Clinical trial NCT03241173
Conditions: Advanced Malignancies
Keywords: advanced or metastatic cervical cancer endometrial cancer esophageal cancer hepatocellular carcinoma (HCC) melanoma Merkel cell carcinoma mesothelioma microsatellite instability-high colorectal cancer non-small cell lung cancer (NSCLC) ovarian cancer squamous cell carcinoma of the head and neck small cell lung cancer (SLCL) renal cell carcinoma (RCC) triple-negative breast cancer TNBC urothelial carcinoma OX40 ligand (OX40) SCCHN MSI-H CRC gastric cancer (including stomach and gastroesophageal junction [GEJ])
Sponsor: Incyte Biosciences International Sàrl
Start date: 2017-10-09; Completion date: 2019-09-17
Enrollment: 52 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine the safety, tolerability, and efficacy of INCAGN01949 when given in combination with immune therapies in participants with advanced or metastatic malignancies.

Detailed description:

Arms: arm 1: INCAGN01949 (70, 200, 350, or 700 milligrams \[mg\]) combined with nivolumab 240 mg in participants with advanced or metastatic select solid tumors arm 2: INCAGN01949 (70, 200, 350, or 700 mg) combined with ipilimumab 1 mg/kilogram (kg) in participants with advanced or metastatic select solid tumors arm 3: INCAGN01949 combined with nivolumab 3 mg/kg and ipilimumab 1 mg/kg in participants with advanced or metastatic select solid tumors arm 4: Run-in with INCAGN01949 (70, 200, or 350 mg) x 2 doses, followed by INCAGN01949 (70, 200, or 350 mg) combined with nivolumab 240 mg in participants with advanced or metastatic select solid tumors arm 5: Run-in with INCAGN01949 x 2 doses, followed by INCAGN01949 combined with nivolumab 3 mg/kg and ipilimumab 1 mg/kg in participants with advanced or metastatic select solid tumors arm 6: INCAGN01949 combined with nivolumab in programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) refractory participants with gastric cancer, squamous cell carcinoma of the head and neck (SCCHN), non-small cell lung cancer (NSCLC), or renal cell carcinoma (RCC) arm 7: INCAGN01949 alone, combined with nivolumab, and combined with nivolumab and ipilimumab in PD-1/L1 refractory participants with advanced or metastatic gastric cancer, SCCHN, NSCLC, or RCC
Interventions: intervention 1: INCAGN01949 intervention 2: Nivolumab intervention 3: Ipilimumab
Intervention descriptions: intervention 1: In Phase 1, participants will receive INCAGN01949 administered intravenously (IV) at the protocol-defined dose according to cohort enrollment. In Phase 2, participants will receive INCAGN01949 administered IV at the recommended dose from Phase 1. intervention 2: Nivolumab will be administered IV at the protocol-defined dose according to assigned treatment group. intervention 3: Ipilimumab will be administered IV at the protocol-defined dose according to assigned treatment group.

Protocol documents:
SAP_002.pdf: 
Official Title: 
A Phase 1/2 Study Exploring the Safety, Tolerability, and Efficacy of INCAGN01949 
in Combination With Immune Therapies in Subjects With Advanced or Metastatic
NCT Number: 
NCT03241173 
Document Date: 
Statistical Analysis Plan Version 1: 06 February 2018
Malignancies 


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STATISTICAL ANALYSIS PLAN 
INCAGN 1949-201
A Phase 1/2 Study Exploring the Safety, Tolerability, and Efficacy of 
INCAGN01949 in Combination With Immune Therapies in Subjects 
With Advanced or Metastatic Malignancies
IND Number: 
135,378 
Sponsor: 
Incyte Biosciences International Sàrl 
Route de la Corniche 1 
1066 Epalinges, Switzerland  
Protocol Version: 
Protocol Amendment 1 dated 14 JUN 2017 
CRF Approval Date: 
04 OCT 2017 
SAP Version: 
Original 
SAP Author: 
, PhD 
 Biostatistics 
 
 
This study is being conducted in compliance with good clinical practice, 
including the archiving of essential documents. 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................7 
1. 
INTRODUCTION ........................................................................................................9 
2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS...............................10 
2.1. 
Protocol and Case Report Form Version ....................................................................10 
2.2. 
Study Objectives .........................................................................................................10 
2.2.1. 
Primary Objectives .....................................................................................................10 
2.2.2. 
Secondary Objectives .................................................................................................10 
 
10 
2.3. 
Study Endpoints ..........................................................................................................11 
2.3.1. 
Primary Endpoints ......................................................................................................11 
2.3.2. 
Secondary Endpoints ..................................................................................................11 
 
12 
3. 
STUDY DESIGN .......................................................................................................12 
3.1. 
Phase 1 ........................................................................................................................13 
3.1.1. 
Part 1 – Dose Escalation .............................................................................................13 
3.1.2. 
Part 2 – Safety Expansion ...........................................................................................14 
3.2. 
Phase 2 – Dose Expansion ..........................................................................................15 
3.3. 
Control of Type I Error ...............................................................................................16 
3.4. 
Sample Size Considerations .......................................................................................17 
3.4.1. 
Sample Size for Phase 1 Part 1 ...................................................................................17 
3.4.2. 
Sample Size for Phase 1 Part 2 ...................................................................................17 
3.4.3. 
Sample Size for Phase 2 .............................................................................................18 
4. 
DATA HANDLING DEFINITIONS AND CONVENTIONS ..................................19 
4.1. 
Scheduled Study Evaluations and Study Periods .......................................................19 
4.1.1. 
Day 1 ...........................................................................................................................19 
4.1.2. 
Study Day ...................................................................................................................19 
4.1.3. 
Baseline Value ............................................................................................................19 
4.1.4. 
Last Available Value ..................................................................................................19 
4.1.5. 
Handling of Missing and Incomplete Data .................................................................19 
4.1.6. 
Cycle Length and Duration .........................................................................................20 
4.2. 
Variable Definitions ....................................................................................................21 


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4.2.1. 
Variables to Be Derived Only If Not Provided on Case Report Form .......................21 
4.2.2. 
Prior and Concomitant Medication .............................................................................21 
5. 
STATISTICAL METHODOLOGY ...........................................................................21 
5.1. 
General Methodology .................................................................................................21 
5.2. 
Treatment Groups .......................................................................................................21 
5.3. 
Analysis Populations ..................................................................................................22 
5.3.1. 
Full Analysis Set .........................................................................................................22 
5.3.2. 
Response Evaluable Populations ................................................................................22 
 
23 
 
23 
 
23 
 
23 
6. 
BASELINE, EXPOSURE, AND DISPOSITION VARIABLES AND 
ANALYSES ...............................................................................................................24 
6.1. 
Baseline and Demographics, Physical Characteristics, and Disease History .............24 
6.1.1. 
Demographic Characteristics ......................................................................................24 
6.1.2. 
Baseline Disease Characteristics and Disease History ...............................................24 
6.1.3. 
Prior Therapy ..............................................................................................................24 
6.1.4. 
Medical History ..........................................................................................................25 
6.2. 
Disposition of Subjects ...............................................................................................25 
6.3. 
Protocol Deviations and Violations ............................................................................25 
6.4. 
Exposure .....................................................................................................................25 
6.4.1. 
Exposure for INCAGN01949 .....................................................................................25 
6.4.2. 
Exposure for Nivolumab .............................................................................................25 
6.4.3. 
Exposure for Ipilimumab ............................................................................................26 
6.5. 
Prior and Concomitant Medication .............................................................................26 
7. 
EFFICACY .................................................................................................................27 
7.1. 
General Considerations ...............................................................................................27 
7.2. 
Efficacy Hypotheses ...................................................................................................27 
7.3. 
Analysis of the Efficacy Parameter ............................................................................27 
7.3.1. 
Response Criteria ........................................................................................................27 
7.3.2. 
Objective Response Rate and Best Overall Response ................................................27 
7.3.2.1. 
Confirmed ORR and Confirmed BOR by RECIST v1.1 ............................................27 


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7.3.2.2. 
Unconfirmed ORR and Unconfirmed BOR by RECIST v1.1 – Sensitivity 
and Supportive Analyses for Confirmed ORR and Confirmed BOR by 
RECIST v1.1...............................................................................................................29 
7.3.2.3. 
Confirmed ORR and Confirmed BOR by mRECIST.................................................30 
7.3.2.4. 
Unconfirmed ORR and Unconfirmed BOR by mRECIST – Sensitivity and 
Supportive Analyses for Confirmed ORR and Confirmed BOR by 
mRECIST ...................................................................................................................31 
7.3.3. 
Duration of Response .................................................................................................31 
7.3.3.1. 
Duration of Response by RECIST v1.1 ......................................................................31 
7.3.3.2. 
Duration of Response by mRECIST ...........................................................................31 
7.3.4. 
Duration of Disease Control and Disease Control Rate .............................................31 
7.3.5. 
Largest Percentage Reduction in Sum of Diameters of Target Lesions .....................32 
7.3.6. 
Percentage Change in Sum of Diameters of Target Lesions Over Time ....................32 
7.3.7. 
Progression-Free Survival ..........................................................................................32 
7.3.7.1. 
Progression-Free Survival by RECIST v1.1 ...............................................................33 
7.3.7.2. 
Progression-Free Survival by mRECIST ....................................................................33 
7.3.8. 
Overall Survival ..........................................................................................................33 
 
34 
 
34 
8. 
SAFETY AND TOLERABILITY ..............................................................................34 
8.1. 
General Considerations ...............................................................................................34 
8.2. 
Adverse Events ...........................................................................................................34 
8.2.1. 
Adverse Event Definitions ..........................................................................................34 
8.2.2. 
Dose-Limiting Toxicities ............................................................................................35 
8.2.3. 
Adverse Events of Special Interest .............................................................................35 
8.2.3.1. 
Immune-Related Adverse Events ...............................................................................35 
8.2.3.2. 
Infusion-Related Reactions .........................................................................................35 
8.2.4. 
Adverse Event Summaries ..........................................................................................36 
8.3. 
Clinical Laboratory Tests ...........................................................................................37 
8.3.1. 
Laboratory Value Definitions .....................................................................................37 
8.3.2. 
Laboratory Value Summaries .....................................................................................37 
8.4. 
Vital Signs ..................................................................................................................38 
8.5. 
Electrocardiograms .....................................................................................................39 
9. 
INTERIM ANALYSES ..............................................................................................39 


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9.1. 
Overview of Interim Analyses ....................................................................................39 
9.1.1. 
Interim Analyses for Safety ........................................................................................39 
9.1.2. 
Interim Analyses for Futility ......................................................................................40 
9.1.2.1. 
Simon 2-Stage Futility Rules ......................................................................................40 
 
40 
9.2. 
Data Cutoff for Interim Analysis ................................................................................42 
10. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN ........................43 
10.1. 
Changes to Protocol-Defined Analyses ......................................................................43 
10.2. 
Changes to the Statistical Analysis Plan .....................................................................43 
11. 
REFERENCES ...........................................................................................................44 
APPENDIX A. PLANNED TABLES AND FIGURES .............................................................45 
58 
 


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LIST OF TABLES 
Table 1: 
INCAGN01949 Dose Levels and Cohorts .................................................................14 
Table 2: 
Planned Simon 2-Stage Designs for Phase 2 ..............................................................16 
Table 3: 
Probability of Dose Escalation for Various Dose-Limiting Toxicity Rates ...............17 
Table 4: 
Derivation of Confirmed Best Overall Response .......................................................28 
Table 5: 
RECIST Evaluation Criteria for Overall Response:  Measurable Disease at 
Baseline .......................................................................................................................29 
Table 6: 
Rules for Determining PD Event Status After an Unconfirmed PD Under 
mRECIST ...................................................................................................................30 
Table 7: 
Evaluation and Censoring of Progression-Free Survival ............................................33 
Table 8: 
Identification of Records for Postbaseline By-Visit Summaries ................................38 
Table 9: 
Criteria for Clinically Notable Vital Sign Abnormalities ...........................................38 
Table 10: Criteria for Clinically Notable Electrocardiogram Abnormalities .............................39 
Table 11: Probability of Early Termination for Simon 2-Stage Design in Phase 2 in 
Treatment Groups F, G, and H ...................................................................................40 
 
41 
 
42 
Table 14: Statistical Analysis Plan Versions ..............................................................................43 
 
59 
 
60 
 
62 
 
63 
 
LIST OF FIGURES 
Figure 1: 
Overall Study Design ..................................................................................................13 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
 
 
AE 
adverse event 
 
 
 
BOR 
best overall response 
CI 
confidence interval 
 
 
 
 
CR 
complete response 
CRF 
case report form 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
dose-limiting toxicity 
DMC 
Data Monitoring Committee 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOS 
end of study 
EOT 
end of treatment 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
Ipi 
ipilimumab 
irAE 
immune-related AE 
JTc 
corrected JT interval 
KM 
Kaplan-Meier 
λz 
terminal phase rate constant 
MedDRA 
Medical Dictionary for Regulatory Activities  
mRECIST 
modified Response Evaluation Criteria in Solid Tumors 
MTD 
maximum tolerated dose 
NE 
not evaluable 
Nivo 
nivolumab 
ORR 
objective response rate 
OS 
overall survival 
PAD 
pharmacologically active dose 


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Abbreviation 
Term 
PD 
progressive disease 
PD-1 
programmed death-1 
PD-L1 
programmed death ligand-1 
PFS 
progression-free survival 
 
 
PoS 
probability of success 
PR 
partial response 
PT 
preferred term 
Q2W 
every 2 weeks 
QRS 
QRS is the combination of three of the graphical deflections on an ECG. It is usually 
the most central and most visually obvious part of the tracing.  It corresponds to the 
depolarization of the right and left ventricles of the human heart. 
QTcF 
QT interval corrected using the Fridericia formula 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase 2 dose 
RR 
RR is the interval from the beginning of a QRS complex to the beginning of the next 
QRS complex 
SAE 
serious adverse event 
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 
TFLs 
tables, figures, and listings 
 
 
WHO 
World Health Organization  


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1. 
INTRODUCTION 
This is an open-label, nonrandomized, Phase 1/2 study to determine the safety, tolerability, and 
efficacy of INCAGN01949 when given in combination with immune therapies.  Phase 1 will 
consist of 2 parts.  Dose escalation (Part 1) will consist of a 3 + 3 + 3 design to determine the 
MTD, or PAD, defined as a dose that provides a maximal biochemical effect 
 
 of INCAGN01949 when given in combination with immune 
therapies.  The safety expansion (Part 2) will further explore tolerated doses of INCAGN01949 
given as a run-in of 2 doses followed by concomitant immune therapies.  Subjects with advanced 
or metastatic cervical cancer, endometrial cancer, gastric cancer (including stomach and 
gastroesophageal junction cancer), esophageal cancer, hepatocellular carcinoma, melanoma, 
Merkel cell carcinoma, mesothelioma, microsatellite instability-high colorectal cancer, non–
small cell lung cancer, ovarian cancer, SCCHN, small cell lung cancer, RCC, triple-negative 
breast cancer, and urothelial carcinoma who have progressed after treatment with available 
therapies that are known to confer clinical benefit, who are intolerant to treatment, or who refuse 
standard of care will be enrolled in both parts of Phase 1.  The Phase 2 expansion will further 
evaluate the safety, tolerability, and efficacy of the recommended dose(s) of INCAGN01949 
selected in Phase 1 when given in combination with immune therapies.  Subjects with advanced 
or metastatic urothelial carcinoma or RCC will be enrolled in Phase 2. 
The purpose of this SAP is to provide details of the statistical analyses that have been outlined in 
the Study INCAGN 1949-201 Protocol.  The scope of this plan includes the interim and final 
analyses that are planned and will be executed by the Department of Biostatistics or designee. 


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2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS 
2.1. 
Protocol and Case Report Form Version 
This SAP is based on INCAGN 1949-201 Protocol Amendment 1 dated 14 JUN 2017 and CRFs 
approved 04 OCT 2017.  Unless superseded by an amendment, this SAP will be effective for all 
subsequent Protocol amendments and CRF versions. 
2.2. 
Study Objectives 
2.2.1. 
Primary Objectives 
Phase 1 
• To evaluate the safety, tolerability, and DLTs of INCAGN01949 in combination with 
immune therapies and to define the recommended dose(s) of INCAGN01949 when 
given in combination with immune therapies. 
Phase 2 
• To evaluate the efficacy of INCAGN01949 when given in combination with immune 
therapies by assessing ORR per RECIST v1.1. 
2.2.2. 
Secondary Objectives 
Phase 1 and Phase 2 
• To evaluate the efficacy of INCAGN01949 when given in combination with immune 
therapies by assessing ORR, DOR, DCR, duration of disease control, and PFS per 
RECIST v1.1 and mRECIST. 
• To evaluate the efficacy of INCAGN01949 when given in combination with immune 
therapies with respect to 1-year and 2-year OS. 
• To evaluate the safety and tolerability of INCAGN01949 when given in combination 
with immune therapies. 
 
 
 
 
 
 
 
 
 
 
 
 


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2.3. 
Study Endpoints 
2.3.1. 
Primary Endpoints 
• Safety and tolerability will be assessed by monitoring frequency, duration, and 
severity of AEs. 
• ORR, defined as the percentage of subjects having CR or PR, will be determined by 
investigator assessment of radiographic disease assessments per RECIST v1.1. 
2.3.2. 
Secondary Endpoints 
• ORR, defined as the percentage of subjects having CR or PR, will be determined by 
investigator assessment of radiographic disease assessments per RECIST v1.1 and 
mRECIST. 
• DOR, defined as the time from the earliest date of disease response (CR or PR) until 
earliest date of disease progression or death due to any cause, if occurring sooner than 
progression, will be determined by investigator assessment of radiographic disease 
assessments per RECIST v1.1 and mRECIST. 
• Disease control rate, defined as the percentage of subjects having CR, PR, or SD, will 
be determined by investigator assessment of radiographic disease assessments per 
RECIST v1.1 and mRECIST. 
• Duration of disease control (CR, PR, and SD) as measured from first report of SD or 
better until disease progression or death from any cause, if occurring sooner than 
progression, will be determined by investigator assessment of radiographic disease 
per RECIST v1.1 and mRECIST. 
• PFS, defined as the time from the start of combination therapy until the earliest date 
of disease progression or death due to any cause, if occurring sooner than 
progression, as determined by investigator assessment of objective radiographic 
disease assessments per RECIST v1.1 and mRECIST. 
• OS determined from the start of combination therapy until death due to any cause.  
Survival analyses will occur at 1-year, 2-years, and at the end of the study. 
•  Safety and tolerability will be assessed by monitoring frequency, duration, and 
severity of AEs. 


