Conditions: Metastatic Cancer Solid Tumors Colorectal Cancer (CRC) Gastric Cancer Head and Neck Cancer Lung Cancer Renal Cell Carcinoma (RCC) Bladder Cancer UC (Urothelial Cancer) Mesothelioma
Keywords: Immuno-Oncology Checkpoint Inhibitors Tumor Metabolism Programmed cell death protein-1 (PD-1) inhibitor Programmed death ligand 1 (PD-L1) inhibitor Solid Tumors RCC MEL NSCLC Arginase Arginase Inhibitor INCB001158 (CB-1158) SCCHN GEJ Immune Therapy
Allocation: NON_RANDOMIZED | Intervention model: FACTORIAL
Enrollment: 260
Healthy volunteers: no

Brief summary:
This study is an open-label Phase 1/Phase 2 evaluation of INCB001158 as a single agent and in combination with immune checkpoint therapy in patients with advanced/metastatic solid tumors.

Detailed description:
This study is an open-label Phase 1 evaluation of INCB001158 as a single agent and in combination with immune checkpoint therapy in patients with advanced/metastatic solid tumors.

Single Agent INCB001158:

Patients with advanced/metastatic solid tumors will be enrolled into escalating monotherapy dose cohorts to determine the Recommended Phase 2 Dose (RP2D) of INCB001158. Additional patients with NSCLC, Colorectal Cancer (CRC), and other tumors including SCCHN, RCC, Gastric, Bladder and Melanoma will be enrolled at the single agent RP2D.

Combination Treatment:

Patients with advanced/metastatic NSCLC, Melanoma, Urothelial, Microsatellite Instability (MSI)/ Microsatellite Stable (MSS) CRC, Gastric, SCCHN and Mesothelioma will be enrolled into separate cohorts of combination therapy (INCB001158 and Pembrolizumab) to determine the RP2D.

In the dose expansion phase, additional patients with NSCLC, Melanoma, Urothelial, MSI/MSS CRC, Gastric, SCCHN and Mesothelioma will be treated with the combination of INCB001158 and Pembrolizumab at the RP2D.

All patients will be assessed for safety, pharmacokinetics, biomarkers and tumor response.

Arms:
arm 1: Monotherapy Part 1a: INCB001158 administered orally in patients with advanced/metastatic solid tumors. Escalating doses will be explored to determine the recommended phase 2 dose (RP2D). arm 2: Monotherapy Part 2a: INCB001158 administered orally at the RP2D in patients with advanced/metastatic NSCLC (EGFR and Anaplastic Lymphoma Kinase (ALK) negative) previously treated with Standard of Care (SOC). arm 3: Monotherapy Part 2b: INCB001158 administered orally at the RP2D in patients with advanced/metastatic CRC previously treated with SOC. arm 4: Monotherapy Part 2c: INCB001158 administered orally at the RP2D in patients with Bladder Cancer, Gastric or Gastroesophageal Junction (GEJ) Cancer, Renal Cell Cancer (RCC), Squamous Cell Carcinoma of the Head and Neck (SCCHN), Urothelial Cell Cancer (UCC), or Melanoma, previously treated with SOC. arm 5: Monotherapy Part 2d: INCB001158 administered orally at the RP2D in patients with any tumor types in Parts 2a, 2b, or 2c. arm 6: Combination Part 1b: INCB001158 and Pembrolizumab administered in patients with advanced/metastatic NSCLC, Melanoma, Urothelial Cell Cancer, MSI CRC, MSS CRC, Gastric or Gastroesophageal Junction (GEJ) Cancer, SCCHN and Mesothelioma. Multiple dose levels will be explored to determine the recommended phase 2 dose (RP2D). arm 7: Part 3a: INCB001158 and Pembrolizumab the combination RP2D in patients with advanced/metastatic NSCLC (EGFR and ALK negative) with disease progression on anti-PD-1 therapy or prolonged stable disease on Pembrolizumab in the immediate prior line of therapy. arm 8: Part C: evaluated a reduced dose of INCB001158 50 mg BID in combination with pembrolizumab with patients with moderately impaired renal function.

Interventions: intervention 1: INCB001158 intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Arginase Inhibitor intervention 2: PD-1 Inhibitor

Protocol document:
Prot_000.pdf: 
 
Official Title: 
 
Safety, Pharmacokinetics, and Pharmacodynamics of Escalating Oral Doses 
of the Arginase Inhibitor INCB001158 (Formerly Known as CB1158) as a 
Single Agent and in Combination With Immune Checkpoint Therapy in 
Patients With Advanced/Metastatic Solid Tumors 
NCT Number: 
NCT02903914 
 
Document Date: 
 
Clinical Study Protocol Amendment 2–US 3: 10 November 2020 
 
 
 
 
 
 
 
 


INCB001158 
Protocol INCB 01158-101 
10 NOV 2020 Amendment 2-US 3 
CONFIDENTIAL 
1 
VV-CLIN-000684
Title 
Safety, Pharmacokinetics, and Pharmacodynamics of Escalating Oral 
Doses of the Arginase Inhibitor INCB001158 (formerly known as 
CB-1158) as a Single Agent and in Combination with Immune Checkpoint 
Therapy in Patients with Advanced/Metastatic Solid Tumors 
Protocol Number 
INCB 01158-101 (formerly known as CX-1158-101) 
IND Number 
128080 
EudraCT number 2017-002903-82 
Sponsor 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
Date/Version 
10 NOV 2020/Amendment 2-US 3 
TITLE PAGE 
Confidentiality Statement 
This document contains information that is confidential and proprietary to the Sponsor. This 
information is being provided to you solely for the purpose of evaluating and/or conducting a 
clinical study for the Sponsor. You may disclose the contents of this document only to study 
personnel under your supervision, institutional review boards (IRBs)/independent ethics 
committees (IECs), or duly authorized representatives of regulatory agencies for this purpose 
under the condition that they maintain confidentiality. The contents of this document may not be 
used in any other clinical study, disclosed to any other person or entity, and/or published without 
the prior written permission of the Sponsor. The foregoing shall not apply to disclosure required 
by any regulations; however, you will give prompt notice to the Sponsor of any such disclosure. 
All other nonpublic information provided by the Sponsor and any information that may be added 
to this document also is confidential and proprietary to the Sponsor and must be kept in 
confidence in the same manner as the contents of this document. 
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. 


INCB001158 
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10 NOV 2020 Amendment 2-US 3 
 
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INVESTIGATOR'S AGREEMENT 
I have read the INCB 01158-101 Protocol Amendment 2-US 3 (dated 10 NOV 2020) 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) 
 


INCB001158 
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10 NOV 2020 Amendment 2-US 3 
 
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SYNOPSIS 
Name of Investigational Product:  INCB001158 
Title of Study:  Safety, Pharmacokinetics, and Pharmacodynamics of Escalating Oral Doses of the 
Arginase Inhibitor INCB001158 as a Single Agent and in Combination with Immune Checkpoint 
Therapy in Patients with Advanced/Metastatic Solid Tumors. 
Protocol Number:  INCB 01158-101 
Study Phase:  1 
Indication:   
Part 1a (monotherapy dose escalation): all advanced/metastatic solid tumors. 
Parts 1b and 1c (pembrolizumab combination dose escalation): all patient populations included in 
Part 3. 
Part 2 (monotherapy expansion cohorts): advanced/metastatic non-small cell lung cancer (NSCLC), 
advanced/metastatic colorectal cancer (CRC), advanced/metastatic tumors including gastric cancer, 
cancer of the gastroesophageal junction (GEJ), urothelial cell cancer (UCC), renal cell cancer (RCC), 
melanoma, or squamous cell carcinoma of the head and neck (SCCHN) or other advanced/metastatic 
solid tumors (e.g., those demonstrated or expected to have high infiltration with arginase-positive cells) 
may be allowed based on the discretion of the Medical Monitor. 
Part 3 (pembrolizumab combination expansion cohorts): advanced/metastatic NSCLC, melanoma, 
UCC, microsatellite instability-high (MSI-H) CRC, microsatellite stable (MSS) CRC, 
advanced/metastatic Gastric/GEJ cancer, SCCHN and malignant pleural mesothelioma. 


INCB001158 
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Primary Objectives 
Primary Endpoints 
Parts 1a and 2 
To evaluate the safety and tolerability of INCB001158 
for patients with advanced/metastatic and/or treatment-
refractory solid tumors 
Adverse events (AEs) and changes in laboratory 
values, vital signs, and physical examinations 
Parts 1b, 1c, and 3 
To evaluate the safety and tolerability of INCB001158 
in combination with pembrolizumab in patients with 
advanced/metastatic and/or treatment-refractory  solid 
tumors 
AEs and changes in laboratory values, vital signs and 
physical examinations 
Secondary Objectives 
Secondary Endpoints 
Parts 1a and 2 
To select the Recommended Phase 2 Dose (RP2D) of 
INCB001158 for patients with advanced/metastatic 
solid tumors  
Based on an evaluation of AEs, pharmacokinetics 
(PK), pharmacodynamics and evidence of clinical 
activity 
Parts 1b and 3 
To select the RP2D of INCB001158 in combination 
with pembrolizumab for patients with 
advanced/metastatic solid tumors  
Based on an evaluation of AEs, PK, 
pharmacodynamics and evidence of clinical activity 
Parts 1a, 1b, 1c, 2, and 3 
To evaluate the anti-tumor effect of INCB001158 as 
monotherapy and in combination with pembrolizumab 
for patients with advanced/metastatic solid tumors 
Assessed by standard RECIST v1.1 criteria (except for 
pleural mesothelioma, which will be evaluated using 
modified RECIST criteria) [overall response rate 
(ORR), best overall response (BOR), duration of 
response (DOR), and progression-free survival (PFS)]  
Determine PK of INCB001158 alone and in 
combination with pembrolizumab  
Cmax, Tmax, AUCt, AUC0-12 and CL/F in patients with 
CrCl 30-49 mL/min (Part 1c only) or CrCl 
≥ 50 mL/min (Parts 1a, 1b, 2, and 3) 


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Overall Study Design 
Phase 1 open-label, non-randomized study to evaluate the safety, tolerability, pharmacokinetics, 
pharmacodynamics and anti-tumor activity of the arginase inhibitor INCB001158, evaluated both as 
monotherapy and in combination with the immune checkpoint inhibitor pembrolizumab, an 
anti-programmed cell death protein-1 (anti-PD-1) agent. 
The study design is illustrated in the following schematic: 
 
 
 
 
 
 
 


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Part 1a Dose Escalation 
This is a standard 3+3 dose escalation of single agent INCB001158 in patients with 
advanced/metastatic solid tumors.  A minimum of three eligible solid tumor patients will be assigned 
to each dose level during the Dose Escalation period.  The starting dose of 50 mg BID was selected for 
the monotherapy dose escalation on the basis of GLP-compliant preclinical toxicity studies.  The dose 
escalation schedule outlined below will be followed, which is based on the standard Modified 
Fibonacci design.  Real-time PK and pharmacodynamic assessment will be performed on samples 
taken during dose escalation.   
Part 1b Dose Escalation 
The decision to initiate the evaluation of the safety of INCB001158 in combination with 
pembrolizumab (Part 1b) will be made on the basis of PK, pharmacodynamic and safety data from 
patients enrolled in the monotherapy dose escalation (Part 1a) and/or monotherapy expansion cohorts 
(Part 2).  Part 1b may be opened if one of the following is achieved at a dose level that is confirmed to 
be at or below the monotherapy MTD: 
• 
At least half of the patients (minimum of two patients) enrolled at a particular dose level 
achieve a trough (Cmin) plasma concentration of INCB001158 at steady state of ≥ 1 μM, OR 
• 
At least half of the patients (minimum of two patients) at a particular dose level achieve a 
2.5-fold increase in fasting plasma arginine at Cycle 1 Day 15 predose relative to their baseline 
(Cycle 1 Day 1 predose) value. 
When the PK or PD requirement has been satisfied in Part 1a or Part 2 as defined above, the final 
decision to open Part 1b will be made by agreement between the Medical Monitor and the Study 
Investigators.   
Part 1b is a standard 3+3 dose escalation design.  Upon opening Part 1b, a minimum of 3 patients will 
receive pembrolizumab (200 mg IV Q3W) in combination with INCB001158.  Enrollment in Part 1b is 
limited to patients with tumor types that would be eligible for the Expansion Cohorts in Part 3.  In 
Part 1b, the starting dose of INCB001158 will be 50 mg BID, which is 2 dose levels below the 
recommended monotherapy Phase 2 dose of 100 mg BID identified in Part 1a of this study.  Dose 
escalation will proceed according to the Dose Escalation Schedule that is being employed in Part 1a in 
the table below.  A dose level shall not be enrolled in Part 1b until it has been demonstrated to be at or 
below the monotherapy MTD in Part 1a.   
INCB001158 Dose Levels 
Cohort 
BID Dose 
(mg) 
% Increase 
N 
-1 
25 
- 50% 
3 – 6 
1* 
50 
- 
3 – 6 
1.5 
75 
50% 
3 – 6 
2 
100 
33% 
3 – 6 
3 
150 
50% 
3 – 6 
4 
225 
50% 
3 – 6 
5 
300 
33% 
3 – 6 
6 
400 
33% 
3 – 6 
7 
500 
25% 
3 – 6  
8 
600 
20% 
3 – 6 
*starting dose level 
 


INCB001158 
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10 NOV 2020 Amendment 2-US 3 
 
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Part 1c Renal Impairment Cohort 
At US sites only, Cohort 1c will enroll 6 patients who have moderately impaired renal function 
(defined as CrCl 30-49 mL/min calculated by the Cockcroft-Gault formula) AND meet eligibility 
criteria for any of the combination expansion cohorts (3a through 3h).  Based on population PK 
modeling, a dose of 50 mg BID in patients with CrCl 30-49 mL/min is predicted to achieve 
INCB001158 AUC/Cmin values to fall within the known safe exposure range corresponding to doses at 
or below the established RP2D of 100 mg BID.  Therefore, 6 patients meeting eligibility criteria for 
Parts 3a through 3h will be enrolled at a reduced dose of 50 mg BID in order to obtain full PK, PD, and 
safety data.  All data collected during the first cycle (21 days) will be evaluated, along with the 
population PK modeling data, to determine the INCB001158 dose in patients with moderately 
impaired renal function that most closely approximates the PK parameters of the RP2D of 100 mg BID 
in patients with normal renal function.  Patients who do not complete all planned PK assessments or 
have treatment discontinuation or interruptions during the first 21 days of dosing will be replaced until 
6 evaluable patients have been accrued to the cohort.  Efficacy evaluable patients in Cohort 1c who 
achieve the target exposure leading to continuous inhibition of extracellular arginase 1 by > 90% (Cmin 
of > 1 µM) and/or an elevation of fasting plasma arginine of > 2.5-fold at Cycle 1 Day 15 predose 
relative to baseline will be counted towards their respective Part 3 expansion cohorts, provided these 
have not fully enrolled at the time data from these patients become available. 
Dose Escalation Rules and Definition of Maximally Tolerated Dose (MTD) 
Dose limiting toxicities (DLTs) observed in the first 28 days of dosing for monotherapy dose 
escalation (Part 1a) or the first 42 days of dosing for combination dose escalation (Part 1b) will be used 
to determine escalation to the next dose level.  The study is using a traditional 3+3 design and the dose 
escalation rules are as follows: 
• 
An initial cohort of 3 patients is enrolled. 
• 
If 0/3 patients develops a DLT, escalation to the next dose will occur. 
• 
If 1/3 patients develops a DLT: 
o Another 3 patients will be enrolled at this dose level. 
▪ 
If 0 of the 3 new patients develops a DLT (for a total of 1/6 patients with a 
DLT at this dose level), escalation to the next dose level will occur. 
▪ 
If ≥1 of the 3 new patients develops a DLT (for a total of ≥ 2/6 patients with a 
DLT at this dose level), the dose escalation stage of the trial will be 
terminated, and the dose directly below the current dose will be considered the 
MTD. 
• 
If ≥ 2/3 patients develop a DLT, the dose escalation stage of the trial will be terminated, and 
the dose directly below the current dose will be considered the MTD. 
If a dose level below 1000 mg BID is selected as the MTD on the basis of only 2 DLTs and subsequent 
clinical data [e.g., in the expansion cohort(s)] demonstrate that the rate of AEs that qualify as DLTs at 
that dose level is < 10% in > 10 patients, re-escalation to the next dose level previously associated with 
DLTs may be considered.  If re-escalation occurs, up to 6 additional patients may be enrolled and the 
dose level may be considered tolerable if the overall DLT rate for that dose level is ≤ 25%. 
Part 2 Single Agent Cohort Expansion 
Following completion of monotherapy Dose Escalation and selection of the RP2D for INCB001158 in 
Part 1a, the following cohorts of patients will be enrolled to receive single agent INCB001158 at the 
RP2D. 
• 
Cohort 2a will enroll patients with advanced NSCLC. Enrollment to this cohort will follow a 
Simon 2-stage design where the observed clinical activity in the first 11 patients will determine 
whether additional patients will be enrolled for a total of 26 patients. 


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• 
Cohort 2b will enroll patients with advanced/metastatic colorectal cancer. Enrollment to this 
cohort will follow a Simon 2-stage design where the observed clinical activity in the first 
11 patients will determine whether additional patients will be enrolled for a total of 26 patients. 
• 
Cohort 2c will initially enroll 30 patients with various other tumor types expected to have high 
infiltration with arginase positive cells. Up to 2 tumor types in Cohort 2c may then be 
expanded based on a Simon 2-stage design, if the observed clinical activity (1 or more PR or 
CR in a tumor type with up to 11 patients) supports enrollment of additional patients for a total 
of 26 patients per tumor type. 
• 
Cohort 2d will enroll patients at US sites only who meet eligibility criteria for any of the 
monotherapy expansion cohorts (2a, 2b, or 2c). 
 
 
 
 
 
Part 3 Combination Cohort Expansion   
Upon selection of the RP2D for INCB001158 in combination with pembrolizumab in Part 1b, cohorts 
of specific patients will be enrolled to receive INCB001158 in combination with pembrolizumab at the 
RP2D to further evaluate safety and identify an early signal of clinical activity. 
Study Population  
Part 1a (monotherapy dose escalation): all advanced/metastatic solid tumors. 
Parts 1b and 1c (pembrolizumab combination dose escalation): all patient populations included in 
Part 3. 
Part 2 (monotherapy expansion cohorts): advanced/metastatic NSCLC, advanced/metastatic CRC, 
advanced/metastatic tumors including gastric cancer, cancer of the GEJ, UCC, RCC, melanoma, or 
SCCHN or other advanced/metastatic solid tumors (e.g., those demonstrated or expected to have high 
infiltration with arginase-positive cells) may be allowed based on the discretion of the Medical 
Monitor. 
Part 3:  advanced/metastatic NSCLC, melanoma, UCC, microsatellite instability-high (MSI-H) CRC, 
microsatellite stable (MSS) CRC, advanced/metastatic Gastric/GEJ cancer, SCCHN and malignant 
pleural mesothelioma. 
Key Inclusion Criteria 
1. Age ≥ 18 years 
2. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 
3. Adequate organ function as indicated by the laboratory values in  
• 
Absolute neutrophil count (ANC) ≥ 1.500/mcL 
• 
Platelets ≥ 100,000/mcL 
• 
Hemoglobin ≥ 9 g/dL 
• 
CrCl ≥ 50 mL/min (calculated using the Cockcroft-Gault formula), except for Cohort 
1c, which will enroll patients with creatinine clearance 30-49 mL/min (calculated 
using the Cockcroft-Gault formula). 
• 
Serum total bilirubin OR Direct bilirubin (for patients with Gilbert Syndrome and total 
bilirubin levels > 1.5 ULN) ≤ 1.5 X ULN OR ≤ ULN 
• 
AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN 
• 
International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 X ULN- Does 
not apply to patients receiving therapeutic anticoagulation 


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4. Measurable Disease: At least one tumor lesion/lymph node that meets the RECIST v1.1 
criteria for being “measurable.” 
Resolution of all treatment-related toxicities, except alopecia, anemia, or endocrinopathies 
managed by hormone replacement, from any previous cancer therapy to ≤ Grade 1 or to values 
within those required for eligibility on this study prior to the first dose of study treatment.   
Part 1: Inclusion Criteria Specific to the Dose Escalation 
Part 1a: Inclusion Criteria Specific to the Monotherapy Dose Escalation  
1. Histologically or cytologically proven diagnosis of any locally advanced or metastatic 
solid tumor not amenable to local therapy in patients who have disease progression after 
treatment with all available therapies known to confer clinical benefit 
Part 1b: Inclusion Criteria Specific to the PD-1 Combination Dose Escalation 
1. Histologically or cytologically proven diagnosis of advanced/metastatic NSCLC 
(squamous or non-squamous), mesothelioma, gastric/GEJ cancer, MSS CRC, MSI-H 
CRC, UCC, melanoma or SCCHN in patients who have disease progression after 
treatment with all available therapies known to confer clinical benefit.  Patients that have 
not received prior anti-PD-1 therapies are allowed. 
Part 1c: Inclusion Criteria Specific to the PD-1 Combination Moderately Renally Impaired Cohort 
1. Criteria for any of Cohorts 3a to 3h. 
Part 2: Inclusion Criteria Specific to Monotherapy Cohort Expansion  
Part 2a: Inclusion Criteria Specific to the Monotherapy NSCLC Cohort 
1. Histologically or cytologically proven diagnosis of advanced/metastatic NSCLC 
(squamous or non-squamous) in patients who have disease progression after treatment 
with all available therapies known to confer clinical benefit 
Part 2b: Inclusion Criteria Specific to the Monotherapy CRC Cohort 
1. Histologically or cytologically proven diagnosis of advanced/metastatic CRC in patients 
who have disease progression after treatment with all available therapies known to confer 
clinical benefit 
Part 2c: Inclusion Criteria Specific to the Monotherapy in Other Tumors 
1. Histologically or cytologically proven diagnosis of advanced/metastatic tumors including 
gastric cancer, cancer of the GEJ, UCC, RCC, melanoma, or SCCHN in patients who have 
disease progression after treatment with all available therapies known to confer clinical 
benefit.  Other advanced/metastatic solid tumors (e.g., those demonstrated or expected to 
have high infiltration with arginase-positive cells) may be allowed based on the discretion 
of the Medical Monitor. 
Part 2d: 
 
1. 
Meets the criteria for any of Parts 2a, 2b, or 2c. 
 
. 
Part 3: Inclusion Criteria Specific to the PD-1 Combination Cohort Expansion 
Part 3a: Non-small cell lung cancer (NSCLC) – PD/SD on anti-PD-1/PD-L1 therapy 
1. Histological or cytological diagnosis of locally advanced unresectable or metastatic 
NSCLC that does not harbor an activating EGFR or ALK mutation 
2. Prior progression on or after platinum-based chemotherapy or refused/ineligible to receive 
platinum-based chemotherapy. 
 
3. Received an anti-PD-1/PD-L1 agent in a prior line of therapy for advanced/metastatic 
disease and EITHER: 


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a. Had documented radiological disease progression (per Investigator assessment, 
preferably with confirmation of PD after 4 weeks) while receiving 
anti-PD-1/PD-L1 therapy in the most recent line of therapy, OR 
b. Had documented stable disease (per Investigator assessment) for ≥ 24 weeks while 
receiving pembrolizumab therapy in the most recent line of therapy 
Part 3b: Melanoma – PD/SD on anti-PD-1/PD-L1  therapy 
1. Histological or cytological diagnosis of locally advanced unresectable or metastatic 
melanoma 
2. Received an anti-PD-1/PD-L1  agent in the most recent prior line of therapy for 
advanced/metastatic disease and EITHER: 
a. Had documented radiological disease progression (per Investigator assessment, 
preferably with confirmation of PD after 4 weeks) while receiving 
anti-PD-1/PD-L1 therapy in the most recent line of therapy, OR 
b. Had documented stable disease (per Investigator assessment) for ≥ 24 weeks while 
receiving pembrolizumab therapy in the most recent line of therapy  
Part 3c: Urothelial cell carcinoma (UCC) – PD/SD on anti-PD-1/PD-L1 therapy 
1. Histological or cytological diagnosis of locally advanced unresectable or metastatic UCC 
2. Received an anti-PD-1/PD-L1  agent in the most recent prior line of therapy for 
advanced/metastatic disease and EITHER: 
a. Had documented radiological disease progression (per Investigator assessment, 
preferably with confirmation of PD after 4 weeks) while receiving 
anti-PD-1/PD-L1  therapy in the most recent line of therapy, OR 
b. Had documented stable disease (per Investigator assessment) for ≥ 24 weeks while 
receiving pembrolizumab therapy in the most recent line of therapy  
Part 3d: Mismatch repair deficient and/or microsatellite instability-high (MSI-H) colorectal cancer 
(CRC) – PD/SD on anti-PD-1/PD-L1  therapy 
1. Histological or cytological diagnosis of locally advanced unresectable or metastatic CRC 
demonstrated to be mismatch repair deficient or microsatellite instability-high. 
2. Received an anti-PD-1/PD-L1  agent in the most recent prior line of therapy for 
advanced/metastatic disease and EITHER: 
a. Had documented radiological disease progression (per Investigator assessment, 
preferably with confirmation of PD after 4 weeks) while receiving 
anti-PD-1/PD-L1  therapy in the most recent line of therapy, OR 
b. Had documented stable disease (per Investigator assessment) for ≥ 24 weeks while 
receiving pembrolizumab therapy in the most recent line of therapy  
Part 3e: Microsatellite stable (MSS) colorectal cancer (CRC) – Checkpoint inhibitor naive  
1. Histological or cytological diagnosis of locally advanced unresectable or metastatic CRC 
demonstrated to lack mismatch repair deficiency and microsatellite instability (low or 
high). 
2. Received at least one prior fluoropyrimidine-containing systemic therapy for 
advanced/metastatic CRC 
3. Has not received prior anti-PD-1/PD-L1, anti-CTLA4, or other checkpoint inhibitor or 
immune co-stimulator (e.g., anti-OX-40, anti-41BB, etc.) 
 
Part 3f: Gastric/gastro-esophageal (GE) junction cancer – Checkpoint inhibitor naive  


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1. Histological or cytological diagnosis of locally advanced unresectable or metastatic gastric 
or GEJ cancer 
2. Received at least two prior systemic therapies for advanced/metastatic disease; prior 
regimens must have included a platinum and a fluoropyrimidine 
3. Human epidermal growth factor receptor 2 (HER-2/neu) negative, or, if HER2/neu 
positive, must have previously received treatment with trastuzumab 
4. Has not received prior anti-PD-1/PD-L1, anti-CTLA4, or other checkpoint inhibitor or 
immune co-stimulator (e.g., anti-OX-40, anti-41BB, etc.) 
Part 3g: Squamous cell carcinoma of the head and neck (SCCHN) – Checkpoint inhibitor naive 
1. Histological or cytological diagnosis of recurrent or metastatic SCCHN 
2. Had disease progression EITHER: 
a. While receiving or after platinum-containing chemotherapy administered for 
recurrent or metastatic SCCHN, OR 
b. Following platinum-containing chemotherapy administered as part of induction, 
concurrent, or adjuvant therapy. 
3. Has not received prior anti-PD-1/PD-L1, anti-CTLA4, or other checkpoint inhibitor or 
immune co-stimulator (e.g., anti-OX-40, anti-41BB, etc.).  
Part 3h: Mesothelioma – Checkpoint inhibitor naive  
1. Histological or cytological diagnosis of locally advanced incurable or metastatic malignant 
pleural mesothelioma 
2. Has failed or was unable to received standard therapy for malignant pleural mesothelioma 
3. Has not received prior anti-PD-1/PD-L1, anti-CTLA4, or other checkpoint inhibitor or 
immune co-stimulator (e.g., anti-OX-40, anti-41BB, etc.)  
Key Exclusion Criteria 
1. Any other current or previous malignancy within the past three years except a) adequately 
treated basal cell or squamous cell skin cancer, b) carcinoma in situ of the cervix, c) prostate 
cancer with stable prostate specific antigen (PSA) levels for 3 years, d) or other neoplasm that, 
in the opinion of the Principal Investigator and with the agreement of the Medical Monitor, 
will not interfere with study-specific endpoints. 
2. Cytotoxic chemotherapy, tyrosine kinase inhibitor (or other targeted anti-cancer agent), 
radiation therapy, or hormonal therapy within 14 days or 5 half-lives, whichever is longer, 
prior to Cycle 1 Day 1 (42 days for nitrosoureas or mitomycin C). 
3. Immunotherapy or biological therapy (e.g., monoclonal antibodies) within 21 days prior to 
Cycle 1 Day 1 
• 
EXCEPTION: Washout of anti-PD-1 therapy is NOT required in Part 1b Dose 
Escalation or the Part 3 Expansion Cohorts.  
4. Treatment with an unapproved investigational therapeutic agent within 21 days (or 5 half-lives 
for small molecule agents) prior to Cycle 1 Day 1 
• 
EXCEPTION: Washout of anti-PD-1 therapy is NOT required in Part 1b Dose 
Escalation or the Part 3 Expansion Cohorts.  
5. Has a diagnosis of immunodeficiency or any condition requiring systemic treatment with 
either corticosteroids (> 10 mg daily prednisone equivalent) or other systemic 
immunosuppressive medications within 14 days prior to the first dose of study treatment.  
Inhaled steroids and adrenal replacement steroid doses < 10 mg daily prednisone equivalent 
are permitted in the absence of active autoimmune disease. 
6. Concomitant therapy with valproic acid/valproate-containing therapies. 
7. Concomitant therapy with allopurinol and other xanthine oxidase inhibitors. 
8. Exclusion criterion deleted in Protocol Amendment 2-EU. 


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9. Patients with symptomatic ascites or pleural effusion requiring intermittent paracentesis or 
thoracocentesis.  A patient who is clinically stable following treatment for these conditions 
(including therapeutic thoraco- or para-centesis) is eligible. 
10. Unable to receive medications per os (PO) 
11. Unstable/inadequate cardiac function: 
• 
Myocardial infarction or symptomatic ischemia within the last 6 months 
• 
Uncontrolled or clinically significant conduction abnormalities (e.g., ventricular 
tachycardia on antiarrhythmics are excluded; 1st degree AV block or asymptomatic 
LAFB/RBBB are eligible) 
• 
Congestive heart failure (New York Heart Association class III to IV) 
12. 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. 
13. Major surgery within 2 months  prior to first dose of study treatment. 
14. Infection requiring parenteral antibiotics, antivirals, or antifungals within two weeks prior to 
first dose of study treatment. 
15. Patient is known to be positive for Human Immunodeficiency Virus (HIV), Hepatitis B or 
Hepatitis C. 
16. Refractory nausea and vomiting, uncontrolled diarrhea, malabsorption, significant small bowel 
resection or gastric bypass surgery, use of feeding tubes or other situation that may preclude 
adequate absorption 
17. Serious psychiatric or medical conditions that could interfere with treatment or protocol-
related procedures 
18. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.   
Note: Patients with brain metastases or CNS disease are permitted, but must have completed 
treatment and either (1) have no evidence of active CNS disease for at least 4 weeks prior to 
the first dose OR (2) have stable CNS lesions, defined as not requiring intrathecal 
chemotherapy for at least 6 weeks or systemic steroid treatment to prevent CNS complications 
for at least 3 weeks prior to first dose.  Patients with CNS disease must also have a Screening 
head CT or MRI demonstrating stable disease compared to their most recent CNS evaluation.  
This exception does not apply to patients with carcinomatous meningitis who are excluded 
regardless of clinical stability. 
19. Patients in whom oral and/or IV fluid hydration are contraindicated 
20. Patients who are pregnant or lactating 
21. Has received a live-virus vaccination within 30 days of planned treatment start. Seasonal flu 
vaccines that do not contain live virus are permitted. 
22. Has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the trial, interfere with the Patient’s participation for the full 
duration of the trial, or is not in the best interest of the Patient  to participate, in the opinion of 
the treating investigator.   
23. Has had an allogeneic tissue/solid organ transplant. 
 
 
 
 
 
 
Disease-specific Exclusion Criteria 


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Part 1b AND Part 3 
1. Intolerance to prior anti-PD-1/PD-L1 therapy including 1) discontinuation due to immune-
related toxicity or, 2) immune-related toxicities that that required intensive or prolonged 
immunosuppression (including, high-dose IV corticosteroids, > 2 mo of immunosuppressive 
corticosteroids (i.e., equivalent of >10mg oral prednisone daily) or the addition of potent 
immunosuppression to corticosteroids (e.g., mycophenolate mofetil/CellCept or infliximab) to 
manage. 
2. Prior severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients or 
prior severe hypersensitivity reaction to any other monoclonal antibody (mAb). 
3. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis. 
4. Has a history of interstitial lung disease. 
5. Has received transfusion of blood products (including platelets or red blood cells) or 
administration of colony stimulating factors (including G-CSF, GM-CSF or recombinant 
erythropoietin) within 2 weeks prior to study Day 1.  
6. Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use 
of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement 
therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency, etc.) is not considered a form of systemic treatment.  
Part 3 
Part 3a: NSCLC 
1. Documented activating mutations in EGFR or ALK. 
Dosage and Mode of Administration  
INCB001158 
Study drug (INCB001158) will be taken orally using a capsule or tablet formulation in dose strengths 
of 25 mg or 100 mg.  INCB001158 will be administered only to patients who have signed and dated an 
Informed Consent Form.   
Patients in Part 1a and 2: INCB001158 will be taken on Days 1 through 28 of each 28-day cycle and 
should be taken orally using the number of capsules/tablets directed in the Pharmacy Manual.   
Patients in Part 1b, 1c, and 3: INCB001158 will be taken on Days 1 through 21 of each 21-day cycle 
and should be taken orally using the number of capsules/tablets directed in the Pharmacy Manual.  
Pembrolizumab 
Pembrolizumab will be administered on day 1 of each 3-week treatment cycle after all procedures and 
assessments have been completed as detailed on the schedule of assessment.  A 200 mg dose of 
pembrolizumab will be administered as an IV infusion over 30 minutes.  The 200 mg Q3W dose and 
schedule is an approved dose in the United States and EU member states.  Once the pembrolizumab 
infusion is complete, patients will be instructed to take their morning dose of INCB001158. 
Study Schedule/Procedures 
Patients will have regularly scheduled study visits at the clinical site on Day 1 of each cycle.  
Additional study visits may be required during some cycles to monitor for safety, efficacy, or for 
PK/
 
evaluations.  Study visits are as follows:  
Screening: Up to 21 days before enrollment.  Screening will begin at the time that the Patient signs the 
informed consent and will continue until the date that the Patient is enrolled in the study (Cycle 1 
Day 1). 
Part 1a Cycle 1: Day 1, Day 2, Day 8, Day 15, and Day 22 (± 2 days); Cycle 2: Day 1 and Day 8 
(± 5 days). 
Part 2 Cycle 1: Day 1, Day 8, Day 15, and Day 22 (± 2 days). 
Parts 1b, 1c, and 3 Cycle 1: Day 1, Day 8, and Day 15 (± 2 days). 


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All other treatment cycles: Day 1 (± 5 days).  
Part 1a and 2 Efficacy assessments: Every 8 weeks (± 7 days). 
Part 1b, 1c, and 3 Efficacy assessments: Every 9 weeks (± 7 days). 
End of treatment:  The End of Treatment (EOT) visit must occur within 28 days of study treatment 
discontinuation and prior to initiation of any new anti-cancer therapy/regimen. 
Safety follow-up 
30 days (+ 7 days) (all patients) and 90 days (+ 7 days) (Parts 1b and 3 only) after end of study 
treatment. 
Disease follow-up 
Patients who discontinue study treatment for reasons other than disease progression will continue to be 
assessed for their disease status during the follow-up phase and should continue to have tumor 
assessments every 8 weeks (monotherapy) or 9 weeks (pembrolizumab combination) until a new 
cancer therapy is started, disease progression, death, or the end of the study. 
Estimated Duration of Participation 
Up to 21 days for screening, then continuous treatment in consecutive 28 day cycles for Part 1a and 2 
and 21-day cycles for Part 1b and 3 as long as patients are receiving benefit, are tolerating the regimen 
and do not meet any criteria for discontinuation of study treatment, and 30 and 90 days for safety 
follow-up.  Study participation, including post-treatment follow-up, is expected to average 
approximately 24 months per individual Patient. 
Estimated Number of Patients 
Up to 582 Patients may be enrolled in the study.  
Part 1a Dose Escalation – Up to 108 evaluable Patients. 
Part 1b Dose Escalation – Up to 108 evaluable Patients. 
Part 1c Moderate Renal Impairment Cohort – Up to 6 evaluable Patients. 
Part 2 Expansion (Simon 2-Stage) – Approximately 58 to 138 evaluable Patients. 
Part 3 Expansion (Simon 2-Stage) – Approximately 90 to 222 evaluable Patients. 
Principal Coordinating Investigator  
TBD 
Statistical Methods 
Sample Size Method 
The primary objective is to determine a dose level of INCB001158, as monotherapy and in 
combination with pembrolizumab, for which the rate of DLTs is less than 33%.  Up to approximately 
108 patients are planned for single agent dose escalation (Part 1a) and up to 108 patients for 
combination dose escalation (Part 1b).   
Part 1c is intended to enroll the minimum number of patients required to generate sufficient PK data 
for a descriptive comparison of Day 1 and steady state (Day 8, Day 15) exposures between patients 
with moderate renal impairment (CrCl 30-49 mL/min) and normal renal function (CrCl > 50 mL/min).  
Accordingly, the sample size of 6 PK-evaluable patients for Cohort 1c is not based on a predefined 
statistical analysis. 
In Parts 2a, 2b, and 3, the sample size for each tumor type within a treatment group will be guided by 
the Simon 2-stage design.  Part 2c is designed to investigate the potential for clinical activity in a 
variety of tumor types.  The sample size for the initial 30 patients was not based on a predefined 
statistical analysis.  The sample size for each tumor type in any subsequent expansion of Cohort 2c will 
be guided by a Simon 2-stage design. 
 


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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 patients to predict possible target responses worthy of cohort expansion and 
potentially 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.   
Part 2 and 3:  Simon 2-Stage Design-Expansion Cohorts 
Cohort 
p0 
Background 
ORR (%) 
p1 
Target ORR 
(%) 
α 
Power 
(%) 
n1 for 
Stage 1 
(r1) 
n2 (n - n1) 
for Stage 2 
Total n 
(r2) 
2a 
2% 
15% 
0.1 
80 
11 (0) 
15 
26 (1) 
2b 
2% 
15% 
0.1 
80 
11 (0) 
15 
26 (1) 
2c 
expansion 
2% 
15% 
0.1 
80 
11 (0) 
15 
26 (1) 
3a 
2% 
15% 
0.1 
80 
11 (0) 
15 
26 (1) 
3b 
2% 
15% 
0.1 
80 
11 (0) 
15 
26 (1) 
3c 
2% 
15% 
0.1 
80 
11(0) 
15 
26 (1) 
3d 
2% 
15% 
0.1 
80 
11 (0) 
15 
26 (1) 
3e 
2% 
15% 
0.1 
80 
11 (0) 
15 
26 (1) 
3f 
10% 
25% 
0.1 
80 
13 (1) 
21 
34 (5) 
3g 
20% 
40% 
0.1 
80 
12 (2) 
13 
25 (7) 
3h 
13% 
30% 
0.1 
80 
10 (1) 
23 
33 (6) 
 
Primary Analysis  
The following safety analyses will be assessed for all Patients  in each treatment combination: 
Adverse events (AEs) and changes in laboratory values, vital signs, and physical examinations. 
Secondary Analyses 
The following efficacy analyses will be assessed for all Patients  in each treatment combination: 
• 
Based on an evaluation of AEs, pharmacokinetics (PK), pharmacodynamics and evidence of 
clinical activity. 
• 
Assessed by standard RECIST v1.1 criteria (except for pleural mesothelioma, which will be 
evaluated using modified RECIST criteria) [overall response rate (ORR), best overall response 
(BOR), duration of response (DOR), and progression-free survival (PFS)] 
• 
Non-compartmental method of analysis will be used to analyze the plasma concentration of 
INCB001158 
 
 
 
 
 
 


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Interim Analysis  
With the exception of the analyses at the end of Stage 1 of each Simon 2-stage design, no formal 
interim analysis is planned; however, safety data will be examined on an ongoing basis to ensure safety 
of the study patients and compliance with the trial dose escalation and expansion rules. 


