advanced or metastatic setting and achieved either SD for at 
least 24 weeks or PR/CR, but later have confirmed PD (PD confirmed at least 
4 weeks [no less than 28 days] later). 
6. For Phase 2 Part A Cohort B1 – Anti-PD-1/PD-L1–naive melanoma:   
a. Subjects with histologically or cytologically confirmed unresectable Stage III or 
Stage IV melanoma, as per AJCC staging system, not amenable to local therapy. 
b. Have documentation of V600-activating BRAF mutation status or consent to BRAF 
V600 mutation testing during the screening period. 
c. Subjects must not have received more than 2 prior lines of systemic therapy for 
unresectable Stage III or Stage IV melanoma. 
d. Ocular melanoma is excluded. 
7. For Phase 2 Part A Cohort B2 – Primary anti-PD-1/PD-L1–refractory melanoma 
(primary refractory cohort): 
a. Subjects with histologically or cytologically confirmed unresectable Stage III or 
Stage IV melanoma, as per AJCC staging system, not amenable to local therapy. 
b. Have documentation of V600-activating BRAF mutation status or consent to BRAF 
V600 mutation testing during the screening period. 
c. Subjects must have received prior treatment with anti–PD-1 or anti–PD-L1 therapy 
(alone or as part of a combination) in the advanced or metastatic setting and have PD 
as their best response to treatment that is confirmed at least 4 weeks later (no less than 
28 days). 
− Subjects must have received at least 2 doses of a prior anti–PD-1 or anti–PD-L1 
agent. 
− Progressive disease must also be at least 12 weeks from first dose of anti–PD-1 or 
anti–PD-L1 therapy and confirmed 4 weeks (no less than 28 days) later. 
d. Ocular melanoma is excluded. 
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8. For Phase 2 Part A Cohort B3 – Anti-PD-1/PD-L1–relapsed melanoma (relapsed cohort): 
a. Subjects must have received prior anti–PD-1 or anti–PD-L1 therapy (alone or as part 
of a combination) in the advanced or metastatic setting and achieved either SD for at 
least 24 weeks or PR/CR, but later have confirmed PD (PD confirmed at least 
4 weeks [no less than 28 days] later). 
9. For Phase 2 Part A Cohort C – Anti-PD-1/PD-L1–naive urothelial carcinoma:   
a. Subjects with histologically or cytologically confirmed, metastatic or inoperable 
locally advanced urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra 
that is transitional cell or mixed transitional/nontransitional (predominantly 
transitional) cell type. 
b. Subjects must not have received more than 2 prior lines of systemic therapy for 
metastatic or inoperable locally advanced urothelial carcinoma. 
c. For subjects who have received 1 or 2 lines of prior systemic therapy for metastatic or 
inoperable locally advanced urothelial carcinoma, 1 of the prior systemic regimens 
must include a platinum-based therapy.  Subjects who have only received 
non–platinum-based regimens may be enrolled with medical monitor approval.  
10. For Phase 2 Part A Cohort D – Anti-PD-1/PD-L1–naive SCCHN: 
a. Subjects with histologically or cytologically confirmed SCCHN not amenable to local 
therapy with curative intent (surgery or radiation with or without chemotherapy). 
b. Carcinoma of the nasopharynx, salivary gland, or nonsquamous histologies are 
excluded. 
c. Subjects must have received at least 1 prior platinum-based systemic chemotherapy 
regimen, and no more than 2 prior systemic chemotherapy regimens, including 
neoadjuvant and/or adjuvant therapy.  Subjects who relapsed within 6 months of 
adjuvant therapy, including a platinum-containing regimen, may enroll. 
11. For Phase 2 Part A Cohort E – Anti-PD-1/PD-L1–naive SCLC: 
a. Subjects with histologically or cytologically confirmed, advanced or metastatic SCLC 
with PD after at least 1 line of therapy that includes a platinum-based regimen in the 
first-line setting, and after no more than 2 prior lines of chemotherapy, and regardless 
of tumor PD-L1 status. 
12. For Phase 2 Part B Cohort A – Urothelial carcinoma:   
a. Subjects with histologically or cytologically confirmed urothelial carcinoma of the 
renal pelvis, ureter, bladder, or urethra that is transitional cell or mixed 
transitional/nontransitional (predominantly transitional) cell type. 
b. Metastatic or inoperable locally advanced urothelial carcinoma that has progressed on 
prior standard therapy with a platinum-based regimen and a checkpoint inhibitor. 
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24. Willingness to avoid pregnancy or fathering children based on the criteria below: 
a. Woman of nonchildbearing potential (ie, surgically sterile with a hysterectomy and/or 
bilateral oophorectomy OR ≥ 12 months of amenorrhea and at least 50 years of age.) 
b. Woman of childbearing potential who has a negative serum pregnancy test at 
screening and before the first dose on Day 1 and who agrees to take appropriate 
precautions to avoid pregnancy (with at least 99% certainty) from screening through 
safety follow-up (Phase 2 Part B only) or until 120 days after last dose of study 
treatment (Phase 1 and Phase 2 Part A only).  Permitted methods that are at least 99% 
effective in preventing pregnancy (see Appendix A) should be communicated to the 
subject and their understanding confirmed. 
c. Man who agrees to take appropriate precautions to avoid fathering children (with at 
least 99% certainty) from screening through safety follow-up (Phase 2 Part B only) or 
until 120 days after last dose of study treatment (Phase 1 and Phase 2 Part A only).  
Permitted methods that are at least 99% effective in preventing pregnancy (see 
Appendix A) should be communicated to the subject and their understanding 
confirmed. 
3.2. 
Subject Exclusion Criteria 
A subject who meets any of the following criteria will be excluded from the study: 
1. Participation in any other study in which receipt of an investigational study drug or 
device occurred within 2 weeks or 5 half-lives (whichever is longer) before first dose.  
For investigational agents with long half-lives (eg, 5 days), enrollment before the fifth 
half-life requires medical monitor approval. 
2. Has received a prior monoclonal antibody within 4 weeks or 5 half-lives (whichever is 
shorter) before administration of study drug.   
a. Exception:  No time off anti–PD-1 or anti–PD-L1 therapy is required. 
b. Exception:  Denosumab may be used. 
3. Phase 2 Part A Cohorts A1, B1, C, D, and E only:  Has had prior therapy with an anti–
PD-1, anti–PD-L1, anti–PD-L2, anti–CTLA-4, anti-CD137, or any other antibody or drug 
specifically targeting checkpoint pathways. 
a. Exception:  Prior therapy with an anti–CTLA-4 in the adjuvant setting is permitted. 
4. Phase 2 Part A Cohorts A2, A3, B2, and B3 only:  Had any Grade 3/4 or any ocular 
toxicity while receiving prior anti–PD-1 therapy. 
5. Has had prior chemotherapy or targeted small molecule therapy within 2 weeks before 
administration of study treatment. 
6. Has had prior therapy with an IDO1 or arginase 1 inhibitor. 
7. Has received prior radiotherapy within 2 weeks of enrollment (except for radiation to 
CNS, which requires ≥ 4-week washout).  Subjects must have recovered from all 
radiation-related toxicities, not require corticosteroids, and not have had radiation 
pneumonitis. 
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8. Has had major surgery within 4 weeks before enrollment (C1D1). 
9. Has a known additional malignancy that is progressing or requires active treatment, or 
history of other malignancy within 2 years of study entry with the exception of cured 
basal cell or squamous cell carcinoma of the skin, superficial bladder cancer, prostate 
intraepithelial neoplasm, carcinoma in situ of the cervix, or other noninvasive or indolent 
malignancy, or cancers from which the subject has been disease-free for > 1 year, after 
treatment with curative intent. 
10. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dose regimens exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days before the first dose of study treatment. 
11. Has an active autoimmune disease that has required systemic treatment in past 2 years 
(ie, 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) is not considered a form of systemic 
treatment. 
12. Has a known history of HIV infection.  HIV testing is not required unless mandated by 
the local health authority. 
13. Has known history of or is positive for hepatitis B (HBsAg reactive) or hepatitis C (HCV 
RNA).  Note:  Testing must be performed to determine eligibility.  
a. HBV DNA must be undetectable and HBsAg negative at screening visit. 
b. Hepatitis C antibody testing is allowed for screening purposes in countries where 
HCV RNA is not part of standard of care.  In these cases, HCV antibody positive 
patients will be excluded. 
c. Subjects who have had definitive treatment for HCV are permitted if HCV RNA is 
undetectable at screening visit. 
14. Phase 1 and Phase 2 Part A only:  Has a history of (noninfectious) pneumonitis that 
required steroids or has current pneumonitis. 
15. Has known active CNS metastases and/or carcinomatous meningitis.  Subjects with 
previously treated brain metastases may participate provided that they are stable (without 
evidence of progression by imaging for at least 4 weeks before the first dose of study 
treatment, and any neurologic symptoms have returned to baseline), have no evidence of 
new or enlarging brain metastases confirmed by repeat imaging (note that the repeat 
imaging should be performed during study screening), and have not required steroids for 
at least 14 days before study treatment. 
a. Subjects with evidence of cerebral edema will be excluded from participation.  In 
addition, subjects will be excluded from participation in the study if it has been 
< 4 weeks since radiation therapy was delivered to the CNS. 
16. Has had a significant cardiac event within 6 months before Cycle 1 Day 1, including 
myocardial infarction (including severe/unstable angina), coronary/peripheral artery 
bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient 
ischemic attack, or pulmonary embolism.  Medically controlled arrhythmia is permitted. 
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17. Has a history or presence of an abnormal ECG that, in the investigator's opinion, is 
clinically meaningful.  Screening QTc interval > 480 milliseconds is excluded (corrected 
by Fridericia or Bazett formula).  In the event that a single QTc is > 480 milliseconds, the 
screening ECG may be repeated in triplicate, and the subject may enroll if the average 
QTc is < 480 milliseconds. 
18. Has received live vaccine within 30 days before the first dose of study treatment.  
Examples of live vaccines include, but are not limited to, the following:  measles, 
mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid vaccine.  Seasonal 
influenza vaccines for injection are generally killed virus vaccines and are allowed; 
however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are 
not allowed. 
19. Has any history of SS after receiving serotonergic drugs. 
20. Concomitant therapy with valproic acid/valproate-containing therapies. 
21. Concomitant therapy with allopurinol and other xanthine oxidase inhibitors. 
22. Has received therapy with a MAOI or UGT1A9 inhibitor within 21 days before starting 
treatment, or anticipates requiring one of these prohibited medications during the 
treatment phase.  Examples of medications in these classes are found in Section 5.6.3. 
23. Current use of any prohibited medication as described in Section 5.6.3.  
24. Has a known or suspected defect in the function of the urea cycle, including a known 
deficiency of carbamoyl phosphate synthetase I, ornithine transcarbamylase, 
argininosuccinate synthetase, argininosuccinate lyase, N-acetyl glutamate synthetase, or 
arginase. 
25. Has a history of gastrointestinal condition (eg, inflammatory bowel disease, Crohn's 
disease, ulcerative colitis) that may affect drug absorption. 
26. Unable to receive medications PO. 
27. Has known hypersensitivity ≥ Grade 3, or severe reaction, to study treatments or any of 
their excipients. 
28. Pregnant or breastfeeding. 
29. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the subject's participation for 
the full duration of the study, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator. 
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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
This is a Phase 1/2 study, with Phase 1 being a dose-escalation of the triplet combination of 
INCB001158 plus epacadostat and pembrolizumab, and with Phase 2 consisting of tumor 
expansion cohorts to study the RP2D of the triplet combination of INCB001158 plus epacadostat 
and pembrolizumab in Part A and the RP2D of the doublet combination of INCB001158 plus 
epacadostat in Part B.  Figure 2 shows a schematic of the study design.  
Subjects with advanced or metastatic solid tumors will be enrolled in Phase 1.  Subjects with 
select advanced or metastatic solid tumors will be enrolled in Phase 2 Parts A (NSCLC, 
melanoma, urothelial carcinoma, SCCHN, and SCLC) and B (urothelial carcinoma, SCCHN, and 
CRC). 
See Section 4.1.1 for full details of the triplet dose escalation (Phase 1), Sections 4.1.2 and 4.1.3  
for full details of tumor expansion (Phase 2 Parts A and B, respectively), and Section 5.2 for full 
study drug administration information. 
The definition of DLTs is provided in Section 5.4.2. 
Continuous evaluation of toxicity events will be performed in the expansion cohorts.  If the 
cumulative incidence of Grade ≥ 3 immune-related AEs is > 40% after 10 subjects are enrolled 
in a specific expansion cohort within Phase 2, further enrollment in that cohort will be 
interrupted until the sponsor, investigators, and regulatory authorities (if applicable) determines 
the appropriate course of action.  If an expansion cohort is discontinued due to toxicity, a new 
cohort may be initiated at a previously tested lower dose level. 
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INCB001158 plus epacadostat and pembrolizumab combination, the dose escalation and 
de-escalation rules are shown in Table 2.  The BOIN design also includes an elimination rule.  
When ≥ 3 subjects have been treated, if the probability that the estimated toxicity rate that is 
above the target DLT rate is > 95% at a certain dose level, then this dose level and higher dose 
levels are assumed too toxic and will be eliminated.  If the lowest dose level is eliminated, the 
whole dose escalation will be terminated.  Table 2 (in the bottom row) provides the elimination 
rules.  Based on this algorithm, a minimum of 3 evaluable subjects and a maximum of 
9 evaluable subjects will be enrolled at each tested dose level.  The dose escalation will continue, 
based on the rules in Table 2, until the rules require at least 1 of the following: 
• Enrollment of additional subjects in a cohort that already has 9 evaluable subjects, or 
• Dose escalation to a dose level that has already been eliminated, or 
• Dose escalation above the maximum allowable dose level identified in the 
INCB 01158-101 study (see Section 1.2.4).   
At that point, the dose escalation will be stopped. 
Table 2: 
Dose Escalation, De-Escalation, and Elimination Boundaries for Target DLT 
Rate = 33% in Phase 1 
Action 
The Number of Subjects Treated at the Current Dose 
1 
2 
3 
4 
5 
6 
7 
8 
9
a 
Escalate if # of 
DLTs ≤ 
NA 
NA 
0 
1 
1 
1 
1 
2 
2 
De-escalate if 
# of DLTs ≥ 
1 
1 
2 
2 
2 
3 
3 
4 
4 
Elimination if 
# of DLTs ≥ 
NA 
NA 
3 
3 
4 
4 
5 
5 
6 
DLT = dose-limiting toxicity; NA = not applicable. 
a If 9 evaluable subjects are enrolled in a cohort and 3 of those subjects experience a DLT, then the medical monitor 
and the investigators will review the entirety of the data and decide whether to dose-escalate, dose–de-escalate, or 
to stop at that dose level. 
Dose escalation will begin with starting doses of INCB001158 at least 2 dose levels below the 
maximum tolerated and tested dose from the INCB 01158-101 study (likely to be 50 mg BID or 
75 mg BID – see Table 3 and Table 4, respectively.  If the starting dose is not one of those 2 dose 
levels, then a revised dose escalation table will be provided to sites.  However, the starting doses 
of epacadostat (100 mg PO BID continuous dose administration) and pembrolizumab (200 mg 
IV Q3W) will not be changed.  Epacadostat 100 mg BID was selected as the starting dose 
because it has been shown to be active and tolerable in several epacadostat combination clinical 
studies, including with pembrolizumab (eIB, Gangadhar et al 2017, Hamid et al 2017a, 
Hamid et al 2017b, Smith et al 2017).  The starting dose of pembrolizumab is the standard, 
approved dose and schedule (Keytruda PI, Keytruda SPC) and also the dose used in combination 
with epacadostat in Phase 3.   
If the starting doses of the triplet combination of INCB001158, epacadostat, and pembrolizumab 
are tolerable (eg, none of the first 3 evaluable subjects experiences a DLT; see Section 5.4.2), 
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then the INCB001158 dose will be escalated in subsequent cohorts, while keeping the 
epacadostat and pembrolizumab doses constant, until one of the stopping rules (described above 
and in Table 2) is met.   
If the starting doses of INCB001158, epacadostat 100 mg BID, and pembrolizumab 200 mg 
Q3W are not tolerable, then an additional cohort will be enrolled at a reduced dose of either 
INCB001158 or epacadostat, depending on which one is deemed most likely to have caused the 
intolerability, upon agreement between the medical monitor and the study investigators (ie, Dose 