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3. 
STUDY DESIGN 
This is an open-label, nonrandomized, Phase 1/2 study to determine the safety, tolerability, and 
efficacy of INCAGN01949 when given in combination with immune therapies.  The MTD or 
PAD of INCAGN01949 when given in combination with immune therapies will be determined 
in Phase 1 of the study.  The Phase 2 expansion will further evaluate the safety, tolerability, and 
efficacy of the recommended dose(s) of INCAGN01949 selected in Phase 1. 
See Figure 1 for overall study design. 


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Figure 1: 
Overall Study Design 
 
3.1. 
Phase 1 
3.1.1. 
Part 1 – Dose Escalation  
The Part 1 will consist of a 3 + 3 + 3 dose escalation to determine the MTD or PAD, defined as a 
dose that provides a maximal biochemical effect, 
 
 of INCAGN01949 when given in combination with immune therapies.  Phase 1 dose 
escalation will begin with 2 double treatment groups evaluating the MTD or PAD of 
INCAGN01949 plus nivolumab (Treatment A) and the MTD or PAD of INCAGN01949 plus 
ipilimumab (Treatment B), which will be explored in parallel.  Dose escalation of the triplet 
immune therapy combinations (Treatment D) will proceed until the MTD or PAD of 
INCAGN01949 in combination with nivolumab and ipilimumab is determined; however, the 
dose of INCAGN01949 in the triplet combination will not exceed the lowest MTD of 
INCAGN01949 established in the applicable doublet combinations. 
In Part 1 of the study, the MTD is defined as 1 dose level below that at which ≥ one-third of 
subjects in a particular cohort have DLTs.  The PAD is defined as a dose that provides a 
maximal biochemical effect, 
 of INCAGN01949 
when given in combination with immune therapies. 


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A DLT will be defined as the occurrence of any toxicity, with the exception of events clearly 
associated with the underlying disease, disease progression, a concomitant medication, or 
comorbidity; the list of toxicities that will be designated as dose limiting toxicities are provided 
in Table 8 of the Protocol. 
The first 3 evaluable subjects enrolled within an INCAGN01949 dose cohort will be observed 
for the specified DLT observation period before the next dose cohort begins enrollment.  If 
0 DLTs occur in a cohort of 3 evaluable subjects, a new cohort of 3 evaluable subjects will be 
treated at the next higher dose level.  If 1 of 3 evaluable subjects experiences a DLT, that cohort 
will be expanded to 6 evaluable subjects.  If 1 of 6 evaluable subjects experiences a DLT, a new 
cohort of 3 evaluable subjects will be treated at the next higher dose level.  If 2 of 6 evaluable 
subjects experience a DLT, that cohort will be expanded to 9 evaluable subjects.  If ≥ 2 of 3, 3 of 
6, or 3 of 9 evaluable subjects experience DLTs within a cohort, then that dose level will be 
determined to have exceeded the MTD, and the previous dose level will be considered the MTD.  
If only 3 evaluable subjects were treated at the MTD or PAD, then a minimum of 3 additional 
evaluable subjects will be enrolled before this dose is administered in Phase 2 of the study. 
Additional subjects will be enrolled in a dose cohort to achieve the minimum of 3 evaluable 
subjects.  Depending on treatment group, a subject must receive at least 2 doses of the 
cohort-specified dose of INCAGN01949, 2 doses of nivolumab, and 1 dose of ipilimumab, or 
must have had a DLT during the DLT observation period, to be considered evaluable.  Subjects 
who dropout for reasons other than a DLT (eg, events clearly associated with the underlying 
disease, disease progression, concomitant medication, or comorbidity), during the DLT 
observation period will result in the subject being nonevaluable and the subject being replaced.  
Dose modifications should not be made during the DLT observation period without discussion 
with the medical monitor.  The doses of INCAGN01949 to be evaluated in each treatment group 
are summarized in Table 1. 
Table 1: 
INCAGN01949 Dose Levels and Cohorts 
Cohort 
Dose of INCAGN01949 
-1 
2 mg 
1  
7 mg  
2 
20 mg 
3 (Starting Dose) 
70 mg 
4 
200 mg 
5 
350 mg 
6 
700 mg 
Note:  A higher starting dose of INCAGN01949 was chosen based on safety data from the monotherapy study 
(INCAGN 1949-101). 
3.1.2. 
Part 2 – Safety Expansion 
Once an INCAGN01949 dose cohort in Treatment Group A is deemed tolerable, up to 6 subjects 
will be enrolled in Treatment Group C at the same dose of INCAGN01949.  For example, if 
INCAGN01949 70 mg is tolerated in Treatment Group A, then 70 mg will be explored in up to 


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6 subjects in Treatment Group C.  Likewise, once an INCAGN01949 dose in Treatment Group D 
is deemed tolerable, up to 6 subjects will be enrolled in Treatment Group E at the same dose of 
INCAGN01949.  For example, if INCAGN01949 350 mg is tolerated in Treatment Group D, 
then 350 mg will be explored in up to 6 subjects in Treatment Group E.  Doses of 
INCAGN01949 in Treatment Group C will be escalated in parallel to those explored in 
Treatment Group A but will not exceed the MTD of INCAGN01949 established in Treatment 
Group A.  The same rules will apply with Treatment Groups D and E.  Alternate dose 
administration schedules may also be explored depending on 
 
safety results.  The sponsor may elect to prioritize (or deprioritize) enrollment to specific dose 
cohorts based on emerging safety or efficacy data in collaboration with investigational sites. 
If the cumulative incidence of Grade 3 or higher INCAGN01949-related AEs occurs in > 40% of 
subjects in a particular treatment group, then further enrollment will be interrupted until the 
sponsor, investigators, and regulatory authorities (if applicable) determine the appropriate course 
of action (eg, lower the dose of INCAGN01949, change dose frequency, etc). 
3.2. 
Phase 2 – Dose Expansion  
Phase 2 of the study will further evaluate the safety, tolerability, efficacy, 
 and 
pharmacologic activity of the immune therapy combinations in subjects with advanced or 
metastatic RCC or urothelial carcinoma.  RCC- and urothelial carcinoma–specific cohorts will 
enroll subjects who are naive to immune therapies.  Subjects who have relapsed following prior 
treatment with an anti–PD-1/L1 therapy will be enrolled into a relapsed cohort that will contain 
both RCC and urothelial carcinoma subjects.  Additional tumor-specific cohorts may be added, 
by Protocol amendment, based on emerging data. 
 
 
 
 
 
A Simon 2-stage design will be used with a stopping rule to allow for early termination of a 
particular tumor cohort within a given treatment group at the end of Stage 1 if there are 
insufficient responses observed.  The design parameters for the individual Simon 2-stage designs 
are determined by historical response rates and will result in different sample sizes and different 
futility rules, depending on the historical response rate for the tumor type and treatment 
combination.  The planned Simon 2-stage designs are summarized in Table 2.  The same Simon 
2-stage design parameters will be used for alternative dosing sequences in the same tumor type 
and treatment combination. 


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Table 2: 
Planned Simon 2-Stage Designs for Phase 2 
Indication 
Treatment Groups 
𝒓𝟏 
𝒏𝟏 
𝒓 
𝒏𝟐 
𝒏 
𝒑𝟎 
𝒑𝟏 
RCC  
F, G, H (INCAGN01949 + 
Nivo) 
8 
30 
26 
51 
81 
25% 
40% 
Urothelial  
F, G, H (INCAGN01949 + 
Nivo) 
6 
27 
21 
53 
80 
20% 
35% 
Relapsed to 
anti–PD-1/L1  
F, G, H (INCAGN01949 + 
Nivo) 
2 
20 
8 
30 
50 
10% 
25% 
RCC  
J, K, L (INCAGN01949 + 
Nivo + Ipi)  
14 
33 
48 
68 
101 
40.4% 
55% 
Urothelial  
J, K, L (INCAGN01949 + 
Nivo + Ipi) 
10 
35 
33 
67 
102 
26% 
40% 
Relapsed to 
anti–PD-1/L1  
J, K, L (INCAGN01949 + 
Nivo + Ipi) 
2 
20 
8 
30 
50 
10% 
25% 
• 𝑟1:  if 𝑟1 or fewer responses are observed during Stage 1, the study cohort is stopped 
early for futility. 
• 𝑛1:  number of subjects initially enrolled in Stage 1. 
• 𝑛2:  number of subjects enrolled in Stage 2. 
• 𝑟:  if 𝑟 or fewer responses are observed by the end of Stage 2, then no further 
investigation of the drug combination is warranted in the selected tumor type and 
dosing schedule. 
• 𝑛:  total number of subjects. 
• 𝑝0:  insufficient response rate. 
• 𝑝1:  target response rate. 
In Phase 2 of the study, toxicities will continue to be monitored.  If the cumulative incidence of 
Grade 3 through Grade 5 INCAGN01949-related AEs occurs in > 40% of subjects in a particular 
treatment group after 6 subjects have been enrolled, then further enrollment in that treatment 
group will be interrupted until the sponsor, investigators, and regulatory authorities (if 
applicable) determine the appropriate course of action (eg, lower the dose of INCAGN01949, 
change dose frequency, etc).  If a treatment group is discontinued due to toxicity, it may be 
re-initiated at a previously tested lower dose level and/or alternate dosing schedule.  All AEs, 
regardless of the time of occurrence on study, may be considered for DLT determination 
purposes. 
3.3. 
Control of Type I Error 
For the primary efficacy endpoints, the 1-sided Type I error will be controlled at 0.05 for each 
individual cohort expansion.  Note that this level of significance does not account for the 
multiple expansion cohorts.  For other endpoints, CIs will be reported at a 95% confidence level. 


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During the Phase 1 portion of the study, telephone conferences will be scheduled by the sponsor 
with study investigators in order to review cohort-specific data and overall safety data, to agree 
on dose escalation, adjudicate individual high-grade AEs as potentially dose-limiting, and guide 
other major study decisions.  An internal DMC will be assembled to monitor safety data and 
study conduct on a regular and ongoing basis.  See Section 9 for details regarding the interim 
analyses conducted in this study. 
3.4. 
Sample Size Considerations 
3.4.1. 
Sample Size for Phase 1 Part 1 
The primary objective in Phase 1 of the study is to determine the MTD or PAD of 
INCAGN01949 when given in combination with immune therapies.  The total number of 
subjects will depend on the number of dose levels tested in each treatment group before the MTD 
or PAD is established.  Approximately up to 108 subjects will be evaluated in Phase 1 Part 1 
(9 subjects per dose level for 4 dose levels in 3 treatment groups).  Dose escalation will follow 
the 3 + 3 + 3 design algorithm.  Based on this algorithm, a minimum of 3 evaluable subjects will 
be enrolled in each cohort beginning with Cohort 3 (70 mg; starting dose) and a maximum of 
9 evaluable subjects will be enrolled in each cohort.  The probability of declaring a dose as safe 
for various DLT rates in the 3 + 3 + 3 is summarized in Table 3. 
Table 3: 
Probability of Dose Escalation for Various Dose-Limiting Toxicity Rates 
True DLT Rate 
Probability of Dose Escalation 
20% 
78.4% 
30% 
56.1% 
40% 
35.0% 
50% 
18.9% 
60% 
8.8% 
For example, if the true DLT rate is 50% at a given dose level, there is an 18.9% chance that the 
dose would be escalated.  Furthermore, if the true DLT rate is 20%, there is a 78.4% chance that 
the dose would be escalated.  If the MTD is not determined at the highest dose level tested 
during the study, then the MTD is at or above the highest dose level.  The MTD is below the 
lowest dose level of INCAGN01949 if Cohort -1 is not well-tolerated.  The PAD may be used in 
lieu of the MTD and/or prescribed doses may need to be altered in order to determine the MTD. 
3.4.2. 
Sample Size for Phase 1 Part 2 
Once an INCAGN01949 dose cohort in Treatment Group A is deemed tolerable, 6 subjects will 
be enrolled in Treatment Group C at the same dose of INCAGN01949.  For example, if 
INCAGN01949 70 mg is tolerated in Treatment Group A, then 70 mg will be explored in 
6 subjects in Treatment Group C.  Likewise, once an INCAGN01949 dose cohort in Treatment 
Group D is deemed tolerable, 6 subjects will be enrolled in Treatment Group E at the same dose 
of INCAGN01949.  For example, if 350 mg of INCAGN01949 is tolerated in Treatment 
Group D then 350 mg will be explored in 6 subjects in Treatment Group E. 


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3.4.3. 
Sample Size for Phase 2 
Phase 2 will further evaluate the safety, tolerability, preliminary efficacy, 
 
 of the recommended dose of INCAGN01949 in combination with immune therapies as 
part of doublet and triplet drug expansion cohorts.  In Phase 2, a Simon 2-stage design will be 
run for each tumor type within a given doublet or triplet drug expansion cohort. 
The sample size for each tumor type within a given doublet or triplet expansion cohort will be 
guided by the Simon 2-stage design (Simon 1989).  The planned Simon 2-stage designs are 
summarized in Table 2.  Each Simon 2-stage design will have a stopping rule to allow early 
termination of a particular tumor type within the given treatment combination at the end of 
Stage 1 if there is insufficient response observed (calculated response rate < p0%), while 
enrolling enough subjects to predict possible target responses (≥ p1%) worthy of cohort 
expansion and potentially further evaluation in future studies.  The individual Simon 2-stage 
designs run for each tumor type within each doublet or triplet expansion cohort will have design 
parameters that are determined by historical response rates.  The same Simon 2-stage design 
parameters will be used for alternative dosing sequences in the same tumor type and treatment 
combination.  For example, the urothelial cohorts in Treatment Groups F, G, and H will all use 
the same Simon 2-stage parameters. 
In order to determine whether the target response rate (p1%) is likely, an initial number of 
evaluable subjects (n1 subjects) treated at the MTD or PAD and schedule of INCAGN01949 
within the corresponding doublet or triplet expansion cohort will be enrolled in a cohort 
(Stage 1).  If there are r1 or fewer responses in the cohort, it will be concluded that the true 
response rate is unlikely to be greater than or equal to the target rate, and no more subjects will 
be enrolled in that tumor type in Stage 2.  In the cohorts in which greater than r1 responses are 
observed among the Stage 1 subjects, n2 additional evaluable subjects will be treated in Stage 2 
to estimate the response rate.  At the end of Stage 2, if ≤ r subjects have responded among the 
n evaluable subjects, the doublet or triplet schedule will be declared nonpromising for that 
cohort.  In other words, after the study is finished, if there is a sufficient number of responses in 
the 2 stages combined, the study doublet or triplet is considered promising; otherwise it is 
considered nonpromising.  The detailed calculations for each tumor type–specific doublet and 
triplet cohort are based on a 1-sided Type I error of 0.05 and power of 85%.  The individual p0 
and p1 values for the tumor types within doublet or triplet expansion cohorts are listed in Table 2. 
Formal quarterly safety reviews will be conducted to review efficacy and safety data with the 
obligation to hold a safety review meeting every 6 months. 
 
 


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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 (INCAGN0
, nivolumab, or ipilimumab) is 
administered to the subjects. 
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 
INCAGN0
, nivolumab, or ipilimumab, unless otherwise defined. 
When scheduled assessments and unscheduled assessments occur on the same day and 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. 
Last Available Value 
The last available value is the last nonmissing measurement obtained after starting 
INCAGN0
, nivolumab, or ipilimumab and within 60 days after the last dose of 
INCAGN0
, nivolumab or ipilimumab. 
4.1.5. 
Handling of Missing and Incomplete Data  
In general, values for missing data will not be imputed unless methods for handling missing data 
are specified in this section or relevant sections. 


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Partial disease diagnosis date will be handled as follows:  
• If only the day is missing, then the imputed day will be the first of the month. 
• If both the month and day are missing, then the imputed day and month will be 
01 JAN. 
• No imputation will be done if the date is completely missing. 
Missing or partial date of last dose will be handled as follows:  
• If only the day is missing, then the imputed date of the last dose will be the earlier 
date of the first day of the month or the date that the subject discontinued treatment. 
• Otherwise, the date that the subject discontinued treatment will be used as the date of 
the last dose. 
For relevant efficacy endpoints, partial death date will be imputed as follows:  
• If mmyyyy for the last contact date = mmyyyy for the death date, then the death date 
will be set to the day after the last contact date. 
• If mmyyyy for the last contact 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. 
4.1.6. 
Cycle Length and Duration 
Cycle 1 Day 1 is the day that the first dose of INCAGN01949, nivolumab, or ipilimumab is 
administered. 
• INCAGN01949:  For all treatment groups, INCAGN01949 will be administered IV 
over a 30-minute period on Day 1 of each Q2W (ie, 14-day) cycle. 
• Nivolumab:  In the doublet Treatment Groups A, C, F, G, and H, nivolumab will be 
administered IV per instructions provided in the package insert at a dose of 240 mg 
Q2W (eg, 14 days).  In the triplet Treatment Groups D, E, J, K, and L, nivolumab will 
be administered IV per instructions provided in the package insert at a dose of 
3 mg/kg Q2W (eg, 14 days).  In the concurrent dosing Treatment Groups A, D, F, and 
J, nivolumab dosing will begin on Cycle 1 Day 1.  In the sequenced/run-in dosing 
Treatment Groups C, E, G, H, K, and L, nivolumab dosing will begin on Cycle 3 
Day 1. 
• Ipilimumab: In Treatment Groups B, D, E J, K, and L, ipilimumab will be 
administered IV per instructions provided in the package insert to subjects at a dose 
of 1 mg/kg Q6W (eg, 42 days).  In the concurrent dosing Treatment Groups B, D, and 
J, ipilimumab dosing will begin on Cycle 1 Day 1.  In the sequenced dosing 
Treatment Groups E, K, and L, ipilimumab dosing will begin on Cycle 3 Day 1. 
Subjects will continue to receive INCAGN01949, nivolumab, and ipilimumab as defined in the 
Protocol as long as the subject is deriving benefit and has not met any of the Protocol-defined 
conditions for treatment withdrawal. 