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TABLE OF CONTENTS 
SYNOPSIS ......................................................................................................................................3 
TABLE OF CONTENTS ............................................................................................................17 
1.0 
SAFETY REPORTING CONTACT..............................................................................23 
2.0 
LIST OF ABBREVIATIONS .........................................................................................24 
CORE PROTOCOL ....................................................................................................................27 
3.0 
OBJECTIVES ..................................................................................................................27 
4.0 
POTENTIAL RISKS AND BENEFITS OF THE TREATMENT REGIMEN .........29 
4.1 
Potential Risks of INCB001158 Monotherapy and its Combination with 
Pembrolizumab ......................................................................................................29 
4.2 
Potential Benefit of INCB001158 and its Combination with Pembrolizumab ......29 
5.0 
STUDY DESIGN ..............................................................................................................30 
5.1 
Part 1. Dose Escalation ..........................................................................................31 
5.1.1 
Dose Escalation Rules and Definition of Maximally Tolerated Dose 
(MTD) ...................................................................................................35 
5.1.2 
Dose-Limiting Toxicity .........................................................................35 
5.1.3 
Definition of Recommended Phase 2 Dose (RP2D) .............................40 
5.2 
Part 2. Single Agent Cohort Expansion .................................................................40 
5.3 
Part 3. Combination Cohort Expansion .................................................................42 
6.0 
SAMPLE SIZE .................................................................................................................49 
7.0 
INCLUSION/EXCLUSION CRITERIA .......................................................................50 
7.1 
Inclusion Criteria ...................................................................................................50 
7.2 
Exclusion Criteria ..................................................................................................54 
8.0 
RADIOLOGICAL TUMOR ASSESSMENTS .............................................................58 
 
60 
PROTOCOL DETAILS ..............................................................................................................61 
10.0 
BACKGROUND AND RATIONALE ...........................................................................61 
10.1 
Background ............................................................................................................61 
10.1.1 
Immunosuppressive Myeloid Cells and Arginase ................................61 
10.1.2 
Arginase 1 Expression in Cancer Patients ............................................62 
10.1.3 
Selectivity of INCB001158 ...................................................................63 
10.1.4 
Activity of INCB001158 in Cell-Based Assays ...................................64 
10.1.5 
Immunosuppression by Arginase in Mice Versus Humans ..................65 
10.1.6 
Pharmacodynamics of INCB001158 in Tumors and Tissues in Mice ..65 
10.1.7 
Efficacy of INCB001158 in Tumor-Bearing Syngeneic Mice .............66 
10.1.8 
Nonclinical Toxicity Testing of INCB001158 ......................................68 


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10.1.9 
Previous Human Experience .................................................................70 
10.1.10 
Pharmacokinetics of INCB001158 .......................................................71 
10.1.11 
Pharmacodynamics of INCB001158.....................................................72 
10.1.12 
Safety of Single Agent INCB001158 ....................................................74 
10.2 
Rationale for Study Design ....................................................................................78 
10.2.1 
Rationale for Starting Dose ...................................................................78 
10.2.2 
Rationale for Dose Escalation Strategy.................................................78 
10.2.2.1 
Rationale for Dose in Patients with Moderately Impaired Renal 
Function .........................................................................................79 
10.2.3 
Rationale for Patient Populations ..........................................................81 
10.2.3.1 
Monotherapy ..................................................................................81 
10.2.3.2 
Combination with Anti-PD-1 (Pembrolizumab) ............................82 
11.0 
PROCEDURES ................................................................................................................83 
11.1 
Screening Period ....................................................................................................83 
11.1.1 
Prior Treatment .....................................................................................83 
11.1.2 
Concomitant Treatment .........................................................................83 
11.1.2.1 
Acceptable Concomitant Medications ...........................................84 
11.1.2.2 
Prohibited Concomitant Medications ............................................84 
11.1.3 
Screening Evaluation ............................................................................85 
11.2 
Study Procedures ...................................................................................................86 
11.2.1 
Cycle 1 ..................................................................................................87 
11.2.1.1 
Part 1a and 1c Only: Cycle 1 Day 1 and Day 15 ...........................87 
11.2.2 
Cycle 2 and All Subsequent Cycles ......................................................88 
11.2.2.1 
Part 1a Only: Cycle 2 Days 1-8 .....................................................88 
11.2.2.2 
Part 2d Only ...................................................................................89 
11.3 
Other Schedules and Procedures ............................................................................89 
11.4 
End of Treatment (EOT) ........................................................................................90 
11.5 
Follow-Up ..............................................................................................................90 
11.5.1 
Safety Follow-Up ..................................................................................90 
11.5.2 
Disease Status Follow-Up .....................................................................91 
11.6 
Screen Failures .......................................................................................................91 
11.7 
Safety Evaluation ...................................................................................................91 
11.7.1 
Physical Examination ............................................................................91 
11.7.2 
Vital Signs .............................................................................................92 
11.7.3 
Electrocardiograms ...............................................................................92 
11.7.4 
Safety Laboratory Determinations ........................................................92 


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93 
 
93 
 
95 
 
95 
 
95 
11.9 
Pharmacokinetic Evaluation ..................................................................................96 
11.9.1 
Blood Collection ...................................................................................96 
11.9.2 
Intensive PK Sampling ..........................................................................96 
11.9.3 
Sparse PK Sampling ..............................................................................97 
 
97 
11.9.5 
Bioanalytical Methodology ...................................................................97 
12.0 
POTENTIAL TOXICITIES, DOSE MODIFICATION AND MANAGEMENT 
OF TOXICITIES .............................................................................................................98 
12.1 
Potential Toxicities ................................................................................................98 
12.1.1 
INCB001158 .........................................................................................98 
12.1.2 
Pembrolizumab (Patients Enrolled in Parts 1b, 1c, and 3) ..................101 
12.1.2.1 
INCB001158 + Pembrolizumab Combination ............................101 
12.1.3 
Dose Modifications and Toxicity Management ..................................101 
12.1.3.1 
Dose Modification Guidelines .....................................................102 
12.1.3.2 
Resumption of Study Treatment ..................................................103 
12.1.3.3 
Supportive Care Guidelines .........................................................111 
12.2 
Dose Adjustments, Infusion Delays, and Missed Doses ......................................115 
12.3 
Discontinuation of Treatment and Withdrawal of Patients..................................115 
13.0 
STUDY DRUG AND OTHER STUDY TREATMENTS ..........................................116 
13.1 
Study Treatment Administration..........................................................................116 
13.2 
Packaging and Labeling .......................................................................................118 
13.3 
Storage and Stability ............................................................................................118 
13.4 
INCB001158 Accountability, Reconciliation, and Return ..................................118 
13.5 
Study Treatment Compliance ..............................................................................119 
14.0 
MEASURES TO MINIMIZE/AVOID BIAS ..............................................................120 
15.0 
STATISTICAL ANALYSIS .........................................................................................120 
15.1 
General Statistical Considerations .......................................................................120 
15.2 
Sample Size and Power ........................................................................................120 
15.3 
Analysis Populations ............................................................................................122 
15.3.1 
Safety Population ................................................................................122 
15.3.2 
DLT-Evaluable Populations in Dose Escalation .................................122 


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15.3.3 
Efficacy Evaluable Populations ..........................................................122 
15.4 
Efficacy Analysis .................................................................................................123 
15.5 
Safety Analysis ....................................................................................................124 
15.6 
Pharmacokinetic Analysis ....................................................................................124 
 
125 
15.7 
Precautions ...........................................................................................................125 
16.0 
SAFETY MONITORING AND REPORTING ..........................................................126 
16.1 
Adverse Events ....................................................................................................126 
16.1.1 
Definitions ...........................................................................................126 
16.1.2 
Reporting .............................................................................................126 
16.2 
Laboratory Test Abnormalities ............................................................................128 
16.3 
Serious Adverse Events .......................................................................................129 
16.3.1 
Definitions ...........................................................................................129 
16.3.2 
Reporting .............................................................................................130 
16.4 
Pregnancy .............................................................................................................131 
16.5 
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor ................................................................................................................132 
16.6 
Warnings and Precautions....................................................................................132 
16.7 
Product Complaints ..............................................................................................133 
17.0 
STUDY SUSPENSION, TERMINATION, AND COMPLETION ...........................134 
18.0 
INFORMED CONSENT ...............................................................................................135 
19.0 
PROTOCOL AMENDMENTS ....................................................................................135 
20.0 
QUALITY CONTROL AND ASSURANCE...............................................................135 
21.0 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE PROCEDURES ......136 
21.1 
Investigator Responsibilities ................................................................................136 
21.2 
Accountability, Handling, and Disposal of Study Drug ......................................138 
21.3 
Data Management ................................................................................................139 
21.4 
Data Privacy and Confidentiality of Study Records ............................................139 
21.5 
Financial Disclosure.............................................................................................140 
21.6 
Publication Policy ................................................................................................141 
22.0 
REFERENCES ...............................................................................................................142 
ATTACHMENT 1A:  SCHEDULE OF STUDY ASSESSMENTS FOR PART 1A AND 
PART 2 (INCB001158 MONOTHERAPY).................................................................144 
ATTACHMENT 1B:  SCHEDULE OF STUDY ASSESSMENTS FOR PARTS 1B, 1C, 
AND 3 (INCB001158 + PEMBROLIZUMAB) ...........................................................147 
ATTACHMENT 2A:  PHARMACOKINETIC 
 SAMPLING 
SCHEDULE FOR PART 1A ........................................................................................150 


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ATTACHMENT 2B:  PHARMACOKINETIC 
 SAMPLING 
SCHEDULE FOR PARTS 2A, 2B, AND 2C ...............................................................152 
ATTACHMENT 2C:  PHARMACOKINETIC 
 SAMPLING 
SCHEDULE FOR PARTS 1B, 1C, AND 3 ..................................................................153 
155 
ATTACHMENT 3:  CLINICAL LABORATORY TESTS ...................................................157 
ATTACHMENT 4:  RECIST CRITERIA VERSION 1.1 .....................................................158 
ATTACHMENT 5:  MODIFIED RECIST CRITERIA FOR MALIGNANT PLEURAL 
MESOTHELIOMA .......................................................................................................171 
ATTACHMENT 6:  IMMUNE RELATED RECIST CRITERIA (BASED ON 
RECIST V1.1) ................................................................................................................172 
ATTACHMENT 7:  GUIDANCE FOR POTENTIAL DILI (DRUG-INDUCED LIVER 
INJURY) .........................................................................................................................178 
ATTACHMENT 8:  AMENDMENT 2 EXECUTIVE SUMMARY OF CHANGES..........181 
ATTACHMENT 9:  AMENDMENT 2-EU EXECUTIVE SUMMARY OF CHANGES ...184 
ATTACHMENT 10:  AMENDMENT 2-US EXECUTIVE SUMMARY OF CHANGES .187 
ATTACHMENT 11:  AMENDMENT 2-US 2 EXECUTIVE SUMMARY OF 
CHANGES ......................................................................................................................190 
ATTACHMENT 12:  AMENDMENT 2-US 3 EXECUTIVE SUMMARY OF 
CHANGES ......................................................................................................................191 
ATTACHMENT 13:  ELECTRONIC SIGNATURE PAGE ................................................192 
 


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LIST OF TABLES 
Table 5.1-1:  Dose Escalation Schedule for Monotherapy and PD-1 Combination ......................32 
Table 6.0-1:  Table of Sample Size Estimates ...............................................................................49 
Table 7.1-1:  Laboratory Values for Inclusion...............................................................................50 
Table 10.1-1:  PK Parameters from Phase 1 Patients ....................................................................72 
Table 10.1-2:  INCB001158-Related Treatment-Emergent Adverse Events by Preferred Term ..74 
Table 10.1-3:  Plasma Ammonia Levels by Visit Day* ................................................................76 
Table 10.1-4:  Blood Urea Nitrogen Levels by Visit Day* ...........................................................76 
Table 10.1-5:  Predose Orotic Acid Levels by Visit Day* ............................................................77 
Table 10.2-1:  Projected Human INCB001158 Steady-State AUCs During 1 Dose Interval at 
50, 75, 100, and 150 mg for Patients with Different Creatinine Clearances 
Ranging from 15 to 200 mL/min .....................................................................81 
94 
Table 12.1-1:  INCB001158 Dose Modification Guidelines for Adverse Events in Patients 
Receiving INCB001158 (All Parts) ...............................................................105 
Table 12.1-2:  Dose Modification and Toxicity Management Guidelines for Immune-Related 
Adverse Events Associated With Pembrolizumab (Parts 1b, 1c, and 3) .......108 
Table 12.1-3:  Pembrolizumab Infusion Reaction Dose Modification and 
Treatment Guidelines .....................................................................................114 
Table 15.2-1:  Summary of Sample Size and Power for Expansion Cohorts ..............................121 
 
LIST OF FIGURES 
Figure 5.0-1:  Study design. ...........................................................................................................30 
42 
Figure 10.1-1:  Arginase and arginine in cancer patients. .............................................................63 
Figure 10.1-2:  Inhibition of the immunosuppressive effect of neutrophils and MDSCs on 
T-cells ex vivo. .................................................................................................64 
Figure 10.1-3:  Tumor PK and pharmacodynamics of INCB001158. ...........................................66 
Figure 10.1-4:  Inhibition of LLC tumor growth and pharmacodynamic effects in vivo. .............67 
Figure 10.1-5:  Inhibition of B16 melanoma tumor growth in vivo...............................................68 
Figure 10.1-6:  Peak urine orotic acid levels in rats. .....................................................................70 
Figure 10.1-7: PK profile of INCB001158 in patients enrolled in the Phase 1 study. .................71 
Figure 10.1-8:  Plasma arginine and arginase in Phase 1 patients. ..............................................73 
Figure 10.2-1:  Plot of INCB001158 CrCl versus AUC or Cmax in patients treated with 
INCB001158 alone or in combination with pembrolizumab, from Parts 1a 
and 1b. ..............................................................................................................80 
 


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1.0 
SAFETY REPORTING CONTACT 
Incyte TelerX 
SAE Reporting Details (to be used for submitting the SAE forms): 
Safety Fax: 
 
Email:
 
 


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2.0 
LIST OF ABBREVIATIONS 
Abbreviation or Term1 
Definition/Explanation 
AE 
Adverse event 
ALK 
Anaplastic Lymphoma Kinase 
ALT 
Alanine aminotransferase 
APTT 
Activated partial thromboplastin time 
ARG1 
Arginase 1 gene signature 
ARG2 
Arginase 2 gene signature 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
HCG 
Human chorionic gonadotropin 
BID 
Twice daily 
BUN 
Blood urea nitrogen 
Ca++ 
Calcium 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
Cl- 
Chloride 
CLcr 
Creatinine clearance 
CL/F 
Apparent oral dose clearance 
Cmax 
Maximum observed concentration 
Cmin 
Minimum observed concentration 
CR 
Complete remission 
CRC 
Colorectal Cancer 
CTA 
Clinical Trial Agreement 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation 
CYP450 
Cytochrome P450 
DLT 
Dose Limiting Toxicity 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
EGFR 
Epidermal Growth Factor Receptor 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte Colony-Stimulating Factor 
g/dL 
Grams per deciliter 
GDPR 
General Data Protection Regulation 


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Abbreviation or Term1 
Definition/Explanation 
GEJ 
Gastroesophageal Junction 
GFR 
Glomerular filtration rate 
GLP 
Good Laboratory Practice 
GM-CSF 
Granulocyte Macrophage Colony-Stimulating Factor 
G-MDSC 
Granulocytic Myeloid Derived Suppressor Cells 
GMP 
Good Manufacturing Practice 
Hb 
Hemoglobin 
HCO3- 
Bicarbonate 
hERG 
Human Ether-à-Go-Go Related Gene 
HIV 
Human immunodeficiency virus 
HNSTD 
Highest non-severely toxic dose (non-rodents) 
HPLC 
High-performance liquid chromatography 
HR 
Heart rate 
hr 
Hour or hours 
IC50 
Half maximal inhibitory concentration 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
INR 
International Normalized Ratio 
irAE 
Immune-related Adverse Event 
IRB 
Institutional Review Board 
iRECIST 
Modified RECIST 1.1 for immune-based therapeutics 
IV 
Intravenous, intravenously 
LDH 
Lactate dehydrogenase 
LFT 
Liver Function Test 
LC-MS/MS 
Liquid chromatography-tandem mass spectrometry 
LLC 
Lewis Lung Carcinoma 
mAb 
Monoclonal Antibody 
MDSC 
Myeloid Derived Suppressor Cells 
µL/mcL 
Microliter 
MedRA 
Medical Dictionary for Regulatory Activities 
mL 
Milliliter 
MDSC 
Myeloid Derived Suppressor Cells 
MSI-H 
Microsatellite Instability- High 
MSS 
Microsatellite Stable 
MTD 
Maximum tolerated dose 
NO 
Nitric Oxide 
NOAEL 
No Observable Adverse Event Level 
NSCLC 
Non-small cell lung cancer 
ORR 
Overall response rate 
OTC 
Ornithine transcarbamylase 
PD 
Progressive Disease 


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Abbreviation or Term1 
Definition/Explanation 
PD-1 
Programmed cell death protein-1 
PD-L1 
Programmed death ligand 1 
PFS 
Progression Free Survival 
PK 
Pharmacokinetic(s) 
PO 
Per os (administered by mouth) 
PR 
Partial response 
PSA 
Prostate specific antigen 
PT 
Prothrombin time 
aPTT 
Activated Partial thromboplastin time 
QTcF 
Corrected QT interval, Fridericia’s formula 
RBC 
Red Blood Cell 
RCC 
Renal Cell Cancer 
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious adverse event 
SCCHN 
Squamous Cell Carcinoma of the Head and Neck 
SD 
Stable disease 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SOC 
Standard of Care 
STD10 
Severely toxic dose in 10% of animals (rodents) 
Tmax 
Time of maximum observed concentration 
TEAE 
Treatment-emergent adverse event 
UCC 
Urothelial Cell Cancer 
UCD 
Urea cycle gene defect 
ULN 
Upper limit of normal 
ULQ 
Upper limit of quantitation 
WBC 
White blood cell 
1 
All of these abbreviations may or may not be used in protocol. 
 


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CORE PROTOCOL 
3.0 
OBJECTIVES 
Primary Objectives 
Primary Endpoints 
Parts 1a and 2 
To evaluate the safety and tolerability of 
INCB001158 for patients with 
advanced/metastatic and/or treatment-
refractory solid tumors 
Adverse events (AEs) and changes in 
laboratory values, vital signs, and physical 
examinations 
Parts 1b, 1c, and 3 
To evaluate the safety and tolerability of 
INCB001158 in combination with 
pembrolizumab in patients with 
advanced/metastatic and/or treatment-
refractory  solid tumors 
AEs and changes in laboratory values, vital 
signs and physical examinations 
Secondary Objectives 
Secondary Endpoints 
Parts 1a and 2 
To select the Recommended Phase 2 Dose 
(RP2D) of INCB001158 for patients with 
advanced/metastatic solid tumors  
Based on an evaluation of AEs, 
pharmacokinetics (PK), pharmacodynamics 
and evidence of clinical activity 
Parts 1b and 3 
To select the RP2D of INCB001158 in 
combination with pembrolizumab for patients 
with advanced/metastatic solid tumors  
Based on an evaluation of AEs, PK, 
pharmacodynamics and evidence of clinical 
activity 
Parts 1a, 1b, 1c, 2, and 3 
To evaluate the anti-tumor effect of 
INCB001158 as monotherapy and in 
combination with pembrolizumab for patients 
with advanced/metastatic solid tumors 
Assessed by standard RECIST v1.1 criteria 
(except for pleural mesothelioma, which will 
be evaluated using modified RECIST 
criteria) [overall response rate (ORR), best 
overall response (BOR), duration of response 
(DOR), and progression-free survival (PFS)] 
Determine PK of INCB001158 alone and in 
combination with pembrolizumab  
Cmax, Tmax, AUCt, AUC0-12 and CL/F in 
patients with CrCl 30-49 mL/min (Part 1c 
only) or CrCl ≥ 50 mL/min (Parts 1a, 1b, 2, 
and 3) 


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4.0 
POTENTIAL RISKS AND BENEFITS OF THE TREATMENT REGIMEN 
4.1 Potential Risks of INCB001158 Monotherapy and its Combination with 
Pembrolizumab 
The potential risks of INCB001158, pembrolizumab and the combination of INCB001158 with 
pembrolizumab are outlined in detail in Section 12.1 of the protocol. 
4.2 Potential Benefit of INCB001158 and its Combination with Pembrolizumab 
Since INCB001158 is an experimental therapy, it is not known if it will be of benefit to patients.  
Based on what is known about the expression of Arginase in cancers and the immunosuppressive 
effect of Arginase, though the depletion of arginine, it is hypothesized that the inhibition of 
Arginase will result in an increase in local and systemic arginine levels, which may reverse 
Arginase-induced immunosuppression.  By reversing immunosuppression, an anti-tumor 
immune response may reactivated in patients, either as a monotherapy or in combination with 
anti-PD-1 therapy (e.g., pembrolizumab). 


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5.0 
STUDY DESIGN 
Protocol INCB 01158-101 is a Phase 1 open-label study of the arginase inhibitor INCB001158 
given as monotherapy and in combination with the immune checkpoint inhibitor pembrolizumab, 
an anti-programmed cell death protein-1 (anti-PD-1) agent. 
 
 
Figure 5.0-1:  Study design. 
 


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5.1 Part 1. Dose Escalation 
Part 1a of this Phase 1 study will begin with a standard, open-label, 3+3 dose-escalating design 
of single agent INCB001158 in patients with advanced/metastatic solid tumors.  Dose escalation 
will continue until identification of a maximum tolerated dose (MTD) or to a planned maximum 
daily dose of 2000 mg orally [i.e., 1000 mg twice daily (BID)].  Dose escalation may continue 
beyond 2000 mg daily based on emerging clinical data.  Escalation will be limited by a 
maximum pharmacokinetic (PK) threshold based on the exposure at the highest well tolerated 
doses in GLP-compliant toxicity studies (see Section 10.2.2 for further details). 
After achieving a predefined threshold PK target exposure of INCB001158 and/or clear evidence 
of pharmacodynamic activity (i.e., elevated plasma arginine) during single agent escalation of 
INCB001158, the safety and tolerability of INCB001158 will be evaluated in combination with 
the anti-PD-1 agent pembrolizumab in a separate dose escalation (Part 1b).  Pembrolizumab will 
be administered at the dose of 200 mg intravenously (IV) every 3 weeks.  Only dose levels of 
INCB001158 that have already been demonstrated to be safe as a monotherapy will be tested in 
combination with pembrolizumab.  
Part 1a. INCB001158 Monotherapy Dose Escalation 
Sequential dose escalation of single agent INCB001158 will take place in patients with 
advanced/metastatic solid tumors.  A minimum of three eligible solid tumor patients will be 
assigned to each dose level during the Dose Escalation period.  
Dose escalation plan: The starting dose of 50 mg BID was selected for the monotherapy dose 
escalation on the basis of GLP-compliant preclinical toxicity studies (see Section 10.2.1).  The 
dose escalation schedule outlined in Table 5.1-1 will be followed, which is based on the standard 
Modified Fibonacci design. Real-time PK and pharmacodynamic assessment will be performed 
on samples taken during dose escalation. 


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Table 5.1-1:  Dose Escalation Schedule for Monotherapy and PD-1 Combination 
INCB001158 Dose Levels 
Cohort 
BID Dose 
(mg) 
% Increase 
N 
-1
25 
- 50%
3 – 6 
1* 
50 
- 
3 – 6 
1.5 
75 
50% 
3 – 6 
2 
100 
33% 
3 – 6 
3 
150 
50% 
3 – 6 
4 
225 
50% 
3 – 6 
5 
300 
33% 
3 – 6 
6 
400 
33% 
3 – 6 
7 
500 
25% 
3 – 6 
8 
600 
20% 
3 – 6 
*starting dose level
At the discretion of the Sponsor, up to a total of 6 additional “backfill” patients may be enrolled 
at any tolerable dose level to further investigate safety 
  
 
   
Intermediate dose levels that are between those listed in Table 5.1-1 may be investigated if the 
safety, PK, or pharmacodynamic data warrant.  If that were to occur, the dose escalation rules in 
Section 5.1.1 would apply. 


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Part 1b. INCB001158 Dose Escalation in Combination with Pembrolizumab  
The decision  to initiate the evaluation of the safety of INCB001158 in combination with 
pembrolizumab (Part 1b) will be made on the basis of PK, pharmacodynamic and safety data 
(see Section 10.2.1) from patients enrolled in the monotherapy dose escalation (Part 1a) and/
or monotherapy expansion cohorts (Part 2).  Part 1b may be opened if one of the following is 
achieved at a dose level that is confirmed to be at or below the monotherapy MTD: 
1. At least half of the patients (minimum of two patients) enrolled at a particular dose level
achieve a trough (Cmin) plasma concentration of INCB001158 at steady state of ≥ 1 µM,
OR
2. At least half of the patients (minimum of two patients) at a particular dose level achieve a
2.5-fold increase in fasting plasma arginine at Cycle 1 Day 15 predose relative to their
baseline (Cycle 1 Day 1 predose) value.
When the PK or PD requirement has been satisfied in Part 1a or Part 2 as defined above, the final 
decision to open Part 1b will be made by agreement between the Medical Monitor and the Study 
Investigators.   
Upon opening Part 1b, a minimum of 3 patients will receive pembrolizumab (200 mg IV Q3W) 
in combination with INCB001158.  Enrollment in Part 1b is limited to patients that would be 
eligible for the Expansion Cohorts in Part 3.  In Part 1b, the starting dose of INCB001158 will be 
50 mg BID, which is 2 dose levels below the recommended monotherapy Phase 2 dose of 
100 mg BID identified in Part 1a of this study.  Dose escalation will proceed according to the 
Dose Escalation Schedule that is being employed in Part 1a (Table 5.1-1).  A dose level shall not 
be enrolled in Part 1b until it has been demonstrated to be at or below the monotherapy MTD in 
Part 1a.   
Part 1c. INCB001158 in Combination with Pembrolizumab in Patients with Moderately 
Impaired Renal Function 
At US sites only, Cohort 1c will enroll 6 patients who have moderately impaired renal function 
(defined as CrCl 30-49 mL/min calculated by the Cockcroft-Gault formula) AND meet eligibility 
criteria for any of the combination expansion cohorts (3a through 3h).  The safety of 
INCB001158 in combination with pembrolizumab was fully characterized with a comprehensive 
dose escalation in patients with CrCl > 50 mL/min.  Additionally, pembrolizumab did not have 


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any effect on the PK of INCB001158.  Therefore, Cohort 1c will evaluate a reduced dose of 
INCB001158 50 mg BID (determined using population PK modeling) in combination with 
pembrolizumab in order to determine a pharmacodynamically active dose in patients with 
moderately impaired renal function.  
Based on population PK modeling, a dose of INCB01158 50 mg BID in patients with CrCl 30 to 
49 mL/min is predicted to achieve INCB001158 AUC/Cmin values to fall within the known safe 
exposure range corresponding to doses at the established RP2D of 100 mg BID (see 
Section 10.2).  Six patients meeting eligibility criteria for Parts 3a through 3h will be enrolled at 
the reduced dose of 50 mg BID  to obtain full PK, PD (see Attachment 2C), and safety data.  All 
data collected during the first cycle (21 days) will be evaluated, along with the population PK 
modeling data, to determine the INCB001158 dose in patients with moderately impaired renal 
function that most closely approximates the PK parameters of the RP2D of 100 mg BID in 
patients with normal renal function and specifically meets the following PK and PD criteria: 
•
At least half of the patients (minimum of 2 patients) achieve the target exposure leading
to continuous inhibition of extracellular arginase 1 by > 90% (a trough [Cmin] plasma
concentration of INCB001158 at steady state of ≥ 1 μM), AND/OR
•
At least half of the patients (minimum of 2 patients) achieve a 2.5-fold increase in fasting
plasma arginine at Cycle 1 Day 15 predose relative to their baseline (Cycle 1 Day 1
predose) value.
Population PK modeling showed a highly predictable, linear, inverse relationship between CrCl 
and AUC, Cmax, and half-life for INCB001158 (see Section 10.2.2.1).  Therefore, if the PK-PD 
criteria specified above are not met at the 50 mg BID dose, population PK modeling will be used 
to determine whether a lower dose (25 mg BID) or a previously evaluated intermediate dose 
(75 mg BID) would more closely approximate PK parameters for the established RP2D of 
100 mg BID.  Cohort 1c patients who do not complete all planned PK assessments or have 
treatment discontinuation or interruptions during the first 21 days of dosing will be replaced until 
6 evaluable patients have been accrued to the cohort.  Patients meeting the pre-specified PK and 
PD criteria will be counted towards the Simon 2-stage efficacy assessment in their respective 
Part 3 expansion cohorts, provided these have not fully enrolled at the time data from these 
patients become available. 


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5.1.1 
Dose Escalation Rules and Definition of Maximally Tolerated Dose (MTD) 
Dose limiting toxicities (DLTs) observed in the first 28 days of dosing for monotherapy dose 
escalation (Part 1a) or the first 42 days of dosing for combination dose escalation (Part 1b) will 
be used to determine escalation to the next dose level.  The study is using a traditional 3+3 
design and the dose escalation rules are as follows: 
• An initial cohort of 3 patients is enrolled. 
• If 0/3 patients develops a DLT, escalation to the next dose will occur. 
• If 1/3 patients develops a DLT: 
o Another 3 patients will be enrolled at this dose level. 
▪ If 0 of the 3 new patients develops a DLT (for a total of 1/6 patients with a 
DLT at this dose level), escalation to the next dose level will occur. 
▪ If ≥ 1 of the 3 new patients develops a DLT (for a total of ≥ 2/6 patients 
with a DLT at this dose level), the dose escalation stage of the trial will be  
terminated, and the dose directly below the current dose will be considered 
the MTD. 
• If ≥ 2/3 patients develop a DLT, the dose escalation stage of the trial will be terminated, 
and the dose directly below the current dose will be considered the MTD. 
 
If a dose level below 1000 mg BID is selected as the MTD on the basis of only 2 DLTs and 
subsequent clinical data [e.g., in the expansion cohort(s)] demonstrate that the rate of AEs that 
qualify as DLTs at that dose level is < 10% in > 10 patients, re-escalation to the next dose level 
previously associated with DLTs may be considered.  If re-escalation occurs, up to 6 additional 
patients may be enrolled and the dose level may be considered tolerable if the overall DLT rate 
for that dose level is ≤ 25%. 
5.1.2 
Dose-Limiting Toxicity 
During dose escalation, patients must receive at least 75% of the planned INCB001158 
administrations (Parts 1a and 1b) and two doses of pembrolizumab (Part 1b only) in the DLT 
evaluation window to be considered evaluable for DLT, unless the patient has a DLT or has the 
study treatment held for an adverse event (AE) that may herald a DLT.  The DLT evaluation 
window will be the first 28 days (Part 1a) or the first 42 days (Part 1b) on study, starting from 
Cycle 1 Day 1 (C1D1).  Patients who discontinue the study during the DLT evaluation window 
prior to receiving the requisite study treatment administrations for reasons that include, but are 
not limited to, clinical/radiographic progression, voluntary withdrawal, or complications that the 


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Principal Investigator considers secondary to the patient’s malignancy will not be considered 
evaluable for DLT and will be replaced.  In addition to DLTs, a pharmacokinetic threshold of 
100 µg*hr/mL is included as a dose-limiting event.  This is an exposure that was well tolerated 
in preclinical species and exceeds the expected efficacious exposure by 14-fold. 
During Part 1b, it is likely that Grade 3 AEs associated with pembrolizumab administration will 
occur and, given the small sample size of cohorts, this could occur by chance in 2 of 6 patients, 
the usual threshold for unacceptable toxicity.  It will be important to differentiate between 
immune-related adverse events (irAEs) expected from pembrolizumab toxicity as opposed to an 
increase in frequency or a worsening of severity of irAEs as an indicator of unacceptable toxicity 
related to the combination.  Dose escalation cohorts can be expanded up to 12 patients if DLTs 
occur that are expected pembrolizumab-related irAEs per the pembrolizumab product label.  
The Common Terminology Criteria for Adverse Events (CTCAE v4.03) will be used to identify 
and classify toxicities arising during the study.  The occurrence of any of the following toxicities 
during Cycle 1 will be considered a DLT, if judged by the Investigator to be related (possibly or 
probably) to administration of either or both study treatment(s): 
Non- Hematologic DLTs: 
• Any ≥ Grade 4 non-hematological toxicity 
• Grade 3 non-hematologic toxicity lasting > 3 days despite optimal supportive care with 
the exception of: 
o Grade 3 fatigue lasting ≤ 7 days 
o Grade 3 rash that resolves to ≤ Grade 1 within 3 weeks 
o Grade 3 tumor flare (defined as local pain, irritation or rash localized at sites of 
known or suspected tumor) 
o Grade 3 irAE that resolves to Grade 1 with corticosteroid therapy in ≤ 3 weeks 
(Part 1b ONLY) 
o A transient (resolves within 6 hr of onset) Grade 3 infusion-related AE (Part 1b 
ONLY) 
• Any clinically meaningful Grade 3 non-hematologic laboratory value if: 
o Medical intervention (other than electrolyte repletion) is required to treat the 
patient, OR 
o The abnormality leads to hospitalization, OR 
o The abnormality persists for > 1 week. 
 


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Hematologic DLTs: 
•
Grade ≥ 3 febrile neutropenia (ANC < 1.0 x 109/L with either a single temperature
≥ 38.3ºC or a sustained temperature of ≥ 38ºC for more than 1 hr)
•
Grade 4 neutropenia lasting > 7 days
•
Grade 4 anemia
•
Grade 4 thrombocytopenia (< 25.0 x 109/L)
•
Grade 3 thrombocytopenia resulting in clinically significant bleeding or requiring platelet
transfusion
•
Any other ≥ Grade 3 hematologic toxicity
In addition to the DLTs defined above, clear evidence of urea cycle inhibition (e.g., an increase 
in fasting urinary orotic acid (OA) to ≥ 10X the ULN, any OA value of > 40X ULN (fasting or 
non-fasting) or symptomatic hyperammonemia) would also be considered a dose-limiting event 
and will be monitored closely (see below for urinary OA rationale).  Finally, achieving a 
maximum exposure threshold of an AUC0-12hr that exceeds 100 µg*hr/mL in one patient will 
limit dose escalation.  This exposure is approaching the top of the exposures that were well 
tolerated in preclinical GLP toxicology studies.  Exposure in excess of this threshold will be 
treated the same as a DLT with regard to the dose escalation rules and definition of the MTD 
described in Section 5.1.1. 
The inability to receive ≥ 75% of INCB001158 doses and/or 2 doses of pembrolizumab during 
the DLT-evaluation period (28 days in Part 1a and 42 days in Part 1b) due to a drug-related AE 
will be considered a DLT.  In addition, any other AE that is felt to be treatment-limiting in the 
medical opinions of the Principal Investigator and the Medical Monitor may be considered a 
DLT.  In general, patients who experience a DLT will not receive further treatment with the 
study treatments.  Patients with toxicities that meet the DLT definition but are rapidly reversible 
(≤ Grade 1 within 3 weeks) may be continued on study with Investigator and Medical Monitor 
agreement.    
Rationale for urinary orotic acid threshold 
Urinary OA is being monitored in this study as a sensitive biomarker of hepatic urea cycle 
inhibition.  Substantial elevations (generally to 100-800X the upper limit of normal) occur in 
patients with inherited defects in enzymes of the urea cycle.  A similar magnitude of OA 
elevation (~1000X) was noted in animals that received doses associated with toxicity in 


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preclinical safety studies, although notable elevations in urinary OA were also noted in some 
animals treated at the NOAEL (Figure 10.1-6). 
Due to the limited availability of data describing the clinical sequelae associated with modest 
(5-100X ULN) elevations of urinary OA, a threshold of 5X the ULN was selected to provide 
clear evidence of urea cycle inhibition.  Importantly, elevations in urinary OA are not considered 
a toxicity but, rather, serve as a biomarker of urea cycle function.  In addition to urinary OA, 
patients are also monitored for sustained elevations in ammonia or significant reductions in 
plasma blood urea nitrogen (BUN) as signs of clinically significant effects on the urea cycle. 
There has been no evidence of clinically significant urea cycle inhibition to date.  However, as 
described in Section 10.1.9, transient, reversible elevations in urinary OA have occurred in two 
patients enrolled at the 150 mg dose level.  These elevations were as high as 11.6 and 
9.3 µmol/mmol creatinine (7.7X and 6.2X the ULN, respectively) in the two patients when 
evaluated predose (fasting).  When tested 6 hr postdose (non-fasted), one of the two patients had 
elevated values, which were as high as 131 µmol/mmol creatinine (87.3X ULN).  As described 
in Section 10.1.9, these patients were asymptomatic and had no laboratory evidence of clinically 
significant urea cycle inhibition.   
Since this protocol was first written, additional literature sources have been identified in which 
elevation of urinary OA have been studied in healthy people who are carriers of a single urea 
cycle gene defect (UCD).  In one study, 24 individuals that were carriers of a single defective 
gene for ornithine transcarbamylase (OTC) were studied (Nagasaka 2013).  These individuals 
were considered healthy without clinical evidence of urea cycle dysfunction.  Fasting urinary OA 
was elevated in all of these individuals, with a mean level of 11 µmol/mmol creatinine that 
ranged from 5 to 23 µmol/mmol creatinine.  In addition, other studies in similar populations of 
healthy individuals with a known or presumed single defective urea cycle gene have 
demonstrated that urinary OA elevates significantly following a meal (due to the increased 
processing of ammonia by the liver following a protein meal), as compared to normal individuals 
with a fully intact urea cycle in whom there is a minimal change in urinary OA following a meal.  
Following a meal, the urinary OA in these healthy UCD carriers rose as high as 62 µmol/mmol 
creatinine (Goldstein 1974). 
Based on the clinical experience to date with INCB001158 and the more extensive literature 
evidence of elevations in urinary OA in healthy UCD, the management of elevated urinary OA 


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has been updated in the protocol.  Given the variability of urinary OA following a meal in 
healthy UCD carriers, separate thresholds have been defined for fasting patients (i.e., patients 
tested predose) versus those that have eaten (i.e., patients tested 6 hr postdose).  In addition, 
since urinary OA elevations may be variable and have not been associated with evidence of 
clinically significant urea cycle inhibition, re-testing of urinary OA while the patient continues to 
receive INCB001158 is recommended in patients that have no evidence of clinically significant 
urea cycle inhibition (i.e., asymptomatic, plasma ammonia/BUN without significant change from 
baseline) in order to confirm that the elevation was not spurious.  For elevations of urinary OA of 
> 15 µmol/mmol creatinine (>10X ULN) in fasting patients, dose reduction is recommended.  
This value is within the range of urinary OA elevations that are were seen in the cohort of 
24 healthy UCD carriers tested while fasting in Nagasaka et al (2013).  For patients that are not 
fasting, higher elevations can be expected, based on the elevations in UCD carriers following a 
meal.  Therefore, for elevations of urinary OA of > 60 µmol/mmol creatinine (40X ULN) at any 
time, dose reduction is recommended.   
In summary, there has been no evidence of clinically significant inhibition of the urea cycle to 
date.  Two patients have had asymptomatic transient elevations in urinary OA, a sensitive 
biomarker of hepatic urea cycle inhibition, that were not associated with changes in plasma 
ammonia or BUN, but were dose reduced based on the original protocol defined urinary OA 
threshold of 5X ULN.  Based on this clinical experience and a more extensive evaluation of the 
published data in healthy carriers of UCD genes, the approach to managing INCB001158 study 
drug in response to elevations in urinary OA has been changed in the current amendment.  All of 
these data and the current management approach have been reviewed by an external clinical 
expert in the management of patients with UCD 
.  


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5.1.3 
Definition of Recommended Phase 2 Dose (RP2D) 
The RP2D for INCB001158 both as monotherapy and in combination with pembrolizumab will 
be selected on the basis of emerging safety, PK and pharmacodynamic data and will not exceed 
the maximally tolerated dose (MTD).  The RP2D will either be the MTD or a lower dose if PK, 
pharmacodynamic, tolerability and efficacy data suggest that maximal efficacy is likely achieved 
at a dose below the MTD, particularly if the lower dose is associated with an improved safety 
profile.    
5.2 Part 2. Single Agent Cohort Expansion 
Following completion of monotherapy Dose Escalation and selection of the RP2D for 
INCB001158 in Part 1a, the following cohorts of patients will be enrolled to receive single agent 
INCB001158 at the RP2D. 
Part 2a: Monotherapy Cohort Expansion in NSCLC patients 
This expansion cohort will enroll patients with advanced/metastatic non-small cell lung cancer 
(NSCLC) that lack activating mutations in either the EGFR or ALK oncogenes and have 
received, declined, or are ineligible for standard of care (SOC) therapies.  A Simon’s two-stage 
design will test the null hypothesis that the ORR ≤ 0.02 versus the alternative that ORR ≥ 0.15.  
A minimum of 11 patients with advanced/metastatic NSCLC will receive INCB001158 in 
Stage 1 of the expansion.  If at least 1 of the 11 response-evaluable patients responds (PR or 
better) at a single time point in Stage 1, then an additional 15 evaluable patients (for a total of 
26 response-evaluable patients) will be enrolled in Stage 2. 
Part 2b: Monotherapy Cohort Expansion in CRC patients 
This expansion cohort will enroll patients with advanced/metastatic colorectal cancer (CRC) that 
have received, declined, or are ineligible for SOC therapies.  A Simon’s two-stage design will 
test the null hypothesis that the ORR ≤ 0.02 versus the alternative that ORR ≥ 0.15.  A minimum 
of 11 CRC patients will receive INCB001158 in Stage 1 of the expansion.  If at least 1 of the 
11 response-evaluable patients responds (PR or better) at a single time point in Stage 1, then an 
additional 15 evaluable patients (for a total of 26 response-evaluable patients) will be enrolled in 
Stage 2. 
Part 2c: Monotherapy Cohort Expansion in Patients with Other Cancer Types Likely to have 
High Granulocytic MDSCs or Neutrophils 


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Many tumor types have infiltrating granulocytic myeloid-derived suppressor cells (G-MDSCs) or 
neutrophils.  This expansion cohort will enroll patients with a variety of advanced/metastatic 
cancers that have received, declined, or are ineligible for SOC therapies that are among tumor 
types that have been demonstrated to have infiltrating G-MDSCs or neutrophils, including 
squamous cell carcinoma of the head and neck (SCCHN), renal cell cancer (RCC), gastric or 
gastroesophageal junction (GEJ) cancer, urothelial cell cancer (UCC), and melanoma.  Other 
tumor types may be enrolled with approval from the Sponsor and the Medical Monitor.  A 
maximum of 30 patients will be enrolled initially in this cohort, with no more than 11 patients for 
any particular tumor type.  Up to 2 tumor types in Cohort 2c may then be expanded based on a 
Simon 2-stage design, if the observed clinical activity (1 or more PR or CR in a tumor type with 
up to 11 patients) supports enrollment of additional patients for a total of 26 patients per tumor 
type. 
Part 2d:  
 
 
Cohort 2d will enroll patients at US sites only who meet eligibility criteria for any of the 
monotherapy expansion cohorts (2a, 2b, or 2c). 
 
 
 
 
 
 
 
 
 
 
 
Cohort 2d patients may be counted towards the total number of patients planned in cohorts 2a, 
2b, and 2c (if these have not fully accrued by the time cohort 2d opens). 


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Additional solid tumor cohorts may be added to Part 2 by protocol amendment based upon 
emerging preclinical data and/or observations of clinical benefit. 
5.3 Part 3. Combination Cohort Expansion 
Upon selection of the RP2D for INCB001158 in combination with pembrolizumab in Part 1b, 
cohorts of specific patients will be enrolled to receive INCB001158 in combination with 
pembrolizumab at the RP2D to further evaluate safety and identify an early signal of clinical 
activity. 
Part 3a: INCB001158 in combination with pembrolizumab in patients with NSCLC that lacks 
activating mutations in EGFR or ALK and would be unlikely to have an objective response to 
monotherapy pembrolizumab. 
This cohort will enroll patients with advanced/metastatic NSCLC that does not harbor activating 
mutations in the EGFR or ALK oncogenes and are considered unlikely to have an objective 
response to monotherapy pembrolizumab, as defined by having either: 
1. Disease progression on an anti-PD-1/PD-L1 therapy in the immediate prior line of 
therapy (confirmed progression per iRECIST criteria preferred), OR 
2. Ongoing prolonged stable disease (> 24 weeks) on pembrolizumab therapy in the 
immediate prior line of therapy 
EGFR-mutant and ALK-mutant NSCLC patients have been excluded because they are reported 
to be less responsive to anti-PD-1 therapy (Borghaei 2015).  
 


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A Simon’s two-stage design will test the null hypothesis that the ORR ≤ 0.02 versus the 
alternative that ORR ≥ 0.15.  A total of 11 response-evaluable patients will be enrolled in 
Stage 1.  If at least 1 patient responds (PR or better) out of 11 response-evaluable patients, then 
an additional 15 evaluable patients will be enrolled in Stage 2 (total of 26 response-evaluable 
patients).  If Stages 1 and 2 are completed, a minimum of 2 patients must demonstrate a response 
(PR or better) to reject the null hypothesis.   
Part 3b: INCB001158 in combination with pembrolizumab in patients with melanoma with 
disease progression or prolonged stable disease while receiving an anti-PD-1/PD-L1 agent in 
the immediate prior line of therapy. 
This cohort will enroll patients with advanced/metastatic melanoma that are considered unlikely 
to have an objective response to monotherapy pembrolizumab, as defined by having: 
1. Disease progression on an anti-PD-1/PD-L1 therapy in the immediate prior line of 
therapy (confirmed progression per iRECIST criteria preferred), OR 
2. Ongoing prolonged stable disease (> 24 weeks) on pembrolizumab therapy in the 
immediate prior line of therapy 
The primary endpoint will be ORR.  Predose and postdose biopsies will be collected from 
patients enrolled to this cohort (unless it is not considered to be safe or otherwise is not feasible) 
until approximately 5 evaluable paired specimens are collected.  Predose biopsies will be 
collected for all other patients, if feasible.  
 
 


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A Simon’s two-stage design will test the null hypothesis that the ORR ≤ 0.02 versus the 
alternative that ORR ≥ 0.15.  A total of 11 response-evaluable patients will be enrolled in 
Stage 1.  If at least 1 patient responds (PR or better) out of 11 response-evaluable patients, then 
an additional 15 evaluable patients will be enrolled in Stage 2 (total of 26 response-evaluable 
patients).  If Stages 1 and 2 are completed, a minimum of 2 patients must demonstrate a response 
(PR or better) to reject the null hypothesis.   
Part 3c: INCB001158 in combination with pembrolizumab in patients with urothelial cell 
carcinoma (UCC) that would be unlikely to have an objective response to monotherapy 
pembrolizumab  
This cohort will enroll patients with advanced/metastatic UCC that are considered unlikely to 
have an objective response to monotherapy pembrolizumab, as defined by having: 
1. Disease progression on an anti-PD-1/PD-L1 therapy in the immediate prior line of 
therapy (confirmed progression per iRECIST criteria preferred), OR 
2. Ongoing prolonged stable disease (> 24 weeks) on pembrolizumab therapy in the 
immediate prior line of therapy 
The primary endpoint will be ORR.  Predose and postdose biopsies will be collected from 
patients enrolled to this cohort (unless it is not considered to be safe or otherwise is not feasible) 
until approximately 5 evaluable paired specimens are collected.  Predose biopsies will be 
collected for all other patients, if feasible.  
 
 
 
 
A Simon’s two-stage design will test the null hypothesis that the ORR ≤ 0.02 versus the 
alternative that ORR ≥ 0.15.  A total of 11 response-evaluable patients will be enrolled in 
Stage 1.  If at least 1 patient responds (PR or better) out of 11 response-evaluable patients, then 
an additional 15 evaluable patients will be enrolled in Stage 2 (total of 26 response-evaluable 


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patients).  If Stages 1 and 2 are completed, a minimum of 2 patients must demonstrate a response 
(PR or better) to reject the null hypothesis 
Part 3d: INCB001158 in combination with pembrolizumab in patients with microsatellite 
instability-high (MSI-H) CRC that would be unlikely to have an objective response to 
monotherapy pembrolizumab 
This cohort will enroll advanced/metastatic CRC patients with documented microsatellite 
instability that are considered unlikely to have an objective response to monotherapy 
pembrolizumab, as defined by having either: 
1. Disease progression on an anti-PD-1/PD-L1 therapy in the immediate prior line of 
therapy (confirmed progression per iRECIST criteria preferred), OR 
2. Ongoing prolonged stable disease (>24 weeks) on pembrolizumab therapy in the 
immediate prior line of therapy 
The primary endpoint will be ORR.  Predose and postdose biopsies will be collected from 
patients enrolled to this cohort (unless it is not considered to be safe or otherwise is not feasible) 
until approximately 5 valuable paired specimens are collected.  Predose biopsies will be 
collected for all other patients, if feasible.  
 
 
 
  
A Simon’s two-stage design will test the null hypothesis that the ORR ≤ 0.02 versus the 
alternative that ORR ≥ 0.15.  A total of 11 response-evaluable patients will be enrolled in 
Stage 1.  If at least 1 patient responds (PR or better) out of 11 response-evaluable patients, then 
an additional 15 evaluable patients will be enrolled in Stage 2 (total of 26 response-evaluable 
patients).  If Stages 1 and 2 are completed, a minimum of 2 patients must demonstrate a response 
(PR or better) to reject the null hypothesis.   


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Part 3e: INCB001158 in combination with pembrolizumab in patients with microsatellite 
stable (MSS) CRC. 
This cohort will enroll advanced/metastatic CRC patients that are documented MSS that have 
received at least one prior line of 5-FU-containing systemic therapy in the advanced/metastatic 
setting.  Patients having received prior therapy with anti-PD-1/PD-L1, anti-CTLA4 or any other 
agent that specifically targets an immune checkpoint or co-stimulation pathway will be excluded. 
The primary endpoint will be ORR.  Predose and postdose biopsies will be collected from 
patients enrolled to this cohort (unless it is not considered to be safe or otherwise is not feasible) 
until approximately 5 evaluable paired specimens are collected.  Predose biopsies will be 
collected for all other patients, if feasible.  
 
 
 
  
A Simon’s two-stage design will test the null hypothesis that the ORR ≤ 0.02 versus the 
alternative that ORR ≥ 0.15.  A total of 11 response-evaluable patients will be enrolled in 
Stage 1.  If at least 1 patient responds (PR or better) out of 11 response-evaluable patients, then 
an additional 15 evaluable patients will be enrolled in Stage 2 (total of 26 response-evaluable 
patients).  If Stages 1 and 2 are completed, a minimum of 2 patients must demonstrate a response 
(PR or better) to reject the null hypothesis 
Part 3f: INCB001158 in combination with pembrolizumab in PD-1/PD-L1 naïve patients with 
Gastric/GEJ cancer. 
This cohort will enroll patients with advanced/metastatic gastric/GEJ cancer that have never 
received prior therapy with anti-PD-1/PD-L1, anti-CTLA4 or any other agent that specifically 
targets an immune checkpoint or co-stimulation pathway. 
All patients will have testing for microsatellite stability performed on tumor tissue, either 
archival or a fresh biopsy.  It is expected that ~80-90% of patients will have MSS gastric cancer 


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(Kim 2013).  The primary endpoint will be ORR in patients with MSS disease, since historical 
data suggests a low ORR in response to anti-PD-1 therapy (Topalian 2012, Brahmer 2010).  
Patients with MSI will also be followed but will not be considered for the primary endpoint for 
this cohort.  Predose and postdose biopsies will be collected from patients enrolled to this cohort 
(unless it is not considered to be safe or otherwise is not feasible) until approximately 
5 evaluable paired specimens are collected.  Predose biopsies will be collected for all other 
patients, if feasible.  
 
 
 
 
 
A Simon’s two-stage design will test the null hypothesis that the ORR ≤ 0.10 versus the 
alternative that ORR ≥ 0.25.  A total of 13 response-evaluable MSS patients will be enrolled in 
Stage 1.  If at least 2 patients respond (PR or better) out of 13 response-evaluable MSS patients, 
then an additional 21 evaluable MSS patients will be enrolled in Stage 2 (total of 34 response-
evaluable MSS patients).  If Stages 1 and 2 are completed, a minimum of 6 MSS patients must 
demonstrate a response (PR or better) to reject the null hypothesis 
Part 3g: INCB001158 in combination with pembrolizumab in PD-1/PD-L1 naïve patients with 
SCCHN  
This cohort will enroll patients with SCCHN that have received no more than one prior therapy 
in the advanced/metastatic setting and have never received prior therapy with anti-PD-1/PD-L1, 
anti-CTLA4 or any other agent that specifically targets an immune checkpoint or co-stimulation 
pathway. 
The primary endpoint will be ORR.  Predose and postdose biopsies will be collected from 
patients enrolled to this cohort (unless it is not considered to be safe or otherwise is not feasible) 
until approximately 5 evaluable paired specimens are collected.  Predose biopsies will be 
collected for all other patients, if feasible.  
 