Level -1A or -1B; see Table 3 and Table 4). 
A PAD will be defined as a dose at or below the monotherapy MTD at which at least half of the 
subjects (and at least 2 subjects in total) enrolled at a particular dose level achieve a trough (Cmin) 
plasma concentration of INCB001158 at steady state of ≥1 μM, which is equivalent to the IC90 
for arginase 1.  This definition may be modified based on emerging data from the 
INCB 01158-101 first-in-human study, upon agreement between the medical monitor and the 
study investigators.  The MTD, if reached, is the maximum tested dose of INCB001158, such 
that no more than 33% of the subjects receiving the triplet combination experience a DLT during 
the first 6 weeks on study drug. 
Dose interruptions and/or modifications may be implemented based on toxicity.  Dose 
modifications should not be made during the DLT observation period without discussion with 
the medical monitor.  Intrasubject dose escalation is not permitted. 
After completing the dose escalation per the BOIN rules, one of the INCB001158 dose levels 
that is pharmacologically active (ie, a PAD) and tolerable in combination with epacadostat 
100 mg BID or lower and pembrolizumab 200 mg Q3W (ie, MTD or lower) will be selected, and 
that triplet combination will be the RP2D.  The doublet RP2D would consist of the same doses of 
INCB001158 and epacadostat. 
Note that if a dose level to be assigned as RP2D has fewer than 9 evaluable subjects in it, then 
the medical monitor and study investigators can consider adding subjects to a total of 9 before 
making the final RP2D decision. 
The safety and tolerability of the triplet RP2D will be further assessed in 9 tumor expansion 
cohorts in Phase 2 Part A (see Section 4.1.2), and the safety and tolerability of the doublet RP2D 
will be further assessed in 3 tumor expansion cohorts in Phase 2 Part B (see Section 4.1.3). 
Telephone conferences will be scheduled by the sponsor with study investigators in order to 
review cohort-specific data and overall safety data, agree on dose escalation/de-escalation, 
adjudicate individual high-grade AEs as potentially dose-limiting, and guide other major study 
decisions. 
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4.1.2. 
Phase 2 Part A:  Tumor Expansion of INCB001158 + Epacadostat + 
Pembrolizumab 
The RP2D of the triplet combination of INCB001158, epacadostat, and pembrolizumab 
identified in Phase 1 will be further assessed in Phase 2 Part A in the following 9 tumor 
expansion cohorts, 5 of which include only anti-PD-1/PD-L1–naive subjects, and 4 of which 
include only subjects who have received an anti–PD-1 or anti–PD-L1 agent in a recent line of 
therapy: 
• Cohort A1:  Subjects with anti-PD-1/PD-L1–naive NSCLC who have received no 
more than 2 prior systemic chemotherapy regimens for Stage IV disease, one of 
which must include a platinum-based therapy (see Inclusion Criterion 3 for more 
details).  In a similar population in the INCB 24360-202 study, the ORR for 
epacadostat + pembrolizumab was 39% (Gangadhar et al 2017).  However, in this 
study, a slightly lower ORR of 30% will be used as the background ORR. 
• Cohort A2:  Subjects with locally advanced unresectable or metastatic NSCLC who 
received prior treatment with anti–PD-1 or anti–PD-L1 therapy (alone or as part of a 
combination) in the advanced or metastatic setting and have PD as their best response 
to treatment that is confirmed at least 4 weeks later (see Inclusion Criterion 4 for 
more details).  This population is expected to be refractory to further anti–PD-1/anti–
PD-L1 treatment.  This will be known as the primary anti–PD-1/anti–PD-L1 
refractory cohort (primary refractory).  
• Cohort A3:  Subjects with locally advanced unresectable or metastatic NSCLC who 
have received prior anti–PD-1 or anti–PD-L1 therapy (alone or as part of a 
combination) in the advanced or metastatic setting and achieved either SD for at least 
24 weeks or PR/CR but later have confirmed PD (PD confirmed at least 4 weeks 
later).  See Inclusion Criterion 5 for more details.  This will be known as the 
anti-PD-1/PD-L1–relapsed cohort (relapsed). 
• Cohort B1:  Subjects with anti-PD-1/PD-L1–naive melanoma who have received no 
more than 2 prior lines of systemic therapy for unresectable Stage III or Stage IV 
disease (see Inclusion Criterion 6 for more details).  In a similar population in the 
INCB 24360-202 study, the ORR for epacadostat + pembrolizumab was 56% 
(Gangadhar et al 2016). 
• Cohort B2:  Subjects with unresectable Stage III or Stage IV melanoma who received 
prior treatment with anti–PD-1 or anti–PD-L1 therapy (alone or as part of a 
combination) in the advanced or metastatic setting and have PD as their best response 
to treatment that is confirmed at least 4 weeks later (see Inclusion Criterion 7 for 
more details).  This population is expected to be refractory to further anti–PD-1/anti–
PD-L1 treatment.  This will be known as the primary anti-PD-1/PD-L1–refractory 
cohort (primary refractory). 
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• Cohort B3:  Subjects with unresectable Stage III or Stage IV melanoma who have 
received prior anti–PD-1 or anti–PD-L1 therapy (alone or as part of a combination) in 
the advanced or metastatic setting and achieved either SD for at least 24 weeks or 
PR/CR, but later have confirmed PD (PD confirmed at least 4 weeks later).  See 
Inclusion Criterion 8 for more details.  This will be known as the anti-PD-1/PD-L1–
relapsed cohort (relapsed). 
• Cohort C:  Subjects with PD(L)1-naive urothelial carcinoma who have received no 
more than 2 prior lines of systemic chemotherapy regimens for metastatic or 
inoperable locally advanced disease, one of which must include a platinum-based 
therapy (see Inclusion Criterion 7 for more details).  In a similar population in the 
INCB 24360-202 study, the ORR for epacadostat + pembrolizumab was 38% (first 
and second line) and 25% (third line and beyond; Smith et al 2017). 
• Cohort D:  Subjects with PD(L)1-naive SCCHN not amenable to local therapy with 
curative intent, who have received at least 1 prior platinum-based systemic 
chemotherapy regimen, and no more than 2 prior systemic chemotherapy regimens 
(see Inclusion Criterion 8 for more details).  In a similar population in the 
INCB 24360-202 study, the ORR for epacadostat + pembrolizumab was 39% 
(Hamid et al 2017b). 
• Cohort E:  Subjects with PD(L)1-naive, advanced or metastatic SCLC who have 
received at least 1 line of therapy that includes a platinum-based regimen in the 
first-line setting, and no more than 2 prior lines of chemotherapy (see Inclusion 
Criterion 9 for more details).  In a broadly similar PD-L1–unselected population in 
the CheckMate 032 study, the ORR for nivolumab was 11%, whereas the ORR in a 
PD-L1–positive population treated with pembrolizumab was 33% 
(Hellman et al 2017, Ott et al 2016; see also Section 1.2.3.2).  However, the sample 
sizes were small in each study, so these differences in ORR observed with 
pembrolizumab and nivolumab may not pan out in larger studies.  For the purposes of 
this study, the baseline ORR was selected based on the average ORR of the 2 anti–
PD-1 agents and allowing for some theoretical additive activity from epacadostat.  Of 
note, epacadostat has not been studied in combination with an anti–PD-1 agent. 
In each cohort, the ORR of the triplet combination will be assessed using a Simon 2-stage design 
(see Table 5), to determine whether the combination has sufficient antitumor activity to warrant 
further testing in subsequent clinical studies.  The basis for the background ORR selected for 
each cohort is described above. 
Note that the sponsor may evaluate fewer expansion cohorts or some cohorts in sequence, at their 
discretion. 
If, at the time of completion of enrollment in Stage 1, it is not known whether the target ORR to 
proceed to Stage 2 will be met, then enrollment will be paused until and unless the ORR to 
proceed has been met. 
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4.3. 
Number of Subjects 
4.3.1. 
Planned Number of Subjects 
Under Protocol Amendment 2, up to 5 subjects will be enrolled in the dose-escalation (Phase 1) 
part.  No subjects will be enrolled in Phase 2.   
It is planned to have 4 sites during Phase 1. 
4.3.2. 
Replacement of Subjects 
During dose escalation in Phase 1, up to 4 subjects per cohort will be enrolled at a time, with the 
aim of obtaining at least 3 subjects who are evaluable for DLTs (see Section 5.4.2 for definition).  
If fewer than 3 subjects are evaluable, additional subjects will be enrolled until there are 
3 evaluable subjects. 
4.4. 
Duration of Treatment and Subject Participation 
After signing the ICF, subject study participation, including screening and post-treatment 
follow-up is expected to average approximately 12 to 18 months per individual subject.  Note 
that the treatment period will last as long as subjects are deriving benefit, are tolerating the 
regimen and do not meet withdrawal criteria. 
4.5. 
Overall Study Duration 
The study begins when the first subject signs the ICF.  The end of the study will occur when all 
subjects have 
 been lost to follow-up, or have withdrawn consent for further follow-up.  It 
is anticipated that the study duration will be approximately 3 years. 
If there are ≤ 5 subjects on study for more than 6 months, a database lock of the study may occur 
to allow the analysis of the study data.  Any remaining subjects may continue to receive study 
treatment and be seen by the investigator per the study assessments in Section 6.  The remaining 
subjects are considered to be on study until a discontinuation criterion is met and written 
notification is provided to the sponsor. 
4.6. 
Study Termination 
The investigator retains the right to terminate study participation at any time, according to the 
terms specified in the study contract.  The investigator is to notify the institutional review board 
(IRB)/independent ethics committee (IEC) in writing of the study's completion or early 
termination, send a copy of the notification to the sponsor or sponsor's designee, and retain 
1 copy for the site study regulatory file. 
The sponsor may terminate the study electively or if required by regulatory decision.  If the study 
is terminated prematurely, the sponsor will notify the investigators, the IRBs and IECs, and 
regulatory bodies of the decision and reason for termination of the study. 
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4.6.1. 
Protocol Amendment (Version) 2 
As of this Protocol Amendment (Version) 2, enrollment of subjects into any part of Study 
INCB 01158-202 is halted.  This is based on the results from the ECHO-301/KEYNOTE-252 
melanoma clinical study (Long et al 2018).  In an interim analysis, the study did not meet the 
prespecified endpoint of improvement in progression-free survival for the combination of 
pembrolizumab and epacadostat compared with pembrolizumab and placebo.  The overall 
survival endpoint was also not expected to reach statistical significance.  There were no safety 
concerns with the treatment (pembrolizumab + epacadostat) arm compared with the control 
(pembrolizumab + placebo) arm. 
Given the outcome of study ECHO-301/KEYNOTE-252, the changes to the INCB 01158-202 
study design are summarized below: 
• The ongoing Phase 1 portion (dose escalation and safety evaluation of INCB001158 
in combination with epacadostat and pembrolizumab) will stop further enrollment, 
except for patients who have consented and are in screening as of 08 MAY 2018.  
These subjects will be permitted to enroll if eligibility is determined as outlined per 
the Protocol. 
• The Phase 1 backfill cohorts and the Phase 2 portion of the study (Part A – tumor 
expansion of INCB001158 + epacadostat + pembrolizumab and Part B – tumor 
expansion of INCB001158 + epacadostat) will not be opened. 
• Ongoing Phase 1 subjects may continue treatment with INCB001158 + epacadostat + 
pembrolizumab as long as, per the Protocol, they are deriving clinical benefit, 
tolerating the treatment, and do not meet any withdrawal criteria. 
Sections of the Protocol relating to the parts of the study that will no longer be conducted are 
now not applicable and should be ignored. 
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5. 
TREATMENT 
5.1. 
Treatment Assignment 
5.1.1. 
Subject Numbering and Treatment Assignment 
Each subject will be identified in the study by a subject ID number, which is a combination of 
the site ID and subject number.  Site staff should contact the IRT to obtain the subject ID number 
and confirm a slot is available during prescreening.  This subject ID number will be maintained 
throughout the study and will not be reassigned.  The site staff will contact the IRT to enroll the 
subject and obtain the study drug and treatment group assignment.  All subsequent cycles will 
follow this process.  The IRT will also be contacted for ordering study drug supplies and when 
subjects are discontinued from treatment.  Full details will be provided in the IRT manual. 
5.1.2. 
Randomization and Blinding 
Not applicable, as this is an open-label study. 
5.2. 
Study Drugs and Other Study Treatments 
Study treatment is defined as any investigational treatment(s) or marketed product(s) intended to 
be administered to a study subject according to the study Protocol.  There are 3 investigational 
study treatments in this study – INCB001158, epacadostat, and pembrolizumab (Table 7).  
INCB001158 is also referred to as the study drug in this Protocol.  Although pembrolizumab is 
approved and marketed in various indications (see Section 1.1.3.1), it is investigational in this 
study in combination with INCB001158 and epacadostat.   
Table 7: 
Study Drug and Other Study Treatments 
Drug 
Dose 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment Period 
INCB001158 
25-150 mg
a 
BID 
Oral 
Phase 1 and Phase 2 Part A:  Daily 
until meets discontinuation criteria 
or for 35 cycles
b, whichever is 
sooner  
Phase 2 Part B:  Daily until meets 
discontinuation criteria 
Epacadostat 
50-100 mga 
BID 
Oral 
Phase 1 and Phase 2 Part A:  Daily 
until meets discontinuation criteria 
or for 35 cyclesb, whichever is 
sooner  
Phase 2 Part B:  Daily until meets 
discontinuation criteria 
Pembrolizumab 
200 mg 
Every 
3 weeks 
IV infusion 
Phase 1 and Phase 2 Part A:  Day 1 
of each cycle until meets 
discontinuation criteria or for up to 
35 cyclesb, whichever is sooner 
a See Section 4.1.1 for details of dose levels of INCB001158 and epacadostat during the Phase 1 dose escalation. 
b A cycle length of 21 days. 
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5.2.1. 
INCB001158 
5.2.1.1. 
Description and Administration 
INCB001158 will be administered orally using a capsule (25 mg or 100 mg per capsule) 
formulation.  INCB001158 will be administered only to subjects who have signed and dated an 
ICF.  INCB001158 will be administered on Days 1 through 21 of each 21-day cycle and should 
be taken orally using the number of capsules directed in the Pharmacy Manual.  The starting 
dose will depend on which phase of the study the subject is in.  In Phase 1, the starting dose will 
be based on which dose level cohort the subject is in; in Phase 2, the starting dose will be the 
RP2D identified in Phase 1.  INCB001158 dosing will not be adjusted for body weight or surface 
area. 
In Phase 1 and Phase 2 Part A, INCB001158 and epacadostat will be given daily in combination 
with pembrolizumab for up to 35 cycles, as long as disease progression has not occurred and 
criteria for treatment discontinuation have not been met. 
In Phase 2 Part B, INCB001158 and epacadostat will be given daily for as long as disease 
progression has not occurred and criteria for treatment discontinuation have not been met. 
5.2.1.2. 
Supply, Packaging, and Labeling 
INCB001158 will be provided to sites by Incyte.  The contents of the label will be in accordance 
with all applicable regulatory requirements.  
INCB001158 will be supplied as 25 mg or 100 mg capsules packaged in blister cards.  No 
preparation is required.  All capsule excipients comply with the requirements of the applicable 
compendial monographs (Ph Eur, USP/NF; refer to iIB). 
All Incyte investigational product labels will be in the local language and will comply with the 
legal requirements of each country. 
5.2.1.3. 
Storage 
Blister cards of INCB001158 capsules should be stored at room temperature, 15°C to 30°C (59°F 
to 86°F). 
5.2.1.4. 
Instruction to Subjects for Handling Study Drug (INCB001158) 
The subject must be instructed in the handling of study drug as follows: 
• To store the study drug at room temperature. 
• To only remove from the study drug blister card the number of capsules needed at the 
time of administration. 
• Not to remove doses in advance of the next scheduled administration. 
• To make every effort to take doses on schedule. 
• To report any missed doses. 
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• To take study drug at approximately the same times each day without respect to food 
(except on Protocol-defined clinic days, when the subject should fast for at least 
8 hours before taking study drug; see Section 7.6.5.2) and with a full glass of water.  
The second dose on any given day should be taken approximately 12 hours after the 
first dose. 
• Subjects who vomit their INCB001158 dose should be instructed NOT to make up 
that dose and to report the frequency of vomiting occurrences associated with study 