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4.2. 
Variable Definitions 
4.2.1. 
Variables to Be Derived Only If Not Provided on Case Report Form 
The following variables will only be calculated if not reported on the CRF. 
• Subject age will be calculated as the integer part of the number of years from date of 
birth to the date of signing the informed consent form (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 
INCAGN01949, nivolumab, or ipilimumab. 
Concomitant medication is defined as any nonstudy medication that is started accordingly:  
• Before the date of first administration of INCAGN01949, nivolumab, or ipilimumab 
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 INCAGN01949, nivolumab, or ipilimumab 
and is ongoing or ends during the course of study drug. 
A prior medication could also be classified as "both prior and concomitant medication" if the end 
date is on or after first dose of INCAGN01949, nivolumab, or ipilimumab.  In the listing, it will 
be indicated whether a medication is prior-only, concomitant-only, or both prior and concomitant 
medication. 
For the purposes of analysis, all medications will be considered concomitant medications unless 
the medications can unequivocally be defined as not concomitant. 
5. 
STATISTICAL METHODOLOGY 
5.1. 
General Methodology 
Unless otherwise noted, SAS software (SAS Institute Inc, Cary, NC; Version 9 or later) will be 
used for the generation of all tables, graphs, and statistical analyses.  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 subjects in each category. 
Interim analyses are planned for this study as defined in Section 9. 
5.2. 
Treatment Groups 
This is a Phase 1/2, open-label, nonrandomized, multicenter, dose-escalation study.  The starting 
dose of INCAGN01949 is 70 mg, and up to 4 doses will be tested.  Data will be summarized 
overall and by treatment group.  Treatment group is defined as the dose regimen and dose 
schedule initially assigned. 


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Dose escalation of the triplet immune therapy combinations will begin enrolling once all of the 
applicable doublet combinations have cleared 3 INCAGN01949 dose levels (see Table 1) or the 
MTD or PAD of INCAGN01949 has been determined (whichever occurs first).  The starting 
dose of INCAGN01949 will be 2 dose levels below the last dose cohort deemed safe in the 
doublet combination.  The triplet immune therapy combinations will be explored in parallel. 
• Treatment Group A 
− INCAGN01949 + 240 mg Q2W nivolumab 
• Treatment Group B 
− INCAGN01949 + 1 mg/kg Q6W ipilimumab 
• Treatment Group C 
− Run-in with INCAGN01949 × 2 doses followed by INCAGN01949 + 240 mg 
Q2W nivolumab 
• Treatment Group D 
− INCAGN01949 + 3 mg/kg Q2W nivolumab + 1 mg/kg Q6W ipilimumab 
• Treatment Group E 
− Run-in with INCAGN01949 × 2 doses followed by INCAGN01949 + 3 mg/kg 
Q2W nivolumab + 1 mg/kg Q6W ipilimumab 
5.3. 
Analysis Populations 
5.3.1. 
Full Analysis Set 
The FAS includes all subjects enrolled in the study who received at least 1 dose of 
INCAGN01949, nivolumab, or ipilimumab.  The nivolumab FAS population includes all 
subjects in the FAS population who received at least 1 dose of nivolumab administered in mg or 
mg/kg.  The ipilimumab FAS population includes all subjects in the FAS population who 
received at least 1 dose of ipilimumab. 
Table summaries, unless otherwise indicated, will be provided by treatment group and tumor 
type–specific cohorts. 
5.3.2. 
Response Evaluable Populations 
The response evaluable population includes all subjects who received at least 1 dose of 
INCAGN01949, nivolumab, or ipilimumab, completed a baseline scan, and met at least 1 of the 
following criteria: 
• The subject had ≥ 1 postbaseline scan. 
• The subject was on the study for a minimum of 64 days of follow-up. 
• The subject discontinued from treatment. 


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6. 
BASELINE, EXPOSURE, AND DISPOSITION VARIABLES AND 
ANALYSES 
A list of data displays and sample data displays are provided in Appendix A and the sample data 
displays are provided in a separate document. 
6.1. 
Baseline and Demographics, Physical Characteristics, and Disease 
History 
6.1.1. 
Demographic Characteristics 
The following demographic characteristics will be summarized for the Phase 1 FAS population 
by treatment group and dose level and for the Phase 2 FAS population by tumor type:  age, sex, 
race, ethnicity, and ECOG performance status. 
6.1.2. 
Baseline Disease Characteristics and Disease History 
For each type of tumor, primary tumor histology, time from initial diagnosis in months, stage at 
initial diagnosis, current stage of disease, current site of disease, and tumor markers will be 
summarized for all subjects in the Phase 1 Part 1 FAS population by treatment group and dose 
level and Phase 1 Part 2 FAS population by treatment group and tumor type. 
6.1.3. 
Prior Therapy 
Prior systemic cancer therapy regimens will be summarized by total number and by number of 
prior systemic cancer therapies taken for both advanced and metastatic disease for all subjects in 
the Phase 1 FAS population by dose level and treatment group and Phase 2 FAS population by 
tumor type and treatment group.  Regimen name, component drugs, start and stop date, purpose 
of the regimen, best response, reason for discontinuation, and date of relapse/progression will be 
listed. 
Number of subjects who received prior radiation will be summarized for the Phase 2 FAS 
population.  Radiotherapy type, body site, start and stop date, total dose, and best response will 
be listed. 
Number of subjects who had prior surgery or surgical procedure for the malignancies under 
study will be summarized for the Phase 2 FAS population.  Date and description of the 
surgery/procedure will be listed. 
Number of subjects with prior immunotherapy and prior anti–PD-1/PD-L1 therapy will be 
summarized for the Phase 1 FAS population by dose level and treatment group and the Phase 2 
FAS population by tumor type and treatment group.  Prior immunotherapy type, start and stop 
date, total dose, and best response will be listed. 


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6.1.4. 
Medical History 
For subjects in the Phase 1 FAS population by dose level and Phase 2 FAS population by tumor 
type, medical history will be summarized by assigned treatment group.  This summation will 
include the number and percentage of subjects with significant medical history for each body 
system/organ class as documented on the CRF. 
6.2. 
Disposition of Subjects 
The number and percentage of subjects who were enrolled, treated, completed the study, 
discontinued study treatment with a primary reason for discontinuation, and discontinued from 
the study with a primary reason for withdrawal will be summarized for the Phase 1 FAS 
population by dose level and treatment group and the Phase 2 population by tumor type and 
treatment group.  The number of subjects enrolled by site will also be provided by treatment 
group. 
6.3. 
Protocol Deviations and Violations 
Protocol deviations and violations recorded on the CRF will be presented in a table and listing. 
6.4. 
Exposure 
6.4.1. 
Exposure for INCAGN01949 
For subjects in the FAS population, exposure to INCAGN01949 will be summarized 
descriptively as the following: 
• Total number of infusions:  Total number of infusions per subject with a nonzero 
dose of INCAGN01949. 
• Dose administered per cycle:  The actual dose administered in mg per cycle. 
• Total dose administered in mg:  The total cumulative, actual dose administered (in 
mg) across cycles for each subject will be determined according to the following 
calculation: 
− For an infusion 𝑖, let 𝐶𝑖, 𝑉𝑖, and 𝑁 be defined as above 
− Total dose administered (in mg) = ∑
𝐶𝑖× 𝑉𝑖
𝑁
𝑖=1
 
• Average dose in mg:  The average dose (in mg) will be the total dose administered 
(in mg) divided by the total number of infusions. 
6.4.2. 
Exposure for Nivolumab 
For subjects in the Phase 1 FAS population by dose level and treatment group and the Phase 2 
FAS population by tumor type and treatment group, exposure to nivolumab will be summarized 
descriptively as the following: 
• Number of infusions: Number of infusions of nivolumab for a subject will be the 
number of administered, nonzero infusions of nivolumab recorded on the Nivolumab 
Dosing CRF. 


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• Average fixed dose:  The average fixed dose of nivolumab (mg) will be the sum of 
the doses of nivolumab recorded (mg) on the Nivolumab Dosing CRF divided by the 
number of infusions of nivolumab.  Average dose of nivolumab (mg) will be 
summarized for subjects in the Phase 1 and Phase 2 nivolumab population. 
• Average weight-adjusted dose (mg/kg):  The average weight-adjusted dose of 
nivolumab (mg/kg) will be the sum of the doses of nivolumab recorded (mg/kg) on 
the Nivolumab Dosing CRF divided by the number of infusions of nivolumab.  
Average-weight adjusted dose of nivolumab (mg/kg) will be summarized for subjects 
in the Phase 1 and Phase 2 nivolumab population. 
• Fixed dose administered per cycle (mg):  The actual fixed dose administered in mg 
per cycle.  Fixed dose administered per cycle of nivolumab (mg) will be summarized 
for subjects in the Phase 1 and Phase 2 nivolumab population. 
• Weight-adjusted dose administered per cycle (mg/kg):  The actual weight-adjusted 
dose administered in mg/kg per cycle.  Weight-adjusted dose administered per cycle 
of nivolumab (mg/kg) will be summarized for subjects in the Phase 1 and Phase 2 
nivolumab population. 
6.4.3. 
Exposure for Ipilimumab 
For subjects in the Phase 1 FAS population by dose level and treatment group and the Phase 2 
FAS population by tumor type and treatment group, exposure to ipilimumab will be summarized 
descriptively as the following: 
• Number of infusions:  Number of doses of ipilimumab for a subject will be the 
number of administered, nonzero infusions of ipilimumab recorded on the 
Ipilimumab Dosing CRF. 
• Dose administered per cycle (mg/kg):  The actual dose of ipilimumab administered 
in mg/kg per cycle. 
• Average dose (mg/kg):  The average dose of ipilimumab (mg/kg) will be the sum of 
the doses of ipilimumab recorded on the Ipilimumab Dosing CRF divided by the 
number of infusions of ipilimumab. 
6.5. 
Prior and Concomitant Medication 
Prior medications and concomitant medications will be coded using the WHO Drug Dictionary 
March 2017 version and summarized by WHO drug class and WHO drug term by dose level and 
treatment group in the Phase 1 FAS population and by tumor type and treatment group in the 
Phase 2 FAS population.  Results will be summarized as number and percentage of subjects with 
prior and concomitant medications by PT and WHO drug class. 


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7. 
EFFICACY 
Sample data displays are provided in a separate document. 
7.1. 
General Considerations 
The primary efficacy endpoint for this study is ORR per RECIST v1.1 assessed in the Phase 2 
response evaluable population.  Secondary efficacy endpoints of this study include ORR, DOR, 
duration of disease control, disease control rate, and PFS by investigator assessment based on 
RECIST v1.1 and mRECIST as well as OS assessed at 1 year, 2 years, and EOS. 
7.2. 
Efficacy Hypotheses 
Each Simon 2-stage design 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 the target rate of 𝑝1%.  For each Simon 2-stage design, the value for 𝑝0 is determined 
by a historical response rate.  The same values for 𝑝0and 𝑝1will be used for alternative dosing 
sequences in the same tumor type and treatment combination.  For example, the gastric cohorts 
in Treatment Groups F, G, and H will all use the same value for 𝑝0 and 𝑝1. 
7.3. 
Analysis of the Efficacy Parameter 
7.3.1. 
Response Criteria 
Overall disease status will be categorized using RECIST v1.1.  Subjects will have their overall 
response evaluated as CR, PR, SD, PD, or NE at each postbaseline radiological assessment based 
on changes in target lesions, nontarget lesions, and appearance of new lesions. 
7.3.2. 
Objective Response Rate and Best Overall Response 
7.3.2.1. 
Confirmed ORR and Confirmed BOR by RECIST v1.1 
Per RECIST v1.1, in nonrandomized trials where response is the primary endpoint, confirmation 
of PR and CR is required to ensure responses are not the result of measurement error.  Therefore, 
a subject is defined as a confirmed objective responder if the subject has an overall response of 
CR or PR at any postbaseline visit that is confirmed at a subsequent timepoint at least 4 weeks 
later, before the first occurrence of PD.  Confirmed objective responders will be assessed based 
on RECIST v1.1. 
Confirmed ORR is defined as the proportion of subjects with confirmed overall responses.  
Confirmed ORR will be estimated with 95% CIs.  Confidence intervals will be based on the 
method for Simon 2-stage CIs of response rates outlined in Koyama and Chen (2008). 
Confirmed ORR will be summarized by treatment group and tumor type as primary endpoint for 
the Phase 2 response evaluable population. 
In general, confirmed BOR is the best response recorded postbaseline before and including the 
first PD, in the order of CR, PR, SD, PD and NE, in which CR and PR must be confirmed at a 
subsequent timepoint at least 4 weeks after the CR or PR is observed.  Responses of CR, PR, or 


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SD after the first assessment of PD will not be considered.  In the case of SD, measurements 
must meet the SD criteria at least once after the date of first dose at a minimum interval of 
49 days.  Subjects that fail to meet this criterion will have confirmed BOR of PD if the next 
available assessment indicates PD or NE if there is no additional assessment available. 
Under RECIST v1.1, if radiologic imaging shows CR or PR, a tumor assessment should be 
repeated at a minimum of 4 weeks to confirm the response in order to claim the CR or PR as the 
confirmed BOR.  If there is no second CR or PR tumor assessment, the CR or PR will be 
unconfirmed.  Table 4 lists the scenarios of responses that can occur after an unconfirmed CR or 
PR and provides a rule for determining the confirmed BOR in each scenario.  A sensitivity 
analysis for the ORR, in which BOR is determined using unconfirmed PR and CR, is detailed in 
Section 7.3.2.2. 
For determination of confirmed BOR, confirmatory scans with a response of NE will be 
subsequently followed by another scan at a minimum of 4 weeks.  For example, in the case of PR 
at the first timepoint followed by NE at a subsequent timepoint, if a third scan shows a PR, then 
the confirmed BOR will be PR.  There will be no third confirmatory scans performed for a loss 
of response.  For example, if a response of PR at the first timepoint is followed by a response of 
SD or PD at a subsequent timepoint, the confirmed BOR will be determined using the rules in 
Table 4. 
Table 4: 
Derivation of Confirmed Best Overall Response 
Overall Response at First 
Timepoint 
Overall Response at Subsequent 
Timepoint 
Confirmed Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PRa 
CR 
SD 
SD,a provided minimum criteria for 
SD duration are met; otherwise, PD 
CR 
PD 
SD,a provided minimum criteria for 
SD duration are met; otherwise, PD 
CR 
NE 
SD,a provided minimum criteria for 
SD duration are met; otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for 
SD duration are met; otherwise, PD 
PR 
NE 
SD,a provided minimum criteria for 
SD duration are met; otherwise NE 
NE 
NE 
NE 
a If a CR is truly met at the first timepoint, then any disease seen at a subsequent timepoint, even disease meeting PR criteria 
relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR).  Confirmed BOR would 
depend on whether the 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 subject had a PR, not a CR, at the first timepoint.  Under these 
circumstances, the original CR should be changed to a PR, and the confirmed BOR is PR. 


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For subjects with measurable disease at baseline, the RECIST v1.1 assessment criteria presented 
in Table 5 can be used to determine the overall disease status at a given timepoint based on the 
target lesion, nontarget lesion, and new lesion assessment. 
Table 5: 
RECIST Evaluation Criteria for Overall Response:  Measurable Disease at 
Baseline 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non-PD or NE 
No 
PR 
SD 
Non-PD or NE 
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 
7.3.2.1.1. Subgroup Analyses for Confirmed Best Overall Response Under RECIST v 1.1 
in Phase 2 
Subgroups will be formed based on the following subject characteristics and baseline variables 
for Phase 2 response evaluable subjects whose data are available: 
• PD-L1 expression within tumor type:  high, negative/low, unknown 
• Number of prior therapies for advanced and metastatic disease within tumor type 
• Subjects with > 1 postbaseline scan within tumor type 
• Tumor-type disease characteristics for RCC and urothelial carcinoma 
7.3.2.2. 
Unconfirmed ORR and Unconfirmed BOR by RECIST v1.1 – Sensitivity and 
Supportive Analyses for Confirmed ORR and Confirmed BOR by RECIST v1.1 
A sensitivity analysis for the ORR assessed under RECIST v1.1 will be performed using 
unconfirmed CRs and PRs.  The unconfirmed BOR is defined as the best response recorded 
postbaseline before and including the first PD, in the order of CR, PR, SD, PD, and NE.  For this 
definition, responses of CR and PR do not need to be confirmed at a subsequent timepoint.  In 
the case of SD, measurements must meet the SD criteria at least once after the date of first dose 
at a minimum interval of 49 (56-7) days.  Subjects that fail to meet this criterion will have BOR 
of PD if the next available assessment indicates PD or NE if there is no additional assessment 
available. 