 


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A Simon’s two-stage design will test the null hypothesis that the ORR ≤ 0.20 versus the 
alternative that ORR ≥ 0.40.  A total of 12 response-evaluable patients will be enrolled in 
Stage 1.  If at least 3 patients respond (PR or better) out of 12 response-evaluable patients, then 
an additional 13 evaluable patients will be enrolled in Stage 2 (total of 25 response-evaluable 
patients).  If Stages 1 and 2 are completed, a minimum of 8 patients must demonstrate a response 
(PR or better) to reject the null hypothesis 
Part 3h: INCB001158 in combination with pembrolizumab in patients with malignant pleural 
mesothelioma.  
This cohort will enroll patients with advanced/metastatic malignant pleural mesothelioma that 
have received or were unable to receive standard front-line systemic therapy but have never 
received prior therapy with anti-PD-1/PD-L1, anti-CTLA4 or any other agent that specifically 
targets an immune checkpoint or co-stimulation pathway. 
A Simon’s two-stage design will test the null hypothesis that the ORR ≤ 0.13 versus the 
alternative that ORR ≥ 0.30.  A total of 10 response-evaluable patients will be enrolled in 
Stage 1.  If at least 2 patients respond (PR or better) out of 10 response-evaluable patients, then 
an additional 23 evaluable patients will be enrolled in Stage 2 (total of 33 response-evaluable 
patients).  If Stages 1 and 2 are completed, a minimum of 7 patients must demonstrate a response 
(PR or better) to reject the null hypothesis 
Additional solid tumor cohorts may be added to Part 3 by protocol amendment based upon 
preclinical data, anti-tumor observations in Parts 1 and 2, and observations of clinical benefit.  
Up to 5 additional paired biopsies may be obtained in any cohort for which enrollment in Stage 2 
is opened. 


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6.0 
SAMPLE SIZE 
Approximately 216 patients are planned for recruitment to the monotherapy and combination 
Dose Escalation cohorts.  Approximately 148 patients are planned for recruitment in Stage 1 
monotherapy and combination Expansion Cohorts.  The number of patients may be increased in 
Stage 2 in each Expansion Cohort based upon observed anti-tumor activity.  Assuming full 
enrollment of the Dose Escalation cohorts, including backfill patients (i.e., 12 patients per dose 
level for monotherapy and combination), and positive results in all Expansion Cohorts, up to 
582 evaluable patients would be enrolled.  Approximate recruitment estimates for Dose 
Escalation and each Expansion Cohort is shown in Table 6.0-1. 
Table 6.0-1:  Table of Sample Size Estimates 
 
Approximate N 
Part 1a. Monotherapy Dose Escalation 
up to 108 
Part 1b. Combination Dose Escalation 
up to 108 
Part 1c. Combination in Patients with 
Moderately Impaired Renal Function 
6 (evaluable patients will be counted towards 
Part 3 cohorts) 
Dose Escalation Total 
up to 222 
 
Stage 1 
Stage 2 
Part 2. Monotherapy Cohort Expansion 
2a. NSCLC 
11 
15 
2b. CRC 
11 
15 
2c. Assorted tumor types 
30 
30-50 
2d. 
 
 
6 
N/A 
Monotherapy Expansion Cohorts (Total) 
58 
60-80 
Part 3. Combination Cohort Expansion 
3a. NSCLC Prior Checkpoint 
11 
15 
3b. Melanoma 
11 
15 
3c. Urothelial carcinoma (prior PD-1/PD-L1) 
11 
15 
3d. CRC (MSI-H) (prior PD-1/PD-L1) 
11 
15 
3e. MSS CRC (PD-1/PD-L1 naïve) 
11 
15 
3f. Gastric/GEJ (PD-1/PD-L1 naïve) 
13 
21 
3g. SCCHN (PD-1/PD-L1 naïve ) 
12 
13 
3h. Mesothelioma (PD-1/PD-L1 naïve) 
10 
23 
Combination Expansion Cohorts (Total) 
90 
132 
 


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7.0 
INCLUSION/EXCLUSION CRITERIA 
7.1 Inclusion Criteria 
1. Patients must have a histological or cytological diagnosis of metastatic cancer or locally 
advanced cancer that is not amenable to local therapy.  Additional criteria specific to 
different Parts/Cohorts of the study are provided below. 
2. Ability to provide written informed consent in accordance with federal, local, and 
institutional guidelines 
3. Age ≥ 18 years 
4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 
5. Life Expectancy of at least 3 months 
6. Adequate organ function as indicated by the laboratory values in Table 7.1-1 
Table 7.1-1:  Laboratory Values for Inclusion 
Test 
Value 
Absolute neutrophil count (ANC) 
≥ 1,500/mcL 
Platelets 
≥ 100,000/mcL 
Hemoglobin 
≥ 9 g/dL 
CrCl 
All except Part 1c:  ≥ 50 mL/min (calculated 
using the Cockcroft-Gault formula) 
Part 1c only:  30-49 mL/min (calculated using 
the Cockcroft-Gault formula) 
Serum total bilirubin 
OR 
Direct bilirubin (for patients with Gilbert 
Syndrome and total bilirubin levels 
> 1.5 ULN) 
≤ 1.5 X ULN 
OR 
≤ ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
≤ 1.5 X ULN* 
* Does not apply to patients receiving therapeutic anticoagulation 
7. Measurable Disease: At least one tumor lesion/lymph node that meets the RECIST v1.1 
criteria for being “measurable.” 
8. 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 > 45 years of 
age.) 


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b. Woman of childbearing potential who has a negative serum pregnancy test within 
three days before the first dose of study treatment and who agrees to take appropriate 
precautions to avoid pregnancy (with at least 99% certainty) from screening through 
safety follow-up (for patients receiving INCB001158 monotherapy) and until 
120 days following the last dose of pembrolizumab.  Permitted methods that are at 
least 99% effective in preventing pregnancy should be continued until 120 days after 
discontinuing should be communicated to the patient 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 (3 months following the 
last dose of study treatment).  Permitted methods that are at least 99% effective in 
preventing pregnancy should be communicated to the patient and their understanding 
confirmed. 
9. Resolution of all treatment-related toxicities, except alopecia, anemia, or 
endocrinopathies managed by hormone replacement, from any previous cancer therapy to 
≤ Grade 1 or to values within those required for eligibility on this study prior to the first 
dose of study treatment.  Patients with long-lasting sequelae from prior anti-cancer 
therapy that have been demonstrated to be stable for > 3 mo may be allowed if the 
Investigator and Medical Monitor determine that this will not compromise patient safety 
or interfere with the interpretation of the safety profile of INCB001158. 
 
Part 1: Inclusion Criteria Specific to the Dose Escalation 
Part 1a: Inclusion Criteria Specific to the Monotherapy Dose Escalation  
1. Histologically or cytologically proven diagnosis of any locally advanced or metastatic 
solid tumor not amenable to local therapy in patients who have disease progression 
after treatment with all available therapies known to confer clinical benefit 
 
Part 1b: Inclusion Criteria Specific to the PD-1 Combination Dose Escalation 
1. Histologically or cytologically proven diagnosis of advanced/metastatic NSCLC 
(squamous or non-squamous), mesothelioma, gastric/GEJ cancer, MSS CRC, 
MSI-H CRC, UCC, melanoma or SCCHN in patients who have disease progression 
after treatment with all available therapies known to confer clinical benefit.  Patients 
that have not received prior anti-PD-1 therapies are allowed. 
 
Part 1c: Inclusion Criteria Specific to the PD-1 Combination Moderately Renally Impaired 
Cohort 
1. Criteria for any of Cohorts 3a to 3h. 
 


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Part 2: Inclusion Criteria Specific to Monotherapy Cohort Expansion 
Part 2a: Inclusion Criteria Specific to the Monotherapy NSCLC Cohort 
1. Histologically or cytologically proven diagnosis of advanced/metastatic NSCLC 
(squamous or non-squamous) in patients who have disease progression after treatment 
with all available therapies known to confer clinical benefit 
 
Part 2b: Inclusion Criteria Specific to the Monotherapy CRC Cohort 
1. Histologically or cytologically proven diagnosis of advanced/metastatic CRC in 
patients who have disease progression after treatment with all available therapies 
known to confer clinical benefit 
 
Part 2c: Inclusion Criteria Specific to the Monotherapy in Other Tumors 
1. Histologically or cytologically proven diagnosis of advanced/metastatic tumors 
including gastric cancer, cancer of the GEJ, UCC, RCC, melanoma, or SCCHN in 
patients who have disease progression after treatment with all available therapies 
known to confer clinical benefit.  Other advanced/metastatic solid tumors (e.g., those 
demonstrated or expected to have high infiltration with arginase-positive cells) may 
be allowed based on the discretion of the Medical Monitor. 
 
Part 2d:  
 
1. Meets the criteria for any of Parts 2a, 2b, or 2c. 
2. 
 
 
Part 3: Inclusion Criteria Specific to the PD-1 Combination Cohort Expansion 
Part 3a: Non-small cell lung cancer (NSCLC) – PD/SD on anti-PD-1/PD-L1 therapy 
1. Histological or cytological diagnosis of locally advanced unresectable or metastatic 
NSCLC that does not harbor an activating EGFR or ALK mutation 
2. Prior progression on or after platinum-based chemotherapy or refused/ineligible to 
receive platinum-based chemotherapy. 
3. Received an anti-PD-1/PD-L1 agent in a prior line of therapy for advanced/metastatic 
disease and EITHER: 
a. Had documented radiological disease progression (per Investigator 
assessment, preferably with confirmation of PD after 4 weeks) while receiving 
anti-PD-1/PD-L1 therapy in the most recent line of therapy, OR 
b. Had documented stable disease (per Investigator assessment) for ≥ 24 weeks 
while receiving pembrolizumab therapy in the most recent line of therapy 
 


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Part 3b: Melanoma – PD/SD on anti-PD-1/PD-L1 therapy 
1. Histological or cytological diagnosis of locally advanced unresectable or metastatic 
melanoma 
2. Received an anti-PD-1/PD-L1 agent in the most recent prior line of therapy for 
advanced/metastatic disease and EITHER: 
a. Had documented radiological disease progression (per Investigator 
assessment, preferably with confirmation of PD after 4 weeks) while receiving 
anti-PD-1/PD-L1 therapy in the most recent line of therapy, OR 
b. Had documented stable disease (per Investigator assessment) for ≥ 24 weeks 
while receiving pembrolizumab therapy in the most recent line of therapy  
 
Part 3c: Urothelial cell carcinoma (UCC) – PD/SD on anti-PD-1/PD-L1 therapy 
1. Histological or cytological diagnosis of locally advanced unresectable or metastatic 
UCC 
2. Received an anti-PD-1/PD-L1 agent in the most recent prior line of therapy for 
advanced/metastatic disease and EITHER: 
a. Had documented radiological disease progression (per Investigator 
assessment, preferably with confirmation of PD after 4 weeks) while receiving 
anti-PD-1/PD-L1 therapy in the most recent line of therapy, OR 
b. Had documented stable disease (per Investigator assessment) for ≥ 24 weeks 
while receiving pembrolizumab therapy in the most recent line of therapy  
 
Part 3d: Mismatch repair deficient and/or microsatellite instability-high (MSI-H) colorectal 
cancer (CRC) – PD/SD on anti-PD-1/PD-L1 therapy 
1. Histological or cytological diagnosis of locally advanced unresectable or metastatic 
CRC demonstrated to be mismatch repair deficient or microsatellite instability-high. 
2. Received an anti-PD-1/PD-L1 agent in the most recent prior line of therapy for 
advanced/metastatic disease and EITHER: 
a. Had documented radiological disease progression (per Investigator 
assessment, preferably with confirmation of PD after 4 weeks) while receiving 
anti-PD-1/PD-L1 therapy in the most recent line of therapy, OR 
b. Had documented stable disease (per Investigator assessment) for ≥ 24 weeks 
while receiving pembrolizumab therapy in the most recent line of therapy  
 
Part 3e: Microsatellite stable (MSS) colorectal cancer (CRC) – Checkpoint inhibitor naive  
1. Histological or cytological diagnosis of locally advanced unresectable or metastatic 
CRC demonstrated to lack mismatch repair deficiency and microsatellite instability 
(low or high). 
2. Received at least one prior fluoropyrimidine-containing systemic therapy for 
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3. Has not received prior anti-PD-1/PD-L1, anti-CTLA4, or other checkpoint inhibitor 
or immune co-stimulator (e.g., anti-OX-40, anti-41BB, etc.) 
 
Part 3f: Gastric/gastro-esophageal (GE) junction cancer – Checkpoint inhibitor naive  
1. Histological or cytological diagnosis of locally advanced unresectable or metastatic 
gastric or GEJ cancer 
2. Received at least two prior systemic therapies for advanced/metastatic disease; prior 
regimens must have included a platinum and a fluoropyrimidine 
3. Human epidermal growth factor receptor 2 (HER-2/neu) negative, or, if HER2/neu 
positive, must have previously received treatment with trastuzumab 
4. Has not received prior anti-PD-1/PD-L1, anti-CTLA4, or other checkpoint inhibitor 
or immune co-stimulator (e.g., anti-OX-40, anti-41BB, etc.) 
 
Part 3g: Squamous cell carcinoma of the head and neck (SCCHN) – Checkpoint inhibitor naive 
1. Histological or cytological diagnosis of recurrent or metastatic SCCHN 
2. Had disease progression EITHER: 
a. While receiving or after platinum-containing chemotherapy administered for 
recurrent or metastatic SCCHN, OR 
b. Following platinum-containing chemotherapy administered as part of 
induction, concurrent, or adjuvant therapy. 
3. Has not received prior anti-PD-1/PD-L1, anti-CTLA4, or other checkpoint inhibitor 
or immune co-stimulator (e.g., anti-OX-40, anti-41BB, etc.).  
Part 3h: Mesothelioma – Checkpoint inhibitor naive  
1. Histological or cytological diagnosis of locally advanced incurable or metastatic 
malignant pleural mesothelioma 
2. Has failed or was unable to received standard therapy for malignant pleural mesothelioma 
3. Has not received prior anti-PD-1/PD-L1, anti-CTLA4, or other checkpoint inhibitor or 
immune co-stimulator (e.g., anti-OX-40, anti-41BB, etc.)  
 
7.2 Exclusion Criteria  
1. Any other current or previous malignancy within the past three years except a) 
adequately treated basal cell or squamous cell skin cancer, b) carcinoma in situ of the 
cervix, c) prostate cancer with stable prostate specific antigen (PSA) levels for 
3 years, d) or other neoplasm that, in the opinion of the Principal Investigator and 
with the agreement of the Medical Monitor, will not interfere with study-specific 
endpoints. 
2. Cytotoxic chemotherapy, tyrosine kinase inhibitor (or other targeted anti-cancer 
agent), radiation therapy, or hormonal therapy within 14 days or 5 half-lives, 
whichever is longer, prior to Cycle 1 Day 1 (42 days for nitrosoureas or mitomycin 
C). 


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3. Immunotherapy or biological therapy (e.g., monoclonal antibodies) within 21 days 
prior to Cycle 1 Day 1 
• EXCEPTION: Washout of anti-PD-1 therapy is NOT required in Part 1b Dose 
Escalation or the Part 3 Expansion Cohorts.  
4. Treatment with an unapproved investigational therapeutic agent within 21 days (or 
5 half-lives for small molecule agents) prior to Cycle 1 Day 1 
• EXCEPTION: Washout of anti-PD-1 therapy is NOT required in Part 1b Dose 
Escalation or the Part 3 Expansion Cohorts.  
5. Has a diagnosis of immunodeficiency or any condition requiring systemic treatment 
with either corticosteroids (> 10 mg daily prednisone equivalent) or other systemic 
immunosuppressive medications within 14 days prior to the first dose of study 
treatment.  Inhaled steroids and adrenal replacement steroid doses < 10 mg daily 
prednisone equivalent are permitted in the absence of active autoimmune disease. 
6. Concomitant therapy with valproic acid/valproate-containing therapies. 
7. Concomitant therapy with allopurinol and other xanthine oxidase inhibitors 
8. Exclusion criterion deleted in Protocol Amendment 2-EU. 
9. Patients with symptomatic ascites or pleural effusion requiring intermittent 
paracentesis or thoracocentesis.  A patient who is clinically stable following treatment 
for these conditions (including therapeutic thoraco- or para-centesis) is eligible. 
10. Unable to receive medications per os (PO) 
11. Unstable/inadequate cardiac function: 
• Myocardial infarction or symptomatic ischemia within the last 6 months 
• Uncontrolled or clinically significant conduction abnormalities (e.g., 
ventricular tachycardia on antiarrhythmics are excluded; 1st degree AV block 
or asymptomatic LAFB/RBBB are eligible) 
• Congestive heart failure (New York Heart Association class III to IV) 
12. 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. 
13. Major surgery within 2 months prior to first dose of study treatment. 
14. Infection requiring parenteral antibiotics, antivirals, or antifungals within two weeks 
prior to first dose of study treatment. 
15. Patient is known to be positive for Human Immunodeficiency Virus (HIV), Hepatitis 
B or Hepatitis C. 
16. Refractory nausea and vomiting, uncontrolled diarrhea, malabsorption, significant 
small bowel resection or gastric bypass surgery, use of feeding tubes or other 
situation that may preclude adequate absorption 
17. Serious psychiatric or medical conditions that could interfere with treatment or 
protocol-related procedures 
18. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.   


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Note: Patients with brain metastases or CNS disease are permitted, but must have 
completed treatment and either (1) have no evidence of active CNS disease for at 
least 4 weeks prior to the first dose OR (2) have stable CNS lesions, defined as 
not requiring intrathecal chemotherapy for at least 6 weeks or systemic steroid 
treatment to prevent CNS complications for at least 3 weeks prior to first dose.  
Patients with CNS disease must also have a Screening head CT or MRI 
demonstrating stable disease compared to their most recent CNS evaluation.  This 
exception does not apply to patients with carcinomatous meningitis who are 
excluded regardless of clinical stability. 
19. Patients in whom oral and/or IV fluid hydration are contraindicated 
20. Patients who are pregnant or lactating 
21. Has received a live-virus vaccination within 30 days of planned treatment start.  
Seasonal flu vaccines that do not contain live virus are permitted. 
22. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the patient’s participation 
for the full duration of the trial, or is not in the best interest of the patient to 
participate, in the opinion of the treating investigator. 
23. Has had an allogeneic tissue/solid organ transplant. 
 
Disease-specific Exclusion Criteria: 
Part 1b AND Part 3 
1. Intolerance to prior anti-PD-1/PD-L1 therapy including 1) discontinuation due to 
immune-related toxicity or, 2) immune-related toxicities that that required intensive 
or prolonged immunosuppression (including, high-dose IV corticosteroids, > 2 mo of 
immunosuppressive corticosteroids (i.e., equivalent of >10mg oral prednisone daily) 
or the addition of potent immunosuppression to corticosteroids (e.g., mycophenolate 
mofetil/CellCept or infliximab) to manage. 
2. Prior severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its 
excipients or prior severe hypersensitivity reaction to any other monoclonal antibody 
(mAb). 
3. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis. 
4. Has a history of interstitial lung disease. 
5. Has received transfusion of blood products (including platelets or red blood cells) or 
administration of colony stimulating factors (including G-CSF, GM-CSF or 
recombinant erythropoietin) within 2 weeks prior to study Day 1.  


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6. Active autoimmune disease that has required systemic treatment in past 2 years (i.e. 
with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a 
form of systemic treatment.  
 
Part 3 
Part 3a: NSCLC 
1. Documented activating mutations in EGFR or ALK. 


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8.0 
RADIOLOGICAL TUMOR ASSESSMENTS 
As part of Protocol Amendment 2-US 3, dated 10 NOV 2020, the irRECIST endpoints have 
been removed.  This Section refers to the radiological tumor assessments before Protocol 
Amendment 2-US 3. 
All patients will be evaluated for tumor response both according to Response Evaluation Criteria 
in Solid Tumors (RECIST) version 1.1 (see Attachment 4) [in mesothelioma patients, modified 
RECIST criteria for pleural mesothelioma (Byrne 2004, Attachment 5)] and according to the 
immune-related response criteria using unidimensional measurements (irRECIST; Perrone 2016, 
see Attachment 6).  The irRECIST guidelines are based on RECIST, immune-related response 
criteria and the findings in Nishino (2013) as described below.  Although the primary endpoint 
for analysis of clinical activity is RECIST v1.1, patient management will follow the principles 
and guidelines that are specifically outlined in the irRECIST criteria (Attachment 6).  On-study 
assessments by irRECIST take into account the observation that some patients with solid tumors 
can have a transient tumor flare in the first few months after start of immunotherapy with 
subsequent disease response.  Clinical decisions will be based on the interpretation of the 
Investigator at the site treating the patient in real time using the irRECIST criteria.  RECIST 
imaging analyses will be performed by the local radiologists and images may be collected and 
held in order to enable future independent image analysis. 
If imaging shows progressive disease per RECIST v1.1, it is at the discretion of the investigator 
to keep a patient on study treatment or to stop study treatment until imaging is repeated 
approximately 4 weeks later in order to confirm PD, as described in the irRECIST 
recommendations (see Attachment 6).  
Patients that are deemed clinically unstable or who have biopsy-proven new metastatic lesions 
are not required to have repeat imaging for confirmation.  This decision will be based on clinical 
judgment of a patient’s overall clinical condition, including performance status, clinical 
symptoms, and laboratory data.  At a minimum, patients must meet the following criteria for 
continued treatment on study after disease progression is identified at a tumor assessment:  
•
Absence of symptoms and signs (including worsening of laboratory values) indicating
disease progression
•
No decline in ECOG performance status


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• Absence of rapid progression of disease or of progressive tumor at critical anatomical 
sites (e.g., cord compression) requiring urgent alternative medical intervention.  
In general, if repeat imaging confirms PD as described in Attachment 6, patients will be 
discontinued from study therapy.  However, if a patient has confirmed radiographic progression, 
but the patient is achieving a clinically meaningful benefit, and there is no further increase in the 
tumor burden at the confirmatory tumor imaging, an exception to continue study treatment may 
be considered following consultation with the Medical Monitor.  If repeat imaging does not 
confirm PD, treatment with study treatments will continue/resume and the next imaging studies 
will be conducted every 8 weeks for parts 1a and 2 or every 9 weeks for parts 1b and 3 as 
previously scheduled.  In patients who discontinue study therapy early without documented 
disease progression, every effort should be made to continue monitoring their disease status by 
radiologic imaging. 


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PROTOCOL DETAILS 
10.0 
BACKGROUND AND RATIONALE 
10.1 Background 
10.1.1 
Immunosuppressive Myeloid Cells and Arginase 
Solid tumors have been shown to have moderate to extensive infiltration of immunosuppressive 
myeloid cells (Solito 2014).  Myeloid Derived Suppressor Cells (MDSCs) and neutrophils are 
present in multiple solid tumors and correlate with poor outcome (Gentles 2015).  Both 
granulocytic MDSCs and neutrophils contain the enzyme arginase within secretory granules.  
Upon stimulation by factors within the tumor microenvironment [e.g., Interleukin-8 (IL-8) and 
tumor necrosis factor-alpha (TNF-α)], arginase is released into the tumor microenvironment via 
degranulation 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.  Antitumor activity has been 
reported in mice when arginase is knocked out in the myeloid lineage in mice (Colegio 2014). 
INCB001158 is a small molecule inhibitor of arginase that is able to restore the local tumor 
concentration of arginine, resulting in the re-activation of quiescent T- and NK-cells.  
INCB001158 has no direct growth inhibitory or cytotoxic activity on tumor cells or on immune 
effector cells. 
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.  
INCB001158 is a competitive inhibitor of both recombinant human arginase 1 and arginase 2 
with IC50s of approximately 100 and 275 nM, respectively.   


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10.1.2 
Arginase 1 Expression in Cancer Patients 
In cancer patients, arginase 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 (PMNs) 
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 (e.g., IL-8, TNF-α). 
Immunohistochemical (IHC) 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 10.1-1).  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 to normal healthy control patients 
(Figure 10.1-1[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. 


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Figure 10.1-1:  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 
volunteers.  Plasma from cancer patients and healthy normal volunteers were assayed for arginase 1 levels 
by ELISA and arginine levels by LC/MS-MS. 
 
10.1.3 
Selectivity of INCB001158 
INCB001158 is a potent, selective, and reversible inhibitor of human recombinant arginase 1 and 
2 (IC50’s of 100 and 275 nM, respectively).  INCB001158 is also able to inhibit the elevated 
arginase activity present in the plasma of renal cancer patients with a similar potency.  To assess 
selectivity, the compound was evaluated as an inhibitor of radioligand binding to a panel of 
87 receptors and ion channels screened at a high concentration of 50 µM, well above the 
estimated 2–3 µM Cmax of INCB001158 in humans at the projected efficacious dose.  
Two targets showed > 50% binding in these assays.  The enzyme cholinesterase showed 59% 
binding inhibition at 50 µM, although there were no clinical observations in mice, rats, or 
monkeys consistent with cholinesterase inhibition in vivo despite achieving a Cmax of > 100 µM 
in mice and rats and > 80 µM in monkeys.  There was also 63% inhibition of ligand binding to 
the dopamine transporter at 50 µM.  It should be noted that INCB001158 has limited brain 
penetration as measured in mice and rats. 


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No inhibition of the arginine-utilizing nitric oxide synthase family of enzymes (eNOS, iNOS, 
and nNOS) was measured at 50 µM INCB001158 and no inhibition was seen in a panel of 
5 serine proteases at the same concentration.  
10.1.4 
Activity of INCB001158 in Cell-Based Assays 
Activated T-cells and NK-cells require the amino acid arginine to proliferate. Arginine is 
metabolized in the tumor environment by arginase that has been secreted from MDSCs and 
neutrophils (Munder 2005).  Arginine depletion leads to a suppression of T-cell and NK-cell 
proliferation thereby blunting the anti-tumor immune response. 
INCB001158 had no direct anti-proliferative activity on cell lines in culture, including human 
HepG2 or murine Lewis Lung Carcinoma (LLC) cell lines.  Furthermore, INCB001158 did not 
inhibit the growth rate of normal human T-cells or NK-cells that were isolated and stimulated in 
culture.  However, INCB001158 did reverse the growth suppressive effects of human neutrophils 
on human T-cells when co-cultured ex vivo with an EC50 of 162 nM as shown in Figure 10.1-2.  
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 MDSCs in a dose-dependent fashion. 
 
Figure 10.1-2:  Inhibition of the immunosuppressive effect of neutrophils and MDSCs on T-cells 
ex vivo.   
Left panel: Normal human neutrophils were co-cultured with normal human T-cells ex vivo in the 
presence of increasing concentrations of INCB001158.  Right panel: Conditioned media from patient-
derived MDSCs generated in the presence of increasing concentrations of INCB001158 was added to a 
culture of normal human T-cells ex vivo in the presence of increasing concentrations of INCB001158. 
 


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10.1.5 
Immunosuppression by Arginase in Mice Versus Humans 
Arginase is an immunosuppressive enzyme in mice and humans that limits the availability of 
extracellular arginine to T-cells in the tumor microenvironment.  MDSCs participate in the 
immunosuppressive process in both species; however, the biology of MDSCs is fundamentally 
different between mice and humans.  In mice, arginase and the arginine transporter are 
upregulated in MDSCs, leading to rapid uptake of arginine from the extracellular milieu and 
subsequent cleavage by arginase intracellularly.  In contrast, in humans, arginine is cleaved by 
extracellular arginase secreted by MDSCs and neutrophils.  INCB001158 inhibition of cellular 
arginase in mouse MDSCs is limited by poor cellular penetration.  Thus, the anti-tumor efficacy 
of INCB001158 in mouse syngeneic tumor models requires higher doses than those anticipated 
for efficacy in humans and may in large part be mediated by the ability of INCB001158 to 
elevate systemic arginine levels, a pharmacodynamic effect. 
10.1.6 
Pharmacodynamics of INCB001158 in Tumors and Tissues in Mice 
The tumor distribution and pharmacodynamic effects of INCB001158 were evaluated in mice 
bearing subcutaneously-implanted murine Lewis Lung Carcinoma (LLC) tumors 2 hr after 
treatment with a single dose or 2 hr after the last of five doses administered on a twice daily 
(BID) schedule.  Plasma and tumor concentrations of both INCB001158 and the 
pharmacodynamic marker arginine were determined in these studies (Figure 10.1-3).  Significant 
exposure to INCB001158 in plasma and tumors was observed after a single dose that was 
moderately higher after five doses on the BID schedule.  With 250 mg/kg dosing, the 
concentration of arginine in plasma increased about 3-fold 2 hr after a single oral dose and 
almost 8-fold 2 hr after five doses on a BID schedule.  INCB001158 accumulated approximately 
2-fold in tumors following a BID schedule, while arginine in tumors increased by more than 
3-fold.  Studies looking at arginine and INCB001158 levels in plasma and tumors after BID 
dosing for 14 days showed similar levels of both INCB001158 and arginine indicating 
steady-state was reached within 3 days. 


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Figure 10.1-3:  Tumor PK and pharmacodynamics of INCB001158.   
INCB001158 was administered as a single dose or as five consecutive doses on a BID schedule to female 
C57.Bl/6 mice implanted with the mouse LLC tumors (N = 10).  2 hr after a single dose, or 2 hr after the 
last dose BID, INCB001158 and arginine concentrations were measured in plasma and tumor.  **p<0.01, 
***p<0.001, ****p<0.0001 vs. vehicle control (T-test) 
 
10.1.7 
Efficacy of INCB001158 in Tumor-Bearing Syngeneic Mice 
Oral BID administration of single agent INCB001158 produced a dose-dependent reduction in 
the growth of subcutaneously implanted LLC tumors with significant activity at doses as low as 
10 mg/kg (Figure 10.1-4[A]).  A dose-related systemic increase in the plasma concentration of 
arginine correlated with this efficacy (Figure 10.1-4[B]).  The efficacy of INCB001158 in LLC 
tumors is immune-mediated.  When LLC tumors were grown in immuno-compromised scid 
mice, there was no anti-tumor activity of INCB001158; furthermore, depleting antibodies that 
target CD8+ T-cells or NK-cells partially reverse the effect of INCB001158 in immune-
competent animals (Figure 10.1-4[C,D]).  Changes in tumor growth rate in the mouse LLC 
model were associated with increases in CD8+ T cells within the tumor (Figure 10.1-4[E]), 
consistent with an immune stimulatory mechanism of action. 


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Figure 10.1-4:  Inhibition of LLC tumor growth and pharmacodynamic effects in vivo.  
Immunocompetent C57Bl.6 mice were implanted subcutaneously with LLC tumor cells and treated orally 
with 10 to 100 mg/kg INCB001158 BID.  A) Dose-dependent reduction in growth rate of mouse LLC 
tumors.  B) Plasma arginine concentration on Day 14, approximately 16 hr after the final dose of 
INCB001158.  C) Partial abrogation of the efficacy of INCB001158 by depletion of CD-8+ T-cells and 
D) Significant abrogation of INCB001158 efficacy by depletion of NK-cells from mice.  E) Increase in 
CD45+/CD8+ T-cells in LLC tumors following oral BID dosing of INCB001158 BID for 14-days as 
determined by flow cytometry.  **p<0.01, ***p<0.01, ****p<0.0001 vs. control (T-test).   
 
Single agent INCB001158 also had activity in the B16.F10 murine melanoma model 
(Figure 10.1-5).  Importantly, the combination of INCB001158 with anti-PD-L1 resulted in 
enhanced anti-tumor activity in the B16 model. 


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Figure 10.1-5:  Inhibition of B16 melanoma tumor growth in vivo.   
Immunocompetent C57Bl.6 mice were implanted subcutaneously with B16.F10 tumor cells were 
implanted subcutaneously in immunocompetent C57Bl.6 mice and treated with either 1) vehicle (water) 
orally twice daily; 2) 100 mg/kg INCB001158 orally BID beginning on Day 1; 3) 5 mg/kg αPD L1 (clone 
10F.9G2) intraperitoneally (IP) on Days 3, 5, 7, 9, 11, and 13; or 4) a combination of INCB001158 and 
αPD-L1. **p<0.01 vs. αPD-L1 alone. 
 
10.1.8 
Nonclinical Toxicity Testing of INCB001158 
INCB001158 is well tolerated in all species at doses that produce robust pharmacodynamic 
effects.  There is a substantial safety margin of ≥ 16-fold from the projected clinical efficacious 
exposure (AUC and Cmax) to the exposures that were well tolerated in the GLP toxicology 
studies in rats and monkeys. 
Very high doses and exposures can result in the on-target toxicity of urea cycle inhibition 
associated with morbidity.  The strongest evidence of urea cycle toxicity was identified in 
non-GLP studies in mice, where a thorough time course of plasma and liver arginine could be 
monitored along with plasma ammonia.  Animals receiving very high doses of INCB001158 that 
caused mortality, showed dose-related increases in the plasma concentration of arginine and 
ammonia, large increases in liver arginine, and reduced serum BUN.  These findings occurred at 
exposures > 45-fold and > 150-fold over the AUC and Cmax projected to be needed to achieve 
efficacy in humans, respectively. 
A dose of 500 mg/kg BID (1000 mg/kg/day) in the rat 28-day GLP toxicity study, produced a 
steady-state peak exposure (Cmax) of > 62 µg/mL (216 µM) and an AUCo- of > 283 µg*hr/mL,   
> 78-fold and > 40-fold above the projected human efficacious exposure, respectively.  This dose 
resulted in mortality in 29% of rats that was associated with clear evidence of urea cycle 


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inhibition including a large elevation in liver arginine, elevated plasma ammonia and sporadic 
decreases in BUN.  Additionally, modest increases (< 2-fold) in alanine (ALT) and aspartate 
aminotransferase (AST) as well as slight to moderate atrophy of the bone marrow, slight to 
moderate cytoplasmic clearing of the pars distalis of the pituitary gland, and non-adverse 
minimal to moderate hepatocellular cytoplasmic vacuolation were observed in the high dose 
animals, all of which were reversible following a two-week non-dosing recovery period.  The 
dose of 150 mg BID (300 mg/kg/day) in rats did not result in adverse findings over 28 days and 
therefore was considered the NOAEL.  The AUC and Cmax in rats at steady-state at the NOAEL 
are expected to be at least 16- and 30-fold, respectively, over those projected to be efficacious in 
humans.  Minimal histological findings were observed in the liver (vacuolation) and pituitary 
gland (cytoplasmic clearing) of rats receiving 300 mg/kg/day INCB001158 that were not 
considered adverse and were fully reversible following a two-week non-dosing recovery period.  
In the 28-day GLP toxicity study in cynomolgus monkeys, INCB001158 dosing at 150 mg/kg 
BID (300 mg/kg/day) resulted in morbidity in one female monkey.  Findings in this animal were 
consistent with urea cycle inhibition with ~120-fold increase in liver arginine.  A dose of 
300 mg/kg/day in male monkeys was generally well-tolerated, as was a dose of 200 mg/kg/day in 
female monkeys.  Findings in surviving high-dose animals included reversible ~2-fold elevations 
in ALT and AST correlating with minimal centrilobular hepatocyte degeneration, as well as 
modest decreases in total protein and albumin.  At the high dose, the steady-state Cmax was 
> 23 µg/mL (80 µM) and the AUC was > 137 µg*hr/mL, over 29-fold and 19-fold above the 
projected human efficacious exposure, respectively.  A dose level of 50 mg/kg BID 
(100 mg/kg/day) in male and female monkeys did not result in any adverse findings and was 
considered the NOAEL.  The dose level of 100 mg/kg BID (200 mg/kg/day) was considered the 
Highest Non-Severely Toxic Dose (HNSTD).  The AUC and Cmax in monkeys at steady-state at 
this dose are expected to be at least 16- and 24 fold, respectively, above the exposure predicted 
to be efficacious in humans. 
A Functional Observational Battery and Locomotor Assessment were incorporated into the rat 
GLP toxicity study to evaluate any potential CNS effects.  There were no findings in either 
evaluation that were attributed to INCB001158.  In the GLP cynomolgus monkey study, ECG 
and blood pressure were monitored.  There were no findings associated with INCB001158 


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treatment, consistent with minimal findings in a human ether-à-go-go (hERG) patch-clamp 
assay, wherein 50 µM INCB001158 inhibited the hERG potassium channel by less than 1%.   
Orotic acid (OA) is a marker of urea cycle inhibition that accumulates in the urine in patients 
with urea cycle defects.  In rats, a single dose of 500 mg/kg (the dose that produced significant 
toxicity during the second week of BID dosing in the GLP toxicity study) produced a dramatic 
increase in urine OA (> 1000-fold; Figure 10.1-6).  Notably, in one rat receiving the NOAEL 
dose of 150 mg/kg an increase in OA of ~100-fold was observed.  Thus, urine OA is a sensitive 
surrogate marker for urea cycle inhibition and will be monitored closely in patients on the 
Phase 1 clinical study.  
 
Figure 10.1-6:  Peak urine orotic acid levels in rats. 
Rats were dosed with INCB001158 orally twice daily for 5-days.  Urine OA was measured via 
LC/MS/MS and normalized to urine creatinine. 
 
INCB001158 did not induce a mutagenic response in a GLP Ames assay at concentrations up to 
5000 µg/plate. 
Additional information on the GLP and non-GLP evaluation of toxicity in animals can be found 
in the Investigator’s Brochure for INCB001158. 
10.1.9 
Previous Human Experience 
As of 23 May 2018, the Phase 1 clinical trial INCB 01158-101, previously referred to as 
CX-1158-101, is enrolling solid tumor patients to receive INCB001158 on a BID schedule as 
single agent and in combination with pembrolizumab.  The recommended phase 2 dose (RP2D) 
for single agent INCB001158 was declared as 100 mg BID, and enrollment to the monotherapy 
expansion cohorts is ongoing.  The combination of INCB001158 with pembrolizumab is 


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undergoing evaluation in dose escalation.  Eighty patients have been enrolled to the study, 29 to 
monotherapy dose escalation, 30 across monotherapy dose expansions, and 21 to combination 
dose escalation.  The preliminary PK, PD, and safety data from this ongoing study are reported 
below.  Please note that this is an ongoing study and, as such, the clinical data are not fully clean 
and subject to change.  Please see the Investigator’s Brochure for additional information. 
10.1.10 
Pharmacokinetics of INCB001158 
Administration of INCB001158 to solid tumor patients resulted in pharmacologically active 
exposure beginning with the first dose of 50 mg.  The first three dose escalation cohorts enrolled 
patients at doses of 50, 100, and 150 mg BID.  The pharmacokinetic data available as of 
26 June 2017 are shown in Figure 10.1-7 and PK parameters are provided in Table 10.1-1.  The 
half- life (t1/2) of INCB001158 was approximately 6 hr and the Cmax ranged from approximately 
3–10 µM and occurred at approximately 4 hr after dosing.  The minimum target for continuous 
exposure of INCB001158 based on preclinical efficacy data was approximately 1.0 µM and the 
steady state Cmin (trough concentration) at 50, 100, and 150 mg BID was well above this target. 
 
Figure 10.1-7: PK profile of INCB001158 in patients enrolled in the Phase 1 study.  
Data from patients receiving 50 (N = 4), 100 (N = 4) and 150 (N = 3) mg BID are plotted.  On C1D1, 
patients received a single dose of INCB001158 and plasma samples were collected through 12-16 hr on 
D1 and prior to the first BID dose on C1D2 (24 hr).  A second PK profile was collected through 12 hr on 
C1D15 at steady state.  The horizontal line indicates the target concentration for continuous exposure of 
INCB001158 to achieve 90% inhibition of arginase enzyme. 
 


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Table 10.1-1:  PK Parameters from Phase 1 Patients 
Cohort 
T1/2 (C1D1) 
(hr) 
Cmax (C1D15) 
(μM) 
Cmin (C1D15) 
(μM) 
AUCt (C1D15) 
(μM*hr) 
50 mg BID 
6.2 ± 1.0 
3.3 ± 0.5 
1.6 ± 0.6 
30.2 ± 6.5 
100 mg BID 
6.0 ± 0.6 
8.4 ± 1.4 
4.1 ± 0.5 
80.6 ± 12.2 
150 mg BID 
5.0 ± 0.5 
9.9 ± 2.4 
4.4 ± 0.8 
85.5 ± 7.6 
Note:  Values represent the mean ± SD. 
 
10.1.11 
Pharmacodynamics of INCB001158 
The pharmacodynamic activity of INCB001158 was determined by direct measurement of 
arginine concentration and arginase activity in plasma.  Comparing to healthy volunteers, the 
cancer patients enrolled in this trial had reduced median plasma arginine concentration  and 
elevated level of arginase protein in predose samples on C1D1 (Figure 10.1-8, Panels A and C).  
Plasma arginine levels increased in all patients on study.  With the exception of two patients at 
50 mg BID, all patients on study had increases of more than 50% in plasma arginine level, and 
even the two patients had further elevations at later time points (Figure 10.1-8, Panel B).  These 
elevations in plasma arginine brought the plasma arginine of all patients into or above the normal 
range of plasma arginine concentration.  Further, direct measurement of plasma arginase activity 
demonstrated >90% inhibition at 6h hours post-dose on C1D1, which was sustained predose on 
C1D15 (Figure 10.1-8, Panel D). 


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Figure 10.1-8:  Plasma arginine and arginase in Phase 1 patients.  
Panel A.  On C1D1 prior to dosing, patients had a plasma arginine concentration that was significantly 
reduced compared with reference data from healthy volunteers (collected separately).  Panel B.  On 
C1D15, plasma arginine increase had reached > 1.5-fold compared with predose on C1D1 in most 
patients on study in 11 pts tested (n=4 at 50 mg, 4 at 100 mg and 3 at 150 mg).  Panel C.  Arginase 
protein levels in plasma were found to be elevated relative to healthy volunteers.  Panel D.  On C1D15, 
plasma arginase activity was reduced to < 10% in all 11 pts tested (n=5 at 50 mg and 6 at 100 mg).  
Arginine concentration in plasma was measured by amino acid analysis.  Arginase protein was measured 
by ELISA and arginase activity was measured by incubating plasma with 13C-arginine and detecting 
formation of 13C ornithine by LC/MS-MS. 
 


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10.1.12 
Safety of Single Agent INCB001158 
The preliminary safety profile of INCB001158 has been evaluated during dose escalation from 
50 to 150 mg BID.  INCB001158 has been well tolerated at all doses tested.  The rate of 
treatment-related adverse events has been low (40% of pts), all of which have been mild to 
moderate (Grade 1/2) and only one of which (fatigue) has occurred in as many as 2 patients. No 
treatment-related serious adverse events (SAEs) or adverse events of Grade ≥ 3 have occurred. 
Treatment-emergent Grade ≥ 3 adverse events have occurred in 6 patients, all of which have 
been considered unrelated or unlikely related to study drug, and have generally been related to 
underlying disease.  Dose interruptions/reductions due to drug-related events have occurred in 
2 patients, both due to asymptomatic elevations in urinary OA (see below) in patients enrolled at 
the 150 mg dose level. 
Table 10.1-2:  INCB001158-Related Treatment-Emergent Adverse Events by 
Preferred Term 
 
 Number (%) of Patients 
(N=23) 
Adverse Event Preferred Term 
All Grades 
≥ Grade 3 
Patients with Any INCB001158-Related 
Treatment-Emergent Adverse Event 
18 (78.3%) 
6 (26.1%) 
Constipation 
6 (26.1%) 
0 (0.0%) 
Abdominal pain 
5 (21.7%) 
2 (8.7%) 
Anaemia 
4 (17.4%) 
1 (4.3%) 
Back pain 
4 (17.4%) 
1 (4.3%) 
Oedema peripheral 
4 (17.4%) 
0 (0.0%) 
Pyrexia 
4 (17.4%) 
0 (0.0%) 
Fatigue 
3 (13.0%) 
0 (0.0%) 
Nausea 
3 (13.0%) 
0 (0.0%) 
Cough 
2 (8.7%) 
0 (0.0%) 
Diarrhoea 
2 (8.7%) 
0 (0.0%) 
Dizziness 
2 (8.7%) 
0 (0.0%) 
Dyspnoea 
2 (8.7%) 
0 (0.0%) 
Peripheral sensory neuropathy 
2 (8.7%) 
0 (0.0%) 
Acute kidney injury 
1 (4.3%) 
0 (0.0%) 


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Table 10.1-2: INCB001158-Related Treatment-Emergent Adverse Events by 
Preferred Term (Continued) 
 
 Number (%) of Patients 
(N=23) 
Adverse Event Preferred Term 
All Grades 
≥ Grade 3 
Alanine aminotransferase increased 
1 (4.3%) 
0 (0.0%) 
Anxiety 
1 (4.3%) 
0 (0.0%) 
Appetite disorder 
1 (4.3%) 
0 (0.0%) 
Arthralgia 
1 (4.3%) 
0 (0.0%) 
Ataxia 
1 (4.3%) 
0 (0.0%) 
Blood creatinine increased 
1 (4.3%) 
0 (0.0%) 
Bone pain 
1 (4.3%) 
0 (0.0%) 
Carpal tunnel syndrome 
1 (4.3%) 
0 (0.0%) 
Cellulitis 
1 (4.3%) 
1 (4.3%) 
Conjunctivitis 
1 (4.3%) 
0 (0.0%) 
Decreased appetite 
1 (4.3%) 
0 (0.0%) 
Dry skin 
1 (4.3%) 
0 (0.0%) 
Ear pain 
1 (4.3%) 
0 (0.0%) 
Embolism 
1 (4.3%) 
0 (0.0%) 
 
Effects on hepatic urea cycle function 
Urinary OA is being monitored as a sensitive biomarker of urea cycle inhibition in the liver.  
(Hepatic urea cycle inhibition leads to the accumulation of carbamoyl phosphate, which is 
metabolized via the pyrimidine synthesis pathway leading the synthesis and urinary excretion of 
OA).  Substantial elevations (generally to 100-800X the upper limit of normal) occur in patients 
with inherited defects in enzymes of the urea cycle.  A similar magnitude of urinary OA 
elevation (~1000X) was noted in animals that received doses of INCB001158 that were 
associated with toxicity in preclinical safety studies, although notable elevations in urinary OA 
were also noted in some animals treated at the NOAEL.   
Due to the limited availability of data describing the clinical sequelae associated with modest 
(5-100X ULN) elevations of urinary OA, a conservative threshold of 5X the ULN was used to 
provide evidence of urea cycle inhibition.  Importantly, elevations in OA are not considered a 
toxicity but, rather, function as a biomarker of urea cycle function.  In addition to urinary OA, 


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patients were also monitored for sustained elevations in ammonia or significant reductions in 
plasma blood urea nitrogen (BUN) as evidence of clinically significant effects on the urea cycle. 
There has been no evidence of clinically significant urea cycle inhibition to date.  Although 
normal variability of plasma ammonia and BUN has been seen, no dose related trends or 
significant outliers have been noted (Tables 10.1-3 and 10.1-4).  In addition, no symptoms 
associated with clinically significant urea cycle inhibition (e.g., unexplained anorexia, nausea, 
vomiting, mental status changes, etc.) have been noted. 
Table 10.1-3:  Plasma Ammonia Levels by Visit Day* 
Dose 
Level 
(mg BID) 
N 
Baseline 
C1D8 
C1D15 
C1D22 
C2D1 
C2D8 
50 
6-8*** 
20 ± 15 
18  ±  11 
24 ± 23 
18 ± 11 
45 ± 52 
36 ± 44 
100 
3-7*** 
20 ± 12 
17 ± 8 
16 ± 8 
16 ± 5.3 
52 ± 66 
18 ± 8.0 
150** 
3*** 
41 ± 23 
30 ± 14 
35 ± 13 
36 ± 26 
29 ± 19 
25 ± 6.1 
* Plasma ammonia units in μM (mean ± SD).  Baseline values are C1D1 predose values.  ULN at the labs where these labs were 
processed ranged from X to X. 
**One patient at the 150 mg BID dose level was dose-reduced to 100 mg BID at C1D22 following a dose interruption of 4 days.   
***Data not available for all patients at all time points. 
 