drug administration to the site.  Subjects who report ≥ 3 incidences of vomiting 
associated with study drug administration will have a blood sample drawn for an 
unscheduled PK analysis. 
• To keep study drug in a safe place and out of reach of children. 
• To bring all used and unused study drug blister cards to the site at each visit. 
• Missed doses of INCB001158 should be skipped.  If a subject forgets to take a dose 
of study drug and he/she is outside of the allotted window period (± 6 h), then he/she 
should be instructed to skip that dose and NOT to take extra study drug at their next 
administration. 
• On Protocol-defined clinic days (see Table 14) subjects should be instructed NOT to 
take their morning dose of INCB001158 at home.  The morning dose must be 
administered at the clinical site after all predose procedures have been performed.  
The time of dose administration will be recorded in the clinic.  The evening doses will 
be self-administered by the subject after all postdose activities have been completed. 
5.2.2. 
Epacadostat 
Epacadostat 25 mg or 100 mg tablets will be self-administered orally BID.  All BID doses will 
be taken morning and evening, approximately 12 hours apart without respect to food.  If a dose is 
missed by more than 4 hours, that dose should be skipped and should be resumed at the 
scheduled time.  Dose reductions or interruptions may be required for safety, see Section 5.4. 
5.2.2.1. 
Description and Administration 
Epacadostat 25 mg or 100 mg tablets will be self-administered orally BID.  All BID doses will 
be taken morning and evening, at the same time as the INCB001158 dose, approximately 
12 hours apart, without respect to food.  If a dose is missed by more than 4 hours, that dose 
should be skipped and should be resumed at the next scheduled time.  Dose reductions or 
interruptions may be required for safety; see Section 5.4.  Subjects will hold the morning dose of 
epacadostat for each clinic visit; study medication will be administered in the clinic. 
In Phase 1 and Phase 2 Part A, epacadostat may be taken in combination with INCB001158 and 
pembrolizumab for up to 35 cycles as long as disease progression has not occurred and criteria 
for treatment discontinuation have not been met. 
In Phase 2 Part B, epacadostat and INCB001158 will be given daily for as long as disease 
progression has not occurred and criteria for treatment discontinuation have not been met. 
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5.2.2.2. 
Supply, Packaging, and Labeling 
Epacadostat will be provided to sites by Incyte.  The contents of the label will be in accordance 
with all applicable regulatory requirements. 
Epacadostat will be supplied as 25 mg and 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 eIB). 
5.2.2.3. 
Storage 
Bottles of tablets should be stored at room temperature, 15°C to 30°C (59°F to 86°F). 
5.2.2.4. 
Instruction to Subjects for Handling Epacadostat  
The subject must be instructed in the handling of epacadostat study treatment as follows: 
• To store the study treatment at room temperature. 
• To only remove from the study treatment bottle/kit the number of tablets needed at the 
time of administration. 
• To make every effort to take doses on schedule. 
• To report any missed doses. 
• Subjects who vomit their epacadostat dose should be instructed NOT to make up that 
dose and to report the frequency of vomiting occurrences associated with study drug 
administration to the site.  Subjects who report ≥ 3 incidences of vomiting associated 
with epacadostat administration will have a blood sample drawn for an unscheduled PK 
analysis. 
• To keep study treatment in a safe place and out of reach of children. 
• To bring all used and unused study treatment kits to the site at each visit. 
• If a dose is missed by more than 4 hours, that dose should be skipped, and the next 
scheduled dose should be administered at the usual time. 
5.2.3. 
Pembrolizumab 
5.2.3.1. 
Description and Administration 
Study treatment with pembrolizumab (Phase 1 and Phase 2 Part A only) should be administered 
on Day 1 of each cycle after all procedures/assessments have been completed.  All study 
treatments will be administered on an outpatient basis. 
Study treatment of pembrolizumab may be administered up to 3 days before or after the 
scheduled Day 1 of each cycle due to administrative reasons except for Cycle 1 Day 1, where 
there is no window.  
Pembrolizumab will be administered as a dose of 200 mg using a 30-minute IV infusion, to start 
directly after the AM doses of INCB001158 and epacadostat.  Sites should make every effort to 
target infusion timing to be as close to 30 minutes as possible.  However, given the variability of 
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infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted 
(ie, infusion time is 30 minutes -5 min/+10 min).  
Pembrolizumab in combination with INCB001158 and epacadostat may be taken for up to 
35 cycles as long as disease progression has not occurred. 
5.2.3.2. 
Supply, Packaging, and Labeling  
Pembrolizumab is supplied either as 50 mg lyophilized powder for reconstitution in single-use 
vials or as 25 mg/mL sterile solution for infusion in 4 mL vials.  The Pharmacy Manual contains 
specific instructions for pembrolizumab, for reconstitution of the lyophilized powder, preparation 
of the infusion fluid, and administration. 
5.2.3.3. 
Storage 
Vials of pembrolizumab must be stored under refrigeration at 2°C to 8°C (36°F to 46°F) in the 
original carton to protect them from light.  Do not freeze.  Do not shake.    
5.3. 
Treatment Compliance 
Compliance with all study-related treatments should be emphasized to the subject by the site 
personnel, and appropriate steps should be taken to optimize compliance during the study.  
Compliance with INCB001158 and epacadostat will be calculated by the sponsor based on the 
drug accountability documented in the patient diaries and by the site staff and will be monitored 
by the sponsor/designee (capsule/tablet counts).  Subjects will be instructed to bring all study 
treatments with them to the study visits from Cycle 2 Day 1 onwards, in order for site personnel 
to conduct capsule/tablet counts to assess study treatment accountability.  The drug 
accountability documentation will be used by the sponsor to calculate treatment compliance. 
Pembrolizumab is administered as an IV infusion by site personnel.  Receipt of infusions will be 
documented by the site staff and monitored by the sponsor/designee. 
5.4. 
Treatment Interruptions and Adjustments 
5.4.1. 
Dose Modifications 
Selections and modifications to the study treatment regimen are planned for dose-escalation 
cohorts in Phase 1.  Dose interruptions and modifications also may occur for individual study 
subjects.  The identification of DLTs will define the doses used in planned cohorts (see 
Section 4.1.1).  Further, the occurrence of DLTs and other toxicities (related or unrelated to 
study treatment) will guide decisions for treatment interruptions and discontinuation for 
individual subjects.  Dose modifications should not be made during the DLT observation period 
without discussion with the medical monitor.  Intrasubject dose escalation will not be permitted. 
5.4.1.1. 
INCB001158 
For subjects in Phase 1, dose reductions of INCB001158 will be permitted during the first 
2 cycles (first 42 days) only if a subject experiences a DLT or a toxicity that may herald a DLT.  
If a subject experiences a DLT, treatment continuation at a lower dose of INCB001158 will be 
permitted as long as the toxicity has returned to ≤ Grade 1 or baseline within 28 days.  When 
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INCB001158 is held or discontinued, epacadostat and pembrolizumab therapy may be continued, 
at the investigator's discretion.  Upon recovery, subjects may restart at 1 INCB001158 dose level 
lower.  Subjects who do not recover within 28 days will not be eligible for resumption of study 
treatment without approval from the medical monitor.  After Cycle 2, dose reductions or 
interruptions for AEs may take place at any time at the discretion of the investigator in 
consultation with the medical monitor.  See also Table 9. 
5.4.1.2. 
Epacadostat 
Doses of epacadostat may need to be decreased because of toxicity, or interrupted and restarted 
with recovery of laboratory values or AEs.  See also Table 9. 
5.4.1.3. 
Pembrolizumab 
In Phase 1 and Phase 2 Part A, pembrolizumab may be interrupted, but no dose modifications are 
permitted.  In all cases where pembrolizumab dosing is held, dosing for INCB001158 and 
epacadostat must also be held.  However, if either or both of INCB001158 and epacadostat is/are 
discontinued due to drug-related AEs, subjects are allowed to continue to receive the other study 
treatments.  See also Table 9. 
5.4.2. 
Dose-Limiting Toxicity and Determination of Maximum Tolerated Dose in 
Phase 1 
Dose-limiting toxicity will be defined as the occurrence of any of the toxicities in Table 8 
occurring up to and including Day 42, except those with a clear alternative explanation 
(eg, disease progression) or transient (≤ 72 hours) abnormal laboratory values without associated 
clinically significant signs or symptoms based on investigator determination.  All DLTs will be 
assessed by the investigator using CTCAE v4.03 criteria.  Subjects who receive at least 63 of 
84 doses (≥ 75%) for each of INCB001158 and epacadostat at the level assigned plus at least 
2 doses of pembrolizumab or who have a DLT, will be considered evaluable for determining 
tolerability of the dose.  Subjects who do not meet these criteria may be replaced to obtain 
sufficient evaluable subjects to be able to assess that dose level using the BOIN design, as 
outlined in Table 2.  
Clear evidence of urea cycle inhibition (eg, an increase in fasting urinary orotic acid to 
> 10 × ULN, any orotic acid value of > 40 × ULN, or symptomatic hyperammonemia) would 
also be considered a dose-limiting event and will be treated the same as a DLT with regard to the 
dose escalation rules and definition of the MTD described in Section 4.1.1.  Refer to the 
INCB001158 IB (iIB) for an explanation of these orotic acid thresholds. 
Individual subject dose reductions for INCB001158 and epacadostat may be made based on 
events observed at any time during treatment; however, for the purposes of dose cohort 
escalation/de-escalation, expanding a dose cohort, and determining the MTD of INCB001158, 
decisions will be made based on events that are observed from the first day of study treatment 
administration through and including the final day of Cycle 2 (Day 42).  A lower MTD may 
subsequently be determined based on relevant toxicities that become evident after Day 42. 
If a subject experiences a DLT that is considered life-threatening, permanently discontinue all 
3 study treatments.  If a subject experiences a DLT that is not considered life-threatening, 
interrupt all 3 study treatments, and follow the management guidelines in Table 9. 
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5.4.5. 
Procedures for Cohort Review and Dose Escalation 
Telephone conferences will be scheduled by the sponsor with study investigators in order to 
review cohort-specific data and overall safety data, agree on dose escalation, adjudicate 
individual high-grade AEs as potentially dose-limiting, and guide other major study decisions. 
5.4.6. 
Dose Modifications for Immune-Related AEs and AEs Related to Urea-Cycle 
Inhibition 
As described in Section 1.3.1, INCB001158 has the potential to cause toxicity related to 
inhibition of arginase 1 in the hepatic urea cycle.  Table 9 provides guidance for INCB001158 
dose modifications and subject management if there is evidence of urea cycle inhibition. 
Dose modification and toxicity management for irAEs associated with INCB001158, 
epacadostat, and/or pembrolizumab should be managed as follows. 
Adverse events (both nonserious and serious) associated with INCB001158, epacadostat, and/or 
pembrolizumab exposure may represent an immunologic etiology.  These irAEs may occur 
shortly after the first dose or several months after the last dose of treatment and may affect more 
than 1 body system simultaneously.  Therefore, early recognition and initiation of treatment is 
critical to reduce complications.  Based on existing clinical study data, most irAEs were 
reversible and could be managed with interruptions of pembrolizumab, administration of 
corticosteroids, and/or other supportive care.  For suspected irAEs, adequate evaluation should 
be ensured to confirm etiology or exclude other causes.  Additional procedures or tests such as 
bronchoscopy, endoscopy, or skin biopsy may be included as part of the evaluation.  Based on 
the severity of irAEs, withhold or permanently discontinue INCB001158, epacadostat, and/or 
pembrolizumab and administer corticosteroids. 
Table 9 summarizes the AE dose modification actions for INCB001158, epacadostat, and/or 
pembrolizumab.  For subjects enrolled in Phase 2 Part B and receiving only INCB001158 and 
epacadostat, the pembrolizumab details in this table should be ignored.  Of note, when indicated 
by Table 9 to mitigate irAEs, the dose of INCB001158 must be reduced using the dose levels 
outlined in Table 3, and the dose of epacadostat must be reduced using the dose levels outlined in 
Table 10.  Once reduced, re-escalation of INCB001158 and epacadostat is not permitted. 
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c For subjects with Grade 3 or 4 immune-related endocrinopathy where withholding of INCB001158, epacadostat, and pembrolizumab is required,  
INCB001158, epacadostat, and pembrolizumab  may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or 
achieved metabolic control (in case of T1DM). 
d Withhold OR permanently discontinue INCB001158, epacadostat and pembrolizumab at the discretion of the investigator. 
e Subjects with Grade 3 rash in the absence of desquamation, no mucosal involvement, does not require systemic steroids, and resolves to Grade 1 within 14 days 
does not have to hold  study medication 
f If Grade 4 lipase/amylase elevation is asymptomatic and abdominal imaging suggests no pathology, study treatment administration dosing may continue (with 
or without dose reduction) with medical monitor approval. 
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Table 10: 
Dose Level Adjustments of Epacadostat 
Starting Dose of 
Epacadostat 
Dose Level -1 
Dose Level -2 
First reduction of epacadostat 
Second reduction of 
epacadostat 
100 mg BID 
50 mg BID 
25 mg BID 
Dose Level -2 is the lowest dose of epacadostat in this Protocol.  If a subject is at Dose Level -2 
and is instructed by Table 9 to further reduce epacadostat by 1 level, the investigator may choose 
to continue at Dose Level -2 when the AE has resolved to Grade 0 or 1 or to discontinue 
epacadostat.  Refer to Section 5.2.2 for details. 
5.4.7. 
Procedures for Subjects Exhibiting Serotonin Syndrome 
As noted in Section 1.3.2, there is a rare chance that epacadostat could cause an increase in 
serotonin levels in the brain that might trigger SS, when administered alone or in combination 
with other serotonergic agents.  This syndrome has been most closely associated with use of 
MAOIs, meperidine, linezolid, or methylene blue; all of these agents are prohibited during the 
study (Section 5.6.3). 
Selective serotonin reuptake inhibitors and SNRIs are permitted in the study.  Serotonin 
syndrome usually manifests with autonomic changes, mental status changes, and neurological 
findings.  These mild, moderate, and severe signs and symptoms of SS (summarized in Table 11) 
should be evaluated in the context of possible comorbid conditions as well. 
The following procedures will be implemented if subjects exhibit the signs/symptoms of SS, 
including tremor; hyperreflexia; spontaneous, ocular, or inducible clonus; together with 
agitation, fever, diaphoresis, or muscle rigidity: 
• Immediately interrupt all study treatment administration. 
• Immediately interrupt any SSRI or SNRI administration. 
• Provide appropriate medical management of the subject until all signs/symptoms are 
resolved (eg, IV fluids and/or sympathomimetic amines for hypotension, 
benzodiazepines for agitation, administration of 5-hydroxytryptamine antagonists 
such as cyproheptadine). 
• If etiologies other than SS are excluded, INCB001158 and pembrolizumab 
administration may be resumed unless other AE management guidelines apply for the 
specific event. 
• If subject chooses to remain in the study, restart treatment with epacadostat after the 
SSRI or SNRI has been discontinued, no sooner than 5 half-lives have elapsed for the 
specific SSRI or SNRI in question, and after resolution of signs/symptoms of SS.  
The SSRI or SNRI dosing MAY NOT be restarted. 
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• 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. 
• If a subject had experienced moderate or severe unconfounded SS in the opinion of 
the investigator, without concomitant SSRI or SNRI usage, or serotonergic 
concomitant medications, only INCB001158 and pembrolizumab administration may 
be resumed; epacadostat treatment should be permanently discontinued. 
Table 11: 
Signs and Symptoms of Serotonin Syndrome 
Seriousness 
Autonomic signs                Neurological signs          Mental status       Other 
Mild 
Afebrile or low-grade 
fever 
Tachycardia 
Mydriasis 
Diaphoresis or shivering 
Intermittent tremor 
Akathisia 
Myoclonus 
Mild hyperreflexia 
Restlessness 
Anxiety 
 