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Unconfirmed ORR will be summarized by treatment group and tumor type as a sensitivity 
analysis for the primary endpoint ORR for the Phase 2 response evaluable population and as a 
sensitivity analysis for the secondary endpoint ORR for the Phase 1 response evaluable 
population. 
7.3.2.2.1. Subgroup Analyses for Unconfirmed Best Overall Response by RECIST v 1.1 in 
Phase 1 
For the sensitivity analysis for unconfirmed BOR, subgroups will be formed based on subjects’ 
prior treatment with an anti–PD-1/PD-L1 therapy within their tumor type (Yes/No) for Phase 1 
response evaluable subjects and whose data are available. 
7.3.2.3. 
Confirmed ORR and Confirmed BOR by mRECIST  
Under mRECIST, if radiologic imaging shows CR or PR, a tumor assessment should be repeated 
at a minimum of 4 weeks to confirm the response in order to claim the CR or PR as the 
confirmed BOR.  If there is no second CR or PR tumor assessment, the CR or PR will be 
unconfirmed.  Table 4 lists the scenarios that can occur after an unconfirmed CR or PR and 
provides a rule for determining the confirmed BOR in each scenario.  A sensitivity analysis will 
be performed for the ORR assessed under mRECIST, in which BOR is determined using 
unconfirmed PR and CR. 
The mRECIST was adapted from RECIST v1.1 to include criteria that accounts for new lesions 
that can occur in immuno-oncology subjects before the occurrence of an SD, PR, or CR.  Under 
mRECIST, if radiologic imaging shows PD, tumor assessment should be repeated at a minimum 
of 4 weeks but not more than 6 weeks later to confirm the progression.  If there is no second PD 
tumor assessment in the 4- to 6-week follow-up time, the PD will be defined as unconfirmed.  
Table 6 lists the scenarios that can occur after an unconfirmed PD in at least 4 weeks and no 
more than 6 weeks and provides rules for determining whether or not the unconfirmed PD will 
be counted as an event in the corresponding scenario. 
Table 6: 
Rules for Determining PD Event Status After an Unconfirmed PD Under 
mRECIST  
Event Occurring After Unconfirmed PD in the 
Confirmation Window (4-6 weeks) 
PD Event Status 
Subject had EOS/EOT or started new anticancer 
therapy. 
PD will be confirmed as a PD.   
Subject had a confirmed PD. 
PD will be confirmed as a PD.   
Subject had an CR, PR, SD, or NE. 
PD will not be considered as a PD and counted as 
corresponding CR, PR, SD, or NE for the second 
timepoint only. 
Confirmed ORR by mRECIST will be summarized by treatment group and tumor type for the 
Phase 2 response evaluable population. 


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7.3.2.4. 
Unconfirmed ORR and Unconfirmed BOR by mRECIST – Sensitivity and 
Supportive Analyses for Confirmed ORR and Confirmed BOR by mRECIST  
A sensitivity analysis for the ORR assessed under mRECIST will be performed using 
unconfirmed CRs and PRs.  The unconfirmed BOR is defined as the best response recorded 
postbaseline before and including the first PD, in the order of CR, PR, SD, PD, and NE.  For this 
definition, responses of CR and PR do not need to be confirmed at a subsequent timepoint.  In 
the case of SD, measurements must meet the SD criteria at least once after the date of first dose 
at a minimum interval of 49 (56 – 7) days.  Subjects that fail to meet this criterion will have 
confirmed BOR of PD if the next available assessment indicates PD or NE if there is no 
additional assessment available. 
Unconfirmed ORR as assessed by mRECIST will be summarized by treatment group and dose 
level for the Phase 1 response evaluable population and by treatment group and tumor type for 
the Phase 2 response evaluable population. 
7.3.3. 
Duration of Response 
Duration of response will be assessed with RECIST v1.1 and mRECIST criteria. 
Censoring of DOR will follow the same algorithm as the censoring of PFS (Table 7).  
Kaplan-Meier curves for DOR will be presented by cohort-specific tumor types.  The KM 
estimate of median DOR will be presented with its 95% CI.  The 95% CI will be calculated using 
Brookmeyer and Crowley's method (Brookmeyer and Crowley 1982).  A swim plot for DOR 
will be generated under both RECIST v1.1 and mRECIST criteria. 
Duration of response as assessed by RECIST v1.1 and mRECIST will be summarized by 
treatment group and dose level for the Phase 1 response evaluable population and by treatment 
group and tumor type for the Phase 2 response evaluable population. 
7.3.3.1. 
Duration of Response by RECIST v1.1 
Under RECIST v1.1, for unconfirmed objective responders, DOR is defined as the time from the 
first overall response contributing to an unconfirmed objective response (CR or PR) to the earlier 
of the subject's death from any cause or first assessment of PD. 
7.3.3.2. 
Duration of Response by mRECIST  
Under mRECIST, for unconfirmed objective responders, DOR is the time from the first 
unconfirmed overall response contributing to an unconfirmed objective response (CR or PR) to 
the earlier of the subject's death from any cause or first confirmed assessment of PD.  Note that 
the criteria for the assessment of PD in DOR are the same with ORR, which are presented in 
Section 7.3.2.3. 
7.3.4. 
Duration of Disease Control and Disease Control Rate 
Duration of disease control (CR, PR, and SD) is defined as the time from the first report of SD or 
better until disease progression or death from any cause, if occurring sooner than progression, as 
determined by investigator assessment of radiographic disease per RECIST v1.1 and mRECIST.  
Note that the criteria for the assessment of PD in duration of disease control are the same with 
ORR, which are presented in Section 7.3.2.3. 


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The duration of disease control will be estimated with 95% CIs overall and by treatment group.  
Confidence intervals will be calculated based on the exact method for binomial distributions.  
Swim plots for duration of disease control will be generated separately for RECIST v1.1 and 
mRECIST criteria. 
Disease control rate, defined as the proportion of subjects who have disease control (CR + PR + 
SD), as per RECIST v1.1 and mRECIST will be summarized.  For the determination of DCR, 
response of CR and PR do not need to be confirmed at a subsequent timepoint.  In the case of 
SD, measurements must meet the SD criteria at least after the date of first dose at a minimum of 
49 days.  Subjects who fail to meet this criterion will have confirmed BOR of PD if the next 
available assessment indicated PD or NE if there is no additional assessment available.  Disease 
control rate will be estimated with 95% CIs. 
Duration of disease control and DCR as assessed per RECIST v1.1 and mRECIST will be 
summarized by treatment group and dose level for the Phase 1 response evaluable population and 
by treatment group and tumor type for the Phase 2 response evaluable population. 
7.3.5. 
Largest Percentage Reduction in Sum of Diameters of Target Lesions 
For each subject in the FAS population with target lesions at baseline, target lesion sizes will be 
measured by sum of diameters.  The best percentage change from baseline, defined as the largest 
decrease in target lesion size for each subject, will be summarized descriptively, and a waterfall 
plot of the best percentage change will be generated. 
Per RECIST 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. 
7.3.6. 
Percentage Change in Sum of Diameters of Target Lesions Over Time 
For each subject in the FAS population with target lesions at baseline, target lesion sizes will be 
measured by sum of diameters.  The percentage change in sum of diameter of target lesions over 
time will be listed and a spider plot will be generated. 
7.3.7. 
Progression-Free Survival 
Progression-free survival is defined as the length of time between the baseline visit (Day 1) and 
the earlier of death or PD as assessed by RECIST v1.1 and mRECIST.  Date of death will be 
determined using the Death Report CRF, and analyses will be summarized for the FAS 
population. 
Censoring for PFS will follow the algorithm outlined in Table 7 which is based on the FDA 
Guidance for Industry:  Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics 
(FDA 2007). 
Kaplan-Meier curves for PFS will be presented by cohort-specific tumor types.  The KM 
estimate of median PFS will be presented with its 95% CI.  The 95% CI will be calculated using 
the Brookmeyer and Crowley's method (1982). 


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Table 7: 
Evaluation and Censoring of Progression-Free Survival 
Situation 
Outcome  
Date of Progression or Censoring  
No baseline tumor assessments 
Censored  
Date of Day 1  
No valid postbaseline response assessments 
Censored  
Date of 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).   
Death before first progressive response 
assessment 
Progressed  
Date of death  
Death between adequate response assessments Progressed  
Date of death  
Death or progression after more than 1 missed 
assessment 
Censored  
Date of last valid radiologic assessment 
(not NE and not missing) before death  
NE = not evaluable. 
7.3.7.1. 
Progression-Free Survival by RECIST v1.1 
Under RECIST v1.1, PFS is defined as the length of time between the baseline visit (Day 1) and 
the earlier of death or first assessment of PD as assessed by RECIST v1.1. 
7.3.7.2. 
Progression-Free Survival by mRECIST  
Under mRECIST, PFS is defined as the length of time between the baseline visit (Day 1) and the 
earlier of death or first confirmed assessment of PD (as described in Table 6). 
7.3.8. 
Overall Survival 
Overall survival is defined as the interval between Cycle 1 Day 1 and the date of death due to 
any cause.  Date of death will be determined using the Death Report, the Survival Follow-Up, 
and the Subject Status CRFs.  Subjects who are lost-to-follow-up or still alive at the time of 
analysis will be right-censored at the earlier of the date that the subject was last known alive and 
the clinical data cutoff date for the analysis.  The last known alive date is defined as the later of 
the last study visit and the date the subject was last known alive from the Survival Follow-Up 
and Subject Status CRFs, and the analyses will be summarized for the FAS population. 
Kaplan-Meier time to event curves will be presented by treatment groups.  Median survival will 
be estimated using the Kaplan-Meier method.  Kaplan-Meier estimates of 1-year and 2-year 
survival probabilities will be provided.  Confidence intervals for median survival time will be 
calculated using the method of Brookmeyer and Crowley (1982). 


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8. 
SAFETY AND TOLERABILITY 
Sample data displays are provided 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 subjects. 
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 
first dose of study drug.  For the subjects in the FAS population, 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. 
Adverse events will be tabulated by MedDRA PT and SOC.  Severity of AEs will be graded 
using the National Cancer Institute CTCAE.  The CTCAE version 4.03 is used for this study.  
The CTCAE reporting guidelines and grading details are available on the Cancer Therapy 
Evaluation Program website. 
The subset of AEs considered by the investigator to be related to INCAGN01949, nivolumab, or 
ipilimumab will be considered to be treatment-related AEs and will be summarized.  If the 
investigator does not specify the relationship of the AE to study drug, the AE will be considered 
to be treatment-related.  The incidence of AEs and treatment-related AEs will be tabulated.  In 
addition, SAEs will also be tabulated. 
A grading (severity) scale is provided for each AE term.  If the toxicity is not included in the 
CTCAE v4.03 criteria, it will be rated on a scale of 1 to 5 as follows:  1 = mild, 2 = moderate, 
3 = severe, 4 = life-threatening, and 5 = death related to AE.  All toxicities will be graded based 
on the worst level reached, not the level they may have reached if they had not been treated.  
When the intensity of an AE changes over time for a reporting period (eg, between visits), each 


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change in intensity will be collected as an AE until the event resolves.  Only the worst grade will 
be reported in AE summaries.  Also, the Grade 3 or higher AEs will be summarized. 
Any missing onset date, causality, or severity must be queried for resolution.  Unresolved 
missing causality and severity will be handled according to the following rules: 
• An unresolved missing causality will be considered treatment-related. 
• An unresolved missing severity will be identified as an unknown severity. 
For purposes of analysis, all AEs will be considered TEAEs unless the AE can unequivocally be 
defined as not treatment-emergent. 
8.2.2. 
Dose-Limiting Toxicities 
The number of subjects with DLTs and the type of DLT will be listed by dose level and 
treatment group.  An AE for a subject will be identified as a DLT if the event is recorded as a 
Protocol-defined DLT on the AE CRF. 
8.2.3. 
Adverse Events of Special Interest  
8.2.3.1. 
Immune-Related Adverse Events 
The number of subjects with irAEs and type of irAE will be listed by dose level and treatment 
group for the Phase 1 FAS population and by tumor type and treatment group in the Phase 2 FAS 
population.  Adverse event terms will be reviewed periodically without respect to treatment 
group by the medical monitor and clinical scientist to determine which AE terms correspond to 
irAEs.  This periodic review may also occur after database lock.  The medical monitor and 
clinical scientist will also review investigator-reported irAEs to determine whether they qualify 
as irAEs.  For example, a rash will be counted as an irAE even if the investigator did not report it 
as an irAE. 
8.2.3.1.1. Adverse Events Identified as Incyte MedDRA Queries 
Prospectively defined Incyte MedDRA Queries will be used to conduct analyses to evaluate the 
safety profile.  Incyte MedDRA Queries are queries constructed by Incyte based on MedDRA 
PTs identified through review of standardized MedDRA queries for clinically relevant terms.  
Sets of included terms will be identified and archived before database lock for the individual 
studies.  Incyte MedDRA Queries searches are to be conducted for the following TEAEs:  
hemorrhage events, dizziness, weight gain, thrombotic events, urinary tract infections, herpes 
zoster infections, tuberculosis, hepatitis B reactivation, and infections other than those stated 
previously.  In addition, these other infections will be analyzed by subcategories of upper 
respiratory tract infections, lower respiratory tract infections, skin and soft tissue infections, 
alimentary tract infections, other viral infections, and miscellaneous infections with each 
tabulated by MedDRA PT. 
8.2.3.2. 
Infusion-Related Reactions 
Infusion-related reactions, defined as AEs that are identified as infusion related reaction by the 
investigator on the Infusion-Related Reaction CRF, will be summarized in a table and listing.  
The summaries will include the treatment group, dose level, cycle number, study day, date of 


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onset of AE, date of the associated infusion, and signs and symptoms of the infusion-related 
reaction. 
8.2.4. 
Adverse Event Summaries 
An overall summary of AEs by treatment group and by tumor type as applicable will include the 
following: 
• Number (%) of subjects reporting any TEAEs 
• Number (%) of subjects reporting any DLTs 
• Number (%) of subjects reporting any SAEs 
• Number (%) of subjects reporting any Grade 3 or higher TEAEs 
• Number (%) of subjects reporting any TEAEs related to INCAGN01949 
• Number (%) of subjects reporting any TEAEs related to nivolumab 
• Number (%) of subjects reporting any TEAEs related to ipilimumab 
• Number (%) of subjects who temporarily interrupted INCAGN01949 because of 
TEAEs 
• Number (%) of subjects who temporarily interrupted nivolumab because of TEAEs 
• Number (%) of subjects who temporarily interrupted ipilimumab because of TEAEs 
• Number (%) of subjects who permanently discontinued INCAGN01949 because of 
TEAEs 
• Number (%) of subjects with INCAGN01949 dose reductions because of TEAEs  
• Number (%) of subjects who had a fatal TEAE 
• Number (%) of subjects who withdrew from study because of an TEAE 
The following summaries will be produced by MedDRA term: 
• Summary of TEAEs by SOC and PT 
• Summary of TEAEs by PT in decreasing order of frequency 
• Summary of TEAEs by SOC, PT, and maximum severity 
• Summary of Grade 3 or higher TEAEs by SOC and PT 
• Summary of INCAGN0
 treatment-related AEs by SOC and PT 
• Summary of nivolumab treatment-related AEs by SOC and PT 
• Summary of ipilimumab treatment-related AEs by SOC and PT 
• Summary of Grade 3 or higher INCAGN01949 treatment-related AEs by PT in 
descending order of frequency 
• Summary of Grade 3 or higher nivolumab treatment-related AEs by PT in descending 
order of frequency 


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• Summary of Grade 3 or higher ipilimumab treatment-related AEs by PT  in 
descending order of frequency 
• Summary of treatment-emergent SAEs by SOC and PT 
• Summary of treatment-emergent SAEs by PT in descending order of frequency 
• Summary of treatment-emergent non-SAE by SOC and PT. 
• Summary of treatment-related SAEs by SOC and PT 
• Summary of TEAEs leading to INCAGN01949 dose reduction by SOC and PT 
• Summary of TEAEs leading to INCAGN01949 dose interruption by SOC and PT 
• Summary of TEAEs leading to nivolumab dose interruption by SOC and PT 
• Summary of TEAEs leading to ipilimumab dose interruption by SOC and PT 
• Summary of TEAEs leading to discontinuation of INCAGN01949 by SOC and PT 
• Summary of TEAEs leading to death 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.  
Baseline will be determined according to Section 4.1.3.  If there are multiple values that meet the 
criteria for baseline, additional rules may be provided after consultation with the medical monitor 
to delineate which value will be defined as baseline. 
Laboratory test values outside the normal range will be assessed for severity based on CTCAE 
grade or similar criteria where clinical intervention is required for CTCAE grading.  The 
incidence of abnormal laboratory values and shift tables relative to baseline will be tabulated. 
8.3.2. 
Laboratory Value Summaries 
All test results and associated normal ranges from local laboratories will be reported in SI units.  
All tests with numeric values will have a unique unit per test.  Any laboratory test results and 
associated normal ranges from local laboratories will be converted to SI units.  For the limited 
number of cases where the associated normal ranges from a local laboratory cannot be obtained 
despite due diligence, if query is unsuccessful at resolving the issue and analysis is mandatory, 
then the clinical scientist and medical monitor can provide a suitable normal range to be used in 
determining CTCAE grading and flags for above and below normal. 
When there are multiple laboratory nonmissing values for a subject's particular test at a 
scheduled visit, the laboratory value with the smallest laboratory sequence number will be used 
in by-visit summaries (Table 8). 