Table 10.1-4:  Blood Urea Nitrogen Levels by Visit Day* 
Dose Level 
(mg BID) 
N 
Baseline 
C1D8 
C1D15 
C1D22 
C2D1 
C2D8 
50 
6-8*** 
13 ± 4 
14 ± 4 
14 ± 4 
13 ± 3 
11 ± 3 
12 ± 3 
100 
5-8*** 
17 ± 7 
14 ± 4 
15 ± 6 
15 ± 5 
17 ± 6 
18 ± 3 
150** 
3*** 
13 ± 3 
10 ± 1 
10 ± 2 
11 ± 2 
10 ± 0 
10 ± 2 
* BUN units in mg/dL (mean ± SD).  Baseline values are either the C1D1 predose measurement or the last measurement obtained 
prior to the first dose of INCB001158.  JAMA reference range for BUN is 8-23 mg/dL). 
**One patient at the 150 mg BID dose level was dose-reduced to 100 mg BID at C1D22 following a dose interruption of 4 days.  
*** Data not available for all patients at all time points. 
 


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No significant changes in OA were identified in patients enrolled at the 50 or 100 mg BID dose 
levels (Table 10.1-5).  However, 2 of 3 patients enrolled at the 150 mg BID dose level 
experienced elevations in urinary OA.   
Table 10.1-5:  Predose Orotic Acid Levels by Visit Day*   
Dose 
Level 
(mg BID) 
N 
Baseline 
C1D8 
C1D15 
C1D22 
C2D1 
C2D8 
Absolute Change (% Change from Baseline) 
50 
6-8*** 0.8 ± 0.3 
0.7 ± 0.2 
(-12.5%) 
0.5 ± 0.2 
(-37.5%) 
0.6 ± 0.4 
(-25.0%) 
0.6 ± 0.5 
(-25.0%) 
0.6 ± 0.4 
(-25.0%) 
100 
4-8*** 0.7 ± 0.3 
0.7 ± 0.4 
(0.0%) 
0.7 ± 0.4 
(0.0%) 
0.7 ± 0.2 
(0.0%) 
0.5 ± 0.5 
(-28.6%) 
0.5 ± 0.3 
(-28.6%) 
150** 
2-3*** 0.6 ± 0.3 
0.6 ± 0.5 
-(0.0%) 
4.5 ± 6.2 
(650%) 
0.5 ± 0.2 
(-16.7%) 
0.7 ± 0.1 
(16.7%) 
3.5 ± 5.0 
(480%) 
*Orotic acid units in µmol OA/mmol creatinine (mean ± SD).  Baseline values are C1D1 predose values.  Laboratory reference 
range is 0.2 to 1.5 µmol OA/mmol creatinine. 
**One patient at the 150 mg BID dose level was dose-reduced to 100 mg BID at C1D22 following a dose interruption of 4 days. 
*** Data not available for all patients at all time points. 
 
In one patient at the 150 mg BID dose level, the fasting predose urinary OA on C1D15 was 
11.6 µmol/mmol creatinine (7.7X ULN) and the postdose (non-fasting) level was 47 µmol/mmol 
creatinine (31.3x ULN).  This patient was asymptomatic without any significant changes in 
ammonia or BUN from baseline and the OA returned to baseline within 2 days of withholding 
the INCB001158 dose.  After dose reduction to 100 mg, the predose OA values were normal 
after 2 and 3 weeks of additional dosing.  However, despite the patient remaining asymptomatic, 
postdose elevations were noted at these two time points (27.4 and 131.6 µmol/mmol creatinine, 
respectively), so the patient was dose reduced further to the 50 mg dose level, after which no 
further elevations were noted.  A second patient at the 150 mg dose level had elevated urinary 
OA predose on C2D8 (9.3 µmol/mmol creatinine; 6.2X ULN).  This patient also remained 
asymptomatic and had no significant changes from baseline in plasma ammonia or BUN.  After a 
2-day interruption of study drug, the dose was reduced to 100 mg and no subsequent elevations 
in urinary OA were noted.  
In summary, there has been no evidence of clinically significant inhibition of the urea cycle to 
date.  Two patients have had asymptomatic elevations in urinary OA, a sensitive biomarker of 


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hepatic urea cycle inhibition, that were not associated with changes in plasma ammonia or BUN, 
but were dose reduced based on a protocol defined urinary OA threshold of 5X ULN.  Both 
patients were able to continue on study drug at the reduced dose without subsequent elevations 
in OA. 
10.2 Rationale for Study Design 
10.2.1 
Rationale for Starting Dose 
The starting dose for monotherapy dose escalation will be 50 mg BID.  This dose was selected 
based on the results of the GLP-compliant preclinical toxicology studies conducted in rats and 
cynomolgus monkeys.  This dose is approximately one-thirty-sixth (1/36th) of the No Observable 
Adverse Effect Level (NOAEL) and one-forty-eight (1/48th) of the highest non-severely toxic 
dose (HNSTD) in monkeys.  Monkeys were selected as the most appropriate species for starting 
dose selection based on 1) the greater genetic and, presumably, physiological similarity to 
humans and 2) the fact that they were more sensitive (as defined by plasma exposure associated 
with toxicity) to the toxic effects of INCB001158.  A conservative starting dose was selected 
relative to the FDA S9 Guidance of one sixth (1/6th) the HNSTD in non-rodent species; the 
bioavailability in monkeys (20%) was lower than in other species tested and plasma exposures 
could under-represent exposures that will be achieved in humans.  
This study will also evaluate the safety, tolerability, and efficacy of INCB001158 in combination 
with the FDA-approved anti-PD-1 agent pembrolizumab.  The decision to open the anti-PD-1 
combination dose escalation is dependent on achieving either the target exposure that will lead to 
continuous inhibition of extracellular arginase 1 by > 90% (Cmin of ≥ 1μM) and/or an elevation of 
plasma arginine to levels that correlated with in vivo activity in preclinical models (2.5-fold 
elevation from baseline in plasma arginine).  The starting dose of INCB001158 that will be used 
in combination with full dose pembrolizumab will be 50 mg BID, which is 2 dose levels below 
the recommended monotherapy Phase 2 dose of 100 mg BID identified in Part 1a of this study. 
10.2.2 
Rationale for Dose Escalation Strategy 
The dose escalation for this study will follow standard Modified Fibonacci dose escalation 
schedule for both monotherapy and the pembrolizumab combination (see Table 5.1-1).  As 
described in Section 5.1, the selection of this dose escalation schedule was guided by the 
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safety/tolerability of INCB001158 as well as the PK and pharmacodynamic data generated in the 
first two dose levels of the dose escalation.   
10.2.2.1 Rationale for Dose in Patients with Moderately Impaired Renal Function 
A considerable proportion of patients with the tumor types being evaluated in this study have 
moderately impaired renal function (defined as CrCl 30-49 mL/min) due to multiple factors 
including underlying disease, prior treatments and procedures, or baseline chronic renal 
insufficiency.  Prior to Protocol Amendment 2-US 2, such patients were excluded from this 
study, even though they may well benefit from INCB001158 treatment.  However, since the 
primary mechanism of elimination of INCB001158 is thought to be renal clearance, patients with 
impaired renal function may need a lower dose of INCB001158 to achieve exposure similar to 
patients with normal renal function.  To test this hypothesis, population PK modeling was used 
to determine and evaluate a reduced dose of INCB001158 in patients with moderately impaired 
renal function defined as CrCl 30-49 mL/min as calculated by the Cockcroft-Gault formula. 
The safety of INCB001158 alone and in combination with pembrolizumab has been well-
characterized in the dose escalation Parts 1a and 1b (refer to the iIB).  The MTD was not reached 
across 4 dose levels in monotherapy (50, 75, 100, and 150 mg BID) and 3 dose levels in 
combination with pembrolizumab (50, 75, and 100 mg BID).  Pharmacokinetic data for 
INCB001158 in combination with pembrolizumab were similar to that of INCB001158 
monotherapy, which was expected, since pembrolizumab was not predicted to have any effect on 
INCB001158 exposure.  Additionally, moderate renal impairment (GFR < 60 and 
≥  mL/min/1.73 m2) has no clinically important effect on the clearance of pembrolizumab (refer 
to the pIB).  The minimum target for continuous exposure of INCB001158 based on preclinical 
efficacy data is approximately 1.0 μM.  As monotherapy, INCB001158 had steady-state Cmin 
(trough concentration) well above this target at all dose levels evaluated (50, 75, 100, and 
150 mg BID), indicating strong target inhibition.  Pharmacokinetic data from the 50 and 
75 mg BID dose levels in combination dose escalation also showed steady state Cmin > 1 µM 
with no differences in the overall exposure range between patients in monotherapy and 
combination at steady state. 
The overall safety profile across 3 INCB001158 dose levels evaluated in combination with 
pembrolizumab was favorable, with no DLTs or Grade 3 treatment-related AEs at the maximum 


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dose level of INCB001158 100 mg BID.  INCB001158 PK and PD in combination with 
pembrolizumab were similar to that of INCB001158 monotherapy, with similar exposures at 
equivalent doses and strong target inhibition, as indicated by increases in plasma arginine.  The 
RP2D for INCB001158 alone and in combination with pembrolizumab was declared as 100 mg 
BID.  Therefore, evaluation of INCB001158 in patients with moderate renal impairment will be 
done in combination with pembrolizumab, since pembrolizumab did not have any effect on 
INCB001158 exposure. 
In order to determine the appropriate dose in patients with moderate renal impairment (defined as 
CrCl 30-49 mL/min), population PK modeling was performed, incorporating full PK data from 
patients enrolled to the already completed dose escalation parts in patients with CrCl 
> 50 mL/min.  The PK data showed that INCB001158 AUC, Cmax, and half-life inversely 
correlated with CrCl across all tested doses, as expected (Figure 10.2-1).  Based on the strongly 
inverse linear relationship between CrCl and AUC, extrapolation of the data to CrCl values 
below 50 mL/min indicated that a dose of 50 mg BID in patients with CrCl 30 to 49 mL/min 
predicted INCB001158 AUC values to fall within the known safe exposure range corresponding 
to doses at or below the established RP2D of 100 mg BID (Table 10.2-1). 
 
Figure 10.2-1:  Plot of INCB001158 CrCl versus AUC or Cmax in patients treated with INCB001158 
alone or in combination with pembrolizumab, from Parts 1a and 1b.  
 


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Table 10.2-1:  Projected Human INCB001158 Steady-State AUCs During 1 Dose Interval 
at 50, 75, 100, and 150 mg for Patients with Different Creatinine 
Clearances Ranging from 15 to 200 mL/min 
CrCl 
(mL/min) 
AUC (50 mg) 
AUC (75 mg) 
AUC (100 mg) 
AUC (150 mg) 
15 
41,210 
61,815 
82,420 
123,630 
20 
31,283 
46,924 
62,565 
93,848 
30 
21,355 
32,033 
42,710 
64,065 
40 
16,391 
24,587 
32,783 
49,174 
50 
13,413 
20,120 
26,826 
40,239 
60 
11,428 
17,141 
22,855 
34,283 
70 
10,009 
15,014 
20,019 
30,028 
80 
8,946 
13,418 
17,891 
26,837 
90 
8,118 
12,178 
16,237 
24,355 
100 
7,457 
11,185 
14,913 
22,370 
110 
6,915 
10,373 
13,830 
20,745 
120 
6,464 
9,696 
12,928 
19,391 
130 
6,082 
9,123 
12,164 
18,246 
140 
5,755 
8,632 
11,509 
17,264 
150 
5,471 
8,207 
10,942 
16,413 
200 
4,478 
6,717 
8,957 
13,435 
10.2.3 
Rationale for Patient Populations 
10.2.3.1 
Monotherapy 
This is a Phase 1 study evaluating the safety and tolerability of INCB001158 in cancer patients.  
Since it unknown whether INCB001158 is efficacious, only patients with metastatic disease or 
advanced disease that is not amenable to local therapy will be enrolled.  Further, only patients for 
whom there are no available therapies that have been shown to provide clinical benefit (e.g., 
overall survival benefit) will be enrolled.  In order to maximize the potential for identifying 
clinical benefit, the expansion cohorts will enroll tumor types that have been previously shown to 
have significant infiltration with MDSCs and/or Arg1+ cells.  Two monotherapy expansion 
cohorts identify specific patient populations, NSCLC (Part 2a) and CRC (Part 2b), both of which 
have high infiltration with Arg1+ cells (see Section 10.1.2) and have a large unmet need.  An 
additional expansion cohort (Part 2c) allows a broader group of patient to be enrolled consisting 
of tumor types that also have high infiltration of Arg1+ granulocytic MDSCs and PMNs (by 


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internal data or published accounts), in order to identify a preliminary signal of activity that can 
be subsequently followed up with a dedicated expansion cohort (or a separate clinical study). 
10.2.3.2 
Combination with Anti-PD-1 (Pembrolizumab) 
As of the date when this amendment was authored, the anti-PD-1 agent pembrolizumab has been 
approved for the treatment of metastatic melanoma, NSCLC, SCCHN, urothelial carcinoma, and 
solid tumors that are microsatellite instability-high (MSI-H) or mismatch repair deficient 
(dMMR).  Despite the impressive activity observed for this and other anti-PD-1/PD-L1 agents, a 
majority of patients with these diseases do not achieve an objective response to these agents and 
there is a recognized need for combination agents to either expand the population that benefits or 
amplifies the activity that they provide (Melero 2015). 
Eight patient populations are eligible to enroll into expansion cohorts, including 
advanced/metastatic NSCLC (Part 3a), advanced/metastatic melanoma (Part 3b) 
advanced/metastatic UCC (Part 3c), advanced/metastatic MSI-H CRC (Part 3d), 
advanced/metastatic MSS CRC (Part 3e), advanced/metastatic gastric /GEJ (Part 3f), 
advanced/metastatic SCCHN (Part 3g), and advanced/metastatic malignant pleural mesothelioma 
(Part 3h).  Since a primary objective of the expansion cohorts is to identify a signal of clinical 
activity of INCB001158 in combination with pembrolizumab, some of these cohorts will enroll 
patients that are unlikely to respond to monotherapy pembrolizumab because they either 1) had 
disease progression (even after an objective response) in the immediate prior line of therapy, OR 
2) had prolonged stable disease (≥ 24 weeks) in the immediate prior line of therapy.  The 
attribution of evidence of clinical activity (e.g., objective responses) to INCB001158 in this 
population can be made more confidently given the low likelihood of a response to monotherapy 
anti-PD-1 therapy.  In addition to these “add-on” cohorts, other cohorts will enroll patients that 
have never received prior checkpoint inhibitor therapy.  There are generally two reasons to 
include these cohorts: 1) to identify activity in patient populations that are known to be 
unresponsive to PD-1 therapy (e.g., MSS CRC) and 2) to identify activity of the 
INCB001158/pembrolizumab combination that could be missed in pembrolizumab-refractory 
patients. 
All expansion cohorts target tumor types that have a significant proportion of patients with Arg+ 
infiltrating cells within tumor samples (as presented in Section 10.1) and/or elevated plasma 
arginase (along with depleted plasma arginine) which may contribute to immune suppression. 


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11.0 
PROCEDURES 
All patients must sign an IRB/IEC-approved informed consent prior to starting any protocol-
specific procedures, including screening procedures.  During the consent process, the person 
obtaining consent must inform the patient of all elements of informed consent.  Patients must 
also meet the inclusion and exclusion criteria to be enrolled in the study. 
11.1 Screening Period 
11.1.1 
Prior Treatment 
Reasonable efforts will be made during the screening period to determine all prior therapeutic 
treatments received by the patient.  All previous cancer treatments, including systemic therapies, 
radiation, and/or surgical procedures, should be recorded on the patients’ electronic case report 
forms (eCRFs). 
For some patients progressing on pembrolizumab in Parts 3a, 3b, 3c, and 3d, computerized 
tomography (CT) or magnetic resonance imaging (MRI) scans and/ or radiology reports may be 
requested for tumor evaluations during the course of prior pembrolizumab or other anti-PD-1 
therapy in order to document the status of stable disease and/or progressive disease.   
11.1.2 
Concomitant Treatment 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may be 
required.  The investigator should discuss any questions regarding this with the Sponsor Clinical 
Director.  The final decision on any supportive therapy or vaccination rests with the investigator 
and/or the patient's primary physician.  However, the decision to continue the patient on trial 
therapy or vaccination schedule requires the mutual agreement of the investigator, the Sponsor, 
and the patient. 


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11.1.2.1 Acceptable Concomitant Medications 
Concomitant treatment with other therapies is permitted if the medication is not expected to 
interfere with the evaluation of safety or efficacy of the study treatments.  During the study, if 
the use of any concomitant treatment becomes necessary (e.g., for treatment of an adverse event), 
the treatment must be recorded on the appropriate eCRF, including the reason for treatment, 
name of the drug, dosage, route, and start and stop dates of administration.  
For patients receiving INCB001158 in combination with pembrolizumab (Parts 1b and 3): In 
patients that are currently receiving pembrolizumab (Parts 3a, 3b, 3c, and 3d) as part of their 
prior line of therapy, pembrolizumab should be administered continuously, if possible (i.e., there 
is no need to discontinue or pause pembrolizumab dosing).   
11.1.2.2 Prohibited Concomitant Medications 
Patients are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational therapeutic agents other than the study treatments, INCB001158 and 
pembrolizumab 
• Radiation therapy  
− Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be 
considered on an exceptional case by case basis after consultation with Sponsor.  
The patient must have clear measurable disease outside the radiated field.   
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following:  measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and 
typhoid (oral) vaccine.  Seasonal influenza vaccines for injection are generally killed 
virus vaccines and are allowed.  However, intranasal influenza vaccines (e.g. FluMist®) 
are live attenuated vaccines, and are not allowed. 


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• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  The use of physiologic 
doses of corticosteroids may be approved after consultation with the Sponsor. 
− Note:  Inhaled steroids are allowed for management of asthma. 
• Except for erythropoietin or darbepoetin alpha (Aranesp®), use of growth factors (i.e., 
G-CSF, GM-CSF, etc.) is not permitted in the first treatment cycle unless the patient 
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 2002; 
Wadzinski 2007). 
• Concomitant treatment with allopurinol or other xanthine oxidase inhibitors is not 
allowed during the monotherapy dose escalation of INCB001158 (Part 1a).  Xanthine 
oxidase inhibitors cause an accumulation of OA in the urine, which would confound the 
assessment of safety in these patients.   
11.1.3 
Screening Evaluation 
The following screening assessments must be performed within 21 days before study treatment 
administration on C1D1 according to the Attachment 1 [with the exception of imaging 
(CT/MRI); scans performed within 28 days of study treatment administration on C1D1 are 
acceptable].  Procedures listed below that are performed as part of the normal standard of care 
and within 21 days prior to C1D1 may be used for screening purposes: 
• Sign and date an IRB/IEC-approved Informed Consent Form (ICF) before any study-
specific (i.e., non-standard of care) screening procedures are performed 
• Demographic information including date of birth, sex, and ethnic origin  
• Medical history including review of prior cancer treatments 
• Review of concomitant medications 
• ECOG performance evaluation 
• Complete physical examination including weight (kg) and height (cm) 
• Vital signs and weight  


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• Standard duplicate 12-lead ECG with corrected QT interval by Fridericia’s Formula 
(QTcF) 
• Clinical laboratory evaluation (hematology, coagulation, serum chemistry, and 
urinalysis); see Attachment 3. 
• Serum or urine pregnancy test.  This is only required for females of child-bearing 
potential and must be negative within 3 days prior to C1D1. 
• Radiographic evaluation of tumor burden (e.g., diagnostic CT or MRI).  Scans performed 
within 28 days prior to C1D1 will be accepted and do not need to be repeated.  See 
Attachment 1 and Attachment 2.  Note: For this study, evaluation of tumor burden must 
be based on a diagnostic CT or MRI.  1-3 scans prior to the start of study and redacted 
scan reports will also be collected and sent to a central reader for exploratory evaluation. 
• Fresh tumor biopsies: Predose tumor biopsies are required for some patients enrolled in 
this study.  If fresh biopsies are not available at predose, archival tumor tissues, if 
available, collected within 3 months prior to screening are required.  See Table 11.8-1 for 
additional details.  Coagulation tests must be performed and evaluated within 24 hr prior 
to all biopsy procedures.  
A patient who meets all of the inclusion criteria will enter the study.  Screen failures will be 
marked in the electronic data capture (EDC) system. 
11.2 Study Procedures 
Screening physical exam, urinalysis, serum chemistry, coagulation, and hematology that 
occurred within 3 days prior to C1D1 do not need to be repeated unless a clinically significant 
change in the interim is suspected. 
Patients in Part 1A should be instructed to fast overnight (> 8 hours prior to their clinic visit) on 
Cycle 1:D1, D8, D15, and D22, C2D1, C2D8, and on Day 1 of all subsequent cycles.  Patients in 
Parts 1B and 3 should be instructed to fast overnight (> 8 hours prior to their clinic visit) on 
Cycle 1: D1, D8 and D15, and on Day 1 of all subsequent cycles.  Patients in Part 2 should be 
instructed to fast overnight (> 8 hours prior to their visit) on C1D1, D8, D15, and D22, and on 
Day 1 of all subsequent cycles.  All patients on study should be instructed to void their bladders 
upon waking. 


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On these days, patients will undergo the pre-dose assessments, and receive the INCB001158 
dose in the clinic.  Recommendations on meals can be found in the Meal Recommendations 
section of the Study Reference Manual.  The evening dose will be self-administered by the 
patient after all post-dose activities have been completed. 
A detailed breakdown of the visit schedule and sample collection time points can be found in 
Attachments 1A and 1B. 
11.2.1 
Cycle 1  
During Cycle 1, patients will undergo the following procedures: 
•
AE Monitoring
•
Recording of concomitant medications
•
Vital signs and weight
•
Symptom-directed physical exam
•
ECOG Performance status evaluation
•
Clinical laboratory evaluation (hematology, coagulation, serum chemistry, ammonia, and
urinalysis)
•
Plasma sample collection for PK 
 analysis (Attachment 2)
•
Urine sample for measurement of urine orotic acid levels
•
Duplicate ECG with QTcF between 2-4 hr post-dose
•
Administration of INCB001158.
•
Part 1b and Part 3 patients will also receive pembrolizumab administration in the clinic
on Day 1 of each 21-day cycle.
11.2.1.1 
Part 1a and 1c Only: Cycle 1 Day 1 and Day 15 
Patients in Parts 1a and 1c will have a full pharmacokinetic (PK) and pharmacodynamic 
evaluation on Cycle 1 Day 1 following a single dose of INCB001158.  Dosing on the BID 
schedule will commence on Cycle 1 Day 2.   
On Cycle 1 Day 1 and Day 15, patients will arrive at the clinic in a fasted state and will take their 
assigned dose of INCB001158 after predose assessments have been collected.  Blood for PK and 
pharmacodynamic evaluation will be taken according to the schedule in Attachment 2.  Once 
predose assessments have been completed, patients will take INCB001158 with a full glass of 


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water.  Patients can eat breakfast 2 hours after taking INCB001158.  In Part 1a and 1c only, no 
second dose of drug will be provided on Cycle 1 Day 1.   
11.2.2 
Cycle 2 and All Subsequent Cycles 
A detailed breakdown of the visit schedule and sample collection time points for Cycle 2 and 
subsequent cycles can be found in Attachments 1 and 2.  Patients will return to the clinic and 
undergo the following procedures: 
• AE monitoring 
• Recording of concomitant medications 
• Vital signs and weight 
• Symptom-directed physical exam 
• Clinical laboratory values (hematology, coagulation, serum chemistry, ammonia, and 
urinalysis) 
• Urine sample for measurement of urine orotic acid levels 
• ECOG performance status evaluation 
 
  
 
  
• Administration of INCB001158. 
• Part 1b and Part 3 patients will also receive pembrolizumab administration in the clinic 
on Days 1 of each 21-day cycle.  
• A postdose tumor biopsy will be obtained from all patients who have consented to the 
tumor biopsy and for patients enrolled in the backfill cohorts.  Coagulation tests must be 
performed and evaluated within 24 hr prior to all biopsy procedures. 
• Radiographic evaluation (e.g., diagnostic CT or MRI) of tumor burden will occur 
approximately every 8 weeks (Parts 1a and 2) or every 9 weeks (Parts 1b and 3).  The 
same method of evaluation should be used throughout the course of the study.  The scans 
and redacted reports will be collected and sent to a central reader for exploratory 
evaluation. 
11.2.2.1 
Part 1a Only: Cycle 2 Days 1-8 
Patients in Part 1a will participate in a food effect assessment.  During Cycle 2 Day 1 through 
Day 7, patients will be taking their INCB001158 dose with food.  Recommendations on meals 


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can be found in the Meal Recommendations section of the Study Reference Manual.  On Cycle 2 
Day 8, patients will arrive at the clinic in a fasted state and will be provided breakfast in the 
clinic.  Patients will take their assigned dose of INCB001158 immediately after eating breakfast.  
Blood for PK and pharmacodynamic evaluation will be taken over 8 hours, according to the 
schedule in Attachment 2.   
11.2.2.2 
Part 2d Only 
 
 
 
 
 
 
 
 
 
 
 
11.3 Other Schedules and Procedures 
For Study Parts 1a and 2, radiographic evaluation of tumor burden (e.g., diagnostic CT/MRI) 
will occur at Screening and approximately every 8 weeks after study initiation, or more 
frequently as clinically indicated.  
For Study Parts 1b and 3, radiographic evaluation of tumor burden (e.g., diagnostic CT/MRI) 
will occur at Screening and approximately every 9 weeks after study initiation, or more 
frequently as clinically indicated.  
Optional tumor biopsies may be obtained at variable time points as advised by the Investigator 
and Medical Monitor and agreed by the patient. 
During study treatment, urine pregnancy tests will be performed locally as medically indicated, 
or per country-specific requirement.  If a urine pregnancy test is positive, then the results should 
be confirmed with a serum pregnancy test. 


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If the serum pregnancy test is negative after a urine test was positive, then 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. 
11.4 End of Treatment (EOT) 
The End of Treatment (EOT) visit must occur within 28 days of treatment discontinuation and 
prior to initiation of any new anti-cancer therapy/regimen.  All patients discontinuing study 
treatment for any reason should undergo the following EOT procedures: 
• AE monitoring 
• Recording of concomitant medications 
• Vital signs and weight 
• Complete physical examination  
• ECOG performance status evaluation 
• Clinical laboratory values (hematology, coagulation, serum chemistry and urinalysis) 
• Urine pregnancy test for women of child-bearing potential 
• Duplicate 12-lead ECG with QTcF 
• Radiographic evaluation (e.g., diagnostic CT or MRI) of tumor burden.  Patients who 
discontinue from study due to objective findings of progressive disease during an 
on-treatment evaluation do not need to have repeat scans.  CT or MRI is required for all 
patients who have not had at least 1 post-baseline image. 
11.5 Follow-Up 
11.5.1 
Safety Follow-Up 
The safety follow-up period is the interval between the EOT visit and the scheduled follow-up 
visits, which should occur 30 to 37 days (all patients) and 90 to 97 days (Parts 1b and 3 only) 
after the final dose of study treatments.  
Adverse events (all patients) and SAEs (Parts 1a and 2 only) must be reported up until the date of 
the 30-day follow-up visit, or until toxicities resolve, return to baseline, or are deemed 
irreversible, whichever is longer.  
Serious adverse events (Parts 1b and 3 only) must be reported up until the date of the 90-day 
follow-up visit, or until toxicities resolve, return to baseline, or are deemed irreversible, 
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Reasonable efforts should be made to have the patient return for the follow-up visits and report 
any AEs that may occur during this period.  If the patient cannot return to the site for the safety 
follow-up visit (eg, lives far away), the patient should be contacted by telephone for assessment 
of AEs and SAEs.  Sites should document this contact in the source. 
If a patient is scheduled to begin a new anticancer therapy before the end of the 90-day safety 
follow-up period, the safety follow-up visit should be performed before new anticancer therapy 
is started.  Once new anticancer therapy has been initiated, the patient will have completed the 
follow-up period. 
11.5.2 
Disease Status Follow-Up 
Patients who discontinue study treatment for reasons other than disease progression will continue 
to be assessed for their disease status during the follow-up phase and should continue to have 
tumor assessments every 8 weeks (monotherapy) or 9 weeks (pembrolizumab combination) until 
a new cancer therapy is started, disease progression, death, withdrawal of consent, or the end of 
the study. 
11.6 Screen Failures 
Patients who sign an informed consent form, are not assigned to a treatment, and do not receive 
either INCB001158 or pembrolizumab are defined as screen failures.  For all screen failures, the 
Investigator will enter the screening number, patient initials, and reason(s) for screen failure into 
the electronic data capture (EDC) system.  These data will also be retained in the Investigator’s 
study files and can be printed by the site in log format at the end of the study.  
11.7 Safety Evaluation 
Routine safety and tolerability will be evaluated from the results of reported signs and 
symptoms, scheduled physical examinations, vital sign measurements, duplicate 12-lead ECGs 
(including QTcF intervals), and clinical laboratory test results. 
More frequent safety evaluations may be performed if clinically indicated or at the discretion of 
the Investigator.  All AEs will be recorded from the time the patient receives the first dose of 
study treatment up to 28 days after the last dose. 
11.7.1 
Physical Examination 
Complete physical examinations will be performed by a licensed physician (or physician’s 
assistant or nurse practitioner) at Screening and End of Treatment.  Symptom-directed physical 


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exam are required as clinically indicated.  Please refer to the Schedule of Study Assessments 
(Attachment 1). 
11.7.2 
Vital Signs 
Vital signs (blood pressure, respiratory rate, pulse rate, and temperature) will be obtained in the 
sitting position.  All patients should be sitting for 3-5 min prior to obtaining vital signs.  
Orthostatic vital signs will be measured on Cycle 1 days 1 and 15 at predose and 4 hrs post dose 
during the dose escalation (Part 1a).  Due to the absence of an effect on orthostatic vital signs, 
orthostatic vital signs will only be required for patients enrolled in Part 1a.  If effects on blood 
pressure are eventually noted, additional orthostatic vital sign monitoring will be re-introduced in 
Parts 1b, 2 and 3. 
In Parts 1b and 3, on the day of pembrolizumab infusion, vital signs will be obtained 
pre-infusion, 15 minutes after the start of the infusion, at the end of the infusion, and 15 minutes 
after completion of the infusion.  Vital signs should be collected ± 5 minutes from the scheduled 
times noted above. 
11.7.3 
Electrocardiograms 
Patients should rest in the supine position for at least 5 min before each 12-lead ECG recording 
is started.  Duplicate ECG recordings must be performed using a standard, high-quality, high-
fidelity electrocardiograph machine equipped with computer-based interval measurements.  The 
average of values will used for Inclusion/Exclusion and AE reporting purposes. 
For safety monitoring purposes, the ECG must be reviewed, signed, and dated promptly by a 
qualified physician (or qualified physician’s assistant or nurse practitioner) and any clinically 
important finding recorded on the appropriate eCRF.  The Investigator is responsible for 
providing the interpretation of all ECGs.  The results will include heart rate (HR), R-R interval 
(RR), PR interval, QRS interval, QT interval, and QTcF interval.  The corrected QT interval will 
be corrected for respiratory rate according to the following formula: 
Fridericia’s formula:  QTcF = QT/RR0.33 
11.7.4 
Safety Laboratory Determinations 
Laboratory evaluations will be performed as noted in the Schedule of Study Assessment 
(Attachment 1A and 1B). 


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11.9 Pharmacokinetic Evaluation 
11.9.1 
Blood Collection 
Plasma PK samples will be used to measure concentrations of INCB001158.  
 
 
  Blood samples for PK analysis should be 
collected at the requested time (Attachment 2).  The exact actual time of collection must be noted 
in the source documents and eCRFs. 
11.9.2 
Intensive PK Sampling 
Patients enrolled in Parts 1a and 1c will participate in the intensive PK sampling schedule.  
Plasma PK  samples will be collected on Cycle 1, Days 1 and 15 at pre-dose and post-dose at 0.5, 
1, 2, 4, 6,  8, and 12 hr. 


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In addition, patients assigned to the intensive PK group in Part 1a only will participate in an 
assessment of the effect of food on INCB001158 PK.  On Cycle 2 Days 1 through 7, patients will 
take their INCB001158 doses immediately following a meal.  On Cycle 2, Day 8, patients will 
arrive at the clinic fasted.  The pre-dose assessments will be completed and the patient will take 
INCB001158 immediately after eating a modest breakfast.  PK samples will be drawn at 0.5, 1, 
2, 4, 6, and 8 hr after taking the morning dose.  The evening dose will be taken per protocol 12 hr 
after the morning dose.  Refer to the PK 
 Sampling Schedule (Attachment 2) for 
time points and blood volumes to be collected. 
11.9.3 
Sparse PK Sampling 
Patients that are not part of the intensive PK group will have PK samples collected on Cycle 1 
Days 1 and 15, and on Day 1 of Cycles 2, 3, and 4.  Refer to the PK 
 Sampling 
Schedule (Attachment 2) for time points and blood volumes to be collected. 
 
 
 
 
 
11.9.5 
Bioanalytical Methodology 
The plasma samples will be analyzed for INCB001158 by using a validated liquid 
chromatography tandem mass spectrometry (LC-MS/MS) method of appropriate specificity and 
sensitivity according to Good Laboratory Practices (GLPs).  PK samples taken on Cycle 1 Day 1 
in Part 1a will be analyzed and results will be available prior to enrollment of patients on the 
subsequent dose escalation cohort. 


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12.0 
POTENTIAL TOXICITIES, DOSE MODIFICATION AND MANAGEMENT OF 
TOXICITIES 
12.1 Potential Toxicities 
12.1.1 
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 ~1000-fold more 
potent at inhibition of extracellular arginase 1 than intracellular arginase 1 that is engaged in the 
urea cycle, primarily due to poor penetration of INCB001158 across cell membranes and the 
“enzymatic channeling” phenomenon (Cheung 1989) that restricts access of exogenous arginine 
or INCB001158 to urea cycle enzymes.  Arginase 2 is primarily expressed in the mitochondria of 
many other tissues, including the gut and in kidney.  The functions of Arginase 2 in these tissues 
include regulation of systemic arginine concentration, regulation of the production of 
downstream products (e.g., proline, polyamines) and regulation of arginine availability for nitric 
oxide 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 1996, 
Bode-Böger 1998). 
The results of the GLP-compliant rat and monkey toxicity studies are presented in 
Section 10.1.8.  The low- and mid-dose levels were well tolerated with no adverse findings and 
the mid-dose being considered the NOAEL 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 (e.g., elevated plasma arginine) with no 
significant toxicities noted. 
Potential Urea Cycle Toxicity 
As detailed in Section 10.1.8, high doses of INCB001158 that resulted in significant morbidity 
and mortality in mice, rats, and monkeys achieved exposures over 19-fold above the projected 


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human efficacious exposure.  In the nonclinical animal studies, the toxicity at the high doses was 
associated with evidence or 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 OA levels.  Of particular interest, urinary OA was elevated by 
> 1,000-fold in rats at the high dose following a single dose, prior to any signs of toxicity.  
Smaller elevations in urinary OA were also measured in some animals at the well-tolerated 
mid-dose level.   
Several measures of potential toxicity related to urea cycle inhibition will be evaluated in this 
study (see Attachments 1 and 2).  In particular, urinary OA, plasma (venous) ammonia and BUN 
will be measured on Day 1 and at regular intervals in the dose escalation portion of the study 
(Part 1a).  
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 OA.  The elevated OA 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 
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.  Since 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.  Since it is also effected by other factors (e.g., 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. 
Immune-related AEs (irAEs) 
It is not known to what extent arginine depletion is operative in normal tissues or in non-cancer 
inflammatory states.  However, since arginase-mediated depletion of arginine is an 
immunosuppressive mechanism, irAEs may be associated with the restoration of local arginine 


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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 (e.g., 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 treatment 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 > two weeks with minimal or no improvement 
despite withholding study treatment).  High dose steroids may be used for particularly severe 
irAEs or irAEs that fail to respond to initial oral steroids within 3-4 days.  Non-steroid 
immunosuppressive agents may also be employed for steroid-refractory irAEs. 
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 nitric oxide (NO) in response to the increased availability of circulating 
arginine, a key substrate for the NO-producing Nitric Oxide Synthase (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 1996, Bode-Böger 1998) There has been no preclinical 
evidence of altered hemodynamic status in any preclinical studies of INCB001158.  In order to 
identify modest changes in hemodynamic status, frequent monitoring of blood pressure and 
careful assessment of orthostatic hypotension will be monitored in addition to standard vital 
signs as part of this study. 


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12.1.2 
Pembrolizumab (Patients Enrolled in Parts 1b, 1c, and 3) 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting 
its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 
(PD-L2).  Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor 
blocking activity for PD-1.  Pembrolizumab has an acceptable preclinical safety profile and is in 
clinical development as an intravenous (IV) immunotherapy for advanced malignancies.  
Keytruda™ (pembrolizumab) is indicated for the treatment of patients across a number of 
indications.  For more details on specific indications refer to the Investigator brochure. 
The safety profile of pembrolizumab is fully described in the pembrolizumab 
Label/Investigator’s Brochure and primarily consists of immune-related adverse events (ir-AEs) 
due to activation and proliferation of T-cells.  Ir-AEs 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).  The management of these toxicities is described 
in the pembrolizumab Label/Investigator’s Brochure but generally includes holding drug for 
moderate (Grade 2) toxicities and using systemic immunosuppression for severe (Grade 3/4) or 
prolonged moderate (> 1 week) toxicities.  Additional immunosuppression (e.g., anti-TNFα 
therapy, infliximab) may be used if IV steroids are ineffective. 
12.1.2.1 
INCB001158 + Pembrolizumab Combination 
The safety and tolerability of INCB001158 + pembrolizumab is not known.  A primary objective 
of the current study is to evaluate the safety and tolerability of the combination of 
pembrolizumab and INCB001158.  Preclinical studies of the combination of an anti-PD-1 agent 
and INCB001158 have been performed in mice for the purpose of evaluating the anti-tumor 
activity of the combination.  In these experiments, the combination of anti-PD-1 and 
INCB001158 appeared to be well tolerated, but an extensive safety evaluation was not 
performed. 
12.1.3 
Dose Modifications and Toxicity Management 
The expected toxicity risks for INCB001158 based on preclinical toxicity study data are 
summarized above.  In general, management of AEs related to INCB001158 includes 


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withholding the medication for moderate to severe toxicities and providing the appropriate 
supportive care. 
The safety and tolerability profile of pembrolizumab is well defined and outlined in the 
pembrolizumab Label/Investigator’s Brochure.  Ir-AEs are defined as those that occur while 
receiving pembrolizumab, require immunosuppression and have no clear alternate etiology.  
Guidelines for the management of ir-AEs and study treatment dosing are provided below.  In 
general, for moderate to severe ir-AEs, pembrolizumab should be withheld or permanently 
discontinued and, depending on the nature of the AE, it should be managed with high-dose 
corticosteroids and hormone-replacement therapy, if necessary.  Upon improvement to Grade 1 
or less, a corticosteroid taper should be initiated and continued over at least 1 month.  Restarting 
pembrolizumab may be considered after completion of corticosteroid taper based on the severity 
of the event.  In some cases, the natural history of AEs associated with immunotherapy can differ 
from and be more severe than AEs caused by agents belonging to other therapeutic classes.  
Early recognition and management may mitigate severe toxicity.  Evaluation and management 
guidelines for the following types of ir-AEs are provided in the pembrolizumab 
Label/Investigator’s Brochure: pneumonitis, colitis, hepatitis, endocrinopathies, nephritis/renal 
dysfunction, rash and encephalitis. 
For patients in the Dose Escalation Phase, dose reductions of INCB001158 will be permitted 
during Cycle 1 (first 28 days) only if a patient experiences DLT or a toxicity that may herald a 
DLT.  If a patient 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 and 
pembrolizumab therapy can be continued.  Upon recovery, patients may restart at one 
INCB001158 dose level lower.  Patients who do not recover within 28 days will not be eligible 
for resumption of study treatment without approval from the Medical Monitor.  After Cycle 1, 
dose reductions or interruptions for adverse events may take place at any time at the discretion of 
the Principal Investigator in consultation with the Medical Monitor. 
12.1.3.1 
Dose Modification Guidelines 
Patients will be monitored continuously for AEs while on study.  Treatment modifications (e.g., 
dose delay) will be based on specific laboratory and AE criteria.   
INCB001158: Guidelines for AE management and dose modifications of INCB001158 due to 
AEs are provided in Table 12.1-1.  These guidelines are based on the clinical experience with 


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INCB001158 to date.  These guidelines are intended primarily for toxicities that are not easily 
managed with routine supportive care.  For example, alopecia does not require dose 
modification, nor does Grade 2 nausea/vomiting that is easily managed with anti-emetics.   
INCB001158/pembrolizumab combination: Adverse events associated with pembrolizumab 
exposure may represent an immunologic etiology.  These immune-related AEs (irAEs) may 
occur shortly after the first dose or several months after the last dose of pembrolizumab 
treatment and may affect more than one body system simultaneously.  Therefore, early 
recognition and initiation of treatment is critical to reduce complications.  Based on existing 
clinical study data, most irAEs are reversible and can be managed with interruptions of 
pembrolizumab and administration of corticosteroids and/or other supportive care.  For suspected 
irAEs, ensure adequate evaluation to confirm etiology or exclude other causes.  Additional 
procedures or tests such as bronchoscopy, endoscopy, and skin biopsy may be included as part of 
the evaluation.  Based on the severity of irAEs, withhold or permanently discontinue 
pembrolizumab and administer corticosteroids.  Dose modification and toxicity management 
guidelines for irAEs associated with pembrolizumab are provided in Table 12.1-2.  Management 
of irAES occurring on combination therapy should follow dose interruption/modification 
guidelines for INCB001158 and pembrolizumab outlined in Tables 12.1-1 and 12.1-2, 
respectively. 
These parameters are only guidelines and are not intended to supersede the clinical judgment of 
the treating physician.  Investigators should err on the side of caution in the setting of potential 
ir-AEs.  Investigators should contact the Medical Monitor if 1) a dose modification is planned, 
2) systemic immunosuppression is required (NB: if immediate systemic immunosuppression is 
required, please DO NOT delay the start of immunosuppressive therapy in order to speak with 
the Medical Monitor), or 3) there is a preference to deviate from the guidelines for the 
management of AEs or dose modifications.  Holding of the study treatment and study 
discontinuation for both non-hematological and hematological toxicities will be based on the 
Principal Investigator’s judgment following discussion with the Medical Monitor. 
12.1.3.2 
Resumption of Study Treatment 
For both INCB001158 and pembrolizumab, treatment may be delayed for up to 4 weeks from the 
last dose.  Delays longer than 4 weeks are allowed only in cases where a prolonged steroid taper 
is required to manage drug-related AEs or, in some cases, if the delay was due to a 


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non-drug-related cause.  Prior to re-initiating treatment in a patient with a dosing interruption 
lasting > 4 weeks, the Medical Monitor must be consulted.  Treatment compliance will be 
monitored by drug accountability as well as the patient’s medical record and eCRF. 
Upon withholding study treatments for adverse events, the study treatments may be restarted 
when the AE has returned to ≤ Grade 1.  For patients that require a steroid taper, pembrolizumab 
should not be restarted until the steroid taper is complete.  In cases in which a particular toxicity 
is clearly related to only one of the two study treatments, the study treatment that is not involved 
in causing the AE may be restarted prior to a return to  Grade 1.  If INCB001158 is restarted 
after permanent discontinuation of pembrolizumab, INCB001158 should be permanently 
discontinued for a > Grade 3 recurrence of the AE that resulted in pembrolizumab 
discontinuation. 