Moderate 
Increased tachycardia 
Fever (up to 41°C) 
Diarrhea with hyperactive 
bowel sounds 
Diaphoresis with normal 
skin color 
Hyperreflexia 
Inducible clonus 
Ocular clonus (slow 
continuous lateral eye 
movements) 
Myoclonus 
Easily startled 
Increased 
confusion 
Agitation and 
hypervigilance 
Rhabdomyolysis 
Metabolic acidosis 
Renal failure 
Disseminated 
intravascular 
coagulopathy 
(secondary to 
hyperthermia) 
Severe 
Temperature often more 
than 41 °C (secondary to 
increased tone) 
Increased muscle tone 
(lower limb > upper) 
Spontaneous clonus 
Substantial myoclonus 
or hyperreflexia 
Delirium 
Coma 
As above 
Source:  Boyer and Shannon 2005. 
5.4.8. 
Supportive Care Guidelines for Management of Hyperammonemia 
Subjects should be monitored for elevated venous plasma ammonia.  Asymptomatic clinically 
significant drug-related elevations in ammonia (eg, a repeatable elevation in ammonia 
> 2 × ULN AND > 2 × baseline) should be managed by interrupting INCB001158 and 
monitoring to resolution.  For symptomatic elevations (ie, significant ammonia elevation 
associated with nausea, vomiting, severe anorexia, mental status changes, seizure, or other 
symptoms associated with hyperammonemia), subjects should be admitted for management 
according to the local institutional protocol for hyperammonemia, including 1) sending 
appropriate labs (ammonia [on ice, measured immediately], plasma amino acid profile, liver 
chemistry tests, electrolytes, bicarbonate, BUN, creatinine, glucose, and urine orotic acid), 2) IV 
hydration with dextrose-containing fluids, 3) discontinuation of protein intake, 4) implementing 
therapy to reduce ammonia levels (oral lactulose/lactitol, IV Ammonul®), and 5) identifying and 
treating any potential triggers (eg, discontinue corticosteroids, treat infections). 
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5.4.9. 
Infusion Reaction Dose Modifications 
Pembrolizumab may cause severe or life-threatening infusion-reactions, including severe 
hypersensitivity or anaphylaxis.  Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion.  Dose 
modification and toxicity management guidelines on pembrolizumab-associated infusion 
reaction are provided in Table 12. 
Table 12: 
Pembrolizumab Infusion Reaction Dose Modification and 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 therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤ 24 h 
Stop Infusion. 
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 1 hour of stopping drug 
infusion, the infusion may be restarted at 50% of the 
original infusion rate (eg, from 100 mL/h to 50 mL/h).  
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 treatment with 
pembrolizumab. 
Subject may be 
premedicated 1.5 h 
(± 30 min) before infusion 
of pembrolizumab with: 
Diphenhydramine 50 mg 
PO (or equivalent dose of 
antihistamine). 
Acetaminophen 
500-1000 mg PO (or 
equivalent dose of 
analgesic). 
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Table 12: 
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines (Continued) 
NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
Grades 3 or 4 
Grade 3: 
Prolonged (ie, not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical 
sequelae (eg, 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: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
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. 
**In cases of anaphylaxis, epinephrine should be used 
immediately. 
Subject is permanently discontinued from further 
treatment with pembrolizumab. 
No subsequent dosing. 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during 
the period of drug administration. 
For further information, please refer to the CTCAE v4.03 at http://ctep.cancer.gov. 
CTCAE = Common Terminology Criteria for Adverse Events; IV = intravenous; NCI = National Cancer Institute; 
NSAID = nonsteroidal antiinflammatory drug; PO = oral. 
5.4.10. 
Criteria for Permanent Discontinuation of Study Treatment 
The occurrence of unacceptable toxicity not caused by the underlying malignancy will be 
presumed to be related to study treatment administration and will require that the study treatment 
be permanently discontinued.  Unacceptable toxicity is defined as follows: 
• Occurrence of an AE that is related to treatment with the study treatment that, in the 
judgment of the investigator or the medical monitor, compromises the subject's ability 
to continue study-specific procedures or is considered to not be in the subject's best 
interest. 
• An AE requiring more than 2 dose reductions of INCB001158 or epacadostat. 
• Persistent AE requiring a delay of therapy for more than 4 weeks unless a greater 
delay has been approved by the sponsor, or persistent irAEs (described in Table 9) 
requiring a delay of therapy for more than 12 weeks. 
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5.5. 
Withdrawal of Subjects From Study Treatment 
5.5.1. 
Withdrawal Criteria 
Subjects must be withdrawn from study treatment for the following reasons: 
• The subject becomes pregnant. 
• Consent is withdrawn.  Subjects may choose to withdraw from the study at any time 
without penalty of jeopardizing their health care or loss of benefits to which the 
subject is otherwise entitled.  Note:  Consent withdrawn means that the subject can no 
longer be followed and no additional data can be collected.  Subjects may choose to 
discontinue study treatment and remain in the study to be followed for progression 
and survival. 
• Further participation would be injurious to the subject's health or well-being, in the 
investigator's medical judgment. 
• Unacceptable toxicity (see Sections 5.4.6, 5.4.9, and 5.4.10).  Subjects with 
unacceptable toxicities must be withdrawn from study treatment but will continue in 
the follow-up period of the study (see Section 6.4). 
• The study is terminated by the sponsor. 
• The study is terminated by the local health authority, IRB, or IEC. 
A subject may be discontinued from study treatment as follows: 
• Confirmed radiographic progression of disease per RECIST v1.1 (see 
Section 7.7.1.2).  A subject may be granted an exception to continue on treatment 
with confirmed radiographic progression if clinically stable or clinically improved 
(see Sections 7.7.1.2 and 7.7.1.5). 
Note:  For unconfirmed progression see Section 7.7.1.2. 
• If, during the course of the study, a subject is found not to have met eligibility criteria 
(see Section 3), the medical monitor, in collaboration with the investigator, will 
determine whether the subject should be withdrawn from the study. 
• If a subject is noncompliant with study procedures or study treatment administration 
in the investigator's opinion, the sponsor should be consulted for instruction on 
handling the subject. 
5.5.2. 
Withdrawal Procedures 
In the event that the decision is made to permanently discontinue the study treatment, the subject 
will be withdrawn, and the EOT visit should be conducted.  Reasonable efforts should be made 
to have the subject return for a follow-up visit.  These visits are described in Section 6.  The last 
date of the last dose of study treatment and the reason for subject withdrawal will be recorded in 
the eCRF. 
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resumed no earlier than the next scheduled administration of study therapy.  The specifics of the 
radiation treatment, including the location, will be recorded. 
Note:  The use of bisphosphonates and denosumab are permitted in this study. 
5.6.2. 
Restricted Medications and Measures 
Use of coumarin-based anticoagulants (eg, warfarin) is discouraged.  Low-dose warfarin (1 mg) 
is acceptable; however, doses that increase the INR are discouraged and may require dose 
modification.  If an alternative to coumarin-based anticoagulants cannot be used, investigators 
should follow the guidelines in Table 13 and either closely monitor or closely monitor and 
reduce the subject's dose of coumarin-based anticoagulant upon initiating therapy with 
epacadostat.  The INR should be monitored weekly for the first 4 weeks after initiation of 
therapy and upon discontinuation of epacadostat. 
Table 13: 
Warfarin Dose Adjustment Recommendation When Initiating Concurrent 
Epacadostat Treatment 
Stable INR 
Epacadostat Dose 
≤ 100 mg BID 
INR  ≤ 2.5 
Close INR monitoring 
INR  > 2.5 
Close INR monitoring 
5.6.3. 
Prohibited Medications 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the study, discontinuation from study therapy may be required.  
The investigator should discuss any questions regarding this with the medical monitor.  The final 
decision on any supportive therapy or vaccination rests with the investigator and/or the subject's 
primary physician.  However, the decision to continue the subject on study treatment requires the 
mutual agreement of the investigator, the medical monitor, and the subject. 
Subjects are prohibited from receiving the following therapies during the screening and treatment 
periods of this study: 
• Antineoplastic systemic chemotherapy or biological therapy not specified in this 
Protocol. 
• Immunotherapy not specified in this Protocol. 
• Investigational agents other than INCB001158, epacadostat, and pembrolizumab. 
• Oncologic surgery for tumor control. 
• Radiation therapy for disease control. 
− Note:  Radiation therapy to symptomatic lesions or to the brain may be allowed at 
the investigator's discretion, provided the lesions were not previously defined by 
the site as target lesions. 
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• Live vaccines within 30 days before the first dose of study treatment and while 
participating in the study.  
− Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, chickenpox, yellow fever, nasal seasonal flu, nasal H1N1 flu, 
rabies, BCG, and typhoid. 
• Except for erythropoietin or darbepoetin alpha (Aranesp®), use of growth factors 
(ie, G-CSF, GM-CSF, etc.) is not permitted in the first treatment cycle unless the 
subject experiences a hematologic DLT. 
• Concomitant treatment with valproic acid/valproate-containing therapies is not 
permitted as hyperammonemia is a well-described toxicity of valproic acid, 
particularly at high exposures, potentially through inhibition of the urea cycle 
(Verrotti et al 2002, Wadzinski et al 2007). 
• Concomitant treatment with allopurinol or other xanthine oxidase inhibitors is not 
allowed.  Xanthine oxidase inhibitors (eg, allopurinol) cause an accumulation of 
orotic acid in the urine, which would confound the assessment of safety in these 
subjects. 
• Any MAOI or drug associated with significant MAO inhibitory activity agents is 
prohibited from 21 days before starting study treatment through 2 weeks after the 
final dose of epacadostat has been taken.  See Appendix C for prohibited medications 
associated with MAO inhibition. 
• Any UGT1A9 inhibitor, including, but not limited to acitretin, amitriptyline, 
androsterone, cyclosporine, dasatinib, diclofenac, diflunisal, efavirenz, erlotinib,  
flutamide, gefitinib, gemfibrozil, glycyrrhetinic acid, glycyrrhizin, imatinib, 
imipramine, ketoconazole (systemic), linoleic acid supplements, mefenamic acid, 
mycophenolic acid, niflumic acid, nilotinib, phenobarbital, phenylbutazone, 
phenytoin, probenecid, quinidine, ritonavir, sorafenib, sulfinpyrazone, valproic acid, 
and verapamil.  
• Prolonged therapy with systemic glucocorticoids (> 7 days) for any purpose other 
than to modulate symptoms from an AE, SAE, or event of clinical interest, or for use 
as a premedication for chemotherapy or in participants with a known history of an IV 
contrast allergy administered as part of CT radiography.  Brief, limited use of 
systemic corticosteroids (≤ 7 days) are permitted where such use is considered 
standard of care (eg, for COPD exacerbation).  
− Replacement doses of steroids (eg, prednisone 5 to 7.5 mg daily) are permitted 
while on study, as is the use of local steroids. 
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from treatment but continue in study for 
assessment of disease status and survival. 
The exclusion criteria describe other medications that are prohibited in this study. 
There are no prohibited therapies during the post-treatment follow-up period. 
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6. 
STUDY ASSESSMENTS 
All clinical assessments will be performed as indicated in Table 14, and all laboratory 
assessments will be performed as indicated in Table 15.  Table 16 presents a summary of clinical 
laboratory analytes to be assessed.  The order of assessments is suggested by the order of 
mention within the schedule.  See Section 7 for instructions on each assessment.  Further details 
of study procedures and assessments can be found in the study reference manual. 
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Table 15: 
Schedule of Laboratory Assessments 
 