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Table 8: 
Identification of Records for Postbaseline By-Visit Summaries 
Priority 
Laboratory Visit 
Proximity to Visit 
Window 
Tiebreaker 
1 
Scheduled 
In-window 
Use smallest laboratory 
sequence number 
2 
Unscheduled 
In-window 
3 
Scheduled 
Out-of-window 
Numeric laboratory values will be summarized descriptively in SI units, and non-numeric test 
values will be tabulated when necessary.  In addition, line graphs and box-and-whisker plots will 
be provided for hemoglobin, platelet counts, WBCs, and neutrophils. 
For test results that will be summarized with available normal ranges, the number and percentage 
of subjects with the laboratory values being low (but never high), normal, high (but never low), 
and both low and high will be calculated for each test.  This shift summary will be produced for 
each test for the FAS population.  The denominator for the percentage calculation will use the 
number of subjects in the baseline category (ie, low, high, normal, missing) as the denominator 
for the percentage in each of the categories during the treatment period. 
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, diastolic blood pressure, pulse, respiration rate, and body 
temperature, will be summarized descriptively. 
Criteria for clinically notable vital sign abnormalities are defined in Table 9.  The abnormal 
values for subjects exhibiting clinically notable vital sign abnormalities will be listed along with 
their assigned treatment group.  Alert vital signs are defined as an absolute value outside the 
defined range and percentage change > 25% from baseline.  The abnormal values for subjects 
exhibiting alert vital sign abnormalities will be listed. 
Table 9: 
Criteria for Clinically Notable Vital Sign Abnormalities 
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure 
> 155 mmHg 
< 85 mmHg 
Diastolic blood pressure 
> 100 mmHg 
< 40 mmHg 
Pulse 
> 100 bpm 
< 45 bpm 
Temperature 
> 38ºC 
< 35.5ºC 
Respiratory rate 
> 24/min 
< 8/min 


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8.5. 
Electrocardiograms 
Twelve-lead ECGs including heart rate, PR, QRS, QT, QTcF, QTcB, JTC, and RR intervals will 
be obtained for each subject at the screening, EOT, and safety follow-up visits during the study.  
Values at each scheduled visit, change, and percentage change from baseline will be summarized 
for each ECG parameter.  Baseline will be determined as the average of all nonmissing values 
before the first administration of INCAGN01949, nivolumab, or ipilimumab. 
Criteria for clinically notable ECG abnormalities are defined in Table 10.  Subjects exhibiting 
clinically notable ECG abnormalities will be listed with study visit and assigned treatment group.  
Abnormal values for subjects with alert ECG values, defined as both the absolute value and the 
percentage change from baseline being outside normal ranges, will be identified and listed. 
Table 10: 
Criteria for Clinically Notable Electrocardiogram Abnormalities 
Parameter 
High Threshold 
Low Threshold 
QTcF 
> 460 msec 
< 295 msec 
PR  
> 220 msec 
< 75 msec 
QRS  
> 120 msec 
< 50 msec 
QT  
> 500 msec 
< 300 msec 
RR  
> 1330 msec 
< 600 msec 
QTcF = Fridericia correction. 
9. 
INTERIM ANALYSES 
9.1. 
Overview of Interim Analyses 
9.1.1. 
Interim Analyses for Safety 
There will be no planned, formal interim analyses for the Phase 1 dose escalation portion of the 
study.  The review of accrued clinical data will be conducted by Incyte and provided to study 
investigators via teleconferences at the end of Phase 1 of the study.  Based on review of the most 
current safety data, the sponsor (in consultation with the study investigators and using the 
dose-escalation/de-escalation rules) will determine if and at what dose additional subjects should 
be treated in the study. 
A DMC will be charged with evaluating interim safety results.  The DMC will be composed of 
members who are internal to the sponsor but not members of the study team.  The DMC 
members will include a medical monitor who will serve as the DMC chair and meeting 
facilitator, the head of biostatistics or a designee, the head of regulatory affairs or a designee, and 
the study medical monitor who will be a nonvoting member.  The DMC will meet at least every 
6 months starting after the first 10 subjects have been dosed to review the rate of DLTs and 
irAEs in each treatment group and the overall safety of the subjects treated with INCAGN01949, 
nivolumab, and ipilimumab.  Additional operational details of the interim analyses, including 
TFLs provided to the DMC, will be provided in the DMC Charter.  Additional safety analyses 
may be performed at the discretion of the DMC chair. 


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9.1.2. 
Interim Analyses for Futility 
9.1.2.1. 
Simon 2-Stage Futility Rules 
An interim analysis of efficacy will be conducted in Phase 2 by applying the Simon 2-stage 
design for each tumor within a given treatment group.  During Stage 1, 𝑛1 evaluable subjects 
treated at the recommended dose and schedule will be enrolled, and if 𝑟1 or fewer responses are 
observed by the Week 16 assessment, then the cohort will be discontinued.  To be counted as 
evaluable for the calculation in Stage 1, subjects must have discontinued from the study, reached 
the Week 16 assessment, or had at least 2 scans.  As discussed in Section 3.2, the Simon 2-stage 
designs conducted for each tumor type within each treatment group have design parameters that 
are determined by historical response rates and will have different sample sizes and futility 
results depending on the historical response rate.  The probability of early termination for Stage 1 
in Treatment Groups F, G, and H is summarized in Table 11. 
Table 11: 
Probability of Early Termination for Simon 2-Stage Design in Phase 2 in 
Treatment Groups F, G, and H 
Cohort 
(Tumor Type) 
𝒑𝟎 
𝒑𝟏 
Probability of Early Termination 
Under 𝑯𝟎 
Under 𝑯𝑨 
RCC  
25% 
40% 
0.6736 
0.0940 
Urothelial  
20% 
35% 
0.7134 
0.1148 
Relapsed to anti–PD-1/L1  
10% 
25% 
0.6769 
0.0913 


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9.2. 
Data Cutoff for Interim Analysis 
As discussed in Section 9.1.1, the DMC will meet every 6 months to review safety analyses.  All 
efficacy and safety analyses will use a clinical data cutoff of 3 weeks before execution of the 
planned safety or interim analysis.  This period will help ensure accuracy of the interim data by 
providing the sponsor time to perform data review, issue queries regarding data quality issues to 
sites, and to resolve such queries. 
 
 
  
 
 
   


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10. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN 
All versions of the SAP are listed in Table 14. 
Table 14: 
Statistical Analysis Plan Versions 
SAP Version 
Date 
Original 
06 FEB 2018 
10.1. 
Changes to Protocol-Defined Analyses 
Not applicable. 
10.2. 
Changes to the Statistical Analysis Plan 
Not applicable. 


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INCAGN 1949-201 Statistical Analysis Plan 
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CONFIDENTIAL 
11. 
REFERENCES 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 
1982;38:29-41. 
Food and Drug Administration (FDA). Guidance for Industry: Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics. 2007. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
CM071590.pdf. Accessed December 20, 2017. 
Koyama T, Chen H. Proper inference from Simon’s two-stage designs. Stat Med 
2008;27:3145-3154. 
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 AND FIGURES 
This appendix provides a list of the planned tables and figures for the CSR.  Standard tables will 
follow the conventions in the Standard Safety Tables initial version.  Shells are provided for 
nonstandard tables in a separate document.  In-text tables are identical in structure and content as 
appendix tables, but follow a Rich Text Format. 
The list of tables, figures, and the shells are to be used as guideline.  Modifications of the list or 
shells that do not otherwise affect the nature of the analysis will not warrant an amendment to the 
SAP. 
Tables 
Table No. 
Title 
Population 
Standard 
In-Text 
Baseline and Demographic Characteristics 
1.1 
Disposition 
1.1.1.1 
Analysis Populations 
Phase 1 
FAS 
Population 
X 
X 
1.1.1.2 
Analysis Populations 
Phase 2 
FAS 
Population 
X 
X 
1.1.2.1 
Summary of Subject Disposition 
Phase 1 
FAS 
Population 
X 
X 
1.1.2.2 
Summary of Subject Disposition 
Phase 2 
FAS 
Population 
X 
X 
1.1.2.3 
Summary of Subject Disposition 
FAS 
Population 
X 
 
1.1.3 
Summary of Number of Subjects Enrolled by Country and Site 
FAS 
Population 
X 
 
1.2 Demography 
1.2.1 
Summary of Demographics  
Phase 1 
FAS 
Population 
X 
X 
1.2.2 
Summary of Demographics – by Tumor Type 
Phase 2 
FAS 
Population  
X 
X 
1.3 Baseline Characteristics 
1.3.1.1 
Summary of Baseline Disease Characteristics and Disease 
History for Phase 1 Solid Tumor Types 
Phase 1 
FAS 
Population 
X 
 
1.3.1.2.1 
Summary of Baseline Disease Characteristics and Disease 
History for Phase 2 Solid Tumor Types 
 
Phase 2 
FAS 
Population  
X 
 
1.3.1.2.2 
Summary of Baseline Disease Characteristics and Disease 
History  
RCC Phase 
2 FAS 
Population  
X 
 


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Table No. 
Title 
Population 
Standard 
In-Text 
1.3.1.2.3 
Summary of Baseline Disease Characteristics and Disease 
History  
Urothelial 
Phase 2 
FAS 
Population  
X 
 
1.3.1.2.4 
Summary of Baseline Disease Characteristics and Disease 
History  
Relapsed 
PD-1 Phase 
2 FAS 
Population  
X 
 
1.4 Prior Medication and Concomitant Medication 
1.4.1.1 
Summary of Prior Systemic Therapy  
Phase 1 
FAS 
Population  
 
 
1.4.1.2 
Summary of Prior Systemic Therapy – by Tumor Type 
Phase 2 
FAS 
Population  
 
 
1.4.2.1 
Summary of Prior Medications 
Phase 1 
FAS 
Population 
X 
 
1.4.2.2 
Summary of Prior Medications – by Tumor Type 
Phase 2 
FAS 
Population 
X 
 
1.4.3 
Summary of Prior Radiation – by Tumor Type 
Phase 2 
FAS 
Population 
 
 
1.4.4 
Summary of Prior Surgery – by Tumor Type 
Phase 2 
FAS 
Population 
 
 
1.4.5.1 
Summary of Concomitant Medications 
Phase 1 
FAS 
Population  
X 
 
1.4.5.2 
Summary of Concomitant Medications – by Tumor Type 
Phase 2 
FAS 
Population 
X 
 
1.5 Others 
1.5.1 
Summary of General Medical History 
Phase 1 
FAS 
Population 
X 
 
1.5.2 
Summary of General Medical History – by Tumor Type 
Phase 2 
FAS 
Population 
X 
 
1.5.3 
Summary of Protocol Deviations 
FAS 
Population 
 
X 


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Table No. 
Title 
Population 
Standard 
In-Text 
2.1 Efficacy 
2.1.1.1 
Summary of Confirmed Best Response, Duration of Response, 
and Duration of Disease Control Under RECIST v1.1 – by 
Treatment Group and Dose 
Phase 1 
Response 
Evaluable 
Population 
 
X 
2.1.1.2 
Summary of Unconfirmed Best Response, Duration of 
Response, and Duration of Disease Control Under RECIST 
v1.1 – by Treatment Group and Dose 
Phase 1 
Response 
Evaluable 
Population 
 
X 
2.1.2.1 
Summary of Confirmed Best Response, Duration of Response, 
and Duration of Disease Control Under RECIST v1.1 – by 
Treatment Group and Dose 
Phase 2 
Response 
Evaluable 
Population 
 
X 
2.1.2.2 
Summary of Unconfirmed Best Response, Duration of 
Response, and Duration of Disease Control Under RECIST – 
by Treatment Group and Dose 
Phase 2 
Response 
Evaluable 
Population 
 
X 
2.1.3.1 
Summary of Confirmed Best Response, Duration of Response, 
and Duration of Disease Control under mRECIST – by 
Treatment Group and Tumor Type 
Phase 2 
Response 
Evaluable 
Population 
 
X 
2.1.3.2 
Summary of Unconfirmed Best Response, Duration of 
Response, and Duration of Disease Control Under mRECIST 
– by Treatment Group and Tumor Type 
Phase 2 
Response 
Evaluable 
Population 
 
X 
2.1.4.1 
Summary of Progression-Free Survival Under RECIST v1.1  
Phase 1 
FAS 
Population 
 
X 
2.1.4.2 
Summary of Progression-Free Survival Under RECIST v1.1 – 
by Tumor Type 
Phase 2 
FAS 
Population 
 
X 
2.1.5.1 
Summary of Progression-Free Survival Under mRECIST  
Phase 1 
FAS 
Population 
 
X 
2.1.5.2 
Summary of Progression-Free Survival under mRECIST – by 
Tumor Type 
Phase 2 
FAS 
Population 
 
X 
2.1.6.1 
Summary of Overall Survival  
Phase 1 
FAS 
Population 
 
X 
2.1.6.2 
Summary of Overall Survival – by Tumor Type 
Phase 2 
FAS 
Population 
 
X 


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CONFIDENTIAL 
Table No. 
Title 
Population 
Standard 
In-Text 
Safety 
3.1 Dose Exposure 
3.1.1.1 
Summary of INCAGN01949 Drug Exposure – by Treatment 
Group and Dose 
Phase 1 
FAS 
Population 
X 
X 
3.1.1.2 
Summary of INCAGN01949 Drug Exposure – by Treatment 
Group and Tumor Type 
Phase 2 
FAS 
Population  
X 
X 
3.1.2.1 
Summary of Nivolumab Drug Exposure – by Treatment Group 
and Dose 
Phase 1 
Nivolumab 
FAS 
Population 
X 
X 
3.1.2.2 
Summary of Nivolumab Drug Exposure – by Treatment Group 
and Tumor Type 
Phase 2 
Nivolumab 
FAS 
Population  
X 
X 
3.1.3.1 
Summary of Ipilimumab Drug Exposure – by Treatment 
Group and Dose 
Phase 1 
Ipilimumab 
FAS 
Population 
X 
X 
3.1.3.2 
Summary of Ipilimumab Drug Exposure – by Treatment 
Group and Tumor Type 
Phase 2 
Ipilimumab 
FAS 
Population  
X 
X 
3.1.4.1 
Summary of INCAGN01949 Drug Exposure by Visit – by 
Treatment Group and Dose 
Phase 1 
FAS 
Population 
 
 
3.1.4.2 
Summary of INCAGN01949 Drug Exposure by Visit – by 
Treatment Group and Tumor Type 
Phase 2 
FAS 
Population  
 
 
3.1.5.1 
Summary of Nivolumab Drug Exposure by Visit – by 
Treatment Group and Dose 
Phase 1 
Nivolumab 
FAS 
Population 
 
 
3.1.5.2 
Summary of Nivolumab Drug Exposure by Visit – by 
Treatment Group and Tumor Type 
Phase 2 
Nivolumab 
FAS 
Population  
 
 


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Table No. 
Title 
Population 
Standard 
In-Text 
3.1.6.1 
Summary of Ipilimumab Drug Exposure by Visit – by 
Treatment Group and Dose 
Phase 1 
Ipilimumab 
FAS 
Population 
 
 
3.1.6.2 
Summary of Ipilimumab Drug Exposure by Visit – by 
Treatment Group and Tumor Type 
Phase 2 
Ipilimumab 
FAS 
Population  
 
 
3.2 Adverse Events 
3.2.1.1 
Overall Summary of Treatment-Emergent Adverse Events – 
by Treatment Group and Dose 
Phase 1 
FAS 
Population  
X 
X 
3.2.1.2 
Overall Summary of Treatment-Emergent Adverse Events – 
by Treatment Group and Tumor Type 
Phase 2 
FAS 
Population 
X 
X 
3.2.2.1 
Summary of Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term – by 
Treatment Group and Dose 
Phase 1 
FAS 
Population 
X 
 
3.2.3.1 
Summary of Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term – by 
Treatment Group and Tumor Type 
Phase 2 
FAS 
Population 
X 
 
3.2.4.1 
Summary of Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of Frequency – 
by Treatment Group and Dose 
Phase 1 
FAS 
Population  
X 
X 
3.2.4.2 
Summary of Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of Frequency – 
by Treatment Group and Tumor Type 
Phase 2 
FAS 
Population 
X 
X 
3.2.5.1 
Summary of Treatment-Emergent Adverse Events by 
MedDRA System Organ Class, Preferred Term, and 
Maximum Severity – by Treatment Group and Dose 
Phase 1 
FAS 
Population  
X 
 
3.2.5.2 
Summary of Treatment-Emergent Adverse Events by 
MedDRA System Organ Class, Preferred Term, and 
Maximum Severity – by Treatment Group and Tumor Type 
Phase 2 
FAS 
Population 
X 
 
3.2.6.1 
Summary of Grade 3 or Higher Treatment-Emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term 
– by Treatment Group and Dose 
Phase 1 
FAS 
Population  
X 
X 
3.2.6.2 
Summary of Grade 3 or Higher Treatment-Emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term 
– by Treatment Group and Tumor Type 
Phase 2 
FAS 
Population  
X 
X 
3.2.7.1 
Summary of Any INCAGN01949 Treatment-Related Adverse 
Events by MedDRA System Organ Class and Preferred Term 
– by Treatment Group and Dose 
Phase 1 
FAS 
Population 
X 
X 
3.2.7.2 
Summary of Any INCAGN01949 Treatment-Related Adverse 
Events by MedDRA System Organ Class and Preferred Term 
– by Treatment Group and Tumor Type 
Phase 2 
FAS 
Population  
X 
X 
3.2.8.1 
Summary of Any Nivolumab Treatment-Related Adverse 
Events by MedDRA System Organ Class and Preferred Term 
– by Treatment Group and Dose 
Phase 1 
Nivolumab 
FAS 
Population 
X 
X 


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Table No. 
Title 
Population 
Standard 
In-Text 
3.2.8.2 
Summary of Any Nivolumab Treatment-Related Adverse 
Events by MedDRA System Organ Class and Preferred Term 
– by Treatment Group and Tumor Type 
Phase 2 
Nivolumab 
FAS 
Population 
X 
X 
3.2.9.1 
Summary of Any Ipilimumab Treatment-Related Adverse 
Events by MedDRA System Organ Class and Preferred Term 
– by Treatment Group and Dose 
Phase 1 
Ipilimumab 
FAS 
Population 
X 
X 
3.2.9.2 
Summary of Any Ipilimumab Treatment-Related Adverse 
Events by MedDRA System Organ Class and Preferred Term 
– by Treatment Group and Tumor Type 
Phase 2 
Ipilimumab 
FAS 
Population 
X 
X 
3.2.10.1 
Summary of Any Grade 3 or Higher INCAGN01949 
Treatment-Related Adverse Events by MedDRA Preferred 
Term in Order of Decreasing Frequency – by Treatment Group 
and Dose 
Phase 1 
FAS 
Population 
X 
 
3.2.10.2 
Summary of Any Grade 3 or Higher INCAGN01949 
Treatment-Related Adverse Events by MedDRA Preferred 
Term in Order of Decreasing Frequency – by Treatment Group 
and Tumor Type 
Phase 2 
FAS 
Population 
X 
 