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Table 12.1-1:  INCB001158 Dose Modification Guidelines for Adverse Events in Patients 
Receiving INCB001158 (All Parts) 
Adverse Reaction 
Severity 
Management 
Study Drug Dose 
Modification 
Evidence of urea cycle 
inhibition 
•
Fasting urinary orotic
acid > 2 X and
< 10 X ULN
•
Any urinary orotic
acid > 2 X and
< 40 X ULN
•
Re-test fasting
urinary orotic acid
1 week later.
•
None.
•
Ammonia 2 X ULN
and 2 X baseline
(repeated
measurements or
with symptoms)
•
Fasting urinary orotic
acid > 10 X ULN
•
Any urinary orotic
acid > 40 X ULN
•
BUN < 50% LLN
•
See
Section 12.1.3.3 
for management of 
hyperammonemia. 
•
Interrupt study drug.
•
Consider restarting (at a
lower dose) in
consultation with
Medical Monitor.
Study drug-related 
creatinine increase1 
(patients with CrCl 
30-49 mL/min at
baseline)
Grade 2 (> 1.5-3.0 X 
baseline) 
Weekly testing of 
serum creatinine 
during interruption of 
study drug. 
•
Interrupt study drug.
•
1st event:  Restart at same
dose upon resolution to
≤ Grade 1.
•
2nd event:  Restart at
25 mg BID upon
resolution to ≤ Grade 1.
Grade 3 (> 3.0 baseline) 
or 4 (dialysis indicated) 
Weekly testing of 
serum creatinine 
during interruption of 
study drug. 
•
Interrupt study drug and
do weekly serum
creatinine testing and
urinalysis until serum
creatinine returns to
≤ Grade 1.  Restart study
drug at 25 mg BID.
•
If after 4 weeks the
serum creatinine has not
recovered to ≤ Grade 1,
permanently discontinue
study drug.
•
If after restarting study
drug the toxicity
reoccurs, permanently
discontinue study drug.


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Table 12.1-1:  INCB001158 Dose Modification Guidelines for Adverse Events in Patients 
Receiving INCB001158 (All Parts) (Continued) 
Adverse Reaction 
Severity 
Management 
Study Drug Dose 
Modification 
Study drug-related 
creatinine increase1 
(patients with CrCl 
> 50 mL/min at baseline) 
Grade 2 (> 1.5-3.0 X 
baseline OR > 1.5-3.0 X 
ULN) 
Weekly testing of 
serum creatinine 
during interruption of 
study drug. 
• 
Interrupt study drug. 
• 
1st event:  Restart at same 
dose upon resolution to 
≤ Grade 1. 
• 
2nd event:  Restart at 
25 mg BID upon 
resolution to≤ Grade 1. 
Grade 3 (> 3.0 baseline; 
> 3.0-6.0 X ULN) or 4 
(> 6.0 X ULN) 
Weekly testing of 
serum creatinine 
during interruption of 
study drug. 
• 
Interrupt study drug and 
do weekly serum 
creatinine testing and 
urinalysis until serum 
creatinine returns to 
≤ Grade 1.  Restart study 
drug at 25 mg BID. 
• 
If after 4 weeks the 
serum creatinine has not 
recovered to ≤ Grade 1, 
permanently discontinue 
study drug. 
• 
If after restarting study 
drug the toxicity 
reoccurs, permanently 
discontinue study drug. 
Suspected immune-
related adverse event 
(irAE) including: 
• 
Colitis 
• 
Pneumonitis 
• 
Dermatitis 
• 
Hepatitis 
• 
Hypophysitis 
• 
Adrenal 
insufficiency 
• 
Type I diabetes 
mellitus 
• 
Nephritis 
Grade 1 
• Symptomatic 
therapy, as 
appropriate 
No change 
Grade 2 
• If > 5 days, 0.5 to 
1 mg/kg/day 
prednisone.  If 
worsening or no 
improvement, 
increase to 1 to 
2 mg/kg/day 
prednisone equiv. 
and consider IV. 
• Interrupt study drug. 
• 1st event:  Restart at same 
dose upon resolution to 
< Grade 1.   
• 2nd event:  Restart one 
dose level lower for 
second event of the same 
AE. 
Grade 3 
• 1 to 2 mg/kg/day 
prednisone equiv.  
Consider IV. 
• Interrupt study drug. 
• 1st event:  Consider 
restarting at next lower 
dose level upon resolution 
to < Grade 1.   
• 2nd event:  Permanently 
discontinue. 
Grade 4 
• 1 to 2 mg/kg/day 
prednisone equiv.  
Consider IV. 
• Permanently discontinue. 


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Table 12.1-1:  INCB001158 Dose Modification Guidelines for Adverse Events in Patients 
Receiving INCB001158 (All Parts) (Continued) 
Adverse Reaction 
Severity 
Management 
Study Drug Dose 
Modification 
All others 
Grade 1 
Symptomatic therapy, 
as appropriate. 
No change. 
Grade 2 
Symptomatic therapy, 
as appropriate. 
• Interrupt study drug. 
• 1st event:  Restart at same 
dose upon resolution to 
< Grade 1.   
• 2nd event:  Restart one 
dose level lower for 
second event of the same 
AE. 
Grade 3 
Symptomatic therapy, 
as appropriate. 
• Interrupt study drug. 
• 1st event:  Consider 
restarting at next lower 
dose level upon resolution 
to < Grade 1.   
• 2nd event:  Permanently 
discontinue. 
Grade 4 
Symptomatic therapy, 
as appropriate. 
• Permanently discontinue. 
1 For creatinine increases that are unrelated to study drug (e.g. obstructive uropathy) INCB001158 may 
be continued at a dose appropriate for the new CrCl (as calculated by the Cockcroft-Gault formula) as 
follows: 
• CrCl > 50 mL/min:  Continue INCB001158 at 100 mg BID. 
• CrCl 30-49 mL/min:  Reduce INCB001158 to 50 mg BID. 
• CrCl < 30 mL/min:  Hold INCB001158 and restart once CrCl > 30 mL/min as specified above. 
 


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Table 12.1-2:  Dose Modification and Toxicity Management Guidelines for Immune-
Related Adverse Events Associated With Pembrolizumab (Parts 1b, 1c, and 3) 
General instructions 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids.  Other 
immunosuppressive treatment should begin if the irAEs are not controlled by corticosteroids.  
2. Pembrolizumab must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is 
not ≤ 10 mg/day within 12 weeks of the last pembrolizumab treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If pembrolizumab has been withheld, pembrolizumab may resume after the irAE decreased to ≤ Grade 1 
after corticosteroid taper. 
irAEs 
Toxicity Grade 
(CTCAE V4.0) 
Action With 
Pembrolizumab 
Corticosteroid 
and/or Other 
Therapies  
Monitoring and Follow-up  
Pneumonitis  
Grade 2 
Withhold  
• 
Administer 
corticosteroids 
(initial dose of 
1 - 2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
• 
Add 
prophylactic 
antibiotics for 
opportunistic 
infections 
• 
Monitor participants for 
signs and symptoms of 
pneumonitis 
• 
Evaluate participants 
with suspected 
pneumonitis with 
radiographic imaging and 
initiate corticosteroid 
treatment 
Recurrent 
Grade 2,  
Grade 3 or 4  
Permanently 
discontinue 
Diarrhea / Colitis  
Grade 2 or 3 
Withhold 
• 
Administer 
corticosteroids 
(initial dose of 
1 - 2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
 
• 
Monitor participants for 
signs and symptoms of 
enterocolitis (ie, diarrhea, 
abdominal pain, blood or 
mucus in stool with or 
without fever) and of 
bowel perforation 
(ie, peritoneal signs and 
ileus) 
• 
Participants with ≥Grade 
2 diarrhea suspecting 
colitis should consider GI 
consultation and 
performing endoscopy to 
rule out colitis 
• 
Participants with 
diarrhea/colitis should be 
advised to drink liberal 
quantities of clear fluids. 
If sufficient oral fluid 
intake is not feasible, 
fluid and electrolytes 
should be substituted via 
IV infusion 
Recurrent 
Grade 3 or 
Grade 4 
Permanently 
discontinue 


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Table 12.1-2:  Dose Modification and Toxicity Management Guidelines for Immune-
Related Adverse Events Associated With Pembrolizumab (Parts 1b, 1c, and 3) (Continued) 
irAEs 
Toxicity Grade 
(CTCAE V4.0) 
Action With 
Pembrolizumab 
Corticosteroid 
and/or Other 
Therapies  
Monitoring and Follow-up  
AST or ALT 
elevation or 
Increased 
Bilirubin 
Grade 2 a 
Withhold 
• 
Administer 
corticosteroids 
(initial dose of 
0.5 - 1 mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
• 
Monitor with liver 
function tests (consider 
weekly or more 
frequently until liver 
enzyme value returned to 
baseline or is stable) 
Grade 3 b or 4 c 
Permanently 
discontinue 
• 
Administer 
corticosteroids 
(initial dose of 
1 - 2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
New onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of 
-cell failure 
Withhold d 
• 
Initiate insulin 
replacement 
therapy for 
participants with 
T1DM 
• 
Administer anti-
hyperglycemic 
in participants 
with 
hyperglycemia 
• 
Monitor participants for 
hyperglycemia or other 
signs and symptoms of 
diabetes 
Hypophysitis 
Grade 2 
Withhold 
• 
Administer 
corticosteroids 
and initiate 
hormonal 
replacements as 
clinically 
indicated 
• 
Monitor for signs and 
symptoms of 
hypophysitis (including 
hypopituitarism and 
adrenal insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hyperthyroidism  
Grade 2 
Continue 
• 
Treat with non-
selective beta-
blockers (eg, 
propranolol) or 
thionamides as 
appropriate 
• 
Monitor for signs and 
symptoms of thyroid 
disorders 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hypothyroidism 
Grade 2, 3, 4 
Continue 
• 
Initiate thyroid 
replacement 
hormones (eg, 
levothyroxine or 
liothyronine) per 
standard of care 
• 
Monitor for signs and 
symptoms of thyroid 
disorders 


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Table 12.1-2:  Dose Modification and Toxicity Management Guidelines for Immune-
Related Adverse Events Associated With Pembrolizumab (Parts 1b, 1c, and 3) (Continued) 
irAEs 
Toxicity Grade 
(CTCAE V4.0) 
Action With 
Pembrolizumab 
Corticosteroid 
and/or Other 
Therapies  
Monitoring and Follow-up  
Nephritis: 
grading according 
to increased 
creatinine or 
acute kidney 
injury 
Grade 2 
Withhold 
• 
Administer 
corticosteroids 
(prednisone 
1 – 2 mg/kg or 
equivalent) 
followed by 
taper 
• 
Monitor changes of renal 
function 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
• 
Based on 
severity of AE 
administer 
corticosteroids 
• 
Ensure adequate 
evaluation to confirm 
etiology and/or exclude 
other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
All Other 
immune-related 
AEs 
Persistent 
Grade 2 
Withhold 
• 
Based on 
severity of AE 
administer 
corticosteroids 
• 
Ensure adequate 
evaluation to confirm 
etiology or exclude other 
causes 
Grade 3 
Withhold or 
discontinue 
based on the 
event e  
Recurrent 
Grade 3 or 
Grade 4  
Permanently 
discontinue 
a AST/ALT:  > 3.0 - 5.0 × ULN if baseline normal; > 3.0 - 5.0 × baseline, if baseline abnormal; bilirubin:  > 1.5 - 3.0 × ULN 
if baseline normal; > 1.5 - 3.0 × baseline if baseline abnormal 
b AST/ALT:  > 5.0 to 20.0 × ULN, if baseline normal; > 5.0 - 20.0 × baseline, if baseline abnormal;  
bilirubin:  > 3.0 - 10.0 × ULN if baseline normal; > 3.0 - 10.0 × baseline if baseline abnormal 
c AST/ALT:  > 20.0 × ULN, if baseline normal; > 20.0 × baseline, if baseline abnormal; bilirubin:  > 10.0 × ULN if baseline 
normal; > 10.0 × baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating 
physician.  If control achieved or ≤ Grade 2, pembrolizumab may be resumed. 
e Events that require discontinuation include but are not limited to: Guillain-Barre Syndrome, encephalitis, Stevens-Johnson 
Syndrome and toxic epidermal necrolysis. 


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12.1.3.3 
Supportive Care Guidelines 
Patients should receive appropriate supportive care measures as deemed necessary by the treating 
Investigator.  Guidelines outlined below should be used in conjunction with information 
provided in the pembrolizumab product label: 
Hyperammonemia:  Patients should be monitored for elevated venous plasma ammonia.  
Asymptomatic clinically significant drug-related elevations in ammonia (e.g., a repeatable 
elevation in ammonia > 2x ULN AND > 2x baseline) should managed by interrupting 
INCB001158 study drug and monitoring to resolution.  For symptomatic elevations (i.e., 
significant ammonia elevation associated with nausea, vomiting, severe anorexia, mental status 
changes, seizure, or other symptoms associated with hyperammonemia), patients should be 
admitted for management according to the local institutional protocol for hyperammonemia, 
including 1) sending appropriate labs [ammonia (on ice, measured STAT), plasma amino acid 
profile, LFTs, electrolytes, bicarb, 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/lacitol, IV Ammonul), and 5) identifying and 
treating any potential triggers (e.g., discontinue corticosteroids, treat infections, etc). 
Diarrhea: Patients should be monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).  In symptomatic patients, infectious etiologies 
should be ruled out, and if symptoms are persistent and/or severe, endoscopic evaluation should 
be considered.  In patients with severe enterocolitis, treatment with systemic corticosteroids 
should be initiated at a dose of 1 to 2 mg/kg/day of prednisone or equivalent.  In patients that do 
not respond to high dose steroids with 72 hr, consider initiation of additional immunosuppressive 
therapy (e.g., infliximab).  When symptoms improve to Grade 1 or less, corticosteroid taper 
should be started and continued over at least 1 month. 
In addition, patients with severe enterocolitis that are receiving INCB001158 monotherapy will 
have INCB001158 permanently discontinued, whereas, for patients receiving 
INCB001158/pembrolizumab combination, pembrolizumab will be permanently discontinued 
and INCB001158 will be withheld.  Restarting INCB001158 may be considered in 
INCB001158/pembrolizumab combination patients if enterocolitis is not a toxicity associated 
with monotherapy INCB001158.    


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In patients with moderate enterocolitis, pembrolizumab should be withheld and antidiarrheal 
treatment should be started.  If symptoms are persistent for more than one week, systemic 
corticosteroids should be initiated (e.g., 0.5 mg/kg/day of prednisone or equivalent).  When 
symptoms improve to Grade 1 or less, corticosteroid taper should be started and continued over 
at least 1 month.  Regarding guidelines for continuing treatment with INCB001158 and 
pembrolizumab, see Table 12.1-2. 
All patients who experience diarrhea should be advised to drink liberal quantities of clear fluids. 
If sufficient oral fluid intake is not feasible, fluid and electrolytes should be substituted via IV 
infusion. 
Nausea/vomiting: Nausea and vomiting should be treated aggressively, and consideration 
should be given in subsequent cycles to the administration of prophylactic antiemetic therapy 
according to standard institutional practice.  Patients should be strongly encouraged to maintain 
liberal oral fluid intake.  Since nausea/vomiting can be a symptom of hyperammonemia, there 
should be a low threshold to test plasma ammonia levels for patients with nausea, vomiting, or 
new onset anorexia. 
Anemia: Transfusions and/or erythropoietin may be utilized as clinically indicated for the 
treatment of anemia, but should be clearly noted as concurrent medications. 
Neutropenia: Prophylactic use of colony-stimulating factors including Granulocyte Colony-
Stimulating Factor (G-CSF), pegylated G-CSF or Granulocyte Macrophage Colony-Stimulating 
Factor (GM-CSF) is not allowed in this study.  Therapeutic use of G-CSF is allowed in patients 
with Grade 3-4 febrile neutropenia. 
Thrombocytopenia: Transfusion of platelets may be used if clinically indicated.  Idiopathic 
thrombocytopenic purpura (ITP) should be ruled out before initiation of platelet transfusion. 
Anti-infectives: Patients with a documented infectious complication should receive oral or IV 
antibiotics or other anti-infective agents as considered appropriate by the treating Investigator for 
a given infectious condition, according to standard institutional practice. 


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Immune-related adverse events: Patients who develop a Grade 2 or higher irAE (e.g., colitis, 
skin rash, hepatitis, uveitis, hypo- or hyperthyroidism, hypophysitis, or any other), should be 
discussed immediately with the Medical Monitor.  Depending on the type and severity of an 
irAE, oral or IV treatment with a corticosteroid should be considered, in addition to appropriate 
symptomatic treatment of a given condition.  For severe immune-mediated adverse events that 
do not respond to high dose IV steroids within 72 hours, consider initiation of additional 
immunosuppressive therapy (e.g., infliximab for non-hepatic toxicities or mycophenolate 
mofentil for immune-mediated hepatotoxicity). 
Dose modification and toxicity management of infusion reactions related to 
pembrolizumab:  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 for pembrolizumab-associated 
infusion reactions are provided in Table 12.1-3. 


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Table 12.1-3:  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 patient is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated for 
≤ 24 hours. 
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 patient is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within 1 hour of stopping drug 
infusion, the infusion may be restarted at 50% of the 
original infusion rate (e.g., from 100 mL/hr. to 
50 mL/hr).  Otherwise dosing will be held until 
symptoms resolve and the patient should be 
premedicated for the next scheduled dose. 
Patients who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment. 
Patient may be premedicated 
1.5 hr (± 30 minutes) prior to 
infusion of _____ with: 
Diphenhydramine 50 mg PO 
(or equivalent dose of 
antihistamine). 
Acetaminophen 500-1000 
mg PO (or equivalent dose of 
analgesic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical 
sequelae (e.g., renal 
impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor 
or ventilator 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 patient is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be 
used immediately. 
Patient is permanently discontinued from further 
study drug treatment. 
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 Common Terminology Criteria for 
Adverse Events v4.0 (CTCAE) at http://ctep.cancer.gov. 


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12.2 Dose Adjustments, Infusion Delays, and Missed Doses 
Missed doses of INCB001158 should be skipped.  If a patient forgets to take a dose of 
INCB001158 study drug and he/she is outside of the allotted window period (± 6 hr), he/she 
should be instructed to skip that dose and NOT to take extra INCB001158 study drug at their 
next administration. 
In the case that an infusion cannot be administered at a scheduled visit, it has to be administered 
as soon as possible.  If the delay is between 1 and 7 days, the procedures at the original 
scheduled visit should be performed, and subsequent visits will follow every 2 weeks (the 
infusion at the original schedule visit will be considered a missed dose).  Patients with infusion 
delays > 35 days should discontinue from the study unless approved by the Medical Monitor in 
settings where benefit/ risk may justify continued study therapy. 
12.3  Discontinuation of Treatment and Withdrawal of Patients 
The reasons a patient may discontinue or be withdrawn from the study include, but are not 
limited to, adverse events, disease progression, patient request, Investigator decision, protocol 
violation, patient noncompliance, and study termination by the Sponsor. 
When a patient discontinues or is withdrawn, the Investigator or designee will notify the Sponsor 
(or designee) and should perform all End of Treatment and follow up procedures as indicated in 
the Schedule of Study Assessments (Attachment 1) after discontinuation of study treatment.  The 
Investigator or designee must document in the source if the patient withdrew consent from 
treatment/ study procedure only or from treatment/ study procedures and from further contact.  


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13.0 
STUDY DRUG 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 2 investigational 
study treatments in this study – INCB001158 and pembrolizumab.  INCB001158 is also referred 
to as the study drug in this Protocol.  Although pembrolizumab is approved and marketed in 
various indications, it is investigational in this study in combination with INCB001158. 
13.1 Study Treatment Administration 
INCB001158 
Study drug (INCB001158) needs to be taken orally as capsule or tablet (25 mg or 100 mg per 
capsule or tablet) formulation.  INCB001158 will be administered only to patients who have 
signed and dated an Informed Consent Form.  Patients in Part 1a and 2: INCB001158 needs to be 
taken on Days 1 through 28 of each 28-day cycle and should be taken orally using the number of 
capsules or tablets directed in the Pharmacy Manual.  
 
 
  Patients in Part 1b and 3: INCB001158 needs to be taken on 
Days 1 through 21 of each 21-day cycle and should be taken orally using the number of capsules 
or tablets directed in the Pharmacy Manual.  INCB001158 dosing will not be adjusted for body 
weight or surface area.  Patients will continue to receive INCB001158 until disease progression 
(per irRECIST), intolerable toxicity, patient withdraws consent, or the Investigator determines 
that it is not in the patient’s best interest to remain on study. 
The study drug should be taken by the patient at approximately the same times each day on an 
empty stomach with a full glass of water.  The first dose should be taken at least 2 hr before 
breakfast.  The evening dose of INCB001158 will be taken approximately 12 hr later and at least 
2 hr before or 1 hr after eating a meal.  The effect of food is being evaluated in Part 1a during 
monotherapy dose escalation.  If it is demonstrated that improved bioavailability can be achieved 
by taking INCB001158 with food, then patients thenceforth will take the drug with breakfast and 
dinner. 
On PK days (see Attachment 1) patients 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 
pre-dose procedures have been performed.  The time of dosing will be recorded in the clinic.  


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The evening doses will be self-administered by the patient after all post-dose activities have been 
complete.  
Patients enrolled in the pembrolizumab combination cohorts (Part1b and Part 3) will have all 
pre-dose procedures performed prior to receiving pembrolizumab.  Once the pembrolizumab 
infusion is complete, patients should be instructed to take their morning dose of INCB001158.  
Breakfast should not be eaten until at least 2 hr after taking INCB001158.  The time of dosing 
will be recorded in the clinic.  The evening dose of INCB001158 will be taken by the patient as 
usual.  On non-PK collection days, patients will take INCB001158 per their usual administration 
schedule. 
Patients 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.  Patients who report ≥ 3 incidences of vomiting associated with study drug administration 
will have a blood sample drawn for an unscheduled PK analysis. 
Pembrolizumab  
Pembrolizumab will be administered on day 1 of each 3-week treatment cycle after all 
procedures and assessments have been completed as detailed on the schedule of assessment.  
Pembrolizumab will be administered as a dose of 200 mg using a 30-minute IV infusion.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window between -5 minutes 
and +10 minutes is permitted (i.e., infusion time is 30 minutes -5 min/+10 min).  Patients will 
continue to receive pembrolizumab until disease progression (per irRECIST), intolerable 
toxicity, patient withdraws consent, or the Investigator determines that is not in the patient’s best 
interest to remain on study.  The maximum duration of pembrolizumab treatment on study will 
be up to 35 doses (approximately 2 years).  
Pembrolizumab (Keytruda®) is supplied either as a 50 mg, lyophilized powder in single-use vials 
for reconstitution or as a 25 mg/mL sterile solution for infusion in 4 mL vials.  The dose recently 
approved in the United States and several other countries for treatment of melanoma patients is 
2 mg/kg Q3W.  Please refer to the pembrolizumab Label/Investigator’s Brochure for specific 
instructions on pembrolizumab administration. 


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13.2 Packaging and Labeling 
INCB001158 capsules and tablets (25 and 100 mg) are manufactured, packaged, and labeled 
according to current Good Manufacturing Practices (cGMP).  All product labels will be in the 
local language and will comply with the legal requirements of each country.  For additional 
information, please refer to the Pharmacy Manual. 
Pembrolizumab is available either as 50 mg, lyophilized powder in single-use vials or as a 
25 mg/mL sterile solution for infusion in 4 mL vials (3).  The product label will be in the local 
language and will comply with the legal requirements of each country.  For additional 
information, please refer to the pharmacy manual. 
13.3 Storage and Stability 
INCB001158  
INCB001158 capsules and tablets will be stored at the clinical site, as indicated on the study 
drug label, i.e., room temperature, between 15ºC - 30ºC (59ºF - 86ºF). 
Patients will be requested to store the study drug at the recommended storage conditions noted 
on the label, out of the reach of children. 
Pembrolizumab 
Pembrolizumab vials should be stored under refrigeration at 2°C - 8°C (36°F - 46°F).  Protect 
from light by storing in the original package until time of use.  Do not freeze or shake.  For 
procedures for the proper handling, storage, preparation and administration of pembrolizumab, 
please refer to the Pembrolizumab Label/Investigator’s Brochure. 
13.4 INCB001158 Accountability, Reconciliation, and Return 
On Day 1 of Cycle 1, patients will be provided with enough INCB001158 to last until their next 
clinic visit.  For patients in Parts 1a and 2, patients will return on Day 1 of each cycle thereafter 
and will receive a 28-day supply of INCB001158; the number of capsules or tablets remaining 
from the previous visit will be counted and recorded.  
For patients in Parts 1b and 3, patients will return on Day 1 of each cycle thereafter and will 
receive a 21-day supply of INCB001158; the number of capsules or tablets remaining from the 
previous visit will be counted and recorded. 


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The Investigator or designee must maintain an accurate record of dispensing the study drug in a 
Drug Accountability Log, a copy of which must be given to the Sponsor at the end of the study.  
The Drug Accountability Log will record the study drugs received, dosages prepared, time 
prepared, doses dispensed, and doses destroyed.  The Drug Accountability Log will be reviewed 
by the field monitor during site visits and at the completion of the study. 
If evidence of tampering is observed, notify the Sponsor and return the questionable 
INCB001158 shipment with the appropriate form to the contract distribution center.  Returned 
and unused INCB001158 study drug may also be destroyed and documented at the investigative 
site in accordance with approved site/institution standard operating procedures. 
13.5 Study Treatment Compliance 
Compliance with all study-related treatments should be emphasized to the patient by the site 
personnel, and appropriate steps should be taken to optimize compliance during the study.  
Compliance with INCB001158 will be calculated by the sponsor based on the drug 
accountability documented by the site staff and will be monitored by the sponsor/designee 
(capsule/tablet counts).  Patients will be instructed to bring all unused INCB001158 
capsules/tablets 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. 
Missed doses of INCB001158 should be skipped.  If a patient forgets to take a dose of study drug 
and he/she is outside of the allotted window period (± 6 hr), he/she should be instructed NOT to 
take extra study drug at their next administration. 


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14.0 
MEASURES TO MINIMIZE/AVOID BIAS 
Each patient will be assigned a unique number and will keep this number for the duration of the 
study.  Patient numbers will not be reassigned or reused for any reason.  Patients should be 
identified to the Sponsor only by their assigned number, initials (not required for EU), date of 
birth, and sex.  The Investigator must maintain a patient master log. 
15.0 
STATISTICAL ANALYSIS 
15.1 General Statistical Considerations 
Protocol INCB 01158-101 is a Phase 1 multicenter, open-label study in patients with advanced 
and metastatic solid tumors. 
Since this is an open-label clinical trial, descriptive statistics will be employed to analyze the 
data by tumor type and dose level.  Summary statistics for continuous variables will include the 
mean, standard deviation, median, and range (minimum/maximum).  Categorical variables will 
be presented by tumor type as frequency counts and percentages, and time-to-event variables will 
be summarized by Kaplan-Meier plots, medians, and ranges. 
The data will be tabulated and analyzed with respect to patient enrollment and disposition, 
demographic and baseline characteristics, prior and concomitant medications, efficacy, and 
safety measures.  The efficacy analysis will be conducted on the Efficacy Evaluable Population, 
and the safety analysis will be performed on the Safety Population (see Section 15.3.1). 
All confidence intervals will be constructed at the 95% confidence level.  Data listings will be 
created to support each table and to present all data collected. 
15.2 Sample Size and Power 
Dose Escalation:  The goal is to determine a dose level of INCB001158 for which the rate of 
DLTs is less than 33%.  Up to approximately 108 patients are planned for single agent dose 
escalation (Part 1a) and 108 patients for combination dose escalation (Part 1b), both including 
backfill patients. 
Dose Expansion:  For Expansion Cohorts in Parts 2 and 3 (except the initial part of Cohort 2c), 
Simon's two-stage design (Simon 1989) will be used as outlined in Table 15.2-1 below.  The null 
hypothesis that the true response rate is [p0] will be tested against a one-sided alternative.  In the 
first stage, [n1] patients will be accrued.  If there are [r1] or fewer responses in these [n1] 


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patients, the study will be stopped.  Otherwise, [n - n1] additional patients will be accrued for a 
total of [n].  The null hypothesis will be rejected if [r2 + 1] or more responses are observed in [n] 
patients.  This design yields a type I error rate of 0.1 and power of 80% when the true response 
rate is [p1]. 
Table 15.2-1:  Summary of Sample Size and Power for Expansion Cohorts 
Cohort 
p0 
Background 
ORR (%) 
p1 
Target ORR 
(%) 
α 
Power 
(%) 
n1 for 
Stage 1 
(r1) 
n2 (n - n1) 
for Stage 2 
Total n 
(r2) 
2a 
2% 
15% 
0.1 
80 
11 (0) 
15 
26 (1) 
2b 
2% 
15% 
0.1 
80 
11 (0) 
15 
26 (1) 
2c 
expansion 
2% 
15% 
0.1 
80 
11 (0) 
15 
26 (1) 
3a 
2% 
15% 
0.1 
80 
11 (0) 
15 
26 (1) 
3b 
2% 
15% 
0.1 
80 
11 (0) 
15 
26 (1) 
3c 
2% 
15% 
0.1 
80 
11 (0) 
15 
26 (1) 
3d 
2% 
15% 
0.1 
80 
11 (0) 
15 
26 (1) 
3e 
2% 
15% 
0.1 
80 
11 (0) 
15 
26 (1) 
3f 
10% 
25% 
0.1 
80 
13 (1) 
21 
34 (5) 
3g 
20% 
40% 
0.1 
80 
12 (2) 
13 
25 (7) 
3h 
13% 
30% 
0.1 
80 
10 (1) 
23 
33 (6) 
 
Cohort 2c is designed to generate additional evidence of clinical activity in a variety of tumor 
types.  The sample size for the initial 30 patients was not based on a predefined statistical 
analysis.  The sample size for each tumor type in any subsequent expansion of Cohort 2c will be 
guided by a Simon 2-stage design. 
 
 
 
 
Part 1c is intended to enroll the minimum number of patients required to generate sufficient PK 
data for a descriptive comparison of Day 1 and steady state (Day 8, Day 15) exposures between 
patients with moderate renal impairment (CrCl 30-49 mL/min) and normal renal function (CrCl 


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> 50 mL/min).  Accordingly, the sample size of 6 PK-evaluable patients for Cohort 1c is not 
based on a predefined statistical analysis. 
15.3 Analysis Populations 
15.3.1 
Safety Population 
All patients who receive at least 1 dose of INCB001158 or pembrolizumab will be included in 
the analysis of safety, regardless of the duration of treatment. 
AE and laboratory data from all patients in the safety population will be evaluated for safety.  
Patients from dose escalation will be combined with patients receiving the same dose and 
schedule from cohort expansion for safety evaluation.  Patients with moderate renal impairment 
in Part 1c will be evaluated separately.  Data will be tabulated to examine the frequency, organ 
systems affected, and relationship to study treatments.  No formal interim analysis is planned; 
however, safety data will be examined on an ongoing basis to ensure safety of the study patients 
and compliance with the trial dose escalation and expansion rules. 
15.3.2 
DLT-Evaluable Populations in Dose Escalation 
DLTs will be evaluated during dose escalation.  Unless doses are missed in Cycle 1 due to drug-
related AE(s), a patient must receive at least 75% of the planned INCB001158 doses (43 of 
56 total doses) to be considered evaluable for DLT.  If a patient received less than 43 doses of 
INCB001158 in the first 28 days of treatment for reasons other than a DLT, the patient will be 
considered non-evaluable for DLT and replaced.  For patients in Part 1b and Part 3, patients must 
receive both doses of pembrolizumab in Cycle 1 in order to be evaluable for DLT. 
Patients who discontinue the study prior to receiving the requisite study treatment 
administrations for reasons that include, but are not limited to, clinical/radiographic progression, 
voluntary withdrawal, or complications that the Principal Investigator considers secondary to the 
patient’s malignancy will not be considered evaluable for DLT and will be replaced. 
15.3.3 
Efficacy Evaluable Populations 
The Response Evaluable Population includes all patients who received at least 1 dose of study 
treatment (INCB001158 or pembrolizumab), completed a baseline scan, and met at least 1 of the 
following criteria: 
• The patient had at least 1 post-baseline scan. 


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• The patient discontinued from study treatment for any reason except unrelated toxicity or 
death, or withdrawal of consent. 
The PFS Evaluable Population includes all patients who received at least 1 dose of study 
treatment (INCB001158 or pembrolizumab). 
Patients enrolled in the expansion cohorts who do not meet the requirements for the Response 
Evaluable Population will be considered non-evaluable for response and will be replaced. 
15.4 Efficacy Analysis 
Response to treatment will be evaluated using RECIST v1.1 for patients with solid tumors 
(except for mesothelioma; Eisenhauer 2009).  For patients with pleural mesothelioma, response 
will be evaluated using the modified RECIST criteria for pleural mesothelioma (Byrne 2004, 
Attachment 5).  Responses for patients with pericardial or peritoneal mesothelioma will be 
described based upon RECIST v1.1 for patients with measurable disease combined with clinical 
improvements. 
The Kaplan-Meier method will be used to estimate the median Duration of Response (DOR) and 
Progression-Free Survival (PFS) for each treatment cohort in Dose Expansion (note: Dose 
Escalation patients of the same histology enrolled at the RP2D will be included in this analysis).  
Efficacy analyses will be performed on the Efficacy Evaluable Population.  Additional efficacy 
analyses will also be performed on an expanded population that includes patients that lack post-
treatment scans due to toxicity or death. 
For each patient with objectively measurable disease, response to therapy, will be calculated 
using RECIST v1.1 and Modified RECIST for pleural mesothelioma (DOR, PFS, Best Overall 
Response [BOR], and Overall Response Rate[ORR]). 
• DOR is defined as the number of days from the date of initial response (PR or better) to 
the date of first documented disease progression/relapse or death, whichever occurs first. 
• PFS is defined as the number of days from the date of treatment initiation (i.e., C1D1) to 
the date of documented disease progression or death from any cause, whichever occurs 
first, and will be calculated for all patients.  In the event that no disease progression or 
death is documented prior to study termination, analysis cutoff, or the start of 
confounding anticancer therapy, these endpoints will be censored at the date of last 
available tumor assessment. 


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• BOR is the best RECIST v1.1 /modified RECIST for pleural mesothelioma response 
recorded from the start of the study treatment until disease progression/recurrence. 
• ORR is defined as the response of the proportion of efficacy evaluable patients with 
tumor size reduction from the time the start of treatment until documented tumor 
progression.  ORR includes complete response (CR) and partial response (PR). 
 
 
15.5 Safety Analysis 
Safety variables to be analyzed by dose level and tumor type are AEs, laboratory test results 
(hematology, coagulation, serum chemistry, and urinalysis), ECG, weight, and vital signs. 
Adverse event terms recorded on the eCRFs will be mapped to preferred terms using the most 
recent version of the Medical Dictionary for Drug Regulatory Activities (MedDRA®).  All AEs 
will be summarized according to the system organ class and preferred term within the organ 
class.  Adverse events will be tallied for overall frequency (number and percentage of patients), 
worst reported severity, and relationship to study treatment for each preferred term per patient.  
Serious adverse events will be similarly summarized.  Listings of deaths, SAEs, and AEs leading 
to early termination of study treatment or premature withdrawal from study will also be 
provided. 
Laboratory variables will be examined using mean change in value from baseline to scheduled 
time points.  The baseline value of a variable is defined as the last value obtained on or before 
the date and time of the first dose of INCB001158 or pembrolizumab. 
ECG, weight, and vital signs will also be summarized by changes from baseline to scheduled 
time points using descriptive statistics. 
15.6 Pharmacokinetic Analysis 
For Part 1a- Dose Escalation PK samples, a noncompartmental method of analysis will be used 
to analyze the plasma concentrations of INCB001158.  The maximum plasma concentration 
(Cmax) and the time to attain the Cmax (Tmax) will be determined directly from the observed data.  
In Part 1a, full AUC (AUC0-12 hr) will be calculated on Days 1 and 15 in Cycle 1.   
For Parts 1b, 2a, 2b, 2c, and 3, sparse sampling will be collected to confirm exposure and to 
explore population PK (see Attachment 1A and 1B). 


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For Part 1c, a noncompartmental method of analysis will be used to analyze the plasma 
concentrations of INCB001158.  The log-transformed PK parameters will be compared between 
renally impaired patients (CrCl 30-49 mL/min) and patients with normal renal function (CrCl 
> 50 mL/min) using an analysis of variance.  The geometric mean relative bioavailability and 
90% confidence intervals for INCB01158 Cmax and AUC will be calculated using the intrapatient 
variability from the ANOVA model to assess the magnitude of the difference between the 
patients with normal renal function and those with moderate renal impairment. 
 
 
 
 
 
 
 
 
 
 
 
15.7 Precautions 
Although major adverse events are not anticipated, the Investigator must proceed with utmost 
caution.  Equipment, supplies, and properly skilled medical personnel must be immediately 
available for emergency use in the event of an unexpected reaction.  Patients must be selected 
carefully and closely monitored. 
For a complete description of preclinical studies of INCB001158, please refer to the 
INCB001158 Investigator’s Brochure.  For a description of precautions with pembrolizumab, 
please refer to the Product Label. 


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16.0 
SAFETY MONITORING AND REPORTING 
16.1 Adverse Events 
16.1.1 
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). 
16.1.2 
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 up to 30 days 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 16.3.2.  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 (all Parts) and pembrolizumab (Parts 1b and 3 only).
•
The start and end dates, unless unresolved at final follow-up.
•
The action taken with regard to study drug.
•
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 16.3.1. 
Unlike routine safety assessments, SAEs are monitored continuously and have special reporting 
requirements (see Section 16.3.2). 
All AEs should be treated appropriately.  If an AE is treated with a concomitant medication or 
nondrug therapy, this action should be recorded on the Adverse Event form in the eCRF and the 


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treatment should be specified on the Prior and Concomitant Medications or Procedures 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 drug, the interventions required to 
treat the event, and the outcome. 
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. 
16.2 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 drug) 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. 


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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 16.3.1.  A dose modification for the laboratory abnormality may be 
required (see Section 12.1.3) and should not contribute to the designation of a laboratory test 
abnormality as an SAE. 
16.3 Serious Adverse Events 
16.3.1 
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. 
− 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. 


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16.3.2 
Reporting 
For Parts 1a and 2, every SAE, regardless of suspected causality (eg, relationship to study 
drug(s) or study procedure or disease progression), occurring after the subject has signed the ICF 
through 30 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.   
For Parts 1b and 3, every SAE, regardless of suspected causality (eg, relationship to study 
drug(s) or study procedure or disease progression), occurring after the subject has signed the ICF 
through 90 days after the last dose of study treatment, or within 30 days after the last dose of 
study treatment if 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 30 days [Parts 1a and 2 only] or 90 days [Parts 1b and 3 only] 
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 drug.   
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 
treatment.  Relatedness will be assessed for each of INCB001158 (all Parts) and pembrolizumab 
(Parts 1b and 3 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:  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, 


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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 drug 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. 
If the SAE is not documented in the IBs for the study treatments (new occurrence) and is thought 
to be related to at least one 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. 
16.4 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 patient during maternal or paternal exposure to study 
treatment(s), the following procedures should be followed in order to ensure subject safety: 
• The study treatment implicated 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 patient, to determine whether it is in the patient's 
best interest to resume study treatment and continue participation in the study.  
• The EOT visit evaluations must be performed.  


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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. 
16.5 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 patient 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). 
• Pembrolizumab:  A dose ≥ 1000 mg (5 times the dose). 
No specific information is available on the treatment of overdose of INCB001158 or 
pembrolizumab.  In the event of overdose, the patient 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 treatments, 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. 
16.6 Warnings and Precautions 
Special warnings or precautions for the INCB001158 study drug and for pembrolizumab, derived 
from safety information collected by the sponsor or its designee, are presented in the 
Investigator's Brochures (iIB, pIB). 


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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. 
For guidance for potential DILI (drug induced liver injury), refer to the pembrolizumab 
label/Investigator’s Brochure (pIB) and Attachment 7. 
16.7 Product Complaints 
The sponsor collects product complaints on study drugs 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 16.1.2 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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17.0 
STUDY SUSPENSION, TERMINATION, AND COMPLETION 
The Sponsor may suspend or terminate the study or any part of the study at any time for any 
reason.  If the Investigator suspends or terminates the study, the Investigator will promptly 
inform the Sponsor and the IRB/IEC and provide a detailed written explanation.  The 
Investigator will also return all study treatments, containers, and other study materials to the 
Sponsor or designee, or destroy the materials at the investigative site.  Upon study completion, 
the Investigator will provide the Sponsor, IRB/IEC, and regulatory agency with final reports and 
summaries as required by regulations. 
If at least 6 months elapsed since the last subject was enrolled in the study, and if there are no 
more than 10 subjects still on study treatment, 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 usual standard of care for this population.  The investigator 
will be expected to monitor for and report any SAEs and pregnancies, as detailed in Section 16.0.  
No other data will be collected.  The remaining subjects are considered to be on study until a 
discontinuation criterion is met. 


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18.0 
INFORMED CONSENT 
The Investigator will provide for the protection of the patients by following all applicable 
regulations.  These regulations are available upon request from the Sponsor.  The Informed 
Consent Form used during the informed consent process must be reviewed by the Sponsor and 
approved by the IRB/IEC.  All patients must be consented per the requirements and 
recommendations in 21CFR50, 45CFR46, and ICH/ GCP E6. 
The study begins when the first patient signs the informed consent form.  The end of the study 
will occur when all patients have completed applicable follow-up assessments.  
Before any procedures specified in the protocol are performed, a patient must: 
• Be informed of all pertinent aspects of the study and all elements of informed consent 
• Be given time to ask questions and time to consider the decision to participate 
• Voluntarily agree to participate in the study 
• Sign and date an IRB/IEC approved Informed Consent Form 
19.0 
PROTOCOL AMENDMENTS 
Any significant change in the study requires a protocol amendment.  An Investigator must not 
make any changes to the study without IRB/IEC and Sponsor approval. All protocol amendments 
must be reviewed and approved following the same process as the original protocol. 
20.0 
QUALITY CONTROL AND ASSURANCE 
The Sponsor or designee performs quality control and assurance checks on all clinical studies 
that it sponsors.  Before enrolling any patients in this study, Sponsor personnel and the 
Investigator review the protocol, the Investigator’s Brochure, the eCRFs and instructions for 
their completion, the procedure for obtaining informed consent, and the procedure for reporting 
AEs and SAEs.  A qualified representative of the Sponsor will monitor the conduct of the study.  
During these site visits, information recorded in the eCRFs is verified against source documents.  


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21.0 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE PROCEDURES 
21.1 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 patients. 
− 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 patients' questions have been 
answered and the patients fully understand study procedures: 
− Informed consent must be obtained before any study-related procedures are 
conducted, unless otherwise specified by the Protocol. 


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− Informed consent must be obtained using the IRB/IEC-approved version in a 
language that is native and understandable to the patient.  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 patient records. 
• 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 patients 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 


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available at the site in compliance with applicable record retention regulations.  
The sponsor will retain the original eCRF data and audit trail. 
21.2 Accountability, Handling, and Disposal of Study Drug 
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. 
• Patient use of the study treatments including capsule or unit counts from each supply 
dispensed. 
• Return of the INCB001158 study drug to the investigator or designee by patients. 
The study treatments must be used only in accordance with the Protocol.  The investigator will 
also maintain records adequately documenting that the patients were provided the specified study 
treatments.  These records should include dates, quantities, and any available batch or serial 
numbers or unique code numbers assigned to the study treatments and study patients. 
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 treatments 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. 


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21.3 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 patient.  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 patient'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 by the study monitor in the Monitoring Visit 
report.  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. 
21.4 Data Privacy and Confidentiality of Study Records 
The investigator and the sponsor or its designee must adhere to applicable data protection laws 
and regulations.  The investigator and the sponsor or its designee are responsible for ensuring 
that sensitive personal information is handled in accordance with local data protection laws 
(including but not limited to HIPAA and GDPR) as applicable.  Appropriate consent for 
collection, use and disclosure and/or transfer (if applicable) of personal information must be 
obtained in accordance with local data protection laws. 


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Patient names will not be supplied to the sponsor or its designee.  Only the patient number and 
patient's initials (patient's initials will only be recorded if allowable by local regulations) will be 
recorded in the eCRF, where permitted; if the patient'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 
appropriate technical and organizational measures as required by local data protection laws.  The 
patients will be informed that representatives of 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. 
21.5 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. 


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21.6 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. 
Per the International Committee of Medical Journal Editors recommendations (ICMJE 2015), an 
author is generally considered to be anyone who provides substantive intellectual contributions 
to a published study.  Specifically, authorship credit should be based on 1) substantial 
contributions to study conception and design, or acquisition, analysis and interpretation of data, 
and 2) drafting the article or revising it critically for important intellectual content, 3) final 
approval of the version to be published, and 4) agreement to be accountable for all aspects of the 
work to ensure its accuracy and integrity.  All four conditions should be met. 


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22.0 
REFERENCES 
Bode-Böger, SM., Böger RH, Galland A, Tsikas D, and Frölich JC. Arginine-induced 
vasodilation in healthy humans: Pharmacokinetic-pharmacodynamic relationship. Br J Clin 
Pharmacology 1998;46(5): 489-97. 
 
Borghaei H, Paz-Ares L, Spigel DR, Steins M, Ready, NE, Chow LQ, et al. Nivolumab versus 
docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 
2015;373(17):1627-1639. 
 
Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH et al. Phase I study of 
single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical 
activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 2010;28:3167-3175. 
 
Byrne MJ and Nowak AK.  Modified RECIST criteria for assessment of response in malignant 
pleural mesothelioma. Ann Oncol 2004;15:257-260. 
 
Cheung CW, et al. Channeling of urea cycle intermediates in situ in permeabilized hepatocytes. 
J Biol Chem 1989;263(7): 4038-4044. 
 
Colegio OR, Chu N-Q, Szabo AL, Chu T, Rhebergen AM, Jairam V. Functional polarization of 
tumour-associated macrophages by tumour-derived lactic acid. Nature 2014;513:559-563. 
 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 
2009;45:228-247. 
 
Gentles AJ, Bratman SV, Lee LJ, Harris JP, Feng W, Nair RV et al. Integrating tumor and 
stromal gene expression signatures with clinical indices for survival stratification of early-stage 
non-small cell lung cancer. J Natl Cancer Inst 2015;107:1-11. 
 
Goldstein AS et al.  Metabolic and Genetic Studies of a Family with Ornithine Transcarbamylase 
Deficiency. Pediat. Res.  1974;8:5-12. 
 
ICMJE guidelines (2015) Recommendations for the Conduct, Reporting, Editing, and 
Publication of Scholarly Work in Medical Journals. Retrieved from http://www.icmje.org/icmje-
recommendations.pdf  
 
INCB001158 Investigator's Brochure (iIB). Wilmington, DE: Incyte Corporation. 
 
Kim JY, Shin NR, Kim A, Lee HJ, Park WY, Kim JY, et al. Microsatellite instability status in 
gastric cancer: a reappraisal of its clinical significance and relationship with mucin phenotypes.  
Korean J Pathol 2013;47:28-35. 
 
Mehta S., Stewart DJ, Levy RD. The hypotensive effect of L-arginine is associated with 
increased expired nitric oxide in humans. Chest 1996;109:1550-1555. 