Protocol 
Section 
Screening 
Treatment (21-Day Cycles) 
EOT 
+5d 
Safety Follow-Up 
Notes 
Cycle 1 
Other Cycles 
Days 
-21 to -1 
D1 
D8 
±3d 
D15  
±3d 
D1  
±3d 
30-37d After 
Last Dose of 
INCB001158 
and Epacadostat 
90-97d After Last Dose 
of INCB001158 and 
Epacadostat (Phase 1 
and Phase 2 Part A only) 
Local laboratory tests 
Chemistries 
7.6.5 
X 
X* 
X 
X 
X 
X 
X 
X 
* Does not need to be repeated if the 
screening sample was obtained within 
7 days before C1D1 unless a clinically 
significant change is suspected. 
Hematology 
7.6.5 
X 
X* 
X 
X 
X 
X 
X 
X 
* Does not need to be repeated if the 
screening sample was obtained within 
7 days before C1D1 unless a clinically 
significant change is suspected. 
Lipid panel 
7.6.5 
X 
X* 
X 
X 
X 
X 
X 
X 
* Does not need to be repeated if the 
screening sample was obtained within 
7 days before C1D1 unless a clinically 
significant change is suspected. 
Coagulation 
panel 
7.6.5 
X 
 
 
 
 
X 
 
 
If a Coumadin®-based anticoagulant is 
given, monitor INR weekly for the first 
4 weeks after initiation of therapy and 
upon discontinuation of epacadostat. 
HIV and hepatitis 
B and C 
screening 
7.6.5.5 
X 
 
 
 
 
 
 
 
 
Urinalysis 
7.6.5.1 
X 
X* 
 
 
X 
X 
 
 
* Does not need to be repeated if the 
screening sample was obtained within 
7 days before C1D1 unless a clinically 
significant change is suspected. 
Thyroid panel: 
TSH, FT4, 
FT3/T3 
7.6.5 
X* 
 
 
 
X* 
 
 
 
* Perform within 7 days before 
Cycle 1, then every 2nd cycle 
(Cycles 2, 4, 6, 8, etc).  May use central 
lab only if local lab is not capable. 
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Table 15: 
Schedule of Laboratory Assessments (Continued) 
 
Protocol 
Section 
Screening 
Treatment (21-Day Cycles) 
EOT 
+5d 
Safety Follow-Up 
Notes 
Cycle 1 
Other Cycles 
Days 
-21 to -1 
D1 
D8 
±3d 
D15  
±3d 
D1  
±3d 
30-37d After 
Last Dose of 
INCB001158 
and Epacadostat 
90-97d After Last Dose 
of INCB001158 and 
Epacadostat (Phase 1 
and Phase 2 Part A only) 
Blood sample for 
plasma ammonia 
7.6.5.3 
X 
 
 
 
 
 
 
 
 
Pregnancy test 
7.6.5.4 
X 
 
 
 
 
 
X* 
X** 
All female subjects of childbearing 
potential. 
* Phase 2 Part B only. 
** Phase 1 and Phase 2 Part A only. 
Central laboratory tests 
Urine sample for 
orotic acid 
7.6.5.2 
 
X* 
X*/** 
X* 
X* 
 
 
 
* See Table 17 for sample timings.  
Additional samples may be collected as 
clinically indicated. 
** Phase 1 only. 
Blood sample for 
PK of 
INCB001158/ 
epacadostat 
7.9.1 
 
X* 
 
 
X* 
 
 
 
* See Table 20 and Table 21 for 
extensive and sparse sample timings, 
respectively.  Samples will be drawn on 
C1D1 and C2D1 only. 
Blood sample for 
PK and 
 
testing of 
pembrolizumab 
(Phase 1 and 
Phase 2 Part A 
only) 
7.9.1 
 
X* 
 
 
X* 
 
 
 
* Collect on C1D1 predose and C6D1 
predose, as noted in Table 22. 
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Table 16: 
Laboratory Tests:  Required Analytes 
Serum Chemistries 
Hematology 
Urinalysis With Microscopic 
Examination 
Hepatitis and HIV Screening 
Albumin 
Alkaline phosphatase 
ALT 
 
 
Ammonia 
Amylase 
 
AST  
Bicarbonate 
Blood urea nitrogen  
Calcium 
Chloride  
Creatinine 
Glucose 
 
Lactate dehydrogenase 
Lipase 
 
Phosphate 
Potassium 
Sodium 
Thyroid panel:  TSH, FT4, FT3/T3 
Total bilirubin 
Direct bilirubin (if total bilirubin is 
elevated above ULN) 
Total protein 
Uric acid 
Complete blood count, including: 
Hemoglobin 
Hematocrit 
Platelet count 
Red blood cell count 
White blood cell count 
 
Differential count, including: 
Basophils 
Eosinophils 
Lymphocytes 
Monocytes 
Neutrophils 
 
Absolute values must be provided 
for:  
WBC differential laboratory 
results: 
Lymphocytes 
Neutrophils 
Color and appearance 
pH and specific gravity 
Bilirubin 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Occult blood 
Orotic acida 
Protein 
Urobilinogen 
HBsAg 
HBV-DNA 
HCV antibody 
HCV-RNA 
HIV RNA (if required by local 
regulations) 
Lipid Panel 
Pregnancy Testing 
Total cholesterol 
Triglycerides 
LDL 
HDL 
A urine or serum pregnancy test 
will be required for all women of 
childbearing potential. 
Coagulation 
PT 
PTT 
INR 
Note:  Additional tests may be required, as agreed by investigator and sponsor, based on emerging safety data. 
a Tests to be conducted by central laboratory.  All other tests will be conducted by a local laboratory where possible. 
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6.1. 
Screening 
Screening is the interval between signing the ICF and the day the subject is enrolled in the study 
(Cycle 1 Day 1).  Sites are requested to register the subject in the IRT system on the same day of 
the ICF signature.  Refer to the IRT manual for detailed instructions.  Screening procedures have 
to be completed within 21 days after signing the ICF, and preferably within 14 days.  
Assessments that are required to demonstrate eligibility may be performed over the course of 
1 or more days during the screening process. 
Procedures conducted as part of the subject's routine clinical management (eg, blood count, 
imaging study) and obtained before signing of informed consent may be used for screening or 
baseline purposes provided the procedure meets the Protocol-defined criteria and has been 
performed in the timeframe of the study (ie, within 21 days of Cycle 1 Day 1).  All information 
associated with eligibility requirements must be entered into the appropriate eCRF pages. 
Results from the screening visit evaluations will be reviewed to confirm subject eligibility before 
enrollment or the administration of study treatment.  Tests with results that fail eligibility 
requirements may be repeated once during screening if the investigator believes the results to be 
in error.  For screening assessments that are repeated, the most recent available result before 
treatment assignment will be used to determine subject eligibility.  Additionally, a subject who 
fails screening may repeat the screening process 1 time if the investigator believes there has been 
a change in eligibility status (eg, after recovery from an infection).  Treatment should start as 
soon as possible after the date of enrollment. 
Refer to the Cohort Management plan for the description of the slots management in Phase 1 
Dose Escalation. 
6.2. 
Treatment 
The treatment period begins on the day the subject receives the first dose of study treatment 
(Cycle 1 Day 1), as assigned in the IRT system, through the point at which the investigator 
determines the subject will be permanently discontinued from study treatment.  Cycle 1 Day 1 
must be no more than 21 days after the subject has signed the ICF.  Dates for subsequent study 
visits will be determined based on this day and should occur within 3 days (±) of the scheduled 
date unless delayed for safety reasons.  At Cycle 1 Day 1, results from screening visit evaluations 
should be reviewed to determine whether the subject continues to meet the eligibility 
requirements, as specified in the Protocol. 
Subjects will have regularly scheduled study visits as outlined in Table 14 and Table 15, and 
toxicities will be monitored continuously and will be graded using the NCI CTCAE v4.03 
criteria. 
6.3. 
End of Treatment 
When the subject permanently discontinues all 3 study treatments, as outlined in Section 5.5, the 
EOT visit should be conducted.  If the EOT visit coincides with a regular study visit, the EOT 
evaluations will supersede those of that scheduled visit, and the data should be entered in the 
EOT visit in the eCRF.  The EOT visit may occur up to 5 days after receiving the final dose of 
study treatment.  The subject should be encouraged to return for the safety follow-up visit. 
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Additionally, subjects will be considered as having completed the study if they meet any of the 
following criteria:  
• Subject dies and a date of death is available.  
• Subject is known to have died; however, the date of death cannot be obtained. 
Note:  Every effort must be made to obtain the date of death. 
• Consent is withdrawn for any further contact related to this study.  
− Every reasonable effort should be made to determine the reason a subject 
withdraws prematurely, and this information should be recorded in the eCRF.  
• The study is terminated by the sponsor. 
• The study is terminated by the local health authority or IRB or IEC.  
6.6. 
Unscheduled Visits 
Unscheduled study visits may occur at any time if medically warranted.  Any assessments 
performed at those visits should be recorded in the eCRF. 
7. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES 
7.1. 
Administration of Informed Consent Form 
Valid informed consent must be obtained from the study subject before conducting any 
study-specific procedures using an ICF approved by the local IRB/IEC that contains all elements 
required by ICH E6 and describes the nature, scope, and possible consequences of the study in a 
form understandable to the study subject.  Local and institutional guidelines for ICF content and 
administration must be followed; the original signed ICF must be retained by the investigator, 
and a copy of the signed ICF must be provided to the study subject.  The informed consent 
process for each subject must be documented in writing within the subject source documentation. 
7.2. 
Interactive Response Technology Procedure 
The IRT will be contacted to obtain a subject ID number when a subject enters screening.  Upon 
determining that the subject is eligible for study entry, the IRT will be contacted to obtain the 
treatment group and cohort assignment.  Additionally, the IRT will be contacted to update the 
subject's disposition and for study treatment resupply.  Refer to the IRT manual for detailed 
instructions. 
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7.3. 
Demography and Medical History 
7.3.1. 
Demographics and General Medical History 
Demographic data and a complete medical and medication history will be collected at screening 
by the investigator or qualified designee and will include date of birth, race, ethnicity, medical 
and surgical history, and current illnesses.  Medical history will include relevant medical or 
surgical treatment within the last 10 years that are considered to be clinically significant by the 
investigator. 
7.3.2. 
Disease Characteristics and Treatment History 
A disease-targeted medical and medication history will be collected at screening.  Details 
regarding the subject's malignancy under study including date of diagnosis, initial and current 
cancer stage, tumor histology, relevant disease characteristics (including any available data on 
tumor PD-L1 and MSI status), and prior treatments including systemic, radiation, and surgical 
procedures will be recorded. 
7.4. 
Prior and Concomitant Medications and Procedures 
Prior and concomitant medications and procedures will be reviewed to determine subject 
eligibility.  Any medication received or procedure performed within 21 days before the first dose 
of study treatment up to the end of the safety follow-up period or until the subject starts a new 
anticancer therapy, whichever occurs first, will be recorded in the eCRF.  The medication record 
will be maintained after signing the ICF to document concomitant medications, including any 
changes to the dose or regimen.  Concomitant medications include any prescription, 
over-the-counter, or natural/herbal preparations taken or administered during the study period.  
Concomitant treatments and/or procedures that are required to manage a subject's medical 
condition during the study will also be recorded in the eCRF.  See Section 5.6 for details 
regarding restricted and prohibited medications. 
7.5. 
Post-Treatment Anticancer Therapy Status 
The investigator or qualified designee will review all new anticancer therapy initiated after the 
last dose of study treatment.  If a subject initiates a new anticancer therapy before the 30-day or 
90-day (Phase 1 and Phase 2 Part A only) safety follow-up visit, the safety follow-up visit should 
occur before the first dose of the new anticancer therapy. 
7.6. 
Safety Assessments 
7.6.1. 
Adverse Events 
Adverse events will be monitored from the time the subject signs the ICF.  Subjects will be 
instructed to report all AEs during the study and will be assessed for the occurrence of AEs 
throughout the study.  In order to avoid bias in eliciting AEs, subjects will be asked general, 
nonleading questions such as "How are you feeling?"  All AEs (serious and nonserious) must be 
recorded on the source documents and eCRFs regardless of the assumption of a causal 
relationship with the study treatments.  The definition, reporting, and recording requirements for 
AEs are described in Section 8. 
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7.6.2. 
Physical Examinations 
Physical examinations must be performed by a medically qualified individual such as a licensed 
physician, physician's assistant, or an advanced registered nurse practitioner, as local law 
permits. 
Clinically notable abnormalities that are considered clinically significant in the judgement of the 
investigator are to be reported as AEs. 
7.6.2.1. 
Comprehensive Physical Examination 
The comprehensive physical examination will include height (at screening) and body weight, and 
assessment(s) of the following organ or body systems:  skin; head, eyes, ears, nose, and throat; 
thyroid; lungs; cardiovascular system; abdomen (liver, spleen); extremities; and lymph nodes; as 
well as a brief neurological examination. 
7.6.2.2. 
Targeted Physical Examination 
The targeted physical examination will be a symptom-directed evaluation.  The targeted physical 
examination will include body weight and assessment(s) of the body systems or organs, as 
indicated by subject symptoms, AEs, or other findings.   
7.6.3. 
Vital Signs 
Vital sign measurements include blood pressure, pulse, respiratory rate, and body temperature.  
Blood pressure and pulse will be taken with the subject in the recumbent, semirecumbent, or 
sitting position after 5 minutes of rest.  Clinically notable abnormalities that are considered 
clinically significant in the judgment of the investigator are to be reported as AEs. 
7.6.4. 
Electrocardiograms 
All 12-lead ECGs will be performed with the subject in a recumbent or semirecumbent position 
after 5 minutes of rest.  Timed triplicate ECGs (separated by 5 minutes) will be performed. 
The 12-lead ECGs will be interpreted by the investigator at the site to be used for immediate 
subject management.  The decision to include or exclude a subject or withdraw a subject from 
the study based on an ECG flagged as "Abnormal, Clinically Significant" is the responsibility of 
the investigator, in consultation with the medical monitor, as appropriate.  Clinically notable 
abnormalities that are considered clinically significant in the judgment of the investigator are to 
be reported as AEs. 
7.6.5. 
Laboratory Assessments 
A certified laboratory local to the study site and subject will perform most of the clinical 
laboratory assessments for safety (ie, chemistries, hematology assessments, coagulation panel, 
thyroid panel, lipid panel, and urinalysis).  The investigative site will enter the laboratory results 
and laboratory normal ranges into the eCRF.  All local laboratory assessments should be 
performed using standard procedures on the days indicated in Table 15.  Table 16 lists the 
specific laboratory analytes required for each test.  Some additional tests (ie, 
 