3.2.11.1 
Summary of Any Grade 3 or Higher Nivolumab 
Treatment-Related Adverse Events by MedDRA Preferred 
Term in Order of Decreasing Frequency – by Treatment Group 
and Dose 
Phase 1 
Nivolumab 
FAS  
Population 
X 
 
3.2.11.2 
Summary of Any Grade 3 or Higher Nivolumab 
Treatment-Related Adverse Events by MedDRA Preferred 
Term in Order of Decreasing Frequency – by Treatment Group 
and Tumor Type 
Phase 2 
Nivolumab 
FAS 
Population 
X 
 
3.2.12.1 
Summary of Any Grade 3 or Higher Ipilimumab 
Treatment-Related Adverse Events by MedDRA Preferred 
Term in Order of Decreasing Frequency – by Treatment Group 
and Dose 
Phase 1 
Ipilimumab 
FAS  
Population 
X 
 
3.2.12.2 
Summary of Any Grade 3 or Higher Ipilimumab 
Treatment-Related Adverse Events by MedDRA Preferred 
Term in Order of Decreasing Frequency – by Treatment Group 
and Tumor Type 
Phase 2 
Ipilimumab 
FAS 
Population 
X 
 
3.2.13.1 
Summary of Any INCAGN01949 Treatment-Related Adverse 
Events With a Fatal Outcome by MedDRA System Organ 
Class and Preferred Term– by Treatment Group and Dose 
Phase 1 
FAS 
Population 
X 
 
3.2.13.2 
Summary of Any INCAGN01949 Treatment-Related Adverse 
Events With a Fatal Outcome by MedDRA System Organ 
Class and Preferred Term – by Treatment Group and Tumor 
Type 
Phase 2 
FAS 
Population 
X 
 
3.2.14.1 
Summary of Any Nivolumab Treatment-Related Adverse 
Events With a Fatal Outcome by MedDRA System Organ 
Class and Preferred Term – by Treatment Group and Dose 
Phase 1 
Nivolumab 
FAS 
Population 
X 
 
3.2.14.2 
Summary of Any Nivolumab Treatment-Related Adverse 
Events With a Fatal Outcome by MedDRA System Organ 
Class and Preferred Term – by Treatment Group and Tumor 
Type 
Phase 2 
Nivolumab 
FAS 
Population 
X 
 


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Table No. 
Title 
Population 
Standard 
In-Text 
3.2.15.1 
Summary of Any Ipilimumab Treatment-Related Adverse 
Events With a Fatal Outcome by MedDRA System Organ 
Class and Preferred Term– by Treatment Group and Dose 
Phase 1 
Ipilimumab 
FAS 
Population 
X 
 
3.2.15.2 
Summary of Any Ipilimumab Treatment-Related Adverse 
Events With a Fatal Outcome by MedDRA System Organ 
Class and Preferred Term – by Treatment Group and Tumor 
Type 
Phase 2 
Ipilimumab 
FAS 
Population 
X 
 
3.2.16.1 
Summary of Serious Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term – by 
Treatment Group and Dose 
Phase 1 
FAS 
Population 
X 
 
3.2.16.2 
Summary of Serious Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term – by 
Treatment Group and Tumor Type 
Phase 2 
FAS 
Population 
X 
 
3.2.17.1 
Summary of Serious Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of Frequency – 
by Treatment Group and Dose 
Phase 1 
FAS 
Population 
 
X 
3.2.17.2 
Summary of Serious Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of Frequency – 
by Treatment Group and Tumor Type 
Phase 2 
FAS 
Population 
 
X 
3.2.18.1 
Summary of Non-Serious Treatment-Emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term 
– by Treatment Group and Dose 
Phase 1 
FAS 
Population 
X 
 
3.2.18.2 
Summary of Non-Serious Treatment-Emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term 
– by Treatment Group and Tumor Type 
Phase 2 
FAS 
Population 
X 
 
3.2.19.1 
Summary of Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class and Preferred Term – by 
Treatment Group and Dose 
Phase 1 
FAS 
Population 
X 
 
3.2.19.2 
Summary of Treatment-Related Serious Adverse Events by 
MedDRA System Organ Class and Preferred Term – by 
Treatment Group and Tumor Type 
Phase 2 
FAS 
Population 
X 
 
3.2.20.1 
Summary of Treatment-Emergent Adverse Events Leading to 
INCAGN01949 Dose Reduction by MedDRA System Organ 
Class and Preferred Term – by Treatment Group and Dose 
Phase 1 
FAS 
Population  
X 
 
3.2.20.2 
Summary of Treatment-Emergent Adverse Events Leading to 
INCAGN01949 Dose Reduction by MedDRA System Organ 
Class and Preferred Term – by Treatment Group and Tumor 
Type 
Phase 2 
FAS 
Population 
X 
 
3.2.21.1 
Summary of Treatment-Emergent Adverse Events Leading to 
INCAGN01949 Dose Interruption by MedDRA System Organ 
Class and Preferred Term – by Treatment Group and Dose 
Phase 1 
FAS 
Population 
 
 
3.2.21.2 
Summary of Treatment-Emergent Adverse Events Leading to 
INCAGN01949 Dose Interruption by MedDRA System Organ 
Class and Preferred Term – by Treatment Group and Tumor 
Type 
Phase 2 
FAS 
Population 
 
 
3.2.22.1 
Summary of Treatment-Emergent Adverse Events Leading to 
Nivolumab Dose Interruption by MedDRA System Organ 
Class and Preferred Term – by Treatment Group and Dose 
Phase 1 
FAS 
Population 
 
 


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Table No. 
Title 
Population 
Standard 
In-Text 
3.2.22.2 
Summary of Treatment-Emergent Adverse Events Leading to 
Nivolumab Dose Interruption by MedDRA System Organ 
Class and Preferred Term – by Treatment Group and Tumor 
Type 
Phase 2 
FAS 
Population 
 
 
3.2.23.1 
Summary of Treatment-Emergent Adverse Events Leading to 
Ipilimumab Dose Interruption by MedDRA System Organ 
Class and Preferred Term – by Treatment Group and Dose 
Phase 1 
FAS 
Population 
 
 
3.2.23.2 
Summary of Treatment-Emergent Adverse Events Leading to 
Ipilimumab Dose Interruption by MedDRA System Organ 
Class and Preferred Term – by Treatment Group and Tumor 
Type 
Phase 2 
FAS 
Population 
 
 
3.2.24.1 
Summary of Treatment-Emergent Adverse Events Leading to 
Discontinuation of INCAGN01949 by MedDRA System 
Organ Class and Preferred Term – by Treatment Group and 
Dose 
Phase 1 
FAS 
Population  
X 
 
3.2.24.2 
Summary of Treatment-Emergent Adverse Events Leading to 
Discontinuation of INCAGN01949 by MedDRA System 
Organ Class and Preferred Term – by Treatment Group and 
Tumor Type 
Phase 2 
FAS 
Population 
X 
 
 
3.2.25.1 
Summary of Treatment-Emergent Immune-Related Adverse 
Events (Investigator Identified) by MedDRA System Organ 
Class and Preferred Term – by Treatment Group and Dose 
Phase 1 
FAS 
Population 
 
 
3.2.25.2 
Summary of Treatment-Emergent Immune-Related Adverse 
Events (Investigator Identified) by MedDRA System Organ 
Class and Preferred Term – by Treatment Group and Tumor 
Type 
Phase 2 
FAS 
Population 
 
 
3.2.26.1 
Summary of Treatment-Emergent Immune-Related Adverse 
Events (Investigator Identified) by MedDRA System Organ 
Class, Preferred Term, and Maximum Severity – by Treatment 
Group and Dose 
Phase 1 
FAS 
Population 
 
 
3.2.26.2 
Summary of Treatment-Emergent Immune-Related Adverse 
Events (Investigator Identified) by MedDRA System Organ 
Class, Preferred Term, and Maximum Severity – by Treatment 
Group and Tumor Type 
Phase 2 
FAS 
Population 
 
 
3.2.27.1 
Summary of Grade 3 or Higher Treatment-Emergent 
Immune-Related Adverse Events (Investigator Identified) by 
MedDRA System Organ Class and Preferred Term – by 
Treatment Group and Dose 
Phase 1 
FAS 
Population 
 
X 
3.2.27.2 
Summary of Grade 3 or Higher Treatment-Emergent 
Immune-Related Adverse Events (Investigator Identified) by 
MedDRA System Organ Class and Preferred Term – by 
Treatment Group and Tumor Type 
Phase 2 
FAS 
Population 
 
X 
3.2.28 
Life Table Estimate of Time to First Grade 3 or Higher 
Treatment-Emergent Adverse Event – by Treatment Group 
and Tumor Type 
Phase 2 
FAS 
Population 
X 
 
3.2.29.1 
Summary of Adverse Events With a Fatal Outcome by System 
Organ Class and Preferred Term – by Treatment Group and 
Dose 
Phase 1 
FAS 
Population 
X 
 
3.2.29.2 
Summary of Adverse Events With a Fatal Outcome by System 
Organ Class and Preferred Term – by Treatment Group and 
Tumor Type 
Phase 2 
FAS 
Population 
X 
 


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Table No. 
Title 
Population 
Standard 
In-Text 
3.2.30.1 
Summary of Infusion Reactions – by Treatment Group and 
Dose 
Phase 1 
FAS 
Population 
 
 
3.2.30.2 
Summary of Infusion Reactions – by Treatment Group and 
Tumor Type 
Phase 2 
FAS 
Population 
 
 
3.3 Laboratory 
3.3.1 
Summary of Laboratory Values – Hematology 
Phase 2 
FAS 
Population 
X 
 
3.3.2.1 
Summary of Hematology Laboratory Values in CTC Grade – 
To the Worst Abnormal Value  
Phase 1 
FAS 
Population 
 
 
3.3.2.2 
Summary of Hematology Laboratory Values in CTC Grade – 
To the Worst Abnormal Value 
Phase 2 
FAS 
Population 
 
 
3.3.3 
Summary of Laboratory Values – Chemistry 
Phase 2 
FAS 
Population 
X 
 
3.3.4.1 
Summary of Chemistry Laboratory Values in CTC Grade – to 
the Worst Abnormal Value 
Phase 1 
FAS 
Population 
 
 
3.3.4.2 
Summary of Chemistry Laboratory Values in CTC Grade – to 
the Worst Abnormal Value 
Phase 2 
FAS 
Population 
 
 
3.4 Vital Signs 
3.4.1.1 
Summary of Systolic Blood Pressure (mmHg) 
Phase 1 
FAS 
Population 
X 
 
3.4.1.2 
Summary of Systolic Blood Pressure (mmHg) – by Tumor 
Type 
Phase 2 
FAS 
Population 
X 
 
3.4.2.1 
Summary of Diastolic Blood Pressure (mmHg) 
Phase 1 
FAS 
Population 
X 
 
3.4.2.2 
Summary of Diastolic Blood Pressure (mmHg) – by Tumor 
Type 
Phase 2 
FAS 
Population 
X 
 
3.4.3.1 
Summary of Heart Rate (bpm) 
Phase 1 
FAS 
Population 
X 
 
3.4.3.2 
Summary of Heart Rate (bpm) – by Tumor Type 
Phase 2 
FAS 
Population 
X 
 
3.4.4.1 
Summary of Respiration Rate (bpm) 
Phase 1 
FAS 
Population 
X 
 
3.4.4.2 
Summary of Respiration Rate (bpm) – by Tumor Type 
Phase 2 
FAS 
Population 
X 
 


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Table No. 
Title 
Population 
Standard 
In-Text 
3.4.5.1 
Summary of Body Temperature (°C) 
Phase 1 
FAS 
Population 
X 
 
3.4.5.2 
Summary of Body Temperature (°C) – by Tumor Type 
Phase 2 
FAS 
Population 
X 
 
3.4.6.1 
Summary of Weight (kg) 
Phase 1 
FAS 
Population 
X 
 
3.4.6.2 
Summary of Weight (kg) – by Tumor Type 
Phase 2 
FAS 
Population 
X 
 
3.5 ECG 
3.5.1.1 
Summary of PR Interval (msec) From Local Lab 12-Lead 
ECG 
Phase 1 
FAS 
Population 
X 
 
3.5.1.2 
Summary of PR Interval (msec) From Local Lab 12-Lead 
ECG – by Tumor Type 
Phase 2 
FAS 
Population 
X 
 
3.5.2.1 
Summary of RR Interval (msec) From Local Lab 12-Lead 
ECG 
Phase 1 
FAS 
Population 
X 
 
3.5.2.2 
Summary of RR Interval (msec) From Local Lab 12-Lead 
ECG – by Tumor Type 
Phase 2 
FAS 
Population 
X 
 
3.5.3.1 
Summary of QT Interval (msec) From Local l Lab 12-Lead 
ECG 
Phase 1 
FAS 
Population 
X 
 
3.5.3.2 
Summary of QT Interval (msec) From Local Lab 12-Lead 
ECG – by Tumor Type 
Phase 2 
FAS 
Population 
X 
 
3.5.4.1 
Summary of QRS Interval (msec) From Local Lab 12-Lead 
ECG 
Phase 1 
FAS 
Population 
X 
 
3.5.4.2 
Summary of QRS Interval (msec) From Local Lab 12-Lead 
ECG – by Tumor Type 
Phase 2 
FAS 
Population 
X 
 
3.5.5.1 
Summary of QTcB Interval (msec) From Local Lab 12-Lead 
ECG 
Phase 1 
FAS 
Population 
X 
 
3.5.5.2 
Summary of QTcB Interval (msec) From Local Lab 12-Lead 
ECG – by Tumor Type 
Phase 2 
FAS 
Population 
X 
 
3.5.6.1 
Summary of QTcF Interval (msec) From Local Lab 12-Lead 
ECG 
Phase 1 
FAS 
Population 
X 
 
3.5.6.2 
Summary of QTcF Interval (msec) From Local Lab 12-Lead 
ECG – by Tumor Type 
Phase 2 
FAS 
Population 
X 
 


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Table No. 
Title 
Population 
Standard 
In-Text 
3.5.7.1 
Summary of JTc Interval (msec) From Local Lab 12-Lead 
ECG 
Phase 1 
FAS 
Population 
 
 
3.5.7.2 
Summary of JTc Interval (msec) From Local Lab 12-Lead 
ECG – by Tumor Type 
Phase 2 
FAS 
Population 
 
 
3.5.8.1 
Summary of Heart Rate (beats/min) From Local Lab 12-Lead 
ECG 
Phase 1 
FAS 
Population 
X 
 
3.5.8.2 
Summary of Heart Rate (beats/min) From Local Lab 12-Lead 
ECG – by Tumor Type 
Phase 2 
FAS 
Population 
X 
 
3.5.9.1 
Summary of Alert Values of PR, QRS, QT, RR, and QTcF 
Interval Values From Local Lab 12-Lead ECG by Visit – by 
Treatment Group and Dose 
Phase 1 
FAS 
Population 
X 
X 
3.5.9.2 
Summary of Alert Values of PR, QRS, QT, RR, and QTcF 
Interval Values from Local Lab 12-Lead ECG by Visit – by 
Treatment Group and Dose 
Phase 2 
FAS 
Population 
X 
X 
Figures 
Figure No. 
Title 
Population 
4.1 Efficacy 
4.1.1 
Kaplan-Meier Estimates of Progression-Free Survival 
Phase 2 FAS Population 
4.1.2 
Kaplan-Meier Estimates of Overall Survival 
Phase 2 FAS Population 
4.1.3.1 
Swim Plot of Duration of Response – by Treatment Group 
Phase 1 FAS Population 
4.1.3.2 
Swim Plot of Duration of Response – by Treatment Group and 
Tumor Type 
Phase 2 FAS Population 
4.1.4.1 
Waterfall Plot of Percent Change From Baseline in Sum of 
Target Lesions – by Treatment Group and Dose 
Phase 1 FAS Population 
4.1.4.2 
Waterfall Plot of Percent Change From Baseline in Sum of 
Target Lesions – by Treatment Group and Tumor Type 
Phase 2 FAS Population 
4.1.5.1 
Spider Plot of Percent Change From Baseline in Sum of 
Target Lesions – by Treatment Group 
Phase 1 FAS Population 
4.1.5.2 
Spider Plot of Percent Change From Baseline in Sum of 
Target Lesions – by Treatment Group and Tumor Type 
Phase 2 FAS Population 
4.2 Safety Data 
4.2.1.1 
Line Graph of Selected Laboratory Values by Study Visit 
Phase 1 FAS Population 
4.2.1.2 
Line Graph of Selected Laboratory Values by Study Visit 
Phase 2 FAS Population 
4.2.2.1 
Box-and-Whisker Plot of Selected Laboratory Values by 
Study Visit 
Phase 1 FAS Population 
4.2.2.2 
Box-and-Whisker Plot of Selected Laboratory Values by 
Study Visit 
Phase 2 FAS Population 


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Listings 
Listing 
No. 
Title 
2.1 Discontinued Subjects (Subject Disposition) 
2.1.1 
Subject Enrollment and Disposition Status 
2.1.2 
Subject Inclusion and Exclusion Criteria Violations 
2.2 Protocol Deviation 
2.2.1 
Protocol Deviations and Violations 
2.3 Data Excluded From 
, Efficacy, and/or Safety Analyses 
2.3.1 
Analysis Population 
2.4 Demography and Baseline (Including Prior and Concomitant Medications) 
2.4.1 
Demographic  
2.4.2.1 
Baseline Disease Characteristics for Phase 1 Solid Tumor Types 
2.4.2.2 
Baseline Disease Characteristics for Phase 2 – by Tumor Type 
2.4.3 
Disease History 
2.4.4 
Prior Radiation Treatment 
2.4.5 
Prior Systemic Therapy 
2.4.6 
Prior Surgery or Surgical Procedure 
2.4.7 
Medical History 
2.4.8 
Prior and Concomitant Medication 
2.5 Efficacy 
 
2.5.1.1 
Best Overall Response With Confirmed CRs and PRs Under RECIST v1.1 
2.5.1.2 
Best Overall Response With Unconfirmed CRs and PRs Under RECIST v1.1 
2.5.2.1 
Best Overall Response With Confirmed CRs and PRs Under mRECIST  
2.5.2.2 
Best Overall Response With Unconfirmed CRs and PRs Under mRECIST  
2.5.3 
Overall Response Assessment 
2.5.4 
Response Assessment:  Target Lesions 
2.5.5 
Response Assessment:  Non-target Lesions 
2.5.6 
Response Assessment:  New Lesions 
2.5.7 
ECOG status 
 
  
2.6 Adverse Events (and Exposure) 
2.6.1.1 
Study Drug Administration for INCAGN01949  
2.6.1.2 
Study Drug Administration for Nivolumab 
2.6.1.3 
Study Drug Administration for Ipilimumab 
2.6.2 
Adverse Events 
2.6.3 
Dose-Limiting Toxicities 
2.6.4 
Serious Adverse Events 
2.6.6 
Fatal Adverse Events 
2.6.8 
Adverse Events Leading to Discontinuation of INCAGN01949 
2.6.9 
Investigator-Identified Immune-Related Adverse Events 
2.6.10 
Infusion Reactions  


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2.7 Laboratory Data 
2.7.1 
Clinical Laboratory Values – Hematology 
2.7.2 
Clinical Laboratory Values – Chemistry 
2.7.3 
Abnormal Clinical Laboratory Values 
 
 
2.8 Vital Signs 
2.8.1 
Vital Signs 
2.8.2 
Abnormal Vital Sign Values 
2.8.3 
Alert Vital Sign Values 
2.9 ECG 
2.9.1 
12-Lead Local ECG Values 
2.9.2 
Abnormal 12-Lead Local ECG Values 
2.9.3 
Alert 12-Lead Local ECG Values 
2.10 Physical Examination 
2.10.1 
Body Weight 
 


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Prot_000.pdf: 




Incyte Biosciences International Sàrl 
Page 2 of 128 
Protocol INCAGN 1949-201 Amendment 3 
Version 3 
05 DEC 2018 
CONFIDENTIAL 
INVESTIGATOR'S AGREEMENT 
I have read INCAGN 1949-201 Protocol Amendment 3 (Version 3 dated 05 DEC 2018) and 
agree to conduct the study as outlined.  I agree to maintain the confidentiality of all information 
received or developed in connection with this Protocol. 
 