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Melero, I., Berman DM, Aznar MA, Korman AJ, Perez-Gracia JL, and Haanen J. Evolving 
synergistic combinations of targeted immunotherapies to combat cancer. Rev Cancer 
2015;8:457-472. 
 
Munder M, Schneider H, Luckner C, Giese T, Langhans CD, Fuentes JM et al. Arginase I is 
constitutively expressed in human granulocytes and participates in fungicidal activity. Blood 
2005;105:2549-2556. 
 
Nagasaka H, Yorifuji T, Egawa H, Inui A, Fujisawa T, Komatsu H, et al. , et al. Characteristics 
of NO cycle coupling with urea cycle in non-hyperammonemic carriers of ornithine 
transcarbamylase deficiency. Mol Genet Metab 2013;109:251-254. 
 
Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH and Hodi FS. Developing a 
common language for tumor response to immunotherapy: immune-related response criteria using 
unidimensional measurements, Clinical Cancer Research 2013;19: 3936-3943. 
 
Pembrolizumab Investigator's Brochure (pIB). Whitehouse Station, NJ: Merck Sharp & Dohme 
Corporation. 
 
Perrone A. (2016) Overview of Immune-Related RECIST (irRECIST) for Immunotherapy,  
presentation at IO360 Conference. Retrieved from: 
http://1ffa812hqmlk1ek23x2npii7.wpengine.netdna-cdn.com/wp-
content/uploads/2016/02/Andrea-Perrone-IO360.pdf  
 
Simon R. Optimal two-stage designs for phase II clinical trials. Controlled Clin Trials 
1989;10:1-10. 
 
Solito S, Marigo I, Pinton L, Damuzzo V, Mandruzzato S and Bronte V. Myeloid-derived 
suppressor cell heterogeneity in human cancers. Ann NY Acad Sci 2014;1319:47-65. 
 
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, 
activity, and immune correlates of anti–PD-1 antibody in cancer. N Engl J Med 2012;366:2443-
5244. 
 
Verrotti A., et al. Valproate-associated hyperammonemic encephalopathy. Metab Brain Dis 
2002;17:367-373. 
 
Wadzinski J, Franks R, Roane D and Bayard M. Valproate-associated hyperammonemic 
encephalopathy. J Am Board Fam Med 2007;20:499-502. 
 


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ATTACHMENT 1A:  SCHEDULE OF STUDY ASSESSMENTS FOR PART 1A AND PART 2 (INCB001158 
MONOTHERAPY) 
Cycle Length = 28 Days 
Visit 
Screening 
Cycle 1 
Cycle 2+ 
End of 
Treatment 
Follow-Up 
Safety 
Disease 
Status 
 
Day 
-21 to -1 
Day 1 
(-1 day) 1 
Day 2 
(-1 day) 1,22 
Days 8 
and 22 
(± 2 days) 1 
Day 15 
(± 2 days) 1 
Day 1 
(± 5 days)1,23 
Day 8 (Cycle 2 
only)  
(± 5 days)15,22 
Within 
28 days 
post treatment 
discontin-
uation 
30-37 days after 
last dose of 
INCB001158 
Q8W after 
discontin-
uation 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
Demographics and Medical 
History 
X 
 
 
 
 
 
 
 
 
 
Physical Examination2 
X 
X 
 
X 
X 
X3 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
X 
X 
X3 
X 
X 
X 
 
Vital Signs 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Orthostatic Vital Signs4 
 
X 
 
 
X 
 
 
 
 
 
ECOG Performance Status 
X 
X 
 
 
 
X3 
X 
X 
X 
 
Duplicate 12-lead ECG with 
QTcF5 
X 
X6 
 
 
X6 
 
 
X 
 
 
Urinalysis 
X 
X7 
 
X 
X 
X 
 
X 
 
 
Serum Chemistry levels8 
X 
X7 
X 
X 
X 
X 
X 
X 
 
 
Hematology8 
X 
X7 
X 
X 
X 
X 
X 
X 
 
 
Pregnancy Test9 
X 
X 
X 
 
 
Plasma Ammonia Levels10, 21 
 
X 
X 
X 
X 
X 
X 
 
 
 
 


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Visit 
Screening 
Cycle 1 
Cycle 2+ 
End of 
treatment 
Follow-Up 
Safety 
Disease 
Status 
 
Day 
-21 to -1 
Day 1 
(-1 day) 1 
Day 2 
(-1 day) 1,22 
Days 8 
and 22 
(± 2 days) 1 
Day 15 
(± 2 days) 1 
Day 1 
(± 5 days) 1,23 
Day 8 
(Cycle 2 only) 
(± 5 days)15,22 
Within 
28 days 
post treatment 
discontin-
uation 
30-37 days after 
last dose of 
INCB001158 
Q8W after 
discontin-
uation 
Urine Sample for Orotic 
Acid11, 12, 21 
 
X 
X 
X 
X 
X 
X 
 
 
 
Coagulation tests 
X 
X7 
 
X 
X 
X 
X 
X 
 
 
Pharmacokinetic (PK) 
Assay12, 21, 22 
 
X 
X 
X21 
X 
X 
X 
 
 
 
Amino Acid Panel12 ,21, 22 
 
X 
X 
X21 
X 
X 
X 
 
 
 
INCB001158 Dosing13 
 
X14 
X 
X 
X 
X15 
X15 
 
 
 
Radiographic Evaluation of 
Tumor Burden (diagnostic 
CT or MRI)16 
X17 
 
 
 
 
X18 
 
X 
 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
 
X 
X 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Post-treatment anticancer 
therapy status 
 
 
 
 
 
 
 
X 
X 
X 
Explanation of Superscripts 
1. 
With approval from the sponsor, windows for cycles/ days may be modified due to holidays conflicting with the clinic schedules.  
2. 
Complete physical exam is required at Screening and at End of Treatment.  A symptom-directed physical exam can be done on all other visits.  System exams are only 
required as clinically indicated.  
3. 
Assessment to be completed on Day 1 of every cycle.  
4. 
Phase 1a patients only: orthostatic vital signs to be performed on C1D1 and C1D15, predose and 4 hr postdose. 
5. 
To be performed in duplicate within (2-5 minutes). 
6. 
ECG to be performed 2-4 hr post-dose. 
7. 
Does not need to be repeated if the Screening sample was obtained within 3 days prior to C1D1 unless a clinically significant change is suspected. 


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8.
Serum chemistry, urinalysis, and hematology should be performed and reviewed before dosing.  These labs may be performed up to 48 hours prior to the planned dosing.
Any new ≥Grade 3 laboratory abnormality, or change consistent with a possible irAE (as opposed to disease progression), such as liver function test elevations,
electrolyte fluctuation, or hematologic deterioration should be assessed for potential risk to continue dosing.  In the event of uncertainty, the medical monitor should be
contacted.
9.
Required of all females of child-bearing potential.  Screen pregnancy test must occur within 3 days prior to C1D1.  During study treatment, urine pregnancy tests will be
performed locally as medically indicated or per country-specific requirement.  See Section 11.3 for additional details.
10. Ammonia samples to be sent to local laboratory for analysis.  See Attachments 2A, 2B, and 2D for additional details.
11. A fasting (of  >8 hours) urine sample will be taken for the measurement of orotic acid on day one of every cycle or more frequently as clinically indicated.  See
Attachments 2A, 2B, and 2D for specific time points and volume to be taken. 
12. Samples are sent to a central laboratory.  See Attachments 2A, 2B, 
 for specific time points and volume of collection.
13. INCB001158 is given daily, BID.  During PK days, the morning dose of INCB001158 will be administered during the clinic visit after all pre-dosing procedures, and
pre-dose PK blood sampling, has occurred.
14. Patients in Part 1a only will receive a single dose of INCB001158 on C1D1.
15. Part 1a patients: During C2, D1 through D8, INCB001158 will be taken with food.  The first dose will be taken in the morning right after eating a substantial breakfast
and the second dose will be taken in the evening after eating dinner.  Part 2 patients will not have C2D8 visit.
16. Whenever possible, imaging should be done at the same institution/facility and with the same modality that will be used to measure response during the patient’s
participation in the study.  The redacted copies of the reports will be submitted and the scans must be sent to a reader for exploratory analyses.  If available, 1-3 redacted
scan reports for scans that occurred prior to screening will be requested.
17. Tumor assessments within 28 days prior to C1D1 will be accepted.
18. Completed approximately every 8 weeks per RECIST v1.1.  Evaluations may occur more frequently as clinically indicated.
21. For patients in Part 2, on C1D8 and C1D22, PK and Amino Acid tests are NOT REQUIRED.  Plasma Ammonia and Orotic Acid are required.
22. Part 2 patients will not have C1D2 and C2D8 visits.
23. Orotic acid and plasma ammonia samples will also be collected on Day 1 of every cycle after Cycle 4.


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ATTACHMENT 1B:  SCHEDULE OF STUDY ASSESSMENTS FOR PARTS 1B, 1C, AND 3 (INCB001158 + 
PEMBROLIZUMAB) 
Cycle Length = 21 Days 
Visit 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4+ 
End of 
Treatment 
Follow-Up 
Safety 
 
Day -21 
to -1 
Day 1 
Day 8 
(± 2 days) 1 
Day 15 
(± 2 days) 1 
Day 1 
(± 5 days) 1 
Day 1 
 (± 5 days) 1 
Day 1 
(± 5 days) 1, 20 
Within 
28 days 
post 
treatment 
discontin-
uation 
30-37 days after 
last dose of 
INCB001158 + 
pembrolizumab 
90-97 days after 
last dose of 
INCB001158 + 
pembrolizumab 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
Demographics and Medical 
History 
X 
 
 
 
 
 
 
 
 
 
Physical Examination2 
X 
X 
X 
X 
X 
X 
X3 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X3 
X 
X 
X 
Vital Signs4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
 
 
X 
X 
X3 
X 
X 
X 
Duplicate 12-lead ECG with 
QTcF5 
X 
X6 
 
X6 
 
 
 
X 
 
 
Urinalysis 
X 
X7 
 
 
X 
X 
X 
X 
 
 
Serum Chemistry levels8 
X 
X7 
X 
X 
X 
X 
X 
X 
 
 
Hematology8 
X 
X7 
X 
X 
X 
X 
X 
X 
 
 
Pregnancy Test9 
X 
X 
X 
 
 
 


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Visit 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4+ 
End of 
Treatment 
Follow-Up 
Safety 
Disease Status 
 
Day-21 to -1 C1D1 
C1D8 
(± 2 days) 1 
Day 15 
(± 2 days) 1 
Day 1 
(± 5 days) 1 
Day 1 (± 5 
days) 1 
Day 1 
(± 5 days) 1, 20 
Within 
28 days post 
treatment 
discontin-
uation 
30-37 days after 
last dose of 
INCB001158 + 
pembrolizumab 
90-97 days after 
last dose of 
INCB001158 + 
pembrolizumab 
Q9W after 
discontinuation 
Plasma Ammonia Levels10 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Urine Sample for Orotic 
Acid11, 12 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Coagulation tests 
X 
X7 
X 
X 
X 
X 
X 
X 
 
 
 
Pharmacokinetic (PK) 
Assay12 
 
X 
 
X 
X 
X 
X 
 
 
 
 
Amino Acid Panel12 
 
X 
 
X 
X 
X 
X 
 
 
 
 
Pembrolizumab Dosing13 
 
X 
 
 
X 
X 
X 
 
 
 
 
INCB001158 Dosing14 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Radiographic Evaluation of 
Tumor Burden (diagnostic 
CT or MRI)15 
X16 
 
 
 
 
 
X17 
X 
 
 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Post-treatment anticancer 
therapy status 
 
 
 
 
 
 
 
 
X 
X 
X 
Explanation of Superscripts 
1. 
With approval from the sponsor, windows for cycles/ days may be modified due to holidays conflicting with the clinic schedules.  
2. 
Complete physical exam is required at Screening and at End of Treatment.  A symptom-directed physical exam can be done on all other visits.  System exams are only 
required as clinically indicated.  
3. 
Assessment to be completed on Day 1 of every cycle.  
4. 
Vital sign measurements include temperature, pulse, respiratory rate, and resting systolic and diastolic blood pressure.  On the day of pembrolizumab infusion, vital signs 
will be obtained pre-infusion, 15 min after the start of the infusion, at the end of the infusion, and 15 min after completion of the infusion.  Vital signs should be collected 
± 5 min from the scheduled times noted above.  
5. 
To be performed in duplicate within (2-5 min). 
6. 
ECG to be performed 2-4 hr post-dose. 
7. 
Does not need to be repeated if the Screening sample was obtained within 3 days prior to C1D1 unless a clinically significant change is suspected. 
8. 
Serum chemistry, urinalysis, and hematology should be performed and reviewed before dosing.  These labs may be performed up to 48 hours prior to the planned dosing.  
Any new ≥ Grade 3 laboratory abnormality, or change consistent with a possible irAE (as opposed to disease progression), such as liver function test elevations, 
electrolyte fluctuation, or hematologic deterioration should be assessed for potential risk to continue dosing.  In the event of uncertainty, the medical monitor should be 
contacted. 


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9.
Required of all females of child-bearing potential.  Screen pregnancy test must occur within 3 days prior to C1D1.  During study treatment, urine pregnancy tests will be
performed locally as medically indicated or per country-specific requirement.  See Section 11.3 for additional details.
10. Ammonia samples to be sent to local laboratory for analysis.  See Attachment 2C for additional details.
11. A fasting of > 8hours urine sample will be taken for the measurement of orotic acid on day one of every cycle or more frequently as clinically indicated.  See
Attachment 2C for specific time points and volume to be taken. 
12. Samples are sent to a central laboratory.  See Attachment 2C for specific time points and volume of collection.
13. Patients enrolled in Parts 1b, 1c, and 3: Pembrolizumab dosing will take place on D1 of every cycle.  Study treatment with pembrolizumab 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.  Infusion of pembrolizumab
precede INCB001158 dosing and PK analysis on C1D1 and day one of every cycle.
14. INCB001158 is given daily, BID.  During PK days, the morning dose of INCB001158 will be administered during the clinic visit after all pre-dosing procedures,
including pembrolizumab administration and pre-dose PK blood sampling, has occurred.  INCB001158 will be taken within 5 minutes after pembrolizumab infusion.
15. Whenever possible, imaging should be done at the same institution/facility and with the same modality that will be used to measure response during the patient’s
participation in the study.  The redacted copies of the reports will be submitted and the scans must be sent to a reader for exploratory analyses.  If available, 1-3 redacted
scan reports for scans that occurred prior to screening will be requested.
16. Tumor assessments within 28 days prior to C1D1 will be accepted.
17. Completed approximately every 9 weeks per RECIST v1.1 OR Modified RECIST for pleural mesothelioma.  Evaluations may occur more frequently as clinically
indicated.
20. Orotic acid and plasma ammonia samples will also be collected on day one of every cycle after Cycle 4.


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ATTACHMENT 2A:  PHARMACOKINETIC 
 SAMPLING SCHEDULE FOR PART 1A 
Detailed instructions on sample collection and shipment can be found in the Laboratory manual. 
Study Day 
(C=cycle, D=Day) 
INTENSIVE SAMPLING PK GROUP: Part 1a Patients Only 
Time point 1 
PK
Amino Acid 
Panel4,9 
Urine sample 
for Orotic 
Acid4, 5, 10 
Plasma 
Ammonia5, 6 
Screening 
 
 
 
 
 
C1, D1 & D15 
Predose 
3 mL 
2 mL 
2 mL 
X 
C1, D1 & D15 
0.5 hr 
3 mL 
 
 
 
C1, D1 & D15 
1 hr 
3 mL 
 
 
 
C1, D1 & D15 
2 hr 
3 mL 
 
 
X 
C1, D1 & D15 
4 hr 
3 mL 
 
 
 
C1, D1 & D15 
6 hr 
3 mL 
2 mL 
2 mL 
X 
C1, D1 & D15 
8 hr 
3 mL 
 
 
 
C1, D1 & D15 
12 hr 
3 mL 
 
 
 
C1, D2 
Predose 
3 mL 
2 mL 
2 mL 
X 
C1, D8 
Predose 
3 mL 
2 mL 
2 mL 
X 
C1, D22 
Predose 
3 mL 
2 mL 
2 mL 
X 
C2, D1 
Predose 
3 mL 
2 mL 
2 mL 
X 
C2, D8 
Predose 
3 mL 
2 mL 
2 mL 
X 
C2, D8 
0.5 hr 
3 mL 
 
 
 
C2, D8 
1 hr 
3 mL 
 
 
 
C2, D8 
2 hr 
3 mL 
 
 
X 
C2, D8 
4 hr 
3 mL 
 
 
 
C2, D8 
6 hr 
3 mL 
2 mL 
2 mL 
X 
C2, D8 
8 hr 
3 mL 
 
 
 
C3, D1 
Predose 
3 mL 
2 mL 
2 mL 
X 
C4, D1 
Predose 
3 mL 
2 mL 
2 mL 
X 
Total sample 
collected 
 
63 mL blood 
20 mL blood 
 
 
1. 
Where applicable, the collection window is ±15 minutes.  Post dose time points for urine orotic acid collection window are ± 1 hour.  The collection window for the 
C1D1 and C1D15 12 hr PK sample is ± 1 hr.  The actual sample collection time will be entered in the EDC.  
 
 
 
 


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4. 
The sample collection time points may be modified if the data indicate that these samples are no longer necessary to ensure patient safety.  Pre-dose orotic acid will be 
collected any time prior to patient’s dosing.  Where applicable, the post dose collection window is ± 1hr.  
5. 
The sample collection time points may be modified if the data indicate that these samples are no longer necessary. 
6. 
Plasma ammonia samples will be collected and sent to the sites local laboratory.  
 
 
  
 
9. 
2 mL blood will be collected in to one sodium heparin tube and processed for amino acid. 
10. In addition to Orotic acid samples collected through Cycle 4 Day 1 (C4D1), samples will also be collected on day one of every cycle (example, C5D1, C6D1, etc).  


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ATTACHMENT 2B:  PHARMACOKINETIC 
 SAMPLING SCHEDULE FOR PARTS 2A, 2B, AND 2C 
Detailed instructions on sample collection and shipment can be found in the Laboratory manual. 
Study Day 
(C=cycle, D=Day) 
SPARSE SAMPLING PK GROUP: Patients in Parts 2a, 2b, and 2c 
Time point 1 
PK
Amino Acid 
Panel4,9 
Urine sample 
for Orotic 
Acid4, 10 
Plasma 
Ammonia4,5, 10 
Screening 
 
 
 
 
 
C1, D1  
Predose 
3 mL 
2 mL 
2 mL 
X 
C1, D1 
Postdose 
3 mL7 
2 mL8 
2 mL 8 
X8 
C1, D8 
Predose 
 
 
2 mL 
X 
C1, D15 
Predose 
3 mL 
2 mL 
2 mL 
X 
C1, D15 
Postdose 
3 mL7 
2 mL8 
2 mL 8 
X8 
C1, D22 
Predose 
 
 
2 mL 
X 
C2, D1 
Predose 
3 mL 
2 mL 
2 mL 
X 
C3, D1 
Predose 
3 mL 
2 mL 
2 mL 
X 
C4, D1 
Predose 
3 mL 
2 mL 
2mL 
X 
Total sample collected 
 
21 mL blood 
14 mL blood 
 
 
1. 
Where applicable, the collection window is ±15 minutes.  Post dose time points for urine orotic acid collection window are ± 1 hour.  The actual sample collection time 
will be entered in the EDC. 
 
 
 
 
4. 
The sample collection time points may be modified if the data indicate that these samples are no longer necessary to ensure patient safety.  Pre-dose orotic acid will be 
collected any time prior to patient’s dosing.  Where applicable, the post dose collection window is ± 1hr.  
5. 
Plasma ammonia samples will be collected and sent to the sites local laboratory.  
 
 
  
7. 
The PK postdose sample will be collected 1-4 hours post dose.  
8. 
The Orotic acid, amino acid, and ammonia samples will be collected 4-6 hours post dose.  
9. 
2 mL blood will be collected in to one sodium heparin tube and processed for amino acid 
10. In addition to Orotic acid and plasma ammonia samples collected through Cycle 4 Day 1 (C4D1), samples will also be collected on Day 1 of every cycle (example, 
C5D1, C6D1, etc). 
 


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ATTACHMENT 2C:  PHARMACOKINETIC 
 SAMPLING SCHEDULE FOR PARTS 1B, 1C, AND 3 
Detailed instructions on sample collection and shipment can be found in the Laboratory manual. 
Study Day 
(C=cycle, D=Day) 
SPARSE SAMPLING PK GROUP: All patients in Part 1b and 3 
Below are assessments for patients enrolled in Part 1b and 3 
Time point 1 
PK/ 
 
Amino Acid 
Panel4,9 
Urine sample 
for Orotic 
Acid4, 10 
Plasma 
Ammonia4,5,10 
Screening 
 
 
 
 
 
C1, D1  
Predose 
3 mL 
2 mL 
2 mL 
X 
C1, D1 
Postdose 
3 mL7  
2 mL8 
2 mL 8 
X8 
C1, D8 
Predose 
 
 
2mL 
X 
C1, D15 
Predose 
3 mL 
2 mL 
2 mL 
X 
C1, D15 
Postdose 
3 mL7 
2 mL8 
2 mL 8 
X8 
C2 D1 
Predose 
3 mL 
2 mL 
2 mL 
X 
C3, D1 
Predose 
3 mL 
2 mL 
2 mL 
X 
C4, D1 
Predose 
3 mL 
2 mL 
2 mL 
X 
Total sample collected 
 
21 mL blood 
14 mL blood  
  
 
 


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Study Day 
(C=cycle, D=Day) 
PK/PD ASSESSMENTS FOR PART 1C 
Below are assessments for patients enrolled in Part 1c 
Time point 1 
PK/ 
 
Amino Acid 
Panel4,9 
Urine sample 
for Orotic 
Acid4, 10 
Plasma 
Ammonia4,5,10 
Screening 
 
 
 
 
 
C1, D1  
Predose 
3 mL 
2 mL 
2 mL 
X 
C1, D1  
0.5 hr 
3 mL 
 
 
 
C1, D1  
1 hr 
3 mL 
 
 
 
C1, D1  
2 hr 
3 mL 
 
 
X 
C1, D1  
4 hr 
3 mL 
 
 
 
C1, D1  
6 hr 
3 mL 
2 mL 
2 mL 
X 
C1, D1  
8 hr 
3 mL 
 
 
 
C1, D1  
12 hr 
3 mL 
 
 
 
C1, D8 
Predose 
 
 
2mL 
X 
C1, D15 
Predose 
3 mL 
2 mL 
2 mL 
X 
C1, D15 
Postdose 
3 mL7 
2 mL8 
2 mL 8 
X8 
C2 D1 
Predose 
3 mL 
2 mL 
2 mL 
X 
C3, D1 
Predose 
3 mL 
2 mL 
2 mL 
X 
C4, D1 
Predose 
3 mL 
2 mL 
2 mL 
X 
1. 
Where applicable, the collection window is ±15 min. Post dose time points for urine orotic acid collection window are ± 1 hour.  The actual sample collection time will 
be entered in the EDC. 
 
 
 
 
4. 
The sample collection time points may be modified if the data indicate that these samples are no longer necessary to ensure patient safety.  Pre-dose orotic acid will be 
collected any time prior to patient’s dosing.  Where applicable, the post dose collection window is ± 1 hr.  
5. 
Plasma ammonia samples will be collected and sent to the sites local laboratory.  
 
 
  
7. 
The PK postdose sample will be collected 1-4 hours post dose.  
8. 
The Orotic acid, amino acid, and ammonia samples will be collected 4-6 hours post dose. 
9. 
2 mL blood will be collected in to one sodium heparin tube and processed for amino acid. 
10. In addition to Orotic acid and plasma ammonia samples collected through Cycle 4 Day 1 (C4D1), samples will also be collected on day one of every cycle (example, 
C5D1, C6D1, etc). 


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ATTACHMENT 3:  CLINICAL LABORATORY TESTS 
Hematology (Peripheral Blood Sample): 
• Hemoglobin and hematocrit 
• RBC count 
• White blood cell count with differential 
• Platelet count 
Coagulation Tests 
• PT, aPTT and INR 
Serum Chemistry-Full Metabolic Panel (Peripheral Blood Sample) with additional analytes 
• Sodium 
• Potassium 
• Chloride 
• CO2  
• Magnesium 
• Calcium 
• Phosphorus 
• Glucose1 
• Blood urea nitrogen 
• Amino acid analysis 
• Ammonia (venous) 
• Uric acid 
• Total protein 
• Albumin 
• Total and direct bilirubin2 
• Aspartate aminotransferase (AST) 
• Alanine aminotransferase (ALT) 
• Alkaline phosphatase (AP) 
• Lactate dehydrogenase (LDH) 
• Creatinine  
• Thyroid Function Tests (TFTs) 3 
• Carcinoembryonic antigen (CEA)4 
1 
Fasting glucose (8-10 hour fast) is required on PK days only  
2 
Direct bilirubin is only required if Total Bilirubin is above the upper limit of normal.  
3 
Thyroid functioning will be monitored by measuring thyroid stimulating hormone (TSH) only, with a full 
panel run if there is an abnormal TSH result or if thyroid dysfunction is suspected 
4 
Only in CRC patients 
 
Pregnancy test (urine or serum - HCG):  Women of child-bearing potential 
Urinalysis 


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ATTACHMENT 4:  RECIST CRITERIA VERSION 1.1 
Source: Eisenhauer et al 2009 
Sponsor’s Note: INCB001158, may affect glucose metabolism in both normal and tumor tissues. 
Preclinical data suggest that glucose uptake may increase with arginase inhibition in sensitive 
tissues, reflecting the pharmacodynamics effects of INCB001158. False positive interpretations 
of progressive disease with FDG-PET scans may occur. Therefore, all FDG-PET findings 
suggestive of progressive disease should be confirmed by dedicated anatomic imaging (CT or 
MRI) for this study. 
Measurability of Tumor at Baseline 
Definitions 
At baseline, tumor lesions will be categorized measurable or non-measurable as follows. 
Measurable tumor lesions 
Tumor lesions must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:   
•
10 mm by CT scan (CT scan slice thickness no greater than 5 mm)
•
10 mm by caliper measurement (lesions which cannot be accurately measured with
calipers should be recorded as non-measurable)
•
20 mm by chest X-ray
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a lymph 
node must be  15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will 
be measured and followed.  See also section below on ‘Baseline documentation of target and 
non-target lesions’ for information on lymph node measurement. 
Non-measurable tumor lesions 
Non-measurable tumor lesions encompass small lesions (longest diameter <10 mm or 
pathological lymph nodes with  10 to < 15 mm short axis) as well as truly non-measurable 
lesions.  Lesions considered truly non-measurable include:  leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or 
lung, peritoneal spread, abdominal masses/abdominal organomegaly identified by physical exam 
that is not measurable by reproducible imaging techniques. 


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Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
Bone lesions: 
• Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions.  However, these techniques can be used to confirm the presence or 
disappearance of bone lesions.  
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT or 
MRI can be considered as measurable lesions if the soft tissue component meets the 
definition of measurability described above. 
• Blastic bone lesions are non-measurable.  
Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts. 
• ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above.  However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
Lesions with prior local treatment: 
• Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion.  For this protocol, these tumor lesions will be 
considered non-measurable lesions. 
Specifications by methods of measurements 
Measurement of lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed.  All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 


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Method of assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial 
and  10 mm diameter as assessed using calipers (e.g., skin nodules).  For the case of skin 
lesions, documentation by color photography including a ruler to estimate the size of the lesion is 
suggested.  As noted above, when lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken since it is more objective and may also be reviewed at 
the end of the study. 
Chest X-ray:  Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions.  However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. Still, non-contrast CT is preferred over chest X-ray. 
CT, MRI:  CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  When CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice 
thickness.  MRI is also acceptable in certain situations (e.g., for body scans). 
If prior to enrolment it is known that a patient is not able to undergo CT scans with IV contrast 
due to allergy or renal insufficiency, the decision as to whether a non-contrast CT or MRI (with 
or without IV contrast) will be used to evaluate the patient at baseline and follow-up, should be 
guided by the tumor type under investigation and the anatomic location of the disease.  For 
patients who develop contraindications to contrast after baseline contrast CT is done, the 
decision as to whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed, 
should also be based on the tumor type, anatomic location of the disease and should be optimized 
to allow for comparison to the prior studies if possible.  Each case should be discussed with the 
radiologist to determine if substitution of these other approaches is possible and, if not, the 
patient should be considered not evaluable from that point forward. 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next.  If new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances. 


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Endoscopy, laparoscopy:  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, they can be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete 
response or surgical resection is an endpoint. 
Tumor markers:  Tumor markers alone cannot be used to assess objective tumor response.  If 
markers are initially above the upper normal limit, however, they must normalize for a patient to 
be considered in complete response.  Because tumor markers are disease specific, instructions for 
their measurement should be incorporated into protocols on a disease specific basis.  Specific 
guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA response (in 
recurrent prostate cancer), have been published.  In addition, the Gynecologic Cancer Intergroup 
has developed CA-125 progression criteria which are to be integrated with objective tumor 
assessment for use in first-line trials in ovarian cancer. 
Cytology, histology:  These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain).  When effusions are known to be a 
potential adverse effect of treatment (e.g., with certain taxane compounds or angiogenesis 
inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment can be considered if the measurable tumor has met criteria for response 
or stable disease in order to differentiate between response (or stable disease) and progressive 
disease. 
Tumor response evaluation 
Assessment of overall tumor burden and measurable disease 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements.  Only patients 
with measurable disease at baseline should be included in protocols where objective tumor 
response is the primary endpoint.  Measurable disease is defined by the presence of at least one 
measurable lesion.  In studies where the primary endpoint is tumor progression (either time to 
progression or proportion with progression at a fixed date), the protocol must specify if entry is 
restricted to those with measurable disease or whether patients having non-measurable disease 
only are also eligible.  
Baseline documentation of ‘target’ and ‘non-target’ lesions 
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. 


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This means in instances where patients have only one or two organ sites involved a maximum of 
two (one site) and four lesions (two sites), respectively, will be recorded.  Other lesions in that 
organ will be recorded as non-measurable lesions (even if size is greater than 10 mm by CT 
scan). 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements.  It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor.  Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
15 mm by CT scan.  Only the short axis of these nodes will contribute to the baseline sum.  The 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumor.  Nodal size is normally reported as two dimensions in the plane in which the 
image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, saggital or coronal).  The smaller of these measures is the short axis. 
For example, an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 
20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm should be 
recorded as the node measurement.  All other pathological nodes (those with short axis  10 mm 
but < 15 mm) should be considered non-target lesions.  Nodes that have a short axis < 10 mm are 
considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum.  The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline.  Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression.’  In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case report form (e.g., ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’). 


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Response criteria 
This section provides the definitions of the criteria used to determine objective tumor response 
for target lesions. 
Evaluation of target lesions 
•
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph
nodes (whether target or non-target) must have reduction in short axis to < 10 mm.
•
Partial Response (PR):  At least a 30% decrease in the sum of diameters of target lesions,
taking as reference the baseline sum diameters.
•
Progressive Disease (PD):  At least a 20% increase in the sum of diameters of target
lesions, taking as reference the smallest sum on study (this includes the baseline sum if
that is the smallest on study).  In addition to the relative increase of 20%, the sum must
also demonstrate an absolute increase of at least 5 mm.  (Note:  the appearance of one or
more new lesions is also considered progression).
•
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient
increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Special notes on the assessment of target lesions 
Lymph nodes:  Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to below 10 mm on study.  This means that when lymph nodes are 
included as target lesions, the ‘sum’ of lesions may not be zero even if complete response criteria 
are met, since a normal lymph node is defined as having a short axis of < 10 mm. Case report 
forms or other data collection methods may therefore be designed to have target nodal lesions 
recorded in a separate section where, in order to qualify for CR, each node must achieve a short 
axis < 10 mm.  For PR, SD, and PD, the actual short axis measurement of the nodes is to be 
included in the sum of target lesions. 


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Target lesions that become ‘too small to measure’:  While on study, all lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm). However, sometimes lesions or lymph nodes 
which are recorded as target lesions at baseline become so faint on CT scan that the radiologist 
may not feel comfortable assigning an exact measure and may report them as being ‘too small to 
measure’.  When this occurs it is important that a value be recorded on the case report form: 
• If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm.  If the lesion is believed to be present and 
is faintly seen but too small to measure, a default value of 5 mm should be assigned 
and BML (below measurable limit) should be ticked (Note:  It is less likely that this 
rule will be used for lymph nodes since they usually have a definable size when 
normal and are frequently surrounded by fat such as in the retroperitoneum; however, 
if a lymph node is believed to be present and is faintly seen but too small to measure, 
a default value of 5 mm should be assigned in this circumstance as well and BML 
should also be ticked). 
This default value is derived from the 5 mm CT slice thickness (but should not be changed with 
varying CT slice thickness).  The measurement of these lesions is potentially non-reproducible, 
therefore providing this default value will prevent false responses or progressions based upon 
measurement error. 
To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm and in that case BML should not be ticked.  (BML is 
equivalent to a less than sign <) 
Lesions that split or coalesce on treatment:  When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion.  If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the ‘coalesced lesion’. 


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Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions.  While some non-target lesions may actually be measurable, they 
need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol. 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (< 10 mm short axis). 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD):  Unequivocal progression of existing non-target lesions. (Note:  the 
appearance of one or more new lesions is also considered progression). 
Special notes on assessment of progression of non-target disease 
The concept of progression of non-target disease requires additional explanation as follows: 
When the patient also has measurable disease:  In this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of 
substantial worsening in non-target disease in a magnitude that, even in presence of SD or 
PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest ‘increase’ in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression status.  The designation of overall 
progression solely on the basis of change in non-target disease in the face of SD or PR of target 
disease will therefore be extremely rare. 
When the patient has only non-measurable disease:  This circumstance arises in some phase III 
trials when it is not a criterion of study entry to have measurable disease.  The same general 
concepts apply here as noted above; however, in this instance there is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease burden. 
Because worsening in non-target disease cannot be easily quantified (by definition:  if all lesions 
are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the 
change in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease:  i.e., an increase in tumor burden representing an 
additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a 
measurable lesion).  Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, an 
increase in lymphangitic disease from localized to widespread, or may be described in protocols 
as ‘sufficient to require a change in therapy’.  If ‘unequivocal progression’ is seen, the patient 
should be considered to have had overall PD at that point.  While it would be ideal to have 
objective criteria to apply to non-measurable disease, the very nature of that disease makes it 
impossible to do so; therefore the increase must be substantial. 


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New lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal:  i.e., not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some ‘new’ 
bone lesions may be simply healing or flare of pre-existing lesions).  This is particularly 
important when the patient’s baseline lesions show partial or complete response.  For example, 
necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it is 
not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.  An example of this is 
the patient who has visceral disease at baseline and while on study has a brain CT or MRI 
ordered which reveals metastases.  The patient’s brain metastases are considered to be evidence 
of PD even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-
up evaluation will clarify if it represents truly new disease.  If repeat scans confirm there is 
definitely a new lesion, then progression should be declared using the date of the initial scan. 
(18)F-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET)For the purposes of 
this study, progressive disease should not be made solely on FDG-PET findings because the 
mechanism of the study drug, INCB001158, may affect glucose metabolism in both normal and 
tumor tissues.  All FDG-PET findings suggestive of progressive disease should be confirmed by 
dedicated anatomic imaging (CT or MRI).  The following modifications to RECIST v1.1 will be 
applied to this study: 
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion.  *Confirmation of the new lesion by CT or MRI scan is 
required per protocol. 
• No FDG-PET at baseline and a positive FDG-PET at follow-up: 
− If the positive FDG-PET at follow-up corresponds to a new sign of disease 
confirmed by CT, this is PD 
− If the positive FDG-PET at follow-up is not confirmed as a new site of disease on 
CT, additional follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date of the 
initial abnormal *CT scan). 
− If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease 
on CT that is not progressing on the basis of the anatomic images, this is not PD. 
*reflects study-specific modification to RECIST v.1.1 


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Evaluation of best overall response 
The best overall response is the best response recorded from the start of the study treatment until 
the end of treatment taking into account any requirement for confirmation.  On occasion a 
response may not be documented until after the end of therapy so protocols should be clear if 
post-treatment assessments are to be considered in determination of best overall response. 
Protocols must specify how any new therapy introduced before progression will affect best 
response designation.  The patient’s best overall response assignment will depend on the findings 
of both target and non-target disease and will also take into consideration the appearance of new 
lesions.  Furthermore, depending on the nature of the study and the protocol requirements, it may 
also require confirmatory measurement.  Specifically, in nonrandomized trials where response is 
the primary endpoint, confirmation of PR or CR is needed to deem either one the ‘best overall 
response’.  This is described further below. 
Time point response 
It is assumed that at each protocol specified time point, a response assessment occurs.  Table A 
provides a summary of the overall response status calculation at each time point for patients who 
have measurable disease at baseline. 
When patients have non-measurable (therefore non-target) disease only, Table B is to be used.  
Missing assessments and not-evaluable designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable at that time point.  If only a subset of lesion measurements are made at an assessment, 
usually the case is also considered not evaluable at that time point, unless a convincing argument 
can be made that the contribution of the individual missing lesion(s) would not change the 
assigned time point response.  This would be most likely to happen in the case of PD. 
For example, if a patient had a baseline sum of 50 mm with three measured lesions and at 
follow-up only two lesions were assessed, but those gave a sum of 80 mm, the patient will have 
achieved PD status, regardless of the contribution of the missing lesion. 
If one or more target lesions were not assessed either because the scan was not done, or could not 
be assessed because of poor image quality or obstructed view, the Response for Target Lesions 
should be “Unable to Assess” since the patient is not evaluable.  Similarly, if one or more non-
target lesions are indicated as ‘not assessed’, the response for non-target lesions should be 
“Unable to Assess” (except where there is clear progression).  Overall response would be 
“Unable to Assess” if either the target response or the non-target response is “Unable to Assess” 
(except where this is clear evidence of progression) as this equates with the case being not 
evaluable at that time point. 


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Best overall response:  All time points 
The best overall response (Table C) will be determined by statistical programming once all the 
data for the patient are known. 
Table A: Time Point Response:  Patients with Targets (+/- Non-Target) Disease 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
1. Note:  CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, 
NE = inevaluable. 


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Table B: Time Point Response:  Patients with Non-Target Disease Only 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/non-PDa 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
1. Note:  CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, 
NE = inevaluable. 
a = ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used 
as endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be 
measured is not advised. 
 
Table C: Best Overall Response when Confirmation of CR and PR Required 
Overall Response  
First Time Point 
Overall Response  
Subsequent Time Point 
BEST Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise, NE 
NE 
NE 
NE 
1. Note:  CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, 
NE = inevaluable. 
a = If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease 
meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have 
reappeared after CR). Best response would depend on whether minimum duration for SD was met. 
However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely still 
present and in fact the patient had PR, not CR at the first time point. Under these circumstances, the 
original CR should be changed to PR and the best response is PR. 


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Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ 
size (< 10 mm), they may still have a measurement reported on scans. This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes.  As noted earlier, this means that patients with CR may 
not have a total sum of ‘zero’ on the case report form (CRF). 
In trials where confirmation of response is required, repeated ‘NE’ time point assessments may 
complicate best response determination.  The analysis plan for the trial must address how 
missing data/assessments will be addressed in determination of response and progression.  For 
example, in most trials it is reasonable to consider a patient with time point responses of 
PR-NE-PR as a confirmed response. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration’.  Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response:  it is a reason for stopping study therapy.  The objective response status of 
such patients is to be determined by evaluation of target and non-target disease. 
Conditions that define ‘early progression, early death, and non-evaluability are study specific and 
should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status of 
complete response.  FDG-PET may be used to upgrade a response to a CR in a manner similar to 
a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively described in the 
protocol and supported by disease specific medical literature for the indication.  However, it 
must be acknowledged that both approaches may lead to false positive CR due to limitations of 
FDG-PET and biopsy resolution/sensitivity. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment.  If at 
the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 


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ATTACHMENT 5:  MODIFIED RECIST CRITERIA FOR MALIGNANT PLEURAL 
MESOTHELIOMA 
Source: modified from Byrne MJ and Nowak AK. 2004 
Evaluation of malignant pleural mesothelioma will employ the RECIST v.1.1 criteria, but one of 
the organ site target measurements should reflect the typical mesothelial “rind” as one of the 
target measurements, as follows: 
• Tumor thickness perpendicular to the chest wall or mediastinum will be measured in two 
positions at three separate levels on transverse CT scan cuts. 
− The transverse cuts must be at least 2 cm apart and related to anatomical 
landmarks for future assessments. 
− The pleural thickness must be at least 10 mm to be considered measurable. 
• The sum of the six measurements defines a “pleural unidimensional measure”, similar to 
the “longest unidimensional diameter” of a target tumor mass per RECIST. 
• At disease reassessment, pleural thickness should be measured at the same positions and 
levels as the Screening/Baseline tumor evaluation. 
Nodal, subcutaneous and other bidimensionally measurable lesions will be measured 
unidimensionally per the standard RECIST v 1.1 criteria. 
Objective responses are defined using RECIST v.1.1 criteria: 
• Complete Response (CR):  Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to < 10 mm. 
• Partial Response (PR):  At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
• Progressive Disease (PD):  At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. (Note:  the appearance of one or 
more new lesions is also considered progression) 
Confirmation of a response requires a repeat observation at least 4 weeks apart. 


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ATTACHMENT 6:  IMMUNE RELATED RECIST CRITERIA (BASED ON 
RECIST v1.1) 
As part of Protocol Amendment 2-US 3, dated 10 NOV 2020, the irRECIST endpoints have 
been removed.  However, this attachment, describing irRECIST, has been retained, as 
patient management at the time of PD will continue to follow irRECIST principles under 
Protocol Amendment 2-US 3. 
 
Source: Perrone A. (Oral presentation at IO360 meeting, February 2016)  
 
Immune-related RECIST (irRECIST) is derived from RECIST v1.1 conventions, as described in 
Attachment 4 and Eisenhauer et al 2009.  The implementation of irRECIST (Perrone 2016) is 
identical to RECIST v1.1 until progressive disease (PD) is identified.  Upon demonstration of PD 
(see Attachment 4) per RECIST v1.1, patients may remain on study per Investigator discretion, 
assuming the patient remains clinically stable, as defined in the protocol.  Patients that remain on 
study will have an imaging disease assessment performed at least 4 weeks after the initial PD is 
demonstrated in order to confirm PD. 
 
1 EVALUATION OF LESIONS 
 
1.1 Evaluation of Target Lesions 
 
Immune-related Complete Response (irCR): Disappearance of all target lesions. Any 
pathological lymph nodes (whether target or non-target) must have reduction in short axis to 
<10 mm. 
Immune-related Partial Response (irPR): At least a 30% decrease in the sum of diameters of 
target lesions (i.e., Percentage Change in Tumor Burden), taking as reference the baseline sum 
diameters. 


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Immune-related Progressive Disease (irPD): Same requirements for PD as standard 
RECIST v1.1, with exception that progressive disease must be confirmed.  After demonstration 
of PD by standard RECIST v1.1 criteria, patients remain on study and are re-imaged after 
>4 weeks.  Confirmation of target lesion PD is constituted by the following: 
• Sum of linear diameters (SLD) reaches PD threshold of > 20% increase from 
nadir OR 
• SLD remains >20% increased above baseline (if already > 20% increased at 
initial PD) 
Immune-related Stable Disease (irSD): Neither sufficient shrinkage to qualify for irPR nor 
sufficient increase to qualify for irPD, taking as reference the smallest sum diameters while on 
study. 
 
1.1.1 Special Notes on the Assessment of Target Lesions 
 
1.1.1.1 Lymph Nodes 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
> 15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. 
Nodes that have a short axis < 10 mm are considered non-pathological and should not be 
recorded or followed. 
 
1.1.1.2 Target Lesions that Become “Too Small to Measure” 
All lesions (nodal and non-nodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (eg, 2 mm). If the radiologist is 
able to provide an actual measurement, that should be recorded, even if it is below 5 mm. 
However, when such a lesion becomes difficult to assign an exact measure to then: 
• if it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. 
• if the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned (note: in case of a lymph node believed to be 
present and faintly seen but too small to measure, a default value of 5 mm should be 


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assigned in this circumstance as well). This default value is derived from the 5 mm CT 
slice thickness (but should not be changed with varying CT slice thickness). 
1.1.1.3 Target Lesions that Split or Coalesce on Treatment 
• When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions 
should be added together to calculate the target lesion sum. 
• As lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion. If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the “coalesced lesion”. 
1.2 Evaluation of Non-target Lesions 
 
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol. 
 
Immune-related Complete Response (irCR): Disappearance of all non-target lesions. All lymph 
nodes must be non-pathological in size (< 10 mm short axis). 
 
Immune-related Non-CR/Non-PD (ir-Non-CR/Non-PD):  Persistence of one or more non-target 
lesion(s) and/or maintenance of tumor marker level above the normal limits.  This also includes 
non-target lesions that demonstrated unequivocal progression at the initial demonstration of PD 
but then stabilized or regressed on subsequent scans. 
Immune-related Progressive Disease (irPD):  Unequivocal progression of existing non-target 
lesions on a disease assessment subsequent to initial demonstration of PD.  Therefore, irPD by 
non-target lesions requires one of the following on a disease assessment >4 weeks after the initial 
demonstration of PD: 
• New unequivocal progression  OR 
• Further unequivocal progression (if unequivocal progression present at initial PD) 


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1.3 New Lesions 
The appearance of new lesions that occurs on a disease assessment subsequent to initial 
demonstration of PD.  Therefore, irPD by new lesions requires one of the following on a disease 
assessment >4 weeks after the initial demonstration of PD: 
•
New lesions appear OR
•
Additional new lesions appear or prior new lesions grow (if new lesions were
present at initial PD)
1.4 Confirmation of Progressive Disease 
As described above, irPD requires that an initial demonstration of PD is confirmed in a 
subsequent disease assessment performed >4 weeks after the initial demonstration of PD.  The 
above section describes what constitutes irPD with respect to Target Lesions, Non-target Lesions 
and New Lesions.  For the sake of clarity, the presence of ALL of the following >4 weeks after 
initial PD means that PD IS NOT confirmed: 
Target lesions 
•
SLD is <20% increased from nadir
Non-target lesions 
•
No additional unequivocal progression from prior scan
New lesions 
•
No additional new lesions
•
Any prior new lesions are stable or shrinking (qualitatively)
Clinical status 
•
Patient remains clinically stable


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2  RESPONSE CRITERIA 
 
2.1 Time Point Response 
 
A response assessment should occur at each time point specified in the protocol. 
 