, plus urinary orotic acid; see Table 16) will be 
conducted by one or more central laboratories, on the days indicated in Table 15.  
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7.6.5.3. 
Plasma Ammonia 
Plasma ammonia levels are to be tested during screening.  If above the ULN, repeat the sample 
to confirm the value.  If the subject experiences an elevation in urine orotic acid (> 10 × ULN 
fasted; or > 40 × ULN any value) while on study treatment or during the follow-up period, 
monitor plasma ammonia levels each time the urine orotic acid is tested, at least until orotic acid 
levels have returned to normal, at the investigator's and medical monitor's discretion. 
7.6.5.4. 
Pregnancy Testing 
A serum pregnancy test will be required for all women of childbearing potential during screening 
and must be within 72 hours before the first dose of study treatment.  A serum pregnancy test 
should also be repeated at the 30-day (Phase 2 Part B only) or 90-day (Phase 1 and Phase 2 
Part A only) safety follow-up visit.  Pregnancy testing is not required if a subject is going to 
hospice.  Urine pregnancy tests will be conducted as medically indicated, or per country-specific 
requirement.  Urine pregnancy tests will be performed locally.  If a urine pregnancy test is 
positive, the results should be confirmed with a serum pregnancy test. 
If the serum pregnancy test is negative after a urine test was positive, the investigator will assess 
the potential benefit/risk to the subject and determine whether it is in the subject's best interest to 
resume study treatment and continue participation in the study. 
7.6.5.5. 
Hepatitis and HIV Screening Tests 
Hepatitis and HIV screening assessments will be performed at the screening visit (Table 15) to 
rule out hepatitis and HIV infection, respectively; required analytes are shown in Table 16.  
Generally, hepatitis and HIV tests should be performed early in the screening process due to the 
length of time needed to obtain the results.  Additional tests may be performed if clinically 
indicated. 
Note:  HIV testing is not required unless mandated by the local health authority. 
7.7. 
Efficacy Assessments 
7.7.1. 
Tumor Imaging and Assessment of Disease 
Tumor imaging is strongly preferred to be acquired by CT.  For the abdomen and pelvis, MRI 
may be used when CT with iodinated contrast is contraindicated or when local practice mandates 
it.  Magnetic resonance imaging is the strongly preferred modality for imaging the brain.  The 
same imaging modality (ideally the same scanner) and the use of contrast should be used in a 
subject throughout the study to optimize the reproducibility of the assessment of existing and 
new tumor burden and improve the accuracy of the assessment of response or progression based 
on imaging. 
Subject eligibility will be determined using local assessment (investigator assessment) based on 
RECIST v1.1.  All scheduled images for all study subjects will be assessed by the investigator. 
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7.7.1.1. 
Initial Tumor Imaging 
Initial tumor imaging at screening must be performed within 21 days before Cycle 1 Day 1.  The 
site study team must review screening images to confirm the subject has measurable disease per 
RECIST v1.1.  
Tumor imaging performed as part of routine clinical management is acceptable for use as 
screening tumor imaging if it is of diagnostic quality and performed within 21 days before 
Cycle 1 Day 1. 
Subjects with previously treated brain metastases may participate provided they have stable brain 
metastases, that is, without evidence of progression by imaging (confirmed by MRI or CT 
imaging, whichever was used at prior imaging) for at least 4 weeks before the first dose of study 
treatment.  Any neurologic symptoms must have returned to baseline, subjects must have no 
evidence of new or enlarging brain metastases, and subjects must not have used steroids for brain 
metastases for at least 14 days before initiating study treatment as per investigator assessment.  
This exception does not include carcinomatous meningitis, as subjects with carcinomatous 
meningitis are excluded regardless of clinical stability.  Subjects with evidence of cerebral edema 
will also be excluded from participation.  In addition, subjects will be excluded from 
participation in the study if it has been < 4 weeks since radiation therapy was delivered to the 
CNS. 
7.7.1.2. 
Tumor Imaging During the Study 
The first on study imaging assessment should be performed at 9 weeks (63 days ± 7 days) from 
the date of enrollment.  Imaging then continues every 9 weeks (63 days ± 7 days).  This equates 
to an imaging schedule occurring after Weeks 9, 18, 27, 36, 45, etc.  Imaging timing should 
follow calendar days and should not be adjusted for delays in cycle dosing. 
Imaging should continue to be performed until PD is identified by the investigator, the start of 
new anticancer treatment, withdrawal of consent for imaging, or death, whichever occurs first.  If 
the investigator elects to continue treatment 
 after initial radiographic PD, 
imaging should continue.  
Partial response and CR should be confirmed by a repeat imaging assessment.  The imaging for 
confirmation of response may be performed no earlier than 4 weeks after the first indication of a 
response and no later than at the next scheduled scan (ie, 9 weeks ± 7 days later), whichever is 
clinically indicated.  Subjects will then return to the regular imaging schedule, starting with the 
next scheduled imaging timepoint.  Subjects who receive additional imaging for confirmation do 
not need to undergo the next scheduled tumor imaging if it is less than 4 weeks later; tumor 
imaging may resume at the subsequent scheduled imaging timepoint. 
 disease progression should be confirmed by the site 4 to 8 weeks 
after first radiologic evidence of PD in clinically stable subjects.  Subjects who have 
unconfirmed disease progression may continue on treatment at the discretion of the investigator 
until progression is confirmed by the site 
, provided they have met the conditions 
detailed in Section 7.7.1.5.  Subjects who receive confirmatory imaging do not need to undergo 
the next scheduled tumor imaging if it is less than 4 weeks later; tumor imaging may resume at 
the subsequent scheduled imaging timepoint if clinically stable.  Subjects who have confirmed 
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8. 
SAFETY MONITORING AND REPORTING 
8.1. 
Adverse Events 
8.1.1. 
Definitions 
For the purposes of this Protocol, an adverse event (AE) is defined as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug related, 
that occurs after a subject provides informed consent.  Abnormal laboratory values or test results 
occurring after informed consent constitute AEs only if they induce clinical signs or symptoms, 
are considered clinically meaningful, require therapy (eg, hematologic abnormality that requires 
transfusion), or require changes in the study treatment(s). 
8.1.2. 
Reporting 
Adverse events that begin or worsen after informed consent should be recorded on the Adverse 
Events form of the eCRF.  Conditions that were already present at the time of informed consent 
should be recorded on the Medical History form in the eCRF.  Monitoring for the occurrence of 
new AEs should be continued for at least 90 days (Phase 1 and Phase 2 Part A only) or 30 days 
(Phase 2 Part B only) after the last dose of study treatment or until the start of new anticancer 
therapy, whichever occurs first.  Adverse events (including laboratory abnormalities that 
constitute AEs) should be described using a diagnosis whenever possible rather than by 
individual underlying signs and symptoms.  When a clear diagnosis cannot be identified, each 
sign or symptom should be reported as a separate AE. 
The term "disease progression" should be recorded as an AE/SAE only if there are no other 
identifiable AEs/SAEs associated with the disease progression at the time of reporting.  For 
events associated with disease progression, the relevant signs and symptoms should be reported 
using a diagnosis whenever possible rather than individual underlying signs and symptoms.  
When a clear diagnosis cannot be identified, each sign or symptom should be reported as a 
separate AE.  If the events resulting from disease progression meet the criteria for an SAE 
(eg, resulted in hospitalization, a life-threatening event, or death), the specific event(s) should be 
reported as an SAE(s) as described in Section 8.3.2.  In both cases (ie, AEs or SAEs related to 
disease progression), it should be indicated that each event (reported as a diagnosis or as signs 
and symptoms) is related to disease progression on the Adverse Events form of the eCRF. 
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The severity of AEs will be assessed using CTCAE v4.03 Grades 1 through 5.  If an event is not 
classified by CTCAE, the severity of the AE will be graded according to the scale below to 
estimate the grade of severity: 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2 
Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate activities of daily living. 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Fatal 
The occurrence of AEs should be sought by nondirective questioning of the subject during the 
screening process after signing the ICF and at each visit during the study.  Adverse events may 
also be detected when they are volunteered by the subject during the screening process or 
between visits, or through physical examination, laboratory test, or other assessments.  To the 
extent possible, each AE should be evaluated to determine: 
• The severity grade (CTCAE Grade 1 to 5). 
• Whether there is at least a reasonable possibility that the AE is related to the study 
treatment:  suspected (yes) or not suspected (no).  Relatedness will be assessed for 
each of INCB001158, epacadostat (all Phases and Parts) and pembrolizumab (Phase 1 
and Phase 2 Part A only). 
• The start and end dates, unless unresolved at final follow-up. 
• The action taken with regard to study treatment(s). 
• The event outcome (eg, not recovered/not resolved, recovered/resolved, 
recovering/resolving, recovered/resolved with sequelae, fatal, unknown). 
• The seriousness, as per serious adverse event (SAE) definition provided in 
Section 8.3.1. 
Unlike routine safety assessments, SAEs are monitored continuously and have special reporting 
requirements (see Section 8.3.2). 
All AEs should be treated appropriately.  If an AE is treated with a concomitant medication or 
nondrug therapy, this action should be recorded on Adverse Event form and the treatment should 
be specified on the Prior/Concomitant Medications or Procedures and Non-Drug Therapy form 
in the eCRF. 
Once an AE is detected, it should be followed until it has resolved or until it is judged to be 
permanent; assessment should be made at each visit (or more frequently if necessary) of any 
changes in severity, the suspected relationship to the study treatment(s), the interventions 
required to treat the event, and the outcome. 
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When the severity of an AE changes over time for a reporting period (eg, between visits), each 
change in severity will be reported as a separate AE until the event resolves.  For example, 
2 separate AEs will be reported if a subject has Grade 1 diarrhea, meeting the definition of an 
AE, that lasts for 3 days before worsening to a Grade 3 severity.  The Grade 1 event will be 
reported as an AE with a start date equal to the day the event met the Grade 1 AE definition and 
a stop date equal to the day that the event increased in severity from Grade 1 to Grade 3.  The 
Grade 3 event will also be reported as an AE, with the start date equal to the day the event 
changed in intensity from Grade 1 to Grade 3 and a stop date equal to the day that the event 
either changed severity again or resolved. 
8.2. 
Laboratory Test Abnormalities 
Laboratory abnormalities that constitute an AE in their own right (considered clinically 
meaningful, induce clinical signs or symptoms, require concomitant therapy, or require changes 
in study treatment[s]) should be recorded on the Adverse Event form in the eCRF.  Whenever 
possible, a diagnosis rather than a symptom should be provided (eg, "anemia" instead of "low 
hemoglobin").  Laboratory abnormalities that meet the criteria for AEs should be followed until 
they have returned to normal or an adequate explanation of the abnormality is found.  When an 
abnormal laboratory test result corresponds to a sign or symptom of a previously reported AE, it 
is not necessary to separately record the laboratory test result as an additional event. 
Laboratory abnormalities that do not meet the definition of an AE should not be reported as AEs.  
A Grade 3 or 4 AE does not automatically indicate an SAE unless it meets the definition of 
serious, as defined in Section 8.3.1.  A dose modification for the laboratory abnormality may be 
required (see Section 5.4) and should not contribute to the designation of a laboratory test 
abnormality as an SAE. 
8.3. 
Serious Adverse Events 
8.3.1. 
Definitions 
An SAE is defined as an event that meets at least 1 of the following criteria: 
• Is fatal or life-threatening. 
• Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is a result of: 
− A routine treatment or monitoring of the studied indication not associated with 
any deterioration in condition. 
− An elective surgery or preplanned treatment for a pre-existing condition that is 
unrelated to the indication under study and has not worsened since signing the 
ICF. 
− A treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE and not resulting in hospital admission. 
− Any social reasons and respite care, in the absence of any deterioration in the 
subject's general condition. 
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• Results in persistent or significant disability, incapacity, or a substantial disruption of 
a person's ability to conduct normal life functions. 
• Constitutes a congenital anomaly or birth defect. 
• Is considered to be an important medical event or a medically significant event that 
may not result in death, be immediately life-threatening, or require hospitalization but 
may be considered serious when, based on appropriate medical judgment, the event 
may jeopardize the subject or may require medical or surgical intervention to prevent 
1 of the outcomes listed above. 
8.3.2. 
Reporting 
Every SAE, regardless of suspected causality (eg, relationship to study treatment(s) or study 
procedure or disease progression), occurring after the subject has signed the ICF through the last 
study visit (or 90 days after the last dose of study treatment, or until the subject receives a new 