 
 
 
 
(Printed Name of Investigator) 
 
 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 






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Protocol INCAGN 1949-201 Amendment 3 
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05 DEC 2018 
CONFIDENTIAL 
The Phase 2 expansion will further evaluate the safety, tolerability, and efficacy of immune therapies 
combined with INCAGN01949 in 2 different parts.  In Phase 2 Part A, the selected doses of 
INCAGN01949 will be combined with nivolumab in programmed cell death protein 1 
(PD-1)/programmed cell death protein ligand 1 (PD-L1) refractory subjects with gastric cancer, SCCHN, 
NSCLC, and RCC to further explore the safety and efficacy of different doses of INCAGN01949 in 
combination with nivolumab in this population.  Phase 2 Part B will evaluate the recommended dose(s) of 
INCAGN01949 in combination with nivolumab (and ipilimumab where applicable).  PD-1/L1 refractory 
subjects with advanced or metastatic gastric cancer, SCCHN, NSCLC, or RCC will also be enrolled in 
Phase 2 Part B.  Pretreatment biopsies will be mandatory for subjects enrolled into either part of Phase 2.  
The study diagram is presented in Figure S1. 
The sponsor may elect to prioritize (or deprioritize) enrollment to specific treatment groups or cohorts 
based on emerging safety or efficacy data in collaboration with investigational sites. 
Figure S1:  Study Design 
 
Phase 1 – Dose Escalation (Part 1) 
A minimum of 3 evaluable subjects will be enrolled in each treatment group beginning with 
INCAGN01949 Dose Cohort 1 (7 mg; starting dose).  A higher starting dose of INCAGN01949 may be 
used if safety data are available from the monotherapy study (INCAGN 1949-101) but will not exceed 
1 dose level below the highest tolerated dose of INCAGN01949 monotherapy.  If a higher starting dose is 
used, the new dose will be communicated to investigational sites with an administrative letter.  The doses 
of INCAGN01949 to be evaluated in each treatment group are summarized in Table S1. 
 
 


















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Protocol INCAGN 1949-201 Amendment 3 
Version 3 
05 DEC 2018 
CONFIDENTIAL 
− International normalized ratio, prothrombin time, or activated partial thromboplastin time 
> 1.5 × ULN. 
 Prior treatment with any TNFSF agonist (eg, glucocorticoid-induced tumor necrosis factor receptor, 
OX40, 4-1BB/CD137, CD27, etc), for any indication. 
 Administration of colony stimulating factors within 14 days before study Day 1. 
 Receipt of anticancer medications or investigational drugs within the following intervals before the 
first administration of study drug: 
− ≤ 14 days for chemotherapy, targeted small molecule therapy, or radiation therapy.   
Note:  Subjects must not have had radiation pneumonitis as a result of treatment.  A 1-week washout 
is permitted for palliative radiation to non–central nervous system (CNS) disease with medical 
monitor approval. 
Note:  Bisphosphonates and denosumab are permitted concomitant medications. 
− ≤ 14 days for prior immune therapy or persistence of active cellular therapy (ie, chimeric antigen 
receptor T-cell therapy; other cellular therapies must be discussed with medical monitor to determine 
eligibility). 
− ≤ 28 days for a prior monoclonal antibody used for anticancer therapy with the exception of 
denosumab. 
− ≤ 7 days for immune-suppressive–based treatment for any reason. 
Note:  Use of inhaled or topical steroids or corticosteroid use for radiographic procedures is 
permitted. 
Note:  Must not require chronic use of corticosteroids.  The use of physiologic corticosteroid 
replacement therapy may be approved after consultation with the medical monitor.   
− ≤ 28 days or 5 half-lives (whichever is longer) before the first dose for all other investigational 
agents or devices.  For investigational agents with long half-lives (eg, > 5 days), enrollment before 
the fifth half-life requires medical monitor approval. 
 Has not recovered to ≤ Grade 1 from toxic effects of prior therapy (including prior immune therapy) 
and/or complications from prior surgical intervention before starting therapy 
Note:  Subjects with stable chronic conditions (≤ Grade 2) not expected to resolve (such as neuropathy 
and alopecia) are exceptions and may enroll. 
Note:  Subjects with a history of any grade immune-related ocular AE (eg, episcleritis, scleritis, 
uveitis) will be excluded. 
Note:  Subjects with a history of a Grade 3 or higher immune-related AE from prior immunotherapies 
are excluded from the dose-escalation portion of the study. 
 Active autoimmune disease that required systemic treatment in the past (ie, with use of disease 
modifying agents, corticosteroids, or immunosuppressive drugs). 
Note:  Subjects who have not required systemic treatment in the past 2 years should discuss their case 
with medical monitor to determine eligibility. 
Note:  Subjects with hyper/hypothyroidism, vitiligo, controlled asthma, Type I diabetes, Graves' 
disease, or Hashimoto's disease are eligible to participate. 
Note:  Replacement and symptomatic therapies (eg, levothyroxine, insulin, or physiologic 
corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc) are not considered a form 
of systemic treatment and are allowed. 
 Known active CNS metastases and/or carcinomatous meningitis. 
Note:  Subjects with previously treated brain metastases may participate provided that they are stable 
(without evidence of progression by imaging for at least 28 days before the first dose of study drug and 
any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain 
metastases or CNS edema, and have not required steroids for at least 7 days before the first dose of 
study drug. 


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Protocol INCAGN 1949-201 Amendment 3 
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05 DEC 2018 
CONFIDENTIAL 
 Evidence of active, noninfectious pneumonitis or history of interstitial lung disease. 
 History or presence of an abnormal electrocardiogram that, in the investigator's opinion, is clinically 
meaningful.   
 Evidence of hepatitis B virus or hepatitis C virus infection or risk of reactivation. 
 Known history of human immunodeficiency virus (HIV; HIV 1/2 antibodies). 
INCAGN01949, Dosage, and Mode of Administration:   
Phase 1 and Phase 2:  INCAGN01949 will be administered IV over a 30-minute period on Day 1 of each 
Q2W (ie, 14-day) cycle.  INCAGN01949 will be the first drug administered, followed by a 30-minute 
wait before starting infusion with the next agent.  Subjects can continue to receive INCAGN01949 for up 
to 24 months as long as the subject is considered to derive ongoing clinical benefit at the discretion of the 
investigator, and the subject has not met any of the Protocol-defined conditions for treatment withdrawal. 
Combination Therapies, Dosage, and Mode of Administration: 
Nivolumab: 
In the doublet Treatment Groups A, C, F, G, and H, nivolumab will be administered IV per instructions 
provided in the package insert at a dose of 240 mg Q2W (eg, 14 days).   
In the triplet Treatment Groups D, E, J, K, and L, nivolumab will be administered IV per instructions 
provided in the package insert at a dose of 3 mg/kg Q2W (eg, 14 days).   
In the concurrent dosing Treatment Groups A, D, F, and J, nivolumab dosing will begin on Cycle 1 
Day 1. 
In the sequenced/run-in dosing Treatment Groups C, E, G, H, K, and L, nivolumab dosing will begin on 
Cycle 3 Day 1.  Alternate dose administration schedules may also be explored depending on 
 
 safety results.   
Nivolumab will be administered at least 30 minutes after the end of the infusion of INCAGN01949 (when 
applicable), and subjects will continue to receive nivolumab for up to 24 months as long as the subject is 
considered to derive ongoing clinical benefit at the discretion of the investigator, and the subject has not 
met any of the Protocol-defined conditions for treatment withdrawal. 
Ipilimumab: 
Ipilimumab will be administered IV per instructions provided in the package insert to subjects in 
Treatment Groups B, D, E, J, K, and L, at a dose of 1 mg/kg Q6W (eg, 42 days).  In the concurrent dosing 
Treatment Groups B, D, and J, ipilimumab dosing will begin on Cycle 1 Day 1.  In the sequenced dosing 
Treatment Groups E, K, and L, ipilimumab dosing will begin on Cycle 3 Day 1.  Alternate dose 
administration schedules may also be explored depending on 
 safety 
results. 
Ipilimumab will be administered at least 30 minutes after the end of the infusion of INCAGN01949 
(when administered on the same day).  Ipilimumab will always be administered after INCAGN01949 and 
nivolumab.  Subjects will continue to receive ipilimumab for up to 24 months as long as the subject is 
considered to derive ongoing clinical benefit at the discretion of the investigator, and the subject has not 
met any of the Protocol-defined conditions for treatment withdrawal. 
At the sponsor's discretion, once the MTD or PAD of INCAGN01949 has been established with 
ipilimumab at 1 mg/kg Q6W (eg, 42 days), a higher dose of ipilimumab at 3 mg/kg Q6W (eg, 42 days) 
and/or 3 mg/kg Q3W (eg, 21 days) for 4 doses may be tested. 




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Version 3 
05 DEC 2018 
CONFIDENTIAL 
Statistical Methods:   
In Phase 2, a Simon 2-stage design will be run for each cohort within a given doublet or triplet drug 
expansion.  The planned Simon 2-stage designs are summarized in Table S7.  Each Simon 2-stage design 
will have a stopping rule to allow early termination of a particular cohort within the given treatment 
combination at the end of Stage 1 if there is insufficient response observed (calculated response rate 
< p0%), while enrolling enough subjects to predict possible target responses (≥ p1%) worthy of cohort 
expansion and potentially further evaluation in future studies. 
Table S7:  Planned Simon 2-Stage Designs for Phase 2 
Indication 
Combination 
Stage 1 
Stage 2 
n 
p0 
p1 
n1 
r1 
n2 
r 
Refractory to 
anti–PD-1/L1 
OX40 + Nivo 
20 
2 
30 
8 
50 
10% 
25% 
Refractory to 
anti–PD-1/L1 
OX40 + Nivo + Ipi 
20 
2 
30 
8 
50 
10% 
25% 
 r1:  if r1 or fewer responses are observed during Stage 1, the study cohort is stopped early for futility. 
 n1:  number of subjects initially enrolled in the Stage 1. 
 n2:  number of subjects enrolled in the Stage 2. 
 r:  if r or fewer responses are observed by the end of Stage 2, then no further investigation of the drug 
combination is warranted in the selected cohort. 
 n:  total number of subjects. 
 p0:  insufficient response rate. 
 p1:  target response rate. 
The proposed designs for each cohort will be used for any planned Simon 2-stage design (including 
concurrent and sequential dosing).  Each Simon 2-stage design is set up to have a 1-sided Type I error of 
0.05 and power of 85%.  The response rates for each cohort will be estimated with 95% confidence 
intervals.  Formal safety reviews, to be held at least every 6 months during Phase 2, will be conducted to 
review efficacy and safety data.  


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Version 3 
05 DEC 2018 
CONFIDENTIAL 
TABLE OF CONTENTS 
SYNOPSIS ......................................................................................................................................3 
LIST OF ABBREVIATIONS ........................................................................................................25 
1. 
INTRODUCTION ......................................................................................................28 
1.1. 
Background .................................................................................................................28 
1.1.1. 
The Role of the Immune System in Cancer ................................................................28 
1.1.2. 
OX40 and the Tumor Necrosis Factor Super Family .................................................28 
1.1.3. 
In Vitro and In Vivo Evaluation of OX40 ...................................................................29 
1.1.4. 
Clinical Experience With OX40 Agonists ..................................................................30 
1.1.5. 
Immune Modulators ....................................................................................................31 
1.1.5.1. 
Combined Inhibition With Anti-OX40 and Immune Therapies .................................32 
1.2. 
Overview of INCAGN01949 ......................................................................................33 
1.2.1. 
Pharmacology of INCAGN01949 ..............................................................................33 
1.2.2. 
Pharmacokinetics of INCAGN01949 .........................................................................34 
1.2.3. 
Preclinical Safety of INCAGN01949 .........................................................................34 
1.2.4. 
Clinical Pharmacokinetics ..........................................................................................34 
1.2.5. 
Clinical Safety of INCAGN01949 ..............................................................................35 
1.3. 
Overview of Standard Therapies ................................................................................36 
1.3.1. 
Nivolumab ..................................................................................................................36 
1.3.1.1. 
Nivolumab Summary ..................................................................................................36 
1.3.1.2. 
Risks From Nivolumab ...............................................................................................36 
1.3.2. 
Ipilimumab ..................................................................................................................36 
1.3.2.1. 
Ipilimumab Summary .................................................................................................36 
1.3.2.2. 
Risks From Ipilimumab ..............................................................................................36 
1.4. 
Potential Risks of the Combination Regimens ...........................................................37 
1.5. 
Study Rationale ...........................................................................................................38 
1.5.1. 
Rationale for Phase 1 Subject Population ...................................................................38 
1.5.2. 
Rationale for Phase 2 Subject Population ...................................................................38 
1.5.2.1. 
Renal Cell Carcinoma .................................................................................................39 
1.5.2.2. 
Gastric Cancer ............................................................................................................39 
1.5.2.3. 
Squamous Cell Carcinoma of the Head and Neck ......................................................40 
1.5.2.4. 
Non–Small Cell Lung Cancer .....................................................................................41 


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1.5.3. 
Rationale for Dose and Schedule of Combination Therapies .....................................41 
1.5.4. 
Rationale for the Study Endpoints ..............................................................................42 
1.5.4.1. 
Efficacy Endpoints ......................................................................................................42 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................44 
2.1. 
Study Objectives .........................................................................................................44 
2.1.1. 
Primary Objectives .....................................................................................................44 
2.1.2. 
Secondary Objectives .................................................................................................44 
 
44 
2.2. 
Study Endpoints ..........................................................................................................45 
2.2.1. 
Primary Endpoints ......................................................................................................45 
2.2.2. 
Secondary Endpoints ..................................................................................................45 
 
45 
3. 
SUBJECT ELIGIBILITY ...........................................................................................46 
3.1. 
Subject Inclusion Criteria ...........................................................................................46 
3.2. 
Subject Exclusion Criteria ..........................................................................................47 
4. 
INVESTIGATIONAL PLAN .....................................................................................51 
4.1. 
Overall Study Design ..................................................................................................51 
4.1.1. 
Phase 1 Part 1 – Dose Escalation ................................................................................52 
4.1.1.1. 
Doublet Immune Therapy Combinations ...................................................................53 
4.1.1.2. 
Triplet Immune Therapy Combinations .....................................................................55 
4.1.2. 
Phase 1 Part 2 – Safety Expansion .............................................................................56 
4.1.2.1. 
Doublet Immune Therapy Combination for Safety Expansion ..................................57 
4.1.2.2. 
Triplet Immune Therapy Combination for Safety Expansion ....................................57 
4.1.3. 
Phase 2 – Dose Expansion ..........................................................................................58 
4.2. 
Measures Taken to Avoid Bias ...................................................................................61 
4.3. 
Number of Subjects ....................................................................................................61 
4.3.1. 
Planned Number of Subjects ......................................................................................61 
4.3.2. 
Replacement of Subjects .............................................................................................62 
4.4. 
Duration of Treatment and Subject Participation .......................................................62 
4.5. 
Overall Study Duration ...............................................................................................62 
4.6. 
Study Termination ......................................................................................................62 
5. 
TREATMENT ............................................................................................................63 
5.1. 
Treatment Assignment ................................................................................................63 