• Immune-related Complete Response (irCR): Complete disappearance of all tumor 
lesions (target and non-target), together with no new measurable or unmeasurable lesions, 
for at least 4 weeks from the date of documentation of irCR. All lymph nodes short axes 
must be < 10 mm. 
 
• Immune-related Partial Response (irPR): The sum of the linear diameters (SLD) of all 
target lesions is measured and captured as the sum of diameters at baseline. At each 
subsequent tumor assessment, the SLD of all target lesions is calculated. A decrease in 
SLD, relative to baseline SLD, of 30% or greater is considered an irPR, in the absence of 
irCR or irPD. 
 
• Immune-related Stable Disease (irSD): irSD is defined as the failure to meet criteria for 
irCR, irPR or irPD. 
 
• Immune-related Progressive Disease (irPD): It is recommended for patients that are 
clinically stable to confirm PD at the following tumor assessment. Any of the following 
will constitute progressive disease: 
 
o Overall ir-response of irPD (per Table 2.1) after confirmation of PD with disease 
assessment >4 weeks after initial demonstration of PD 
o PD per RECIST v1.1 in a patient that is not clinically stable enough to remain on 
study for confirmation 


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Table 2.1: irRECIST v1.1 Definitions 
 
Target Lesion 
Response per 
RECIST v1.1 
Non-target Lesion 
Response 
New Lesions 
Overall ir-
response 
CR 
CR 
• None, OR 
• Completely resolved 
irCR 
PR 
ir-Non-CR/Non-PD 
• None, OR 
• Stable/shrinking 
relative to first PD scan 
 
irPR 
SD 
ir-Non-CR/Non-PD 
• None, OR 
• Stable/shrinking 
relative to first PD scan 
 
irSD 
PD (with 
confirmation) 
Any 
Any 
 
 
irPD 
Any 
Presence of unequivocal 
progression >4 weeks after 
initial PD scan 
Any 
Any 
Any 
• Appearance of new 
lesions after initial PD 
scan 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, 
ir = immune-related. 
 
2.2 Best overall response: All time points 
Best Overall Response and Date of Progression Using irRECIST v1.1 (irBOR): The investigator 
will be asked to provide all responses on study and date(s) of progression, if applicable, and the 
best overall response will be calculated by the sponsor or designee based on the time point 
responses and tumor measurements provided by the investigator. 


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ATTACHMENT 7:  GUIDANCE FOR POTENTIAL DILI (DRUG-INDUCED LIVER 
INJURY) 
Evaluation algorithm for potential DILI if there are no other clinical reasons 
Note: If clear etiology for the laboratory abnormalities has been confirmed, Stage 1 and 2 
testing may not be required.  In this case, consultation with the Sponsor is recommended. 
Stage 1 work-up should be performed within 48-72 hours:  
• ALT 
• AST 
• Bilirubin: total, direct, indirect 
• Alkaline phosphatase (ALP)  
• Prothrombin Time (PT)/international normalized ratio (INR)  
• Creatine phosphokinase (CPK) 
• Manual eosinophil count (if automated count was elevated)  
• Toxicology 
screen 
for 
drugs 
of 
abuse 
(including 
ethanol) 
and 
for 
acetaminophen/paracetamol level should also be sent.  Investigators may order additional 
toxicology tests as clinically indicated. 
• Evaluate patient for the following signs and symptoms: fatigue, nausea, vomiting, right 
upper quadrant abdominal pain or tenderness, fever, rash. 
• Obtain the following additional history and assessment for associated risk/confounding 
factors: 
✓ More detailed history of symptoms and prior or concurrent illness 
✓ Aminotransferase values obtained prior to the study or administration of study 
medication 
✓ Alcohol consumption (recent and historical) 
✓ Acetaminophen (APAP)/paracetamol use  
✓ New prescription, concomitant, or non-prescription (including herbal and other 
dietary supplements) medications 
✓ Unusual foods (e.g. mushrooms) or special diets. Consumption of seasonal foods. 
✓ Recreational drug use 
✓ Prior history of liver injury or disease, including but not limited to Gilbert's 
syndrome, autoimmune disorders, cancer, Wilson's disease, NASH, alcoholic or 
infectious hepatitis, biliary tract disease, hypoxic/ischaemic hepatopathy 
✓ Obesity/abdominal adiposity (record weight, height, and waist circumference) 
✓ Occupational history and history of exposure to chemical agents or other 
environmental toxins 
✓ Recent travel (last three [3] years) 
✓ Transfusion history 
• Perform the following required laboratory tests:  
✓ Albumin 
✓ Eosinophils (percentage and absolute; obtain manual count if automated count is 
elevated) 


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✓ Viral hepatitis serologies (obtain appropriate consent prior to testing, if required 
locally) 
▪ A (IgG, IgM) 
▪ B (HepBs Ag, Hep Bs Ab, Hep Bc Ab, Hep Be Ag) 
▪ C (RNA) 
▪ D (requires concomitant hepatitis B infection) 
✓ Human Immunodeficiency Virus (HIV) testing (obtain appropriate consent prior 
to testing, if required locally) 
✓ Evaluation for autoimmune hepatitis:  
▪ Serum gamma globulin levels/ serum protein electrophoresis   
▪ Antinuclear antibody (ANA)  
▪ Anti-mitochondrial antibody (if ALP or TBL >ULN) 
✓ If AST/ALT ratio is greater than one (1) with suspicions of increased alcohol 
intake, perform the following: 
▪ Gamma-glutamyl transferase (GGT) 
• Obtain a right upper quadrant ultrasound 
Stage 2 work-up tests should be drawn within one (1) week of receiving the Stage 1 work-
up results and the results of Stage 1 evaluation are negative. 
Note: A specific test may be performed earlier if the investigator determines that the 
clinical presentation leads to a certain diagnosis. 
Stage 2 work-up: 
• Perform the following laboratory tests: 
✓ Genetic test for Gilbert's disease if there is a suspicious history. Ensure 
appropriate patient consent is obtained for this test. 
✓ Viral hepatitis E (IgG and IgM, obtain appropriate consent prior to testing, if 
required locally)  
✓ Anti-smooth muscle antibody  
✓ Anti-liver-kidney microsomal antibody  
✓ Anti-soluble liver antigen 
✓ Serologies for the following: 
▪ Cytomegalovirus (CMV) (IgG, IgM) 
▪ Epstein-Barr Virus (EBV) (IgG, IgM) 
▪ Herpes simplex 
▪ Toxoplasmosis 
▪ Varicella 
▪ Parvovirus 


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✓ Ceruloplasmin 
✓ Serum alpha-1 anti trypsin 
✓ Genetic test for hemochromatosis. Ensure appropriate patient consent is obtained 
for this test  
✓ Iron Studies:  
▪ serum ferritin,  
▪ serum iron,   
▪ total iron binding capacity 
• Consider referral to hepatologist/gastroenterologist 
• Consider screen for celiac disease and cystic fibrosis if clinically indicated  
• If laboratory tests or ultrasound evidence of biliary tract obstruction, consider obtaining 
Endoscopic Retrograde Cholangiopancreatography (ERCP) or Magnetic Resonance 
Cholangiopancreatography (MRCP) 
If applicable, request copies of hospital discharge summaries, consultation reports, pathology 
reports, special studies (e.g. imaging or biopsy), etc. 


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ATTACHMENT 8:  AMENDMENT 2 EXECUTIVE SUMMARY OF CHANGES 
Amendment 2 of protocol INCB 01158-101 (formerly CX-1158-101) is being submitted in order to 
address four primary goals.  First, the anti-PD-1 agent is being changed from nivolumab to 
pembrolizumab.  Second, the patient populations in which the INCB001158/PD-1 combination is being 
studied are being expanded.  Third, the management of urinary orotic acid values has been modified 
based on the clinical experience to date, a more extensive evaluation of the urea cycle defect literature and 
feedback from an expert in the management of urea cycle defects.  On the basis of these data, the 
threshold of acceptable urinary orotic acid elevations has been redefined for patients that are fasting and 
non-fasting at the time of the assessment.  
 
 
 In addition to these 
primary goals of the Amendment, other minor changes have also been made to clarify protocol 
requirements. 
The following important changes were implemented to protocol INCB 01158-101 (formerly known as 
CX-1158-101) under Amendment 2: 
•
Throughout: The investigational product identifier was changed from “CB 1158” to “INCB001158”
and the protocol identifier was changed from “Protocol CX-1158-101” to “Protocol INCB 01158-
101” to reflect the new partnership with Incyte Pharmaceuticals.
•
Added- EudraCT number
•
Throughout: The design of the study was changed. INCB001158 is now tested in combination with
pembrolizumab instead of nivolumab. It is also tested as a monotherapy. In the appropriate sections
“pembrolizumab” replaces “nivolumab,” and instructions for administration of pembrolizumab are
provided.
•
•
•
Sponsor Contact: deleted contacts from the protocol except for safety reporting
•
Section 8.0, Study Design: Added 6 cohorts to part 3 of the combination expansion.
•
Section 8.1, Table 8.1-1 Dose Escalation Schedule: Added Cohort 1.5 with 75mg dose.
•
Section 8.1.2, Dose-Limiting Toxicity: Increased fasting urinary orotic acid (OA) to ≥ 10X the
ULN, any OA value of > 40X ULN (fasting or non-fasting). Added rationale for urinary orotic acid
threshold.
•
Section 8.3, Part 3 Combination Cohort Expansion: Revised criteria for entry into cohort 3b and
created 6 new cohorts, with all cohorts investigating INCB001158 in combination with
pembrolizumab; providing null hypotheses and primary endpoints for newly created cohorts.
•
Cohort 3b: patients with melanoma with disease progression or prolonged stable disease while
receiving an anti-PD-1 agent in the immediate prior line of therapy


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•
Cohort 3c: patients with urothelial cell carcinoma (UCC) that would be unlikely to have an
objective response to monotherapy pembrolizumab
•
Cohort 3d: patients with microsatellite instability-high (MSI-H) CRC that would be unlikely to
have an objective response to monotherapy pembrolizumab
•
Cohort 3e: patients with microsatellite stable (MSS) CRC
•
Cohort 3f: in PD-1/PD-L1 naïve patients with Gastric/GEJ cancer
•
Cohort 3g: in PD-1/PD-L1 naïve patients with SCCHN
•
Cohort 3h: patients with malignant pleural mesothelioma
•
Section 9.0, Sample Size: The sample size estimates were revised for Cohorts in Part 2 Monotherapy
Cohort Expansion and cohorts in Part 3 Combination Cohort Expansion (table 9.0-1).
•
Section 10.1, Inclusion Criteria:
•
Parts 3a, b, c and d: Removed PD-L1 from prior therapies allowed in the most recent line of
therapy. Add-on cohorts are restricted to patients that received PD-1 therapy in prior therapy
•
Revised criterion No. 8 to provide specific contraceptive requirements for women of
nonchildbearing potential, women of childbearing potential, and men. Also clarified that female
contraception to continue until 120 days beyond last dose
•
Revised inclusion criteria for patients with non-small cell lung cancer (NSCLC) and melanoma
•
Added exclusion criteria for patients with urothelial cell carcinoma (UCC); mismatch repair
deficient and/or microsatellite instability-high (MSI-H) colorectal cancer (CRC); microsatellite
stable (MSS) colorectal cancer (CRC); gastric/gastro-esophageal (GE) junction cancer; squamous
cell carcinoma of the head and neck; and mesothelioma
•
Section 10.2, Disease-specific exclusion criteria:  Modified criterion with known active CNS and
Part 3 so as to exclude all patients with NSCLC who have documented activating mutations in EGFR
or ALK. Added criterion liver virus vaccination and history or evidence of any condition, therapy or
laboratory abnormality that confound with trial results. Also added language to exclude pneumonitis
in combination cohort.
•
Section 11.0, Radiological Tumor Assessments: Specified that response criteria for patients with
pleural mesothelioma is modified RECIST criteria and modified language if repeat imaging
confirmed disease progression for patient receiving clinically meaningful benefit.
•
Section 13.1.9, Previous Human Experience: Added data on pharmacokinetic, pharmacodynamic
and safety to previous human experience on INCB001158 and the Effects on hepatic urea cycle
function.
•
Section 13.2.2, Rationale for Dose Escalation Strategy: Provides updated rationale for the dose
escalation strategy.
•
Section 13.2.3.2, Combination with anti-PD-1 (Pembrolizumab): Provides rationale for use of
pembrolizumab in combination with INCB001158. Also updated approvals for pembrolizumab to
include SCCHN and MSI/MMR cancers.
•
Section 14.1.2.2 Prohibited Concomitant Medications:  Updated to reflect the pembrolizumab con
meds.
•
Section 14.2 Study procedures: Clarified fasting to >8 hours.


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•
Section 14.3 other Schedules and Procedures: Clarified time for radiographic evaluation of tumor
burden for part 1b and 3.
•
Section 14.6.2 Vital signs: Clarified orthostatic vital signs collection requirement.
•
Section 15.1.2 Pembrolizumab: Added standard pembrolizumab background information.
•
Section 15.1.2 (and elsewhere): Added language to refer to pembrolizumab IB, as well as the
product label, as a reference for the product safety profile.
•
Section 15.1.2.1:  Added “safety” to 1st sentence to read "The safety and tolerability of CB-1158 +
pembrolizumab is not known."
•
Section 15.1.3.1 Dose modification guidelines:
•
Provided a new table (15.1-2) that is based on the Merck table for the management of
pembrolizumab. The table also includes information for the management of CB-1158. Please note
that the Table is almost identical to the table that Incyte has used in their clinical combination
studies with pembrolizumab, with the exception that CB-1158 (and unique AE’s such as urea
cycle inhibition) has been included and epacadostat has been removed.
•
In Table 15.1-1, listed the most likely immune related AEs in the table.
•
In Table 15.1-2, included the individual immune related AEs.
•
Section 16.1 Test Article Administration: Added text stating that the maximum duration of
pembrolizumab treatment on study will be up to 35 doses (approximately 2 years).
•
Section 18.4, Efficacy Analysis: An analysis that included patients that did not have a post-treatment
scan due to toxicity or death.
•
Section 19.0 Adverse Events: Added guidance for potential DILI(drug induced injury) in
Attachment 7.
•
Section 19.1: Added language regarding the definition and management of pembrolizumab overdose.
•
Section 19.2 Recording and Reporting: Added language regarding reporting of pregnancy and
lactation out to 120 days following study medication (or 30 days if new therapy is started).
•
Attachments: The schedule of assessments was changed and additional schedules of assessments
were added to reflect investigation of the combination of INCB001158 with pembrolizumab.
•
In Attachment 1A, Schedule of Study Assessments for Part 1A and 2 INCB001158 Monotherapy
the collection of orotic acid was expanded to Day 1 of every cycle. Collection (note: under
Amendment 1, this is entitled “Attachment 1A, Schedule of Study Assessments”).
•
Collection of orotic acid also occur Cycle 1 day 8 and on Day 1 of every cycle in also occurs in
the Attachment 1b, Schedule of Assessments for Part 1b and Part 3 (INCB001158 +
Pembrolizumab.
•
Modifications were modified to reflect current data and combination drug.
Important Note: A redline version of the document showing changes made from Amendment 1 to 
Amendment 2 is available upon request. 


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ATTACHMENT 9:  AMENDMENT 2-EU EXECUTIVE SUMMARY OF CHANGES 
The purpose of this amendment is to make additional changes and correct known inconsistencies in the 
protocol. The specific changes are as follows: 
Synopsis:  Updated the patient population for Part 2 to match the rest of the protocol. 
Synopsis; Attachments 1A and 1B:  Clarified scheduled visits for each study part. 
Synopsis; Section 5 Study Design:  Updated study design schema to reflect that for cohorts 3a, 3b, 3c, 
and 3d, subjects must have received an anti-PD-1/PD-L1 agent in the most recent prior line of therapy for 
advanced/metastatic disease.  Previously subjects were required to have received an anti-PD-1 agent in 
the most recent prior line of therapy.  The reason for the change is that anti-PD-1 and anti-PD-L1 agents 
target the same PD-1/PD-L1 interaction, and the effect of treatment with either type of agent is expected 
to be similar in these subjects. 
Synopsis; Section 5.1 Part 1. Dose Escalation; Section 10.2.1 Rationale for Starting Dose:  Added the 
starting dose of 50 mg BID for the dose escalation of INCB001158 plus pembrolizumab in Part 1b, as this 
has now been determined in Part 1a as 2 dose levels below the RP2D of 100 mg BID. 
Synopsis; Section 7.1 Inclusion Criteria:  Broadened exception for PT and INR inclusion cutoffs to 
include patients receiving therapeutic anticoagulation with drugs other than warfarin, as all of these drugs 
can affect PT and INR. 
Synopsis; Section 7.1 Inclusion Criteria, Part 1b Dose Escalation Criteria:  Removed reference to 
RCC and added mesothelioma, gastric/GEJ cancer, MSS CRC, MSI CRC, UCC, and SCCHN, to match 
the rest of the protocol. 
Synopsis; Section 7.1 Inclusion Criteria, Part 3 Expansion:   For Part 3a, corrected an inconsistency in 
bullet 2 to make consistent with exclusion of patients with EGFR or ALK mutations 
For cohorts 3a, 3b, 3c, and 3d, specified that subjects must have received an anti-PD-1/PD-L1 agent in the 
most recent prior line of therapy for advanced/metastatic disease.  Previously subjects were required to 
have received an anti-PD-1 agent in the most recent prior line of therapy.  The reason for the change is 
that anti-PD-1 and anti-PD-L1 agents target the same PD-1/PD-L1 interaction, and the effect of treatment 
with either type of agent is expected to be similar in these subjects. 
Synopsis; Section 7.2 Exclusion Criteria:  Removed exclusion criterion #8 prohibiting patients with 
history of diverticulitis, intra-abdominal abscess, GI obstruction, and abdominal carcinomatosis from 
enrolling to the study.  This exclusion criterion has been limiting on a number of occasions to date on this 
study, as it covers a lot of commonly occurring bowel pathology in patients, particularly those with GI 
malignancies.   There is no known safety concern with allowing such patients onto this study. 
Section 11.3.1 Distribution of Subject Reminder Cards and Subject Diaries; Section 13.4 
INCB001158 Accountability, Reconciliation, and Return; Section 13.5 Study Treatment 
Compliance:  Section 11.3.1 is new and describes subject reminder cards and diaries, which are being 
introduced in this study to facilitate drug compliance and the quantification of that compliance.  
Sections 13.4 and 13.5 describe how the subject diaries will be used and how compliance will be 


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assessed.  Section 13.5 also now contains standard Incyte protocol template language for compliance 
assessment. 
Section 11.2 Study Procedures:  Corrected an inconsistency between this section and Attachments 2A, 
2B, and 2C regarding when subjects in Parts 1a, 1b, 2, and 3 should come to the clinic fasted.  
Section 11.6.2 Vital Signs; Attachment 1B: Clarified vital sign collection requirement. 
 
 
 
 
 
 
 
  
Section 12.1.3.1 Dose Modification Guidelines:  Clarified that guidelines for AE management for 
INCB001158 apply to subjects in all parts of the study, not just monotherapy.  Added language providing 
additional guidance on pembrolizumab-related irAEs and further clarified which dose modification tables 
to follow for subjects treated with the combination of INCB001158 and pembrolizumab. 
Table 12.1-1: INCB001158 Dose Modification Guidelines:  Changed the title to specify that dose 
modification guidelines described in the table are for INCB001158 and apply to subjects in all parts of the 
study. 
Table 12.1-2: Pembrolizumab Dose Modification Guidelines:  Changed title to specify that dose 
modification and toxicity management guidelines described in the table are for irAEs associated with 
pembrolizumab and apply to subjects treated in the combination Parts 1b and 3 and revised the table 
accordingly. 
Section 12.1.3.3: Supportive Care Guidelines:  Added more detailed guidance on management of 
pembrolizumab-related infusion reactions, including addition of Table 12.1-3. 
Section 13.0 Test Article/Study Drug:  The section title was changed to "Study Drug and Other Study 
Treatments" and study drug was defined as INCB001158, and study treatments were defined as any 
mention of INCB001158 or pembrolizumab.  This has been clarified throughout the protocol where 
INCB001158 and/or pembrolizumab are mentioned. 
Section 13.1 Test Article Administration; Section 13.2, Packaging and Labeling:  Clarified that the 
pembrolizumab drug product may also be provided to sites as a 100 mg/4 mL (25 mg/mL) sterile solution 
in a single-dose vial. 
Section 16.0 Adverse Events:  This section has been replaced with equivalent section from the Incyte 
protocol template (Safety Monitoring and Reporting), to align with other Incyte-sponsored studies.  The 
new sub-sections are 16.1 Adverse Events, 16.2 Laboratory Test Abnormalities, 16.3 Serious Adverse 
Events, 16.4 Pregnancy, 16.5 Definition of an Overdose for this Protocol and Reporting of Overdose to 
the Sponsor, 16.6 Warnings and Precautions, and 16.7 Product Complaints. 


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Section 21.0 Direct Access, Data Handling, and Record Keeping; Section 22.0 Pre-Study 
Documentation; Section 23.0 Records Retention:  These 3 sections have been replaced with a single 
section (21.0 Ethical Considerations and Administrative Procedures) taken from the Incyte protocol 
template.  This covers the same topics as the former Sections 21.0, 22.0, and 23.0. 
Attachments: Attachments 1A, 1B, 2A, 2B and 2C have time point discrepancies for Plasma Ammonia, 
Orotic Acid, PK, 
: 
•
For patients in Part 1a, on C1D2, Plasma Ammonia, Orotic Acid, PK and Amino Acid are
required.
•
Patients in Part 2 will not have a C1D2 visit
•
For patients in Part 2, on C1D8, PK and Amino Acid tests are NOT REQUIRED. Plasma
Ammonia and Orotic Acid are required.
•
For patients in Part 2, on C1D22, PK and Amino Acid tests are NOT REQUIRED. Plasma
Ammonia and Orotic Acid are required.
•
For patients in Part 1b and Part 3, on C1D8, Plasma Ammonia and Orotic Acid are required. PK
and Amino Acid are NOT REQUIRED.
•
Patients in Part 2 will not have a C2D8 visit
•
In the Attachment 1B footnotes, the “Attachment 2” hyperlinks should direct to “Attachment 2C”
which is the PK 
 schedule for Parts 1b and 3.
•
In all parts, orotic acid and plasma ammonia samples will also be collected on Day 1 of every
cycle after Cycle 4.
Attachment 3: Clinical Laboratory Tests - CEA was added to the table of "Serum Chemistry-Full 
Metabolic Panel (Peripheral Blood Sample) with additional analytes" as an additional analyte to test in 
CRC patients.  CEA is a frequently elevated tumor marker in colon cancer that is routinely monitored 
during therapy and will be collected in all CRC patients enrolled to the study. 
Throughout:  "Package insert" (a US-specific term) was changed to "label" (more generic term) 
throughout as this protocol is now opening in EU. 
Important Note: A redline version of the document showing changes made from Amendment 2 
to Amendment 2-EU is available upon request. 


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ATTACHMENT 10:  AMENDMENT 2-US EXECUTIVE SUMMARY OF CHANGES 
Revisions from an EU-specific amendment (Amendment 2-EU, see Attachment 9) have also been 
incorporated in this US-specific amendment, with the exception of the item related to subject reminder 
cards and diaries. 
Amendment 2-US of protocol INCB 01158-101 has the following main goals: 
2.
Expansion of the Monotherapy basket Cohort 2c
Since monotherapy expansion Cohort 2c is a basket cohort enrolling multiple tumor types thought
to have infiltration with arginase-expressing cells, the current protocol does not have a
mechanism to further evaluate those tumor types in which INCB001158 monotherapy may show
evidence of clinical activity. Therefore, this amendment allows the option to expand the
monotherapy basket cohort to enroll additional patients with a specific tumor type from part 2c
where INCB001158 shows meaningful clinical activity as a single agent.
The specific changes in Amendment 2-US are as follows: 
 
 
Synopsis; Section 5.0: Overall Study Design:  
•
Updated section on Part 2 single agent cohort expansion to show expansion of Part 2c basket
cohort and addition of Cohort 2d
•
Corrected errors in sample sizes of Parts 3f and 3g expansion cohorts
•
Updated study schematic to show expansion of Part 2c basket cohort and addition of cohort 2d
.
Synopsis; Section 5.2 Study Design:  Added subsections describing the designs and patient populations 
for the existing and new Part 2 cohorts. 
Synopsis; Dosage and Mode of Administration:  Specified that INCB001158 may be taken orally using 
a capsule or tablet formulation in dose strengths of 25 mg or 100 mg. 
Synopsis: Study Schedule/Procedures:  Organized study visit days by study part. 


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Synopsis; Section 6.0 Sample Size: 
-
Updated number of patients to be enrolled in Part 2 to account for expansion of Cohort 2c basket
cohort and addition of Cohort 2d.
-
Corrected the potential maximum number of evaluable patients who could be enrolled in dose
escalation of INCB001158 monotherapy (Part 1a) and of the INCB001158 plus pembrolizumab
combination (Part 1b), to account for all possible dose levels being needed and for up to
12 backfill patients being enrolled at each possible dose level.
Synopsis; Section 7.1 Inclusion Criteria:  Added inclusion criteria specific to the newly added 
Cohort 2d. 
Synopsis; Section 7.2 Exclusion Criteria:  Added criterion to exclude patients who have had prior 
allogeneic tissue/solid organ transplant, as there is a risk for such patients developing graft-versus-host 
disease after receiving pembrolizumab. 
Synopsis, Statistical Methods; Section 15.2 Sample Size and Power:  Updated to describe sample sizes 
for expansion of Cohort 2c basket cohort and addition of Cohort 2d. 
Section 5.1.2 Dose-Limiting Toxicity:  Removed the exception to non-hematologic DLTs that required 
testing of serum amylase and lipase in the absence of symptoms of pancreatitis, as neither analyte is tested 
in this study. 
Section 5.2 Part 2.  Single Agent Cohort Expansion:  Clarified that the assessment of ORR in the 
Simon 2-Stage is based on responses at single time points, and not requiring subsequent confirmation. 
Section 10.1.9 Previous Human Experience:  Updated the available data from this study, as of 
23 May 2018.  This includes the RP2D of INCB001158 monotherapy of 100 mg BID. 
Section 10.1.10 Pharmacokinetics of INCB001158:  Added a footnote to Table 10.1-1 (PK Parameters 
from Phase 1 Patients) to clarify that the values represent the mean ± SD. 
Section 11.2; Study Procedures:  Added subsection 11.2.2.2 specifying study procedures specific to 
Cohort 2d. 
Section 11.3 Other Schedules and Procedures; Attachment 1A Schedule of Study Assessments for 
Part 1A and Part 2; Attachment 1B, Schedule of Study Assessments for Part 1B and Part 3:  
Added urine pregnancy tests during study treatment that will be performed locally as medically indicated 
or per country-specific requirement. 
Synopsis; Section 11.5 Follow-Up;  Attachment 1A Schedule of Study Assessments for Part 1A and 
Part 2; Attachment 1B, Schedule of Study Assessments for Part 1B and Part 3: 
-
Added new section (11.5) that explains the safety and disease follow-up procedures, which are
already summarised in the Synopsis.
-
Added these visits to the Schedules of Study Assessments.


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Section 13.0; Study Drug and Other Study Treatments:  
-
Inserted that INCB001158 will be administered as capsules or tablets, where applicable.
Section 15.3.3; Efficacy Evaluable Populations:  The Efficacy Evaluable Population has been split into 
2 populations - Response Evaluable and PFS Evaluable Populations, and the definitions have been 
aligned with other Sponsor studies. 
Synopsis; Section 15.4; Efficacy Analysis:  All mention of survival follow-up and an overall survival 
analysis has been removed to align with the endpoints, which do not include overall survival. 
 
 
 
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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ATTACHMENT 11:  AMENDMENT 2-US 2 EXECUTIVE SUMMARY OF CHANGES 
The purpose of this US-specific amendment is to add a cohort of patients with moderate renal impairment 
to determine the PK of INCB001158 50 mg BID (in combination with pembrolizumab), which is 
predicted by modelling to have comparable exposure to the RP2D of INCB001158 100 mg BID in 
patients with normal renal function.  This cohort will be in a new sub-part of Part 1, namely Part 1c. 
The specific changes are as follows: 
Synopsis; Section 3.0 Objectives:  Part 1c was added to the following objectives/endpoints:  primary 
safety, secondary anti-tumor effect and PK, 
. 
Synopsis; Section 5.0 Study Design:  The study design figure was updated to include Part 1c. 
Synopsis; Section 5.1 Part 1. Dose Escalation:  A full description of the new renal impairment cohort 
(Part 1c) was added. 
Synopsis; Section 6.0 Sample Size; Section 15.2 Sample Size and Power:  Part 1c (6 patients) was 
added, and the total number of evaluable patients was updated accordingly.  An explanation for the 
sample size of Part 1c was added. 
Synopsis; Section 7.1 Inclusion Criteria:  Inclusion criterion #6 was updated to include Part 1c patients 
with CrCl 30 to 49 mL/min.  Also, inclusion criteria specific to Part 1c were added to the section for 
“Part 1: Inclusion Criteria Specific to the Dose Escalation”. 
Synopsis; Section 11.2.1.1 Part 1a and 1c Only: Cycle 1 Day 1 and Day 15; Section 11.8.1 Fresh 
Pre-Dose and Post-Dose Tumor Biopsies; Section 11.9.2 Intensive PK Sampling; Section 12.1.2 
Pembrolizumab (Patients Enrolled in Parts 1b, 1c, and 3); Section 15.3.1 Safety Population; 
Section 15.6 Pharmacokinetic Analysis:  Part 1c was added.  The safety population was updated to state 
that patients with moderate renal impairment in Part 1c will be evaluated separately. 
Section 10.2.2.1 Rationale for Dose in Patients with Moderately Impaired Renal Function:  New 
section added. 
Section 12.1.3.2 Resumption of Study Treatment:  Dose modification guidelines were added to 
Table 12.1-1 for patients with moderately impaired renal function and patients with normal renal function 
who have AEs of study drug–related creatinine increase.  Part 1c was added to the title of Table 12.1-2. 
Section 21.4 Data Privacy and Confidentiality of Study Records:  Language was updated to reflect 
recent changes in privacy laws. 
Attachment 1B Schedule of Study Assessments for Parts 1b, 1c, and 3 (INCB001158 + 
Pembrolizumab):  Title and footnotes of Attachment 1B were updated to include Part 1c. 
Attachment 2C Pharmacokinetic 
 Sampling Schedule for Parts 1b, 1c, and 3:  Part 1c 
schedule was added. 
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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ATTACHMENT 12:  AMENDMENT 2-US 3 EXECUTIVE SUMMARY OF CHANGES 
For studies that have been ongoing beyond enrollment of the final subject where sufficient data have been 
collected to address the primary and secondary objectives, and only a limited number of subjects remain 
on study treatment, it is appropriate to discontinue protocol study assessments and data collection (except 
for SAEs and pregnancies) for these active subjects, while allowing them to continue receiving study 
treatment.  The main purpose of this US-specific amendment is to introduce language that will allow such 
a switch to take place.  
The specific changes are as follows: 
Title page:  Study execution responsibilities have been transferred from Calithera Biosciences, Inc. to the 
Sponsor, Incyte Corporation.  The title page of the protocol has been updated to reflect this change. 
Synopsis; List of Abbreviations; Section 3.0 Objectives; Section 8.0 Radiological Tumor 
Assessments; Section 15.4 Efficacy Analysis; Attachment 6 Immune-Related RECIST Criteria 
(Based on RECIST v1.1):  The efficacy analyses will no longer include any of the irRECIST endpoints.  
Instead efficacy will be assessed solely by RECIST v1.1.  Patient management beyond PD will continue 
to follow irRECIST guidelines. 
Section 12.1.3 Dose Modifications and Toxicity Management:  The dose modification guidelines for 
immune-related AEs associated with pembrolizumab (Table 12.1-2) have been updated to match the most 
recent guidelines from Merck.  
Section 16.3.2 Reporting:  The rules for reporting SAEs for subjects in Parts 1b and 3 have been updated 
to match the most recent guidelines from Merck.  Site personnel must report SAEs that occur within 
30 days after the last dose of study treatment if a subject receives a new anticancer therapy within that 
30 day period. 
Section 17.0 Study Suspension, Termination, and Completion:  Language has been added to define 
criteria for discontinuing study assessments (except SAEs and pregnancies) for remaining active study 
subjects. 


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ATTACHMENT 13:  ELECTRONIC SIGNATURE PAGE  


Signature Page for VV-CLIN-000684 v3.0
Signature Page for VV-CLIN-000684 v3.0
Approval
Approver
11-Nov-2020 17:21:13 GMT+0000
Approval
Approver
11-Nov-2020 17:47:25 GMT+0000
Approval
11-Nov-2020 20:18:47 GMT+0000
Approval
Approver
12-Nov-2020 14:20:12 GMT+0000
Approval
Approver
12-Nov-2020 21:13:23 GMT+0000

SAP_001.pdf: 
 
Official Title: 
Safety, Pharmacokinetics, and Pharmacodynamics of Escalating Oral Doses 
of the Arginase Inhibitor INCB001158 (Formerly Known as CB1158) as a 
Single Agent and in Combination With Immune Checkpoint Therapy in 
Patients With Advanced/Metastatic Solid Tumors 
NCT Number: 
NCT02903914 
 
Document Date: 
Statistical Analysis Plan: 22 Feb 2021 
 
 
 
 
 
 
 
 


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Statistical Analysis Plan 
 
TITLE PAGE 
INCB 01158-101 
Safety, Pharmacokinetics, and Pharmacodynamics of Escalating 
Oral Doses of the Arginase Inhibitor INCB001158 (Formerly 
Known as CB-1158) as a Single Agent and in Combination With 
Immune Checkpoint Therapy in Patients With Advanced/Metastatic 
Solid Tumors 
 
 
IND Number: 
128,080 
EudraCT Number: 
2017-002903-82 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
United States 
Protocol Version: 
Protocol Amendment 2-US 3 dated 10 NOV 2020 
CRF Approval Date: 
08 APR 2019 
SAP Version: 
Original 
SAP Author:  
, 
 
,
Date of Plan: 
22 FEB 2021 
 
 
This study is being conducted in compliance with Good Clinical Practice, 
including the archiving of essential documents. 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
TABLE OF CONTENTS .................................................................................................................2 
LIST OF ABBREVIATIONS ..........................................................................................................5 
1. 
INTRODUCTION ........................................................................................................7 
2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS .................................8 
2.1. 
Protocol and Case Report Form Version ......................................................................8 
2.2. 
Study Objectives and Endpoints ...................................................................................8 
3. 
STUDY DESIGN .......................................................................................................10 
3.1. 
Randomization ............................................................................................................11 
3.2. 
Control of Type I Error ...............................................................................................11 
3.3. 
Sample Size Considerations .......................................................................................11 
3.4. 
Schedule of Assessments ............................................................................................11 
4. 
DATA HANDLING DEFINITIONS AND CONVENTIONS ..................................11 
4.1. 
Scheduled Study Evaluations and Study Periods .......................................................11 
4.1.1. 
Day 1 ...........................................................................................................................11 
4.1.2. 
Study Day ...................................................................................................................11 
4.1.3. 
Baseline Value ............................................................................................................11 
4.1.4. 
Handling of Missing and Incomplete Dates ...............................................................12 
4.1.5. 
Cycle Length and Duration .........................................................................................12 
4.2. 
Variable Definitions ....................................................................................................13 
4.2.1. 
Age ..............................................................................................................................13 
4.2.2. 
Prior and Concomitant Medication .............................................................................13 
5. 
STATISTICAL METHODOLOGY ...........................................................................14 
5.1. 
General Methodology .................................................................................................14 
5.2. 
Treatment Groups .......................................................................................................14 
5.3. 
Analysis Populations ..................................................................................................15 
5.3.1. 
Full Analysis Set .........................................................................................................15 
5.3.2. 
Safety Population ........................................................................................................15 
5.3.3. 
DLT-Evaluable Population in Dose Escalation ..........................................................15 
5.3.4. 
Efficacy-Evaluable Population ...................................................................................15 
6. 
BASELINE, EXPOSURE, AND DISPOSITION ......................................................16 


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6.1. 
Demographics, Baseline Characteristics, and Disease History ..................................16 
6.1.1. 
Demographics and Baseline Characteristics ...............................................................16 
6.1.2. 
Baseline Disease Characteristics and Disease History ...............................................16 
6.1.3. 
Prior Therapy ..............................................................................................................16 
6.1.4. 
Medical History ..........................................................................................................16 
6.2. 
Disposition of Participant ...........................................................................................16 
6.3. 
Protocol Deviations ....................................................................................................16 
6.4. 
Exposure .....................................................................................................................17 
6.5. 
Study Drug Compliance .............................................................................................17 
6.6. 
Prior and Concomitant Medication .............................................................................17 
7. 
EFFICACY .................................................................................................................18 
7.1. 
General Considerations ...............................................................................................18 
7.2. 
Efficacy Hypotheses ...................................................................................................18 
7.3. 
Analysis of the Efficacy Parameters ...........................................................................18 
7.3.1. 
Response Criteria ........................................................................................................18 
7.3.2. 
Unconfirmed and Confirmed Best Overall Response ................................................18 
7.3.3. 
Objective Response Rate ............................................................................................20 
7.3.4. 
Duration of Response .................................................................................................20 
7.3.5. 
Largest Percentage Reduction in Sum of Diameters of Target Lesions .....................20 
7.3.6. 
Progression-Free Survival ..........................................................................................21 
8. 
SAFETY AND TOLERABILITY ..............................................................................22 
8.1. 
General Considerations ...............................................................................................22 
8.2. 
Adverse Events ...........................................................................................................22 
8.2.1. 
Adverse Event Definitions ..........................................................................................22 
8.2.2. 
Dose-Limiting Toxicities ............................................................................................22 
8.2.3. 
Adverse Event Summaries ..........................................................................................22 
8.3. 
Clinical Laboratory Tests ...........................................................................................24 
8.3.1. 
Laboratory Value Definitions .....................................................................................24 
8.3.2. 
Laboratory Value Summaries .....................................................................................24 
8.4. 
Vital Signs ..................................................................................................................25 
8.5. 
Electrocardiograms .....................................................................................................26 
9. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN ........................26 
9.1. 
Changes to Protocol-Defined Analyses ......................................................................26 


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9.2. 
Changes to the Statistical Analysis Plan .....................................................................26 
10. 
REFERENCES ...........................................................................................................27 
APPENDIX A. PLANNED TABLES, FIGURES, AND LISTINGS ........................................28 
 
LIST OF TABLES 
Table 1: 
Objectives and Endpoints .............................................................................................8 
Table 2:  
Treatment Groups for Participants Enrolled ...............................................................14 
Table 3: 
Confirmed Response Based on Subsequent Assessments ..........................................19 
Table 4: 
Evaluation and Censoring of Progression-Free Survival ............................................21 
Table 5: 
Identification of Baseline Record ...............................................................................24 
Table 6: 
Identification of Records for Postbaseline By-Visit Summaries ................................25 
Table 7: 
Normal Ranges for Vital Sign Values ........................................................................25 
Table 8: 
Normal Ranges for Electrocardiogram Intervals ........................................................26 
Table 9: 
Statistical Analysis Plan Versions ..............................................................................26 
 
LIST OF FIGURES 
Figure 1: 
Overall Study Design ..................................................................................................10 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
adverse event 
AUC0-12 
area under the steady-state plasma or serum concentration-time curve over 1 dose 
interval 
AUCt 
area under the plasma or serum concentration-time curve from time = 0 to the last 
measurable concentration at time = t 
BID 
twice daily 
BOR 
best overall response 
CI 
confidence interval 
CL/F 
apparent oral dose clearance 
Cmax 
maximum observed plasma or serum concentration 
CR 
complete response 
CRC 
colorectal cancer 
CrCL 
creatinine clearance 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
dose-limiting toxicity 
dMMR 
mismatch repair deficient 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
iRECIST 
modified form of RECIST v1.1 for immune-based therapeutics 
IV 
intravenous(ly) 
MedDRA 
Medical Dictionary for Regulatory Activities  
MSI-H 
microsatellite instability-high 
NCI 
National Cancer Institute 
NE 
not evaluable 
NSCLC 
non–small cell lung cancer 
ORR 
objective response rate 
PD 
progressive disease 
PD-1 
programmed cell death protein-1 
PD-L1 
programmed death ligand 1 
PFS 
progression-free survival 


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Abbreviation 
Term 
PK 
pharmacokinetic(s) 
PO 
per os (orally) 
PR 
partial response 
PT 
preferred term 
QTcF 
QT interval corrected using Fridericia's formula 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase 2 dose 
SAP 
Statistical Analysis Plan 
SCCHN 
squamous cell carcinoma of the head and neck 
SD 
stable disease 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
tmax 
time to maximum observed concentration 
UC 
urothelial carcinoma 
WHO 
World Health Organization  


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1. 
INTRODUCTION 
This is a Phase 1 open-label, nonrandomized study to evaluate the safety, tolerability, PK, 
pharmacodynamics, and antitumor activity of the arginase inhibitor INCB001158 (formerly 
known as CB-1158), both as monotherapy and in combination with the immune checkpoint 
inhibitor pembrolizumab, an anti–PD-1 agent, in participants with advanced/metastatic solid 
tumors.  The background and rationale for the study can be found in the study protocol. 
The purpose of this SAP is to provide details of the statistical analyses that have been outlined in 
the INCB 01158-101 Protocol. 
Detailed methodology of PK, 
 pharmacodynamic analyses will be presented 
separately. 


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2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS 
2.1. 
Protocol and Case Report Form Version 
This SAP is based on INCB 01158-101 Protocol Amendment 2-US 3 dated 10 NOV 2020 and 
CRFs approved 08 APR 2019.  Unless superseded by an amendment, this SAP will be effective 
for all subsequent protocol amendments and eCRF versions. 
2.2. 
Study Objectives and Endpoints 
Table 1 presents the objectives and endpoints. 
Table 1: 
Objectives and Endpoints 
Primary Objectives 
Primary Endpoints 
Parts 1a and 2 
To evaluate the safety and tolerability of 
INCB001158 for participants with 
advanced/metastatic and/or treatment refractory 
solid tumors 
AEs and changes in laboratory values, vital signs, 
and physical examinations 
Parts 1b, 1c, and 3 
To evaluate the safety and tolerability of 
INCB001158 in combination with pembrolizumab 
in participants with advanced/metastatic and/or 
treatment-refractory solid tumors 
AEs and changes in laboratory values, vital signs, 
and physical examinations 
Secondary Objectives 
Secondary Endpoints 
Parts 1a and 2 
To select the RP2D of INCB001158 for 
participants with advanced/metastatic solid 
tumors 
Based on an evaluation of AEs, PK, 
pharmacodynamics, and evidence of clinical 
activity 
Parts 1b and 3 
To select the RP2D of INCB001158 in 
combination with pembrolizumab for participants 
with advanced/metastatic solid tumors 
Based on an evaluation of AEs, PK, 
pharmacodynamics, and evidence of clinical 
activity 
Parts 1a, 1b, 1c, 2, and 3 
To evaluate the antitumor effect of INCB001158 
as monotherapy and in combination with 
pembrolizumab for participants with 
advanced/metastatic solid tumors 
Assessed by standard RECIST v1.1 criteria, 
except for pleural mesothelioma, which will be 
evaluated using modified RECIST criteria (ORR, 
BOR, DOR, and PFS) 
Determine PK of INCB001158 alone and in 
combination with pembrolizumab 
Cmax, tmax, AUCt, AUC0-12, and CL/F in participants 
with CrCL 30-49 mL/min (Part 1c only) or 
CrCL ≥ 50 mL/min (Parts 1a, 1b, 2, and 3) 


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Table 1: 
Objectives and Endpoints (Continued) 


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3. 
STUDY DESIGN 
Part 1 will consist of dose-escalation using a 3 + 3 design and will determine the RP2D of 
INCB001158 as monotherapy (Part 1a) and in combination with pembrolizumab (Part 1b and 
Part 1c); efficacy will also be explored. 
Part 2 and Part 3 will consist of tumor expansion cohorts and use a Simon 2-stage design 
(Simon 1989) to determine whether INCB001158 as monotherapy (Part 2) or in combination 
with pembrolizumab (Part 3) has sufficient antitumor activity to warrant further testing in 
subsequent clinical studies.  Part 2 and Part 3, respectively, will further evaluate the safety and 
tolerability of the RP2D of INCB001158 as monotherapy and in combination with 
pembrolizumab. 
The study design is illustrated in Figure 1.  The details can be found in the study protocol. 
Figure 1: 
Overall Study Design 
 


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3.1. 
Randomization 
Not applicable. 
3.2. 
Control of Type I Error 
All statistical analyses are exploratory in nature.  Unless otherwise specified, all CIs provided 
will be at the 95% confidence level. 
3.3. 
Sample Size Considerations 
Refer to Protocol Amendment 2-US 3 dated 10 NOV 2020 for the sample size considerations. 
3.4. 
Schedule of Assessments 
Refer to Protocol Amendment 2-US 3 dated 10 NOV 2020 for a full description of all study 
procedures and assessment schedules for this study. 
4. 
DATA HANDLING DEFINITIONS AND CONVENTIONS 
4.1. 
Scheduled Study Evaluations and Study Periods 
4.1.1. 
Day 1 
Day 1 is the date that the first dose of study drug (INCB001158 or pembrolizumab) is 
administered to the participants. 
4.1.2. 
Study Day 
If a visit/reporting date is on or after Day 1, then the study day at the visit/reporting date will be 
calculated as 
Day # = (visit/reporting date – Day 1 date + 1). 
If the visit/reporting date is before Day 1, then the study day at the visit/reporting date will be 
calculated as 
Day # = (visit/reporting date – Day 1 date). 
A study day of –1 indicates 1 day before Day 1. 
4.1.3. 
Baseline Value 
Baseline is the last nonmissing measurement obtained before the first administration of 
INCB001158 or pembrolizumab, unless otherwise defined. 