anticancer therapy, whichever occurs earlier) must be reported to the sponsor (or designee) 
within 24 hours of learning of its occurrence, unless otherwise specified by the Protocol.  Any 
SAEs occurring more than 90 days after the last dose of study treatment should be reported to the 
sponsor or its designee only if the investigator suspects a causal relationship to the study 
treatment(s).   
Information about all SAEs is collected and recorded on the Adverse Event form of the eCRF.  
The investigator must assess and record the causal relationship of each SAE to the study 
treatments.  Relatedness will be assessed for each of INCB001158, epacadostat (all Phases and 
Parts) and pembrolizumab (Phase 1 and Phase 2 Part A only). 
The investigator must also complete the Incyte Serious Adverse Event Report Form, in English, 
and send the completed and signed form to the sponsor or designee within 24 hours of becoming 
aware of the SAE.  The investigator must provide a causality assessment, that is, assess whether 
there is at least a reasonable possibility that the SAE is related to the study treatment(s):  
suspected (yes) or not suspected (no).  Refer to the Incyte Reference Guide for Completing the 
Serious Adverse Event Report Form. 
The contact information of the sponsor's study-specific representatives is listed in the 
investigator manual provided to each site.  The original copy of the SAE Report Form and the 
confirmation sheet must be kept at the study site. 
Investigational site personnel must report any new information regarding the SAE within 
24 hours of becoming aware of the information in the same manner that the initial SAE Report 
Form was sent.  Follow-up information is recorded on an amended or new SAE Report Form, 
with an indication that it is follow-up to the previously reported SAE and the date of the original 
report.  The follow-up report should include information that was not provided on the previous 
SAE Report Form, such as the outcome of the event (eg, resolved or ongoing), treatment 
provided, action taken with study treatment(s) because of the SAE (eg, dose reduced, interrupted, 
or discontinued), or subject disposition (eg, continued or withdrew from study participation).  
Each recurrence, complication, or progression of the original event should be reported as 
follow-up to that event, regardless of when it occurs. 
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If the SAE is not documented in the IBs for the study treatments (new occurrence) and is thought 
to be related to at least 1 of the study treatments, the sponsor or its designee may urgently require 
further information from the investigator for reporting to health authorities.  The sponsor or its 
designee may need to issue an Investigator Notification (IN) to inform all investigators involved 
in any study with the same drug that this SAE has been reported.  Suspected Unexpected Serious 
Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and 
relevant ethics committees in accordance with Directive 2001/20/EC, or as per national 
regulatory requirements in participating countries. 
8.4. 
Emergency Unblinding of Treatment Assignment 
Not applicable.  
8.5. 
Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that the study 
treatment(s) may have interfered with the effectiveness of a contraceptive medication or method.  
When a pregnancy has been confirmed in a subject during maternal or paternal exposure to study 
treatments, the following procedures should be followed in order to ensure subject safety: 
• The study treatments must be discontinued immediately (female subjects only). 
• The investigator must complete and submit the Incyte Clinical Trial Pregnancy form 
to the sponsor or its designee within 24 hours of learning of the pregnancy. 
• A serum pregnancy test must be performed to confirm the urine pregnancy test result.  
If a negative serum test does not confirm the urine pregnancy result, then:  
− The investigator will use his or her expert judgment, based on an assessment of 
the potential benefit/risk to the subject, to determine whether it is in the subject's 
best interest to resume study treatment and continue participation in the study.  
• The EOT visit evaluations must be performed.  
Data on fetal outcome and breastfeeding are collected for regulatory reporting and drug safety 
evaluation.  Follow-up should be conducted for each pregnancy to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence of any 
birth defects, congenital abnormalities, or maternal and/or newborn complications, by following 
until the first well-baby visit.  Pregnancy should be recorded on a Clinical Trial Pregnancy form 
and reported by the investigator to the sponsor or its designee.  Pregnancy follow-up information 
should be recorded on the same form and should include an assessment of the possible causal 
relationship of each study treatment to any pregnancy outcome, as well as follow-up to the first 
well-baby visit or the duration specified in local regulations, whichever is later.  Refer to the 
Incyte Reference Guide for Completing the Clinical Trial Pregnancy Form. 
Any SAE occurring during pregnancy must be recorded on the SAE report form and 
submitted to the sponsor or designee. 
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8.6. 
Definition of an Overdose for This Protocol and Reporting of 
Overdose to the Sponsor 
For this study, an overdose of each study treatment is defined as follows: 
• INCB001158:  A dose that is higher than the dose that subject has been intended to 
receive, which could be either the originally assigned dose (if not subsequently 
modified) or a modified dose (eg, following a dose reduction). 
• Epacadostat:  A dose > 1000 mg. 
• Pembrolizumab:  A dose ≥ 1000 mg (5 times the dose). 
No specific information is available on the treatment of overdose of INCB001158, 
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 AE(s) is associated with ("results from") the overdose of study therapies, then the AE(s) is 
reported as an SAE, even if no other seriousness criteria are met. 
All reports of overdose must be reported within 24 hours to the sponsor either by electronic 
media or paper. 
8.7. 
Warnings and Precautions 
Special warnings or precautions for the INCB001158 study drug and for epacadostat and 
pembrolizumab, derived from safety information collected by the sponsor or its designee, are 
presented in the Investigator's Brochure (iIB, eIB, pIB).  Additional safety information collected 
between IB updates will be communicated in the form of Investigator Notifications (INs).  Any 
important new safety information should be discussed with the subject during the study, as 
necessary.  If new significant risks are identified, they will be added to the ICF. 
8.8. 
Data Monitoring Committee 
Not applicable.  However, continuous evaluation of toxicity events will be performed throughout 
the study by the sponsor with study investigators, in order to review cohort-specific data and 
overall safety data, to agree on dose escalation/de-escalation in Phase 1, adjudicate individual 
high-grade AEs as potentially dose-limiting, and guide other major study decisions.  The 
representatives from the sponsor will include the medical monitor, the Pharmacovigilance 
physician, and the Clinical Research Scientist, or designees thereof.  See Sections 4.1 and 4.1.1 
for further details. 
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8.9. 
Events of Clinical Interest 
Selected nonserious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be recorded as such in the eCRF and reported to the sponsor within 24 hours 
either by electronic media or paper.  Sponsor contact information can be found in the 
Investigator Study File Binder (or equivalent).  Events of Clinical Interest for this study include 
the following:  
1. An overdose of study treatment, as defined in Section 8.6, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. An elevated AST or ALT laboratory value that is ≥ 3 × ULN and an elevated total 
bilirubin laboratory value that is ≥ 2 × ULN and, at the same time, an alkaline 
phosphatase laboratory value that is < 2 × ULN, as determined by way of 
Protocol-specified laboratory testing or unscheduled laboratory testing. 
Note:  These criteria are based on available regulatory guidance documents.  The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology.  The study site guidance for assessment 
and follow-up of these criteria can be found in the Investigator Study File Binder (or 
equivalent). 
3. Serotonin syndrome – see Section 1.3.2 and Section 5.4.7. 
8.10. 
Product Complaints 
The sponsor collects product complaints on study treatment(s) and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and facilitate 
process and product improvements. 
All product complaints associated with material packaged, labeled, and released by the sponsor 
or its designee will be reported to the sponsor.  All product complaints associated with other 
study material will be reported directly to the respective manufacturer. 
The investigator or his/her designee is responsible for reporting a complete description of the 
product complaint via email or other written communication to the sponsor contact or respective 
manufacturer as noted in the packaging information.  Any AE associated with a product 
complaint should be reported as described in Section 8.1.2 of this Protocol. 
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint communication with the product. 
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epacadostat ± pembrolizumab, within the corresponding tumor type and treatment group will be 
enrolled in a cohort (Stage 1).  If there are r1 or fewer responses in the cohort, it will be 
concluded that the true response rate is unlikely to be greater than or equal to the target rate, and 
no more subjects will be enrolled in that tumor type for that treatment group in Stage 2.  In the 
cohorts in which greater than r1 responses are observed among the Stage 1 subjects, n2 additional 
evaluable subjects will be treated in Stage 2 to estimate the response rate.  At the end of Stage 2, 
if ≤ r subjects have responded among the n evaluable subjects, then the drug will be declared 
nonpromising for that cohort.  The detailed calculations for each tumor type-specific cohort are 
based on a 1-sided Type I error of 0.1 and power of 80%. 
9.3. 
Level of Significance 
For the primary efficacy endpoint, the 1-sided Type I error will be controlled at 0.1 for each 
individual cohort expansion.  Of note, this level of significance does not account for the multiple 
expansion cohorts.  For other endpoints, CIs will be reported at a 95% confidence level. 
9.4. 
Statistical Analyses 
9.4.1. 
Efficacy Analyses 
9.4.1.1. 
Primary Efficacy Analyses 
Objective response rate, defined as the percentage of subjects enrolled in Phase 2 Part A or 
Phase 2 Part B having a CR or PR, as determined by investigator assessment of radiographic 
disease as per RECIST v1.1 will be summarized by treatment cohort. 
For the hypothesis tests in the Simon 2-stage design, the null response rate is p0% and alternative 
response rate is p1%, where p0 and p1 are specific to the tumor type and are determined from 
historical response rates. 
9.4.1.2. 
Secondary Efficacy Analyses 
The following efficacy analyses will be assessed for all subjects in each treatment combination: 
• ORR, defined as the percentage of subjects having a CR or PR, as determined by 
investigator assessment of radiographic disease as per RECIST v1.1 (Phase 1 only). 
• DCR, defined as the percentage of subjects having CR, PR, or SD for at least 56 days, 
as determined by investigator assessment of radiographic disease as per RECIST 
v1.1. 
• DoR, determined by radiographic disease assessment, defined as the time from 
earliest date of disease response until the earliest date of disease progression per 
RECIST v1.1, or death due to any cause, if occurring sooner than progression. 
• PFS, defined as the time from date of first dose of study treatment until the earliest 
date of disease progression, as determined by investigator assessment of objective 
radiographic disease assessments per RECIST v1.1, or death due to any cause, if 
occurring sooner than progression. 
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• For laboratory parameters where CTCAE grades are not defined, shift tables to the 
worst postbaseline value using the low/normal/high classifications based on 
laboratory reference ranges. 
9.4.2.3. 
Vital Signs 
Descriptive statistics and mean change from baseline will be determined for vital signs (blood 
pressure, pulse, respiratory rate, and body temperature) at each assessment time.  Vital sign 
results will be reviewed for clinically notable abnormalities (see Table 23), and subjects 
exhibiting clinically notable vital sign abnormalities will be listed.  A value will be considered an 
"alert" value if it is outside the established range and shows a > 25% change from baseline. 
Table 23: 
Criteria for Clinically Notable Vital Sign Abnormalities 
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure 
> 155 mmHg 
< 85 mmHg 
Diastolic blood pressure 
> 100 mmHg 
< 40 mmHg 
Pulse 
> 100 bpm 
< 45 bpm 
Temperature 
> 38ºC 
< 35.5ºC 
Respiratory rate 
> 24/min 
< 8/min 
9.4.2.4. 
Electrocardiograms 
Descriptive statistics and mean change from baseline will be determined for each ECG parameter 
at each assessment time.  Electrocardiogram results will be reviewed for clinically notable 
abnormalities according to predefined criteria (Table 24).  Subjects exhibiting clinically notable 
ECG abnormalities will be listed. 
Table 24: 
Criteria for Clinically Notable Electrocardiogram Abnormalities 
Parameter 
High Threshold 
Low Threshold 
QTcF 
> 480 ms 
< 295 ms 
PR 
> 220 ms 
< 75 ms 
QRS 
> 120 ms 
< 50 ms 
QT 
> 500 ms 
< 300 ms 
RR 
> 1330 ms 
< 600 ms 
QTcF = Fridericia correction. 
9.4.3. 
Pharmacokinetic Analysis 
The PK parameters of  Cmax, tmax, Cmin, AUC0-t, and Cl/F (INCB001158 and epacadostat) for the 
first twelve subjects enrolled in Phase 2 Part B will be calculated from the plasma concentrations 
of INCB001158 and epacadostat using standard noncompartmental (model independent) PK 
methods.  Pharmacokinetic calculations will be performed, if appropriate, using commercial 
software such as WinNonlin®.  Nominal times will be used in all cases, except when the 
difference between the actual time and nominal time is > 15 minutes for samples collected 
≤ 4 hours after administration and > 30 minutes for samples collected > 4 hours after 
administration; in these cases, actual time will be used for PK analysis.   
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Table 25: 
Probability of Early Termination for Simon 2-Stage Design in Phase 2 
Cohort 
(Tumor Type) 
p0 
p1 
Probability of Early Termination 
Under H0 
Under HA 
Part A 
 