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When scheduled assessments and unscheduled assessments occur on the same day and the time 
of the assessment or time of first dose is not available, use the following convention to determine 
baseline: 
• If both a scheduled and an unscheduled visit are available on the day of the first dose 
and the time is missing, use the scheduled assessment as baseline. 
• If all scheduled assessments are missing on the day of the first dose and an 
unscheduled assessment is available, use the unscheduled assessment as baseline. 
4.1.4. 
Handling of Missing and Incomplete Dates 
In general, values for missing dates will not be imputed unless methods for handling missing 
dates are specified in this section or relevant sections.  The original reported dates collected on 
the eCRF should be used in all relevant listings.  The following rules will be used for handling 
partial dates for analyses requiring dates. 
When calculating the time since diagnosis of disease/cancer, a partial disease/cancer diagnosis 
date will be handled as follows in the calculation: 
• If only the day is missing, then the first day of the month will be used. 
• If both the month and day are missing, then 01 JAN of the year will be used. 
• If the diagnosis date is completely missing, then the time since diagnosis will not be 
calculated. 
When the date of the last dose is used in deriving variables such as duration of treatment or 
TEAE flag, a missing or partial date of the last dose will be handled as follows: 
• If only the day is missing, then the earlier date of the last day of the month or the date 
that the participant discontinued treatment will be used. 
• If both the month and day are missing, then the earlier date of 31 DEC of the year or 
the date that the participant discontinued treatment will be used.  
• Otherwise, the date that the participant discontinued treatment will be used as the date 
of the last dose. 
For relevant efficacy endpoints, a partial date of the death date will be handled as follows in the 
calculation: 
• If mmyyyy for the last known alive date = mmyyyy for the death date, then the death 
date will be set to the day after the last known alive date. 
• If mmyyyy for the last known alive date < mmyyyy for the death date, then the death 
date will be set to the first day of the death month. 
• Otherwise, the partial death date will not be imputed. 
4.1.5. 
Cycle Length and Duration 
Cycle 1 Day 1 is the day that the first dose of INCB001158 or pembrolizumab is administered.  
The scheduled cycle length is 28 days for participants in Parts 1a and 2.  The scheduled cycle 
length is 21 days for participants in Parts 1b, 1c, and 3. 


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INCB001158 dosing will not be adjusted for body weight or surface area.  Participants will 
continue to receive INCB001158 until disease progression (confirmed per iRECIST), intolerable 
toxicity, consent withdrawal, or the investigator determines that it is not in the participant's best 
interest to remain on-study. 
• INCB001158:  In Part 1, INCB001158 will be administrated PO BID with the dose 
corresponding to cohort assignment.  In Parts 2 and 3, INCB001158 will be 
administrated PO BID at the RP2D determined in Part 1 as long as the participant is 
deriving benefit and has not met any of the protocol-defined conditions for treatment 
withdrawal. 
• Pembrolizumab:  200 mg IV on Day 1 of each 21-day cycle.  The maximum 
duration of pembrolizumab treatment on-study will be up to 35 doses (approximately 
2 years). 
4.2. 
Variable Definitions 
The following variables will only be calculated if not reported on the eCRF. 
4.2.1. 
Age 
Participant age will be calculated as the integer part of the number of years from date of birth to 
the date of signing the ICF, using the following formula: 
Age = integer part of (date of informed consent – date of birth + 1) / 365.25. 
4.2.2. 
Prior and Concomitant Medication 
Prior medication is defined as any nonstudy medication started before the first dose of 
INCB001158 or pembrolizumab. 
Concomitant medication is defined as any nonstudy medication that is started accordingly: 
• Before the date of first administration of INCB001158 or pembrolizumab and is 
ongoing throughout the study or ends on/after the date of first study drug 
administration. 
• On/after the date of first administration of INCB001158 or pembrolizumab and is 
ongoing or ends during the course of study. 
A prior medication could also be classified as "both prior and concomitant medication" if the end 
date is on or after first dose of INCB001158 or pembrolizumab.  In the listing, it will be 
indicated whether a medication is only prior, only concomitant, or both prior and concomitant. 
For the purposes of analysis, all medications will be considered concomitant medications unless 
the medications can unequivocally be defined as not concomitant. 


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5. 
STATISTICAL METHODOLOGY 
5.1. 
General Methodology 
Unless otherwise noted, SAS® software (SAS Institute Inc, Cary, NC; v9 or later) will be used 
for the generation of all tables, graphs, and statistical analyses. 
Since this is an open-label clinical trial, descriptive statistics will be employed to analyze the 
data.  Descriptive summaries for continuous variables will include but not be limited to the 
number of observations, mean, standard deviation, median, minimum, and maximum.  
Descriptive summaries for categorical variables will include the number and percentage of 
participants in each category, and time-to-event variables will be summarized by Kaplan-Meier 
plots, medians, and ranges. 
Safety data may be presented by treatment group (INCB001158 monotherapy in Parts 1a and 2, 
INCB001158 + pembrolizumab in Parts 1b and 3, INCB001158 + pembrolizumab in participants 
with impaired renal functions in Part 1c) and by INCB001158 dose level. 
Efficacy data may be presented by treatment group and dose level in the dose-escalation parts 
(Parts 1a and 1b) and by treatment group and tumor type for participants in the expansion cohorts 
(Parts 2 and 3) with data from the renal impairment cohort (Part 1c) included with Part 3. 
Data listings will be created to support each table and to present all data collected. 
5.2. 
Treatment Groups 
In Part 1a, participants with advanced or metastatic solid tumors will be enrolled in INCB001158 
monotherapy treatment groups for dose escalation.  In Part 2, participants with specific tumor 
types will be enrolled to receive INCB001158 monotherapy at the RP2D. 
In Parts 1b and 1c, participants with advanced or metastatic solid tumors specified in the 
expansion cohorts will be enrolled in INCB001158 + pembrolizumab combination treatment 
groups for dose escalation (Part 1b) and safety assessments for participants with renal 
impairment (Part 1c).  In Part 3, participants with specific tumor types will be enrolled to receive 
INCB001158 at the RP2D + pembrolizumab.  Treatment groups and INCB001158 and 
pembrolizumab dose levels are outlined in Table 2. 
Table 2:  
Treatment Groups for Participants Enrolled 
Part 
Treatment Group 
Drug 
Dose 
Part 1a 
INCB001158 monotherapy 
INCB001158 
50-150 mg PO BID 
Part 1b 
INCB001158 + pembrolizumab 
INCB001158 
50-100 mg PO BID 
Pembrolizumab 
200 mg IV on Day 1 of each 21-day cycle 
Part 1c 
INCB001158 + pembrolizumaba 
INCB001158 
50 mg PO BID 
Pembrolizumab 
200 mg IV on Day 1 of each 21-day cycle 
Part 2 
INCB001158 monotherapy 
INCB001158 
RP2D from Part 1a 
Part 3 
INCB001158 + pembrolizumab 
INCB001158 
RP2D from Part 1b 
Pembrolizumab 
200 mg IV on Day 1 of each 21-day cycle 
a Participants with impaired renal function. 


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5.3. 
Analysis Populations 
5.3.1. 
Full Analysis Set 
The FAS will include all participants who received at least 1 dose of INCB001158 or 
pembrolizumab.  Participants will be analyzed according to the treatment to which they have 
been initially assigned. 
The FAS will be used for the summary of demographics, baseline characteristics, participant 
disposition, and analyses of PFS. 
5.3.2. 
Safety Population 
The safety population will include all participants who received at least 1 dose of INCB001158 
or pembrolizumab.  Treatment groups for this population will be determined according to the 
actual treatment the participant received regardless of assigned study treatment. 
All safety analyses will be conducted using the safety population. 
5.3.3. 
DLT-Evaluable Population in Dose Escalation 
The DLT-evaluable population in the dose-escalation part will include participants treated with 
the assigned dose level of INCB001158 who have had a DLT or those who have received at least 
75% of the planned doses (ie, ≥ 32 of the maximum 42 doses to be given in a 21-day cycle or 
≥ 42 of the maximum 56 doses to be given in a 28-day cycle).  For participants in Part 1b, 
participants must receive the planned doses of pembrolizumab in Cycle 1 in order to be 
evaluable for DLTs.  This population will be considered evaluable for determining the 
tolerability of the given dose. 
5.3.4. 
Efficacy-Evaluable Population 
See Protocol Section 15.3.3.  The efficacy-evaluable population will be used for the analysis of 
efficacy data except PFS. 


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6. 
BASELINE, EXPOSURE, AND DISPOSITION 
Appendix A provides a list of data displays.  Sample data displays are included in a separate 
document. 
6.1. 
Demographics, Baseline Characteristics, and Disease History 
6.1.1. 
Demographics and Baseline Characteristics 
The following demographics and baseline characteristics will be summarized for the FAS:  age, 
sex, race, ethnicity, weight, and height. 
6.1.2. 
Baseline Disease Characteristics and Disease History 
The following baseline disease characteristics may be summarized for all or applicable 
participants in the FAS:  primary diagnosis, time since diagnosis, time since metastatic disease or 
diagnosis of locally advanced inoperable cancer, stage at initial diagnosis, disease histology, 
histological grade, P16/HPV (for participants with SCCHN)/PD-L1 status, MSI-h/dMMR status, 
mutation status (listing), and ECOG performance status. 
6.1.3. 
Prior Therapy 
The number of participants receiving any prior therapy and the number of prior systemic cancer 
therapy regimens will be summarized for all participants in the FAS.  The regimen name, 
component drugs, start and stop dates, purpose of the regimen, best response, reason for 
discontinuation, and date of relapse/progression will be listed. 
For participants who received prior radiation, the body site, start and stop dates, and total dose 
will be listed. 
For participants who had prior surgery or surgical procedure for the malignancies under study, 
the date and description of the surgery/procedure will be listed. 
6.1.4. 
Medical History 
For participants in the FAS who experienced past and/or concomitant medical conditions, the 
medical history condition/event, start and end dates, and whether the condition was ongoing or 
intermittent will be listed. 
6.2. 
Disposition of Participant 
The number and percentage of participants who were enrolled, who were treated, who were 
ongoing with study treatment, who discontinued study treatment with a primary reason for 
discontinuation, who were still in the study, who completed the study, and who withdrew from 
the study with a primary reason for withdrawal will be summarized for the FAS.  The number of 
participants enrolled by country and/or site will also be provided by treatment group. 
6.3. 
Protocol Deviations 
Protocol deviations recorded may be summarized and listed. 


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6.4. 
Exposure 
For participants in the safety population, exposure to INCB001158 and pembrolizumab will be 
summarized descriptively as follows: 
• Exposure to INCB001158 
− Total actual dose (mg):  total actual dose taken of INCB001158. 
− Duration of treatment with INCB001158 (days):  date of last dose of 
INCB001158 – date of first dose of INCB001158 + 1. 
− Average daily dose of INCB001158 (mg/day):  total actual INCB001158 dose 
taken (mg) / duration of treatment with INCB001158 with nonzero dosing (days). 
• Exposure to pembrolizumab 
− Number of cycles:  number of cycles with a nonzero dose of pembrolizumab. 
− Total number of infusions:  total number of infusions per participant with a 
nonzero dose of pembrolizumab. 
− Total dose administered (mg):   sum of the cumulative dose of pembrolizumab 
that has been administered to the participant. 
For an infusion i, let Ci be the concentration (mg/mL) of pembrolizumab and Vi 
be the total volume administered (in mL) reported on the pembrolizumab dosing 
eCRF; let N be the total number of infusions: 
total dose administered (mg) = ∑
𝐶𝑖× 𝑉𝑖
𝑁
𝑖=1
. 
− Average dose (mg):  total dose administered (mg) / the total number of infusions. 
6.5. 
Study Drug Compliance 
For participants in the safety population, overall compliance (%) for INCB001158 will be 
calculated as follows: 
compliance (%) = 100  [total dose actually taken] / [total prescribed dose]. 
The total prescribed dose is defined as the sum of the doses prescribed by the investigator 
accounting for dose modifications. 
The total actual dose taken will be calculated based on information entered on the Drug 
Accountability eCRF.  If there are dispensed drugs that have not been returned yet, the actual 
dose taken starting from the dispense date of the unreturned drugs will be imputed by the dose 
taken as reported on the Dosing eCRF. 
6.6. 
Prior and Concomitant Medication 
Prior medications and concomitant medications will be coded using the WHO Drug Dictionary.  
The number and percentage of participants in the FAS for each prior and concomitant medication 
will be summarized by WHO drug class and WHO drug PT. 


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7. 
EFFICACY 
Appendix A provides a list of data displays.  Sample data displays are included in a separate 
document. 
7.1. 
General Considerations 
This study had no primary efficacy endpoint.  The secondary efficacy endpoints include ORR, 
BOR, DOR, and PFS by investigator assessment based on RECIST v1.1. 
7.2. 
Efficacy Hypotheses 
Each Simon 2-stage design (Simon 1989) will test the null hypothesis that the true ORR is less 
than or equal to the clinically insignificant response rate p0% against the alternative hypothesis 
that the true ORR is equal to or greater than the target rate of p1%.  For each Simon 2-stage 
design, the value for p0 is determined by a historical response rate (refer to Protocol 
Section 15.2). 
7.3. 
Analysis of the Efficacy Parameters 
7.3.1. 
Response Criteria 
Overall disease status will be categorized using RECIST v1.1 (Eisenhauer et al 2009) based on 
investigator assessment.  Participants will have their overall response evaluated as CR, PR, SD, 
non-CR/non-PD (only for participants with nonmeasureable disease alone at baseline), PD, or 
NE at each postbaseline radiologic assessment based on changes in target lesions, nontarget 
lesions, and appearance of new lesions. 
7.3.2. 
Unconfirmed and Confirmed Best Overall Response 
In general, under RECIST v1.1, the unconfirmed best overall response is the best response 
recorded postbaseline prior to and including the first PD, in the order of CR, PR, SD 
(non-CR/non-PD), PD, and NE.  The best overall response will be determined from response 
assessments prior to or on the same day as new anticancer therapy.  If any alternative cancer 
therapy is taken while on study, any subsequent assessments will be excluded from the best 
overall response determination. 
In the case of SD (non-CR/non-PD), measurements must meet the SD (non-CR/non-PD) criteria 
at least once after the date of first dose at a minimum interval of 8 weeks.  Participants that fail to 
meet this criterion will have best overall response of PD if the next available assessment 
indicates PD or NE if there is no additional assessment available. 
The participant's confirmed best overall response assessment will depend on the achievement of 
both measurement and confirmation criteria in Table 3. 


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Table 3: 
Confirmed Response Based on Subsequent Assessments 
First Timepoint Response 
Second Timepoint Response 
Confirmed Response 
CR 
CR 
CR or SD or NEa 
CR 
PRb 
SD or NEc 
CR 
PRa 
SD or NEa 
CR 
Non-CR/Non-PDd 
Non-CR/Non-PDa or NE 
CR 
PD 
SD or NEa or Non-CR/Non-PDa 
CR 
NE 
SD or NEa or Non-CR/Non-PDa 
CR 
No further evaluation 
SD or NEa or Non-CR/Non-PDa 
PR 
CR 
PR or SD or NEe 
PR 
PR 
PR or SD or NEa 
PR 
SD 
SD or NEa 
PR 
NE 
SD or NEa 
PR 
PD 
SD or NEa 
PR 
No further evaluation 
SD or NEa 
SD 
CR 
SD or NEa 
SD 
PR 
SD or NEa 
SD 
SD 
SD or NEa 
SD 
PD 
SD or NEa 
SD 
NE 
SD or NEa 
SD 
No further evaluation 
SD or NEa 
Non-CR/Non-PDa 
CR 
Non-CR/Non-PDa or NE 
Non-CR/Non-PDa 
Non-CR/Non-PDa 
Non-CR/Non-PDa or NE 
Non-CR/Non-PDa 
PD 
Non-CR/Non-PDa or NE 
Non-CR/Non-PDa 
NE 
Non-CR/Non-PDa or NE 
Non-CR/Non-PDa 
No further evaluation 
Non-CR/Non-PDa or NE 
PD 
No further evaluation 
PD 
NE 
CR 
NE 
NE 
PR 
NE 
NE 
SD 
NE 
NE 
Non-CR/Non-PDa 
NE 
NE 
PD 
NE 
NE 
NE 
NE 
NE 
No further evaluation 
NE 
Note:  A confirmed response of SD can only be made after the participant is on-study for a minimum of 8 weeks according to 
study protocol or SAP.  If the participant is on-study less than 8 weeks, any tumor assessment indicating stable disease before 
this time period will have a confirmed response of NE.  NE is not required to be confirmed according to the table. 
Note:  Subsequent documentation of CR may provide confirmation of a previously identified CR for participants where the 
second integrated response was NE.  Subsequent documentation of PR may provide confirmation of a previously identified PR 
for participants where the second integrated response was NE or SD.  If the third tumor assessment confirms the CR (or PR) 
then the confirmed response will be CR (or PR).  Only 1 intervening NE is allowed between CRs/PRs.  For example:  
CR NE CR = CR; PR NE PR/CR = PR.  Additionally, 1 SD (≥ 25% reduction in target lesions comparing with baseline) is 
allowed between PRs (eg, PR SD PR/CR = PR).  Note:  in the following scenario, PR SD NE PR, the second PR is not a 
confirmed PR. 


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a Confirmed response is CR if gap (4 weeks) is met.  Otherwise, confirmed response is SD if at least 8 weeks on study, or NE if 
within 8 weeks on study. 
a Special case programming:  assign PR or SD following CR as PD in confirmed response. 
a Confirmed response will be SD if the first tumor assessment is at least 8 weeks on-study.  Otherwise, the confirmed response 
will be NE. 
a Non-CR/Non-PD applies to participants with nonmeasurable disease at baseline.  A confirmed response of Non-CR/Non-PD 
can only be made after the participant is on-study for a minimum of 8 weeks according to study protocol or SAP.  If the 
participant is on-study less than 8 weeks, any tumor assessment indicating stable disease before this time period will have a 
confirmed response of NE. 
a Confirmed response is PR if gap (4 weeks) is met.  Otherwise, confirmed response is SD if at least 8 weeks/days on study, or 
NE if within 8 weeks on study. 
7.3.3. 
Objective Response Rate 
A participant is considered an objective responder if they have a best overall response of CR or 
PR before first PD and start of any subsequent anticancer therapy. 
The ORR based on both unconfirmed and confirmed best overall responses will be estimated 
with 95% CIs.  Confidence intervals will be calculated based on the exact method for binomial 
distributions. 
7.3.4. 
Duration of Response 
For objective responders, the DOR is the time from the first overall response contributing to an 
objective response to the earlier of the participant's death or first overall response of PD as 
assessed by RECIST v1.1 occurring after the first overall response contributing to the objective 
response.  Partial death dates will be handled using the rules described in Section 4.1.4.  
Censoring of DOR will follow the same algorithm as the censoring of PFS (see Section 7.3.6). 
Kaplan-Meier curves for DOR based on both unconfirmed and confirmed responses will be 
presented by treatment group.  The Kaplan-Meier estimate of median DOR will be presented 
with its 95% CI.  The 95% CI will be calculated using the generalization of Brookmeyer and 
Crowley's method (1982) with log-log transformation (Klein and Moeschberger 1997). 
Duration of response analyses will only include responders, and any Kaplan-Meier analyses will 
only be provided if appropriate.  For example, if there are a very small number of responders, 
Kaplan-Meier analysis will not be provided. 
7.3.5. 
Largest Percentage Reduction in Sum of Diameters of Target Lesions 
For each participant in the FAS with target lesions at baseline, target lesion sizes will be 
measured by the sum of the diameters.  The best percent change from baseline, defined as the 
largest decrease in target lesion size for each participant, will be summarized descriptively, and a 
waterfall plot of the best percent change will be generated.  Note that for participants who only 
have increases in target lesion sizes from baseline, the smallest increase will be considered as the 
best change from baseline. 
Per RECIST v1.1 criteria, target lesions considered "too small to measure" will be assigned a 
default value of 5 mm for purposes of this analysis.  Likewise, target lesions identified as "not 
present" at postbaseline assessments will be assigned 0 mm for this analysis.  In the event a 
target lesion is unaccounted for in a particular postbaseline timepoint (ie, assessment missing or 
NE), then the overall sum of diameters for target lesions will not be evaluable for that 
postbaseline timepoint. 


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7.3.6. 
Progression-Free Survival 
Progression-free survival is defined as the length of time between the date of first dose and the 
earlier of death or PD as assessed by RECIST v1.1 per investigator assessment.  Partial death 
dates will be handled using the rules described in Section 4.1.4.  Censoring for PFS will follow 
the algorithm outlined in Table 4, which is based on FDA guidance (FDA 2015, FDA 2018). 
Table 4: 
Evaluation and Censoring of Progression-Free Survival 
Situation 
Outcome 
Date of Progression or Censoring 
No baseline tumor assessments 
Censored 
Day 1 
No valid postbaseline response 
assessments 
Censored 
Day 1 
Progression documented between 
scheduled response assessments 
Progressed 
Date of first overall response of PD 
No progression 
Censored 
Date of last valid radiologic assessment 
(not NE and not missing) 
Study discontinuation for 
undocumented progression 
Censored 
Date of last valid radiologic assessment 
(not NE and not missing) 
Study discontinuation for toxicity 
or other reason 
Censored 
Date of last valid radiologic assessment 
(not NE and not missing) 
New anticancer treatment started 
Censored 
Date of last valid radiologic assessment 
(not NE and not missing) on/before starting a 
new anticancer treatment 
Death before first progressive 
response assessment 
Progressed 
Date of death 
Death between adequate response 
assessments 
Progressed 
Date of death 
Death or progression after 2 or 
more missed assessments 
Censored 
Date of last valid radiologic assessment 
(not NE and not missing) 
Kaplan-Meier curves for PFS will be presented by treatment groups.  The Kaplan-Meier estimate 
of median PFS will be presented with its 95% CI.  The 95% CI will be calculated using the 
generalization of Brookmeyer and Crowley's method (1982) with log-log transformation (Klein 
and Moeschberger 1997). 


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8. 
SAFETY AND TOLERABILITY 
Appendix A provides a list of data displays.  Sample data displays are included in a separate 
document. 
8.1. 
General Considerations 
Summary tables may be replaced with listings when appropriate.  For instance, an AE frequency 
table may be replaced with a listing if it only contains a few unique PTs reported on relatively 
few participants.  Unless otherwise stated, table summaries will be limited to TEAEs. 
8.2. 
Adverse Events 
8.2.1. 
Adverse Event Definitions 
A TEAE is any AE either reported for the first time or worsening of a pre-existing event after the 
first dose of study drug.  Analysis of AEs (as discussed below) will be limited to TEAEs, but 
data listings will include all AEs regardless of their timing in relation to study drug 
administration.  For purposes of analysis, all AEs will be considered TEAEs unless the AE can 
unequivocally be defined as not treatment-emergent. 
Adverse events will be tabulated by MedDRA (v19.0) PT and SOC.  Severity of AEs will be 
graded using the NCI CTCAE v4.03.  The CTCAE reporting guidelines and grading details are 
available on the Cancer Therapy Evaluation Program website. 
The subset of TEAEs considered by the investigator to be related to any study drug will be 
considered to be treatment-related TEAEs.  If the investigator does not specify the relationship of 
the TEAE to study drug, the TEAE will be considered to be treatment-related.  The incidence of 
TEAEs and treatment-related TEAEs will be tabulated.  In addition, serious TEAEs will also be 
tabulated. 
8.2.2. 
Dose-Limiting Toxicities 
The participants with DLTs and the type of DLT will be listed by dose level. 
8.2.3. 
Adverse Event Summaries 
An overall summary of AEs by treatment group will include the following: 
• Number (%) of participants who had any TEAEs 
• Number (%) of participants who had any serious TEAEs 
• Number (%) of participants who had any Grade 3 or higher TEAEs 
• Number (%) of participants who had any TEAEs related to INCB001158 
• Number (%) of participants who had any TEAEs related to pembrolizumab 
• Number (%) of participants who had any TEAE leading to temporary interruption of 
INCB001158  
• Number (%) of participants who had any TEAE leading to temporary interruption of 
pembrolizumab  


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• Number (%) of participants who had any TEAE leading to permanent discontinuation 
of INCB001158 
• Number (%) of participants who had any TEAE leading to permanent discontinuation 
of pembrolizumab  
• Number (%) of participants who had any TEAE leading to INCB001158 dose 
reductions  
• Number (%) of participants who had any fatal TEAEs 
• Number (%) of participants who had an irAE 
An overall summary of irAEs by treatment group will include the following: 
• Number (%) of participants who had an irAE 
• Number (%) of participants who had any Grade 3 or higher irAEs 
• Number (%) of participants who had any irAEs related to INCB001158 
• Number (%) of participants who had any irAEs related to pembrolizumab 
• Number (%) of participants who had any irAEs leading to discontinuation of 
INCB001158  
• Number (%) of participants who had any irAEs leading to discontinuation of 
pembrolizumab  
• Number (%) of participants who had any irAEs leading to discontinuation of 
INCB001158 and pembrolizumab  
• Number (%) of participants who had any irAEs leading to discontinuation of 
INCB001158 or pembrolizumab  
• Number (%) of participants who had irAEs leading to INCB001158 dose interruption 
and/or reductions 
• Number (%) of participants who had irAEs leading to pembrolizumab dose 
interruption  
• Number (%) of participants who had any fatal irAEs 
The following summaries will be produced by MedDRA term (if 10 or fewer participants appear 
in a table, a listing may be appropriate): 
• Summary of TEAEs by MedDRA SOC and PT 
• Summary of TEAEs by MedDRA PT in decreasing order of frequency 
• Summary of Grade 3 or higher TEAEs by MedDRA SOC and PT 
• Summary of Grade 3 or higher TEAEs by MedDRA PT in decreasing order of 
frequency 
• Summary of serious TEAEs by MedDRA PT in decreasing order of frequency 


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• Summary of pembrolizumab treatment-related TEAEs by PT in decreasing order of 
frequency  
• Summary of INCB001158 treatment-related TEAEs by MedDRA PT in decreasing 
order of frequency 
• Summary of TEAEs with a fatal outcome by MedDRA SOC and PT 
• Summary of TEAEs leading to INCB001158 dose reduction by MedDRA SOC and 
PT 
• Summary of TEAEs leading to discontinuation of INCB001158 by MedDRA SOC 
and PT 
• Summary of TEAEs leading to discontinuation of pembrolizumab by MedDRA SOC 
and PT 
• Summary of immune-related TEAEs by SOC and PT 
8.3. 
Clinical Laboratory Tests 
8.3.1. 
Laboratory Value Definitions 
Laboratory values and change from baseline values will be summarized descriptively by visit.  
The baseline value will be determined using the nonmissing values collected before the first dose 
using the priority defined in Table 5.  The last record before administration in the highest priority 
will be considered the baseline record.  For baseline laboratory candidates with the same date 
and time in the same priority category, additional rules may be provided after consultation with 
the medical monitor to delineate which value will be defined as baseline. 
Table 5: 
Identification of Baseline Record 
Priority 
Laboratory Visit 
Central or Local Laboratory 
1 
Scheduled 
Central 
2 
Scheduled 
Local 
3 
Unscheduled 
Central 
4 
Unscheduled 
Local 
Laboratory test values will be assessed for severity based on the numerical component of 
CTCAE v4.03. 
8.3.2. 
Laboratory Value Summaries 
All test results and associated normal ranges from central laboratories will be reported in SI 
units.  Any laboratory test results and associated normal ranges from local laboratories will be 
converted to SI units. 
When there are multiple nonmissing laboratory values for a participant's particular test within a 
visit window, the convention described in Table 6 will be used to determine the record used for 
by-visit tabulations and summaries.  If a tie still exists, the laboratory value with the smallest 
laboratory sequence number will be used. 


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Table 6: 
Identification of Records for Postbaseline By-Visit Summaries 
Priority 
Laboratory Visit 
Central or Local 
Laboratory 
Proximity to Visit 
Window 
Tiebreaker 
1 
Scheduled 
Central 
In-window 
Use smallest 
laboratory sequence 
number 
2 
Scheduled 
Local 
In-window 
3 
Unscheduled 
Central 
In-window 
4 
Unscheduled 
Local 
In-window 
5 
Scheduled 
Central 
Out-of-window 
6 
Scheduled 
Local 
Out-of-window 
For coagulation and urinalysis laboratory values, listings will be provided. 
Numeric chemistry and hematology laboratory values will be summarized descriptively in SI 
units, and non-numeric test values will be tabulated when necessary.  
Severity grades will be assigned to laboratory test values based on the numerical component of 
CTCAE v4.03.  The number of participants who experienced worsening of laboratory 
abnormalities will be summarized by maximum severity. 
In cases where differentials of hematology parameters are obtained without corresponding 
absolute count data, efforts will be made to investigate if the conversion to an absolute value will 
lead to additional abnormalities.  This will be discussed with the clinical team regarding 
appropriate documentation and action. 
8.4. 
Vital Signs 
Values at each scheduled visit, change, and percentage change from baseline for vital signs, 
including systolic blood pressure and diastolic blood pressure will be summarized descriptively.  
Listings will be provided for all vital-sign parameters. 
Normal ranges for vital sign values are defined in Table 7.  For participants exhibiting vital sign 
abnormalities, the abnormal values will be listed along with their assigned treatment group.   
Table 7: 
Normal Ranges for Vital Sign Values 
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 
≤ 38°C 
≥ 35.5°C 
Respiratory rate 
≤ 24 breaths/min 
≥ 8 breaths/min 


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8.5. 
Electrocardiograms 
Twelve-lead ECGs including PR, RR, QT, QRS, and QTcF intervals will be obtained for each 
participant during the study.  Baseline will be determined as the average of all nonmissing values 
before the first administration of INCB001158 or pembrolizumab.  Listings will be provided for 
all ECG parameters. 
Normal ranges for ECG values are defined in Table 8.  Electrocardiogram values will also be 
considered abnormal if the absolute percentage change from baseline is more than 25% (30% for 
QRS interval).  Participants exhibiting ECG abnormalities will be listed with study visit and 
assigned treatment group.  Outliers of QT and QTcF values, defined as absolute values 
> 450 milliseconds, > 500 milliseconds, or change from baseline > 30 milliseconds, will be 
summarized. 
Table 8: 
Normal Ranges for Electrocardiogram Intervals 
Parameter 
High Threshold 
Low Threshold 
PR 
≤ 220 ms 
≥ 75 ms 
RR 
≤ 1330 ms 
≥ 600 ms 
QT 
≤ 500 ms 
≥ 300 ms 
QRS 
≤ 120 ms 
≥ 50 ms 
QTcF 
≤ 450 ms 
≥ 295 ms 
9. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN 
All versions of the SAP are listed in Table 9. 
Table 9: 
Statistical Analysis Plan Versions 
SAP Version 
Date 
Original 
22 FEB 2021 
9.1. 
Changes to Protocol-Defined Analyses 
Not applicable. 
9.2. 
Changes to the Statistical Analysis Plan 
Not applicable. 


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10. 
REFERENCES 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 
1982;38:29-41. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: 
revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-247. 
Food and Drug Administration. Guidance for Industry: Clinical Trial Endpoints for the Approval 
of Non-Small Cell Lung Cancer Drugs and Biologics. 2015. 
Food and Drug Administration. Guidance for Industry: Clinical Trial Endpoints for the Approval 
of Cancer Drugs and Biologics. 2018. 
Klein JP, Moeschberger ML. Survival analysis: techniques for censored and truncated data. New 
York: Springer-Verlag. 1997. 
Simon R. Optimal two-stage designs for Phase II clinical trials. Control Clin Trials 
1989;10:1-10. 


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APPENDIX A. PLANNED TABLES, FIGURES, AND LISTINGS 
This appendix provides a list of the planned tables, figures, and listings for the Clinical Study 
Report. 
The lists of tables, figures, and listings are to be used as guidelines.  Modifications of the lists 
that do not otherwise affect the nature of the analysis will not warrant an amendment to the SAP. 
Tables 
Table No. 
Title 
Population 
Standard 
Baseline and Demographic Characteristics 
1.1  Disposition 
1.1.1.1 
Analysis Populations  
Part 1a, Part 2 FAS 
X 
1.1.1.2 
Analysis Populations  
Part 1b, Part 3 FAS 
X 
1.1.1.3 
Analysis Populations 
Part 1c FAS 
X 
1.1.2.1 
Summary of Participant Disposition 
Part 1a, Part 2 FAS 
X 
1.1.2.2 
Summary of Participant Disposition 
Part 1b, Part 3 FAS 
X 
1.1.2.3 
Summary of Participant Disposition 
Part 1c FAS 
X 
1.1.3.1 
Summary of Number of Participants Enrolled by Country and 
Site 
FAS 
X 
1.1.4.1 
Summary of Protocol Deviations 
FAS 
X 
1.2  Demography and Baseline Characteristics 
1.2.1.1 
Summary of Demographics and Baseline Characteristics 
Part 1a, Part 2 FAS 
X 
1.2.1.2 
Summary of Demographics and Baseline Characteristics 
Part 1b, Part 3 FAS 
X 
1.2.1.3 
Summary of Demographics and Baseline Characteristics 
Part 1c FAS 
X 
1.3  Baseline Disease Characteristics 
1.3.1.1 
Summary of Baseline Disease Characteristics 
Part 1a, Part 2 FAS 
X 
1.3.1.2 
Summary of Baseline Disease Characteristics 
Part 1b, Part 3 FAS 
X 
1.3.1.3 
Summary of Baseline Disease Characteristics 
Part 1c FAS 
X 
1.3.2.1 
Summary of Prior Systemic Cancer Therapy  
Part 1a, Part 2 FAS 
 
1.3.2.2 
Summary of Prior Systemic Cancer Therapy  
Part 1b, Part 3 FAS 
 
1.3.2.3 
Summary of Prior Systemic Cancer Therapy  
Part 1c FAS 
 
1.4  Prior Medication and Concomitant Medication 
1.4.1.1 
Summary of Prior Medications 
Part 1a, Part 2 FAS 
X 
1.4.1.2 
Summary of Prior Medications 
Part 1b, Part 3 FAS 
X 
1.4.1.3 
Summary of Prior Medications 
Part 1c FAS 
X 
1.4.2.1 
Summary of Concomitant Medications 
Part 1a, Part 2 FAS 
X 
1.4.2.2 
Summary of Concomitant Medications 
Part 1b, Part 3 FAS 
X 
1.4.2.3 
Summary of Concomitant Medications 
Part 1c FAS 
X 
Efficacy 
2.1  Efficacy 
2.1.1.1.1 
Summary of Confirmed Best Overall Response and Objective 
Response Rate Under RECIST v1.1 
Part 1a Efficacy 
Evaluable Population 
 
2.1.1.1.2 
Summary of Confirmed Best Overall Response and Objective 
Response Rate Under RECIST v1.1 
Part 1b Efficacy 
Evaluable Population 
 
2.1.1.1.3 
Summary of Confirmed Best Overall Response and Objective 
Response Rate Under RECIST v1.1 
Part 2 Efficacy 
Evaluable Population 
 


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Table No. 
Title 
Population 
Standard 
2.1.1.1.4 
Summary of Confirmed Best Overall Response and Objective 
Response Rate Under RECIST v1.1 
Part 1c, Part 3 Efficacy 
Evaluable Population 
 
2.1.1.2.1 
Summary of Confirmed Duration of Response Under RECIST 
v1.1 
Part 1a Efficacy 
Evaluable Population 
 
2.1.1.2.2 
Summary of Confirmed Duration of Response Under RECIST 
v1.1 
Part 1b Efficacy 
Evaluable Population 
 
2.1.1.2.3 
Summary of Confirmed Duration of Response Under RECIST 
v1.1 
Part 2 Efficacy 
Evaluable Population 
 
2.1.1.2.4 
Summary of Confirmed Duration of Response Under RECIST 
v1.1 
Part 1c, Part 3 Efficacy 
Evaluable Population 
 
2.1.1.3.1 
Summary of Unconfirmed Best Overall Response and 
Objective Response Rate Under RECIST v1.1 
Part 1a Efficacy 
Evaluable Population 
 
2.1.1.3.2 
Summary of Unconfirmed Best Overall Response and 
Objective Response Rate Under RECIST v1.1 
Part 1b Efficacy 
Evaluable Population 
 
2.1.1.3.3 
Summary of Unconfirmed Best Overall Response and 
Objective Response Rate Under RECIST v1.1 
Part 2 Efficacy 
Evaluable Population 
 
2.1.1.3.4 
Summary of Unconfirmed Best Overall Response and 
Objective Response Rate Under RECIST v1.1 
Part 1c, Part 3 Efficacy 
Evaluable Population 
 
2.1.1.4.1 
Summary of Unconfirmed Duration of Response Under 
RECIST v1.1 
Part 1a Efficacy 
Evaluable Population 
 
2.1.1.4.2 
Summary of Unconfirmed Duration of Response Under 
RECIST v1.1 
Part 1b Efficacy 
Evaluable Population 
 
2.1.1.4.3 
Summary of Unconfirmed Duration of Response Under 
RECIST v1.1 
Part 2 Efficacy 
Evaluable Population 
 
2.1.1.4.4 
Summary of Unconfirmed Duration of Response Under 
RECIST v1.1 
Part 1c, Part 3 Efficacy 
Evaluable Population 
 
2.1.2.1 
Summary of Progression-Free Survival Under RECIST v1.1 
Part 1a FAS 
 
2.1.2.2 
Summary of Progression-Free Survival Under RECIST v1.1 
Part 1b FAS 
 
2.1.2.3 
Summary of Progression-Free Survival Under RECIST v1.1 
Part 2 FAS 
 
2.1.2.4 
Summary of Progression-Free Survival Under RECIST v1.1 
Part 1c, Part 3 FAS 
 
Safety 
3.1  Dose Exposure 
3.1.1.1 
Summary of Total Dose, Duration of Exposure, and Average 
Daily Dose of INCB001158 
Part 1a, Part 2 Safety 
X 
3.1.1.2 
Summary of Total Dose, Duration of Exposure, and Average 
Daily Dose of INCB001158 
Part 1b, Part 3 Safety 
X 
3.1.1.3 
Summary of Total Dose, Duration of Exposure, and Average 
Daily Dose of INCB001158 
Part 1c Safety 
X 
3.1.2.2 
Summary of Pembrolizumab Exposure 
Part 1b, Part 3 Safety 
X 
3.1.2.3 
Summary of Pembrolizumab Exposure 
Part 1c Safety 
X 
3.2  Adverse Events 
3.2.1.1 
Overall Summary of Treatment-Emergent Adverse Events 
Part 1a, Part 2 Safety 
X 
3.2.1.2 
Overall Summary of Treatment-Emergent Adverse Events 
Part 1b, Part 3 Safety 
X 
3.2.1.4 
Overall Summary of Immune-Related Adverse Event 
Part 1a, Part 2 Safety 
 
3.2.1.5 
Overall Summary of Immune-Related Adverse Event 
Part 1b, Part 3 Safety 
 
3.2.2.1 
Summary of Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term 
Part 1a, Part 2 Safety 
X 


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Table No. 
Title 
Population 
Standard 
3.2.2.2 
Summary of Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term 
Part 1b, Part 3 Safety 
X 
3.2.3.1 
Summary of Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of Frequency 
Part 1a, Part 2 Safety 
X 
3.2.3.2 
Summary of Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of Frequency 
Part 1b, Part 3 Safety 
X 
3.2.5.1 
Summary of Grade 3 or Higher Treatment-Emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term 
Part 1a, Part 2 Safety 
X 
3.2.5.2 
Summary of Grade 3 or Higher Treatment-Emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term 
Part 1b, Part 3 Safety 
X 
3.2.6.1 
Summary of Grade 3 or Higher Treatment-Emergent Adverse 
Events by MedDRA Preferred Term in Decreasing Order of 
Frequency 
Part 1a, Part 2 Safety 
X 
3.2.6.2 
Summary of Grade 3 or Higher Treatment-Emergent Adverse 
Events by MedDRA Preferred Term in Decreasing Order of 
Frequency 
Part 1b, Part 3 Safety 
X 
3.2.8.1 
Summary of Serious Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of Frequency 
Part 1a, Part 2 Safety 
X 
3.2.8.2 
Summary of Serious Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of Frequency 
Part 1b, Part 3 Safety 
X 
3.2.10.1.1 
Summary of INCB001158 Treatment-Related 
Treatment-Emergent Adverse Events by MedDRA Preferred 
Term in Decreasing Order of Frequency 
Part 1a, Part 2 Safety 
X 
3.2.10.1.2 
Summary of INCB001158 Treatment-Related 
Treatment-Emergent Adverse Events by MedDRA Preferred 
Term in Decreasing Order of Frequency 
Part 1b, Part 3 Safety 
X 
3.2.10.2.2 
Summary of Pembrolizumab Treatment-Related 
Treatment-Emergent Adverse Events by MedDRA Preferred 
Term in Decreasing Order of Frequency 
Part 1b, Part 3 Safety 
X 
3.2.13.1 
Summary of Treatment-Emergent Adverse Events With a Fatal 
Outcome by MedDRA System Organ Class and Preferred 
Term 
Part 1a, Part 2 Safety 
X 
3.2.13.2 
Summary of Treatment-Emergent Adverse Events With a Fatal 
Outcome by MedDRA System Organ Class and Preferred 
Term 
Part 1b, Part 3 Safety 
X 
3.2.14.1 
Summary of Treatment-Emergent Adverse Events Leading to 
INCB001158 Dose Reduction by MedDRA System Organ 
Class and Preferred Term 
Part 1a, Part 2 Safety 
X 
3.2.14.2 
Summary of Treatment-Emergent Adverse Events Leading to 
INCB001158 Dose Reduction by MedDRA System Organ 
Class and Preferred Term 
Part 1b, Part 3 Safety 
X 
3.2.15.1.1 
Summary of Treatment-Emergent Adverse Events Leading to 
Discontinuation of INCB001158 by MedDRA System Organ 
Class and Preferred Term 
Part 1a, Part 2 Safety 
X 
3.2.15.1.2 
Summary of Treatment-Emergent Adverse Events Leading to 
Discontinuation of INCB001158 by MedDRA System Organ 
Class and Preferred Term 
Part 1b, Part 3 Safety 
X 
3.2.15.2.2 
Summary of Treatment-Emergent Adverse Events Leading to 
Discontinuation of Pembrolizumab by MedDRA System 
Organ Class and Preferred Term 
Part 1b, Part 3 Safety 
X 


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Table No. 
Title 
Population 
Standard 
3.2.16.1 
Summary of Immune-Related Treatment-Emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term 
Part 1a, Part 2 Safety 
X 
3.2.16.2 
Summary of Immune-Related Treatment-Emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term 
Part 1b, Part 3 Safety 
X 
3.3  Laboratory 
3.3.1.1.1 
Summary of Laboratory Values - Hematology 
Part 1a, Part 2 Safety 
X 
3.3.1.1.2 
Summary of Laboratory Values - Hematology 
Part 1b, Part 3 Safety 
X 
3.3.1.2.1 
Summary of Laboratory Values - Chemistry 
Part 1a, Part 2 Safety 
X 
3.3.1.2.2 
Summary of Laboratory Values - Chemistry 
Part 1b, Part 3 Safety 
X 
3.3.2.1.1 
Treatment-Emergent Worsening of Laboratory Abnormalities - 
Hematology 
Part 1a, Part 2 Safety 
X 
3.3.2.1.2 
Treatment-Emergent Worsening of Laboratory Abnormalities - 
Hematology 
Part 1b, Part 3 Safety 
X 
3.3.2.2.1 
Treatment-Emergent Worsening of Laboratory Abnormalities - 
Chemistry 
Part 1a, Part 2 Safety 
X 
3.3.2.2.2 
Treatment-Emergent Worsening of Laboratory Abnormalities - 
Chemistry 
Part 1b, Part 3 Safety 
X 
3.4  Vital Signs 
3.4.1.1 
Summary of Systolic Blood Pressure 
Part 1a, Part 2 Safety 
X 
3.4.1.2 
Summary of Systolic Blood Pressure 
Part 1b, Part 3 Safety 
X 
3.4.2.1 
Summary of Diastolic Blood Pressure 
Part 1a, Part 2 Safety 
X 
3.4.2.2 
Summary of Diastolic Blood Pressure 
Part 1b, Part 3 Safety 
X 
3.5  ECG 
3.5.1.1 
Summary of Outliers of QT and QTcF Interval Values (ms) 
From 12-Lead ECG 
Part 1a, Part 2 Safety 
X 
3.5.1.2 
Summary of Outliers of QT and QTcF Interval Values (ms) 
From 12-Lead ECG 
Part 1b, Part 3 Safety 
X 
Figures 
Figure No. 
Title 
4.1  Efficacy 
4.1.1 
Kaplan-Meier Estimates of Progression-Free Survival 
4.1.2 
Kaplan-Meier Estimates of Duration of Response 
4.1.3 
Waterfall Plot of Best Percentage Change From Baseline in Sum of Target Lesions 
4.1.4 
Spider Plot of Sum of Target Lesions 


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Listings 
Listing No. 
Title 
2.1.1 
Participant Enrollment and Disposition Status 
2.1.2 
Participant Inclusion and Exclusion Criteria Violations 
2.2 
Protocol Deviations 
2.3 
Analysis Population 
2.4.1 
Demographic and Baseline Characteristics 
2.4.2 
Disease History 
2.4.3 
Prior Radiation Treatment 
2.4.4 
Prior Systemic Therapy 
2.4.5 
Prior Surgery or Surgical Procedure 
2.4.6 
Medical History 
2.4.7 
Prior and Concomitant Medication 
2.4.8 
Concomitant Procedures 
2.5.1 
Study Drug Compliance 
2.5.2 
Study Drug Administration 
2.6.2 
Best Overall Response, Duration of Response, and Progression-Free Survival 
2.6.3 
Response Assessment (Investigator Assessments)  
2.6.4 
Summary (Target Lesions) 
2.6.5 
Summary (Non-Target Lesions) 
2.6.6 
Summary (New Lesions) 
2.6.7 
ECOG Status 
2.7.1 
Adverse Events  
2.7.2 
Dose-Limiting Toxicities 
2.7.3 
Serious Adverse Events 
2.7.4 
Grade 3 and Higher Adverse Events 
2.7.5 
Adverse Events Leading to Interruption, Reduction, or Discontinuation of INCB001158 or 
Pembrolizumab 
2.8.1 
Clinical Laboratory Values – Hematology 
2.8.2 
Clinical Laboratory Values – Chemistry 
2.8.3 
Clinical Laboratory Values – Coagulation 
2.8.4 
Clinical Laboratory Values – Urinalysis 
2.8..5 
Clinical Laboratory Values – Orotic Acid, BUN/UREA, and Ammonia for Potential Urea Cycle 
Inhibition 
2.8.6 
Abnormal Clinical Laboratory Values 
2.9.1 
Vital Signs 
2.9.2 
Abnormal Vital Sign Values 
2.10.1 
12-Lead ECG Values 
2.10.2 
Abnormal 12-Lead ECG Values