 
 
 
A1 
30% 
50% 
0.7216 
0.1509 
A2 
2% 
15% 
0.8007 
0.1673 
A3 
15% 
35% 
0.5995 
0.1211 
B1 
56% 
76% 
0.6704 
0.1377 
B2 
2% 
15% 
0.8007 
0.1673 
B3 
15% 
35% 
0.5995 
0.1211 
C 
30% 
50% 
0.7216 
0.1509 
D 
39% 
59% 
0.6405 
0.1095 
E 
25% 
45% 
0.6865 
0.1204 
Part B 
 
 
 
 
A, B, C 
2% 
15% 
0.8007 
0.1673 
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10. 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES 
10.1. 
Investigator Responsibilities 
This study will be performed in accordance with ethical principles that originate in the 
Declaration of Helsinki and conducted in adherence to the study Protocol; GCPs as defined in 
Title 21 of the US CFR Parts 11, 50, 54, 56, and 312; ICH E6 GCP consolidated guidelines; and 
local regulatory requirements as applicable to the study locations. 
The investigator will be responsible for: 
• Permitting study-related monitoring, sponsor audits, IRB/IEC review, and regulatory 
inspections by providing direct access to source data and other relevant clinical study 
documents. 
− Monitoring:  Qualified representatives of the sponsor or its designee, study 
monitors, will monitor the study according to a predetermined plan.  The 
investigator must allow the study monitors to review any study materials and 
subject records at each monitoring visit. 
− Auditing:  Qualified representatives of the sponsor or its designee may audit the 
clinical study site and study data to evaluate compliance with the Protocol, 
applicable local clinical study regulations, and overall study conduct.  The 
investigator must allow the auditors to review original source records and study 
documentation for all subjects. 
− Regulatory inspection:  Regulatory authorities may conduct an inspection of the 
study and the site at any time during the development of an investigational 
product.  The investigator and staff are expected to cooperate with the inspectors 
and allow access to all source documents supporting the eCRFs and other 
study-related documents.  The investigator must immediately notify the sponsor 
when contacted by any regulatory authority for the purposes of conducting an 
inspection. 
• Obtaining informed consent and ensuring that the study subjects' questions have been 
answered and the subjects fully understand study procedures: 
− Informed consent must be obtained before any study-related procedures are 
conducted, unless otherwise specified by the Protocol. 
− Informed consent must be obtained using the IRB/IEC-approved version in a 
language that is native and understandable to the subject.  A template will be 
provided by the sponsor or its designee.  The sponsor or its designee must review 
and acknowledge the site-specific changes to the ICF template.  The ICF must 
include a statement that the sponsor or its designee and regulatory authorities have 
direct access to subject records. 
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• Obtaining approval from the IRB/IEC before the start of the study and for any 
changes to the clinical study Protocol, important Protocol deviations, routine updates, 
and safety information in accordance with institutional requirements and local law. 
− The investigator is responsible for ensuring that the safety reports provided by the 
sponsor are reviewed and processed in accordance with regulatory requirements 
and with the policies and procedures established by the IRB/IEC. 
• Adhering to the Protocol as described in this document and agreeing that changes to 
the Protocol procedures, with the exception of medical emergencies, must be 
discussed and approved, first, by the sponsor or its designee and, second, by the 
IRB/IEC.  Each investigator is responsible for enrolling subjects who have met the 
specified eligibility criteria. 
• Retaining records in accordance with all local, national, and regulatory laws, but for a 
minimum period of at least 2 years after the last marketing application approval in an 
ICH region and until there are no pending or contemplated marketing applications in 
an ICH region, or if not approved, 2 years after the termination of the test article for 
investigation to ensure the availability of study documentation should it become 
necessary for the sponsor or a regulatory authority to review. 
− The investigator must not destroy any records associated with the study without 
receiving approval from the sponsor.  The investigator must notify the sponsor or 
its designee in the event of accidental loss or destruction of any study records.  If 
the investigator leaves the institution where the study was conducted, the sponsor 
or its designee must be contacted to arrange alternative record storage options. 
− All eCRF data entered by the site (including audit trail), as well as computer 
hardware and software (for accessing the data), will be maintained or made 
available at the site in compliance with applicable record retention regulations.  
The sponsor will retain the original eCRF data and audit trail. 
10.2. 
Accountability, Handling, and Disposal of Study Treatments 
The investigator is responsible for drug accountability at the study site; however, some of the 
drug accountability duties may be assigned to an appropriate pharmacist or other designee.  
Inventory and accountability records must be maintained and readily available for inspection by 
the study monitor and are open to inspection at any time by any applicable regulatory authorities.  
The investigator or designee must maintain records that document: 
• Delivery of study treatments to the study site. 
• Inventory of study treatments at the site. 
• Subject use of the study treatments including pill or unit counts from each supply 
dispensed. 
• Return of study treatments to the investigator or designee by subjects. 
The investigational product must be used only in accordance with the Protocol.  The investigator 
will also maintain records adequately documenting that the subjects were provided the specified 
study treatments.  These records should include dates, quantities, and any available batch or 
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serial numbers or unique code numbers assigned to the investigational product and study 
subjects. 
Completed accountability records will be archived by the site.  The investigator or designee will 
be expected to collect and retain all used, unused, and partially used containers of study 
treatment until verified by the study monitor (unless otherwise agreed to by the sponsor).  At the 
conclusion of the study, the investigator or designee will oversee shipment of any remaining 
study treatment back to the sponsor or its designee for destruction according to institutional 
standard operating procedures.  If local procedures mandate on-site destruction of investigational 
supply, the site should (where local procedures allow) maintain the investigational supply until 
the study monitor inspects the accountability records in order to evaluate compliance and 
accuracy of accountability by the investigative site.  At sites where the study treatment is 
destroyed before monitor inspection, the monitors rely on documentation of destruction per the 
site SOP. 
10.3. 
Data Management 
Data management will be performed in a validated database via an Electronic Data Capture 
(EDC) system.  All data entry, verification, and validation will be performed in accordance with 
the current standard operating procedures of the Data Management Department at the sponsor or 
its designee.  The database will be authorized for lock once all defined procedures are completed. 
The investigator will be provided with access to an EDC system so that an eCRF can be 
completed for each subject.  Entries made in the eCRF must be verifiable against source 
documents; if updates to the database are not possible, any discrepancies should be explained 
and documented.  The investigator will be responsible for reviewing all data and eCRF entries, 
and will sign and date the designated forms in each subject's eCRF, verifying that the 
information is true and correct.  The investigator is responsible for the review and approval of all 
query responses. 
Protocol deviations will be identified and recorded in the Protocol Deviation form of the eCRF.  
The study monitor will reference the Monitoring Plan in order to ensure that each issue identified 
is appropriately documented, reported, and resolved in a timely manner in accordance with the 
plan's requirements. 
10.4. 
Data Privacy and Confidentiality of Study Records 
The investigator and the sponsor or its designee must adhere to applicable data privacy laws and 
regulations.  The investigator and the sponsor or its designee are responsible for ensuring that 
sensitive information is handled in accordance with local requirements (eg, HIPAA).  
Appropriate consent and authorizations for use and disclosure and/or transfer (if applicable) of 
protected information must be obtained. 
Subject names will not be supplied to the sponsor or its designee, if applicable.  Only the subject 
number and subject's initials (subject's initials will only be recorded if allowable by local 
regulations) will be recorded in the eCRF, where permitted; if the subject's name appears on any 
other document (eg, laboratory report), it must be obliterated on the copy of the document to be 
supplied to the sponsor or its designee.  Study findings stored on a computer will be stored in 
accordance with local data protection laws.  The subjects will be informed that representatives of 
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the sponsor or its designee, IRB or IEC, or regulatory authorities may inspect their medical 
records to verify the information collected, and that all personal information made available for 
inspection will be handled in strictest confidence and in accordance with local data protection 
laws. 
10.5. 
Financial Disclosure 
Before study initiation, all clinical investigators participating in clinical studies subject to FDA 
Regulation Title 21 Code of Federal Regulations (CFR) Part 54 – Financial Disclosure by 
Clinical Investigators (ie, "covered studies") are required to submit a completed Clinical 
Investigator Financial Disclosure form that sufficiently details any financial interests and 
arrangements that apply.  For the purpose of this regulation, "clinical investigator" is defined as 
any investigator or subinvestigator who is directly involved in the treatment or evaluation of 
research subjects, including the spouse and each dependent child of the clinical investigator or 
subinvestigator.  These requirements apply to both US and foreign clinical investigators 
conducting covered clinical studies. 
Any new clinical investigators added to the covered clinical study during its conduct must also 
submit a completed Investigator Financial Disclosure Form.  During a covered clinical study, 
any changes to the financial information previously reported by a clinical investigator must be 
reported to the sponsor or its designee.  At the conclusion of the covered clinical study, the 
clinical investigators will be reminded of their obligations.  In the event that the clinical 
investigator is not reminded, they nevertheless will remain obligated to report to the sponsor or 
its designee any changes to the financial information previously reported, as well as any changes 
in their financial information for a period of 1 year after completion of the covered clinical study. 
10.6. 
Publication Policy 
By signing the study Protocol, the investigator and his or her institution agree that the results of 
the study may be used by the sponsor, Incyte Corporation (Incyte), for the purposes of national 
and international registration, publication, and information for medical and pharmaceutical 
professionals.  Study results will be published in accordance with applicable local and national 
regulations.  If necessary, the authorities will be notified of the investigator's name, address, 
qualifications, and extent of involvement.  The terms regarding the publication of study results 
are contained in the agreement signed with the sponsor or its designee.  A signed agreement will 
be retained by the sponsor or its designee. 
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11. 
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APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS 
For Subjects Participating in the Study: 
The following methods that can achieve a failure rate of less than 1% per year when used 
consistently and correctly are considered as highly effective birth control methods.  
Such methods include: 
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation1 
− oral 
− intravaginal 
− transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation1 
− oral 
− injectable 
− implantable2 
• Intrauterine device (IUD)2 
• Intrauterine hormone-releasing system (IUS)2 
• Bilateral tubal occlusion2 
• Vasectomised partner2,3 
• Sexual abstinence4 
 
1  Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the 
contraception method. 
2  Contraception methods that in the context of this guidance are considered to have low user dependency. 
3  Vasectomised partner is a highly effective method provided of avoiding pregnancy that partner is the sole sexual 
partner of the WOCBP trial participant and that the vasectomised partner has received medical assessment of the 
surgical success.  
4  In the context of this guidance, sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments.  The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the subject. 
Source:  CTFG 2014. 
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APPENDIX B. PHARMACOKINETIC ANALYTICAL PARAMETERS 
Cave 
Average steady-state plasma concentration (AUC0-12h/12h or 
AUC0-24h/24h) 
Cmax 
Maximum observed plasma concentration 
Cmin 
Minimum observed plasma concentration during the dosing interval 
Tmax 
Time to maximum plasma concentration 
AUC0-t 
Area under the single-dose plasma concentration-time curve from 
Hour 0 to the last quantifiable measurable plasma concentration, 
calculated by the linear trapezoidal rule for increasing concentrations 
and the log trapezoidal rule for decreasing concentrations 
AUC0-τ (ie, 
AUC0-12h or 
AUC0-24h) 
Area under the steady-state plasma concentration-time curve over 
1 dosing interval (ie, from Hour 0 to 12 for BID administration or from 
Hour 0 to 24 for QD administration), calculated by the linear trapezoidal 
rule for increasing concentrations and the log trapezoidal rule for 
decreasing concentrations 
λz 
Apparent terminal phase disposition rate constant, where λz is the 
magnitude of the slope of the linear regression of the log concentration 
versus time profile during the terminal phase 
t½ 
Apparent plasma terminal phase disposition half-life (whenever 
possible), where t½ = (ln2) / λz 
Cl/F 
Oral dose clearance 
Vz/F 
Apparent oral dose volume of distribution 
Fluctuation 
Steady-state fluctuation ([Cmax – Cmin]/Cave) 
Pharmacokinetic calculations will be performed, if appropriate, using commercial software such 
as WinNonlin®.  Additional details of analyses will be described in the statistical analysis plan. 
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APPENDIX C. PROHIBITED MONOAMINE OXIDASE INHIBITORS 
Monoamine Oxidase Inhibitors 
Drugs Associated With Significant Monoamine 
Oxidase Inhibitory Activity 
Hydrazines (eg, phenelzine) 
Meperidine 
Caroxazone 
Linezolid 
Echinopsidine 
Methylene blue 
Furazolidone 
 
Tranylcypromine 
 
Brofaromine 
 
Metralindole 
 
Minaprine 
 
Moclobemide 
 
Pirlindole 
 
Toloxatone 
 
Lazabemide 
 
Pargyline 
 
Rasagiline 
 
Selegiline 
 
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APPENDIX D. PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
Document 
Date 
Amendment (Version) 1: 
27 OCT 2017 
Amendment (Version) 2: 
01 JUN 2018 
Amendment 2 (Version 2 dated 01 JUN 2018) 
The main reason for the Amendment is to halt enrollment into the study, based on emergent data 
from the ECHO-301/KEYNOTE-252 melanoma clinical study in which an interim analysis 
revealed that the study did not meet the prespecified endpoint of improvement in 
progression-free survival for the combination of pembrolizumab and epacadostat compared with 
pembrolizumab and placebo (Long et al 2018). 
In addition, this amendment includes some corrected errors and a few updates based on new 
information (updated epacadostat safety information and the defined INCB001158 starting dose).   
This amendment includes the changes to the Protocol INCB 01158-202 Amendment (Version) 1 
(27 OCT 2017) summarized below. 
1. Synopsis; Section 4.3, Number of Subjects 
Description of change:  The estimated number of subjects to be enrolled and number of 
study sites in this study has been updated. 
Rationale for change:  The early termination of enrollment will limit the number of 
subjects to be enrolled. 
2. Synopsis; Section 4.6.1, Protocol Amendment 2 
Description of change:  All further enrollment into this study was halted.  Subjects who 
have consented and are in screening as of 08 MAY 2018 are permitted to enroll if 
eligibility is determined per Section 3, and subjects currently on treatment may continue 
as long as they are deriving clinical benefit, tolerating the treatment, and do not meet any 
withdrawal criteria.  Phase 1 backfill cohorts and Phase 2 will not be opened. 
Rationale for change:  The premise of this study was based on epacadostat + 
pembrolizumab having greater antitumor activity than pembrolizumab alone.  However, 
because the ECHO-301/KEYNOTE-252 melanoma clinical study did not meet the 
prespecified endpoint of improvement in progression-free survival for the combination of 
pembrolizumab + epacadostat compared with pembrolizumab + placebo, it was decided 
to close all further enrollment into the INCB 01158-202 study. 
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3. Synopsis; Section 9, Statistics 
Description of change:  All efficacy analyses will now only be exploratory; some 
planned tables and figures may be replaced by listings. 
Rationale for change:  Due to enrollment into this study halting during the Phase 1 
portion, there will not be sufficient efficacy data to warrant carrying out the planned 
efficacy analyses and producing all of the planned tables.  Instead, efficacy analyses will 
now be exploratory, and tables will be replaced with listings as appropriate.   
4. Section 1.3.2, Risks for Epacadostat; Section 5.4.7, Procedures for Subjects 
Exhibiting Serotonin Syndrome 
Description of change:  Language regarding serotonin syndrome was updated. 
Rationale for change:  Language was revised based on updated data from epacadostat 
studies. 
5. Section 5.2.3.2, Pembrolizumab Supply, Packaging, and Labeling 
Description of change:  Added an alternative pharmaceutical form in which the study 
treatment pembrolizumab could be provided, namely 50 mg lyophilized powder for 
reconstitution in single-use vials. 
Rationale for change:  Pembrolizumab may be supplied in this form at some sites. 
6. Section 5.4.10,  Criteria for Permanent Discontinuation of Study Treatment 
Description of change:  One of the definitions of “unacceptable toxicity” was changed 
from “An AE requiring more than 2 dose reductions of INCB001158 (and no lower than 
50 mg BID) or epacadostat” to “An AE requiring more than 2 dose reductions of 
INCB001158 or epacadostat.” 
Rationale for change:  The restriction of "no lower than 50 mg BID" was an error. 
7. Section 6, Study Assessments (Table 14, Schedule of Clinical Assessments) 
Description of change:  Changed the section reference from 0 to 3 in the "Review 
inclusion and exclusion criteria" row. 
Rationale for change:  Correction. 
8. Section 6, Study Assessments (Table 15, Schedule of Laboratory Assessments); 
Section 7.10.1, Timing of Assessments; 
 
 
Description of change:  Changed the type of sample from 
 
. 
Rationale for change:  Correction. 
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9. Section 7.6.1, Adverse Events; Section 8, Safety Monitoring and Reporting; 
Section 10.2, Accountability, Handling, and Disposal of Study Treatments 
Description of change:  All mentions of safety monitoring and reporting, accountability, 
handling, and disposal related to “study drug” have been changed to “study treatment” or 
“study treatments.” 
Rationale for change:  The safety monitoring and reporting, accountability, handling, 
and disposal relates to any or all of the 3 study treatments, not just the INCB001158 
study drug. 
10. Section 8.9, Events of Clinical Interest 
Description of change:  Serotonin syndrome was added to the list of Events of Clinical 
Interest. 
Rationale for change:  The epacadostat clinical program now requires events of 
serotonin syndrome to be reported to the sponsor within 24 hours. 
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Amendment 1 (Version 1 dated 27 OCT 2017) 
Overall Rationale for the Amendment:  To address comments from FDA. 
This amendment includes the changes to the Protocol INCB 01158-202 (02 OCT 2017) 
summarized below.  A redline version of the amendment depicting the updated and previous text 
is also provided. 
1. Synopsis; Section 1.2.3.1, Phase 1:  Dose Escalation of INCB00158-202 + 
Epacadostat + Pembrolizumab; Section 3.1, Subject Inclusion Criteria 
Description of change:  Revised the eligibility criteria so that subjects who refuse 
standard-of-care treatment are not eligible. 
Rationale for change:  FDA request. 
2. Synopsis; Section 3.1, Subject Inclusion Criteria; Section 4.1.3, Phase 2 Part B:  
Tumor Expansion of INCB001158 + Epacadostat 
Description of change:  Revised the eligibility criteria for Phase 2 Part B Cohort A 
(urothelial carcinoma) to require progression of disease after treatment with a 
platinum-based regimen and a checkpoint inhibitor. 
Rationale for change:  FDA request. 
3. Synopsis, Section 3.1 Subject Inclusion Criteria; Section 4.1.3, Phase 2 Part B:  
Tumor Expansion of INCB001158 + Epacadostat 
Description of change:  Revised the eligibility criteria for Phase 2 Part B Cohort B 
(SCCHN) to require progression of disease after prior treatment with a 
platinum-based therapy and a PD-1 inhibitor. 
Rationale for change:  FDA request. 
4. Section 5.4.2 Dose-Limiting Toxicity and Determination of Maximum Tolerated 
Dose in Phase 1 
Description of change:  Revised to specify that subjects who experienced a DLT that 
is considered life-threatening must permanently discontinue all 3 study treatments.  
For DLTs that are not life-threatening, all 3 treatments should be interrupted and then 
restarted following the management guidelines in Table 9. 
Rationale for change:  FDA request.  Relevant details were missing. 
5. Section 5.4.6, Dose Modifications for Immune-Related AEs and AEs Related to 
Urea-Cycle Inhibition 
Description of change:  Revised Table 9 to include the action that will be taken if 
fasting urinary orotic acid after 1 week of the initial one is abnormal. 
Rationale for change:  FDA request.  Relevant details were missing. 
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6. Section 5.4.10, Criteria for Permanent Discontinuation of Study Treatment 
Description of change:  Specified that only irAEs might require a 12-week treatment 
interruption, and that for all other AEs permanent discontinuation of study treatments 
would be required after 4 weeks. 
Rationale for change:  FDA request. Provides important clarification. 
7. Incorporation of administrative changes.  Other minor, administrative changes 
have been incorporated throughout the Protocol and are noted in the redline version 
of the amendment. 
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