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5.1.1. 
Subject Numbering and Treatment Assignment .........................................................63 
5.1.2. 
Randomization and Blinding ......................................................................................63 
5.2. 
Study Drugs ................................................................................................................63 
5.2.1. 
INCAGN01949 ...........................................................................................................63 
5.2.1.1. 
Description and Administration ..................................................................................63 
5.2.1.2. 
Supply, Packaging, and Labeling ...............................................................................64 
5.2.1.3. 
INCAGN01949 Storage ..............................................................................................64 
5.2.2. 
Standard Immune Therapies .......................................................................................64 
5.2.2.1. 
Nivolumab ..................................................................................................................64 
5.2.2.2. 
Ipilimumab ..................................................................................................................65 
5.3. 
Treatment Compliance ................................................................................................65 
5.3.1. 
Treatment Compliance of INCAGN01949, Nivolumab, and Ipilimumab .................65 
5.4. 
Treatment Interruptions and Adjustments ..................................................................66 
5.4.1. 
Dose Modifications .....................................................................................................66 
5.4.2. 
Dose-Limiting Toxicity and Determination of Maximum Tolerated Dose ................66 
5.4.3. 
Management of Dose-Limiting Toxicities or Other Urgent Situations ......................68 
5.4.4. 
Follow-Up of Dose-Limiting Toxicities .....................................................................68 
5.4.5. 
Procedures for Cohort Review and Dose Escalation ..................................................68 
5.4.6. 
Criteria and Procedures for Dose Interruptions of Study Drug ..................................68 
5.4.7. 
Management of Immune-Related Adverse Events .....................................................69 
5.4.8. 
Management of Infusion Reactions ............................................................................70 
5.4.9. 
Criteria for Permanent Discontinuation of Study Drug ..............................................72 
5.5. 
Withdrawal of Subjects From Study Treatment .........................................................72 
5.5.1. 
Withdrawal Criteria ....................................................................................................72 
5.5.2. 
Withdrawal Procedures ...............................................................................................73 
5.6. 
Concomitant Medications ...........................................................................................74 
5.6.1. 
Permitted Medications ................................................................................................74 
5.6.2. 
Restricted Medications ...............................................................................................74 
5.6.3. 
Prohibited Medications ...............................................................................................74 
6. 
STUDY ASSESSMENTS ..........................................................................................75 
6.1. 
Screening ....................................................................................................................81 
6.2. 
Treatment ....................................................................................................................81 
6.3. 
End of Treatment ........................................................................................................81 


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6.4. 
Safety Follow-Up ........................................................................................................81 
6.5. 
End of Study ...............................................................................................................82 
6.6. 
Unscheduled Visits .....................................................................................................82 
7. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES ...........................83 
7.1. 
Administration of Informed Consent Form ................................................................83 
7.2. 
Interactive Response Technology System Procedure .................................................83 
7.3. 
Demography and Medical History ..............................................................................83 
7.3.1. 
Demographics and General Medical History .............................................................83 
7.3.2. 
Disease Characteristics and Treatment History ..........................................................83 
7.4. 
Prior and Concomitant Medications and Procedures ..................................................84 
7.5. 
Poststudy Anticancer Therapy Status .........................................................................84 
7.6. 
Safety Assessments .....................................................................................................84 
7.6.1. 
Adverse Events ...........................................................................................................84 
7.6.2. 
Physical Examinations ................................................................................................84 
7.6.2.1. 
Comprehensive Physical Examination .......................................................................84 
7.6.2.2. 
Targeted Physical Examination ..................................................................................85 
7.6.3. 
Vital Signs ..................................................................................................................85 
7.6.4. 
Electrocardiograms .....................................................................................................85 
7.6.5. 
Laboratory Assessments .............................................................................................85 
7.6.5.1. 
Pregnancy Testing ......................................................................................................86 
7.6.5.2. 
Hepatitis Screening Tests ...........................................................................................86 
7.7. 
Efficacy Assessments .................................................................................................86 
7.7.1. 
Modified RECIST Assessment Disease .....................................................................86 
7.7.1.1. 
Tumor Imaging ...........................................................................................................88 
7.8. 
Performance and Quality-of-Life Assessments ..........................................................89 
7.8.1. 
Eastern Cooperative Oncology Group Performance Status ........................................89 
 
89 
 
89 
 
89 
 
90 
 
91 
 
91 
 
91 


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92 
 
92 
 
92 
 
92 
7.11. 
Other Study Procedures ..............................................................................................93 
7.11.1. 
Distribution of Subject Reminder Cards .....................................................................93 
8. 
SAFETY MONITORING AND REPORTING .........................................................94 
8.1. 
Adverse Events ...........................................................................................................94 
8.1.1. 
Definitions ..................................................................................................................94 
8.1.2. 
Reporting ....................................................................................................................94 
8.2. 
Laboratory Test Abnormalities ...................................................................................96 
8.3. 
Serious Adverse Events ..............................................................................................96 
8.3.1. 
Definitions ..................................................................................................................96 
8.3.2. 
Reporting ....................................................................................................................97 
8.4. 
Emergency Unblinding of Treatment Assignment .....................................................97 
8.5. 
Pregnancy ...................................................................................................................98 
8.6. 
Warnings and Precautions ..........................................................................................98 
8.7. 
Data Monitoring Committee .......................................................................................98 
8.8. 
Product Complaints ....................................................................................................99 
9. 
STATISTICS ............................................................................................................100 
9.1. 
Study Populations .....................................................................................................100 
9.2. 
Selection of Sample Size ..........................................................................................100 
9.2.1. 
Sample Size for Phase 1 ...........................................................................................100 
9.2.1.1. 
Sample Size for Phase 1 Part 1 .................................................................................100 
9.2.1.2. 
Sample Size for Phase 1 Part 2 .................................................................................101 
9.2.2. 
Sample Size for Phase 2 ...........................................................................................101 
9.3. 
Level of Significance ................................................................................................102 
9.4. 
Statistical Analyses ...................................................................................................103 
9.4.1. 
Efficacy Analyses .....................................................................................................103 
9.4.1.1. 
Primary Efficacy Analyses .......................................................................................103 
9.4.1.2. 
Secondary Efficacy Analyses ...................................................................................103 
9.4.2. 
Safety Analyses ........................................................................................................103 
9.4.2.1. 
Adverse Events .........................................................................................................103 


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9.4.2.2. 
Clinical Laboratory Tests .........................................................................................104 
9.4.2.3. 
Vital Signs ................................................................................................................104 
9.4.2.4. 
Electrocardiograms ...................................................................................................104 
 
105 
 
105 
9.5. 
Analyses for the Data Monitoring Committee ..........................................................105 
9.6. 
Interim Analysis ........................................................................................................105 
9.6.1. 
Simon 2-Stage Design ..............................................................................................105 
10. 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES ........................................................................................................106 
10.1. 
Investigator Responsibilities .....................................................................................106 
10.2. 
Accountability, Handling, and Disposal of Study Drug ...........................................107 
10.3. 
Data Management .....................................................................................................108 
10.4. 
Data Privacy and Confidentiality of Study Records .................................................108 
10.5. 
Financial Disclosure .................................................................................................109 
10.6. 
Publication Policy .....................................................................................................109 
11. 
REFERENCES .........................................................................................................110 
APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS .............................................................................115 
APPENDIX B. PROCEDURES AND SUPPORTIVE CARE GUIDELINES FOR 
SUBJECTS EXHIBITING IMMUNE-RELATED ADVERSE EVENTS ..............116 
APPENDIX C. PROTOCOL AMENDMENT SUMMARY OF CHANGES ..........................122 
 




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LIST OF ABBREVIATIONS 
The following abbreviations and special terms are used in this clinical study Protocol. 
Abbreviation 
Definition 
ADA 
antidrug antibody 
ADCC 
antibody-dependent cell-mediated cytotoxicity 
ADCP 
antibody-dependent cell-mediated phagocytosis 
AE 
adverse event 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
CFR 
Code of Federal Regulations 
CNS 
central nervous system 
CR 
complete response 
CRC 
colorectal cancer 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T-lymphocyteassociated protein 4 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOT 
end of treatment 
Fc 
fragment, crystallizable 
FcγR 
Fc-gamma receptor 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GEJ 
gastroesophageal junction 
GI 
gastrointestinal 
GITR 
glucocorticoid-induced tumor necrosis factor receptor 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 


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Abbreviation 
Definition 
HCC 
hepatocellular carcinoma 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
human immunodeficiency virus 
HPV 
human papillomavirus 
ICF 
informed consent form  
ICH 
International Conference on Harmonization 
IDO 
indoleamine 2,3-dioxygenase 
IEC 
independent ethics committee 
IFN 
interferon 
IgG 
immunoglobulin G 
IL 
interleukin 
INR 
international normalized ratio 
Ipi 
ipilimumab 
irAE 
immune-related adverse event 
IRB 
institutional review board 
IRT 
interactive response technology 
IV 
intravenous 
mAb 
monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRECIST 
modified Response Evaluation Criteria in Solid Tumors 
MRI 
magnetic resonance imaging 
MSI 
microsatellite instability 
MSI-H 
microsatellite instability-high 
MTD 
maximum tolerated dose 
NF-κB 
nuclear factor kappa-light-chain-enhancer of activated B cells 
Nivo 
nivolumab 
NK 
natural killer 
NSCLC 
non–small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
OX40L 
OX40 ligand 
PAD 
pharmacologically active dose 
PD-1 
programmed cell death protein 1 
PD-L1 
programmed cell death protein ligand 1 
PFS 
progression-free survival 
PK 
pharmacokinetic 


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Abbreviation 
Definition 
PoS 
probability of success  
PR 
partial response 
PT 
prothrombin time 
Q2W 
every 2 weeks 
Q6W 
every 6 weeks 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SCCHN 
squamous cell carcinoma of the head and neck 
SCLC 
small cell lung cancer 
SD 
stable disease 
SmPC 
summary of product characteristics 
TCR 
T-cell receptor 
TEAE 
treatment emergent adverse event 
Teff 
effector T cells 
TNBC 
triple-negative breast cancer 
TNF 
tumor necrosis factor 
TNFR 
tumor necrosis factor receptor 
TNFSF 
tumor necrosis factor super family 
Treg 
regulatory T cell 
ULN 
upper limit of normal 




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Expression of OX40 has been observed on activated T cells (including CD4+ T cells, CD8+ 
T cells, and Tregs) (Weinberg et al 2011).  OX40 expression is up-regulated on the surface of 
T cells after TCR engagement and costimulation through CD28 or the presence of inflammatory 
cytokines, including IL-1, IL-2, and TNF-α (Weinberg et al 2000, Jensen et al 2010).  Following 
antigen activation of naive T cells, OX40 expression occurs between 24 hours and 4 to 5 days 
following TCR engagement.  The upregulation of OX40 on memory T cells after the rechallenge 
of antigen occurs much more rapidly (within 4 hours) compared with naive T cells 
(Jensen et al 2010, Croft et al 2009, Gramaglia et al 1998).   
Several groups have demonstrated that OX40 is expressed on T cells in the tumor 
microenvironment.  In samples surgically obtained from patients with breast cancer, OX40 
expressing T cells were observed in areas surrounding tumor cells, and those cells were thought 
to be tumor-specific T cells (Weinberg et al 2000).  Other groups have shown that OX40+ T cells 
are present in samples from patients with melanoma, head and neck cancer, breast cancer, and 
colon cancer (Petty et al 2002, Ladányi et al 2004, Weinberg et al 2000, Vetto et al 1997).  In 
addition, it is thought that the proportion of OX40+ T cells may correlate with improved survival 
(Petty et al 2002, Ladányi et al 2004).   
OX40L is mainly expressed on antigen-presenting cells that include B cells, dendritic cells, 
endothelial cells, and macrophages (Weinberg et al 2000).  OX40L is not expressed at high 
levels in noninflamed tissues, but is observed at sites of active autoimmune disease.  To date, 
OX40L has not been identified within the tumor microenvironment (Gough et al 2008, 
Weinberg et al 2011). 
Given its role in immune activation, targeting OX40 with an agonistic antibody would be 
expected to enhance the response of memory and Teff to tumor-specific antigens.  The use of an 
antibody with ADCC capabilities may also selectively deplete Tregs (Gonzalez et al 2016, 
Bulliard et al 2013).  Therefore the use of an anti-OX40 mAb with both agonistic and ADCC 
properties may be beneficial in boosting the immune response to malignant cells within the body.  
This hypothesis will be tested in this study. 
1.1.3. 
In Vitro and In Vivo Evaluation of OX40 
Several groups have explored the function of OX40 using both in vitro and in vivo models.  
OX40 signaling has been shown to promote T-cell division and survival, suppress the 
differentiation of Tregs, and modulate cytokine production and signaling.  One way this is 
thought to occur is that OX40L binding to the OX40 receptor results in intracellular recruitment 
of TNFR-associated molecules, which then activates the NF-κB pathway known to be important 
in cell survival (Jensen et al 2010).  This is consistent with the observation that OX40 receptor 
engagement has been shown to increase survival, cytokine production, and migration of CD4+ 
T cells; increase granzyme B, IFN-γ, and perforin production of CD8+ T cells; and increase 
proliferation and overcome the anergic state in both CD4+ and CD8+ T cells (Moran et al 2013, 
Weinberg et al 2000). 


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Murine studies have shown that OX40 agonists promote tumor-specific memory T-cell 
expansion leading to rejection of tumor growth after inoculation with 4 different tumor cell lines   
(Weinberg et al 2000).  Subsequent experiments performed in mice with established tumors 
showed that administration of an OX40 agonist led to an increase in the number of CD8+ T cells 
at the tumor site (Gough et al 2008).  This combined with the lack of OX40L expression in the 
tumor environment indicates that there is a lack of OX40 signaling in the tumor 
microenvironment and provides additional rationale for OX40 agonist therapy in cancer. 
While a contributing factor to the improved proportion of CD8+ T cells to Tregs is likely the 
activation and proliferation of CD8+ T cells after OX40 engagement, the role of Treg depletion 
must also be considered.  Several studies have shown that OX40 expression is highest in the 
population of Treg cells within a tumor (Bulliard et al 2014, Marabelle et al 2013).  OX40 has 
been shown to inhibit the suppressing ability of Tregs (Kroemer et al 2007, Valzasina et al 
2005).  OX40 has been shown to suppress Treg development and function in vitro, and in in vivo 
studies, the population of CD4+CD25+FoxP3+ Treg cells was decreased following treatment 
with an OX40 agonist (Gough et al 2008).  Bulliard et al (2014) demonstrated that the 
administration of an agonistic anti-OX40 mAb induced the depletion of Tregs via an 
FcγR-mediated ADCC/ADCP manner.  Experiments performed in mice showed that this 
mechanism contributed to the control of tumor growth in mice (Bulliard et al 2014). 
1.1.4. 
Clinical Experience With OX40 Agonists 
INCAGN01949 has been evaluated in a Phase 1 dose escalation study, and multiple doses have 
been tolerated in subjects with advanced or metastatic solid tumors.  Other OX40 antibodies 
have been tested in humans, including a murine antibody and a humanized antibody.  Curti 
et al (2013) developed a 9B12 murine anti-human OX40 mAb and tested this antibody in a 
Phase 1 dose-escalation study.  Thirty subjects with metastatic solid tumors that were refractory 
to conventional therapy were enrolled and administered doses of anti-OX40 mAb at 0.1 mg/kg, 
0.4 mg/kg, or 2 mg/kg on Days 1, 3, and 5 of the study.  The murine origin of the antibody 
precluded further administration of this agent.  Results of this study showed that the OX40 
agonist was well-tolerated, with observed toxicities mostly Grade 1 or Grade 2.  Events of 
Grade 3 and Grade 4 lymphopenia were observed; however, the lymphopenia that was seen 
typically resolved by Day 15 or Day 28 in a dose-dependent manner.  The most common AEs 
reported were lymphopenia, fatigue, rash, and flu-like symptoms with fever and chills.  The 
MTD was not reached for this mAb.  Tumor shrinkage or SD was seen in subjects with 
melanoma, renal cell cancer, squamous cell carcinoma of the urethra, prostate cancer, and 
cholangiocarcinoma, including 1 subject with renal cell cancer that had SD for 470 days. 
Correlative studies used Ki-67 to identify proliferating T cells after treatment with the OX40 
mAb.  Following treatment, the percentage of Ki-67+CD4+ T cells increased by Day 8 and Ki 
67+CD8+ T cells increased by Day 15.  Compared with the controls, numbers of CD4+/FoxP3- 
T cells, CD8+ T cells, and CD3-/NK cells were significantly increased; however, the number of 
CD4+/FoxP3+ Tregs was unchanged.  Additional studies showed that treatment with the OX40 
mAb increased proliferation and activation of CD8+ T cells.  The T cell population of subjects 
who had some benefit (an initial decrease or stabilization of their disease) were compared with 
those considered initial progressors, and an increase was seen in Ki-67+ CD4+/FoxP3- and 
CD8+ T lymphocytes of those subjects who benefited from this treatment.  This study shows 
evidence that OX40 agonists may provide benefit to subjects with late stage metastatic disease 


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and that treatment with these agents may have long term effects on the T cell population 
(Curti et al 2013).  
Clinical data of a humanized IgG1 anti-OX40 agonistic mAb (MOXR0916) were described at 
the  annual meeting (Hansen et al 2016).  MOXR0916 was administered to 70 subjects with a 
variety of solid tumors within a dose-escalation study (standard 3 + 3 design with doses ranging 
from 0.2 to 1200 mg).  No DLTs were observed; there were no study related deaths, and there 
were no drug-related Grade 4 AEs.  On-study paired biopsies evaluating the tumor 
microenvironment pre- and post-treatment revealed increases in CD8 T-cell infiltration, 
upregulation in gene expression of T effector cells, and increased PD-L1 expression in some 
subjects, which may reflect an increase in IFN-γ.  Two objective responses were reported, both 
in subjects with previously treated RCC. 
MOXR0916 was also studied in combination with an anti–PD-L1 antibody, atezolizumab 
(Infante et al 2016).  MOXR0916 was well-tolerated in combination with atezolizumab with no 
DLTs, deaths, or Grade 4 AEs reported.  Induction of PD-L1 expression was observed in 
subjects who were previously treated with anti-OX40 or anti–PD-1.  Partial responses were 
reported in subjects with RCC and urothelial carcinoma.   
1.1.5. 
Immune Modulators 
Immune cell receptors known as checkpoint modulators (collectively known as immune 
modulators) provide a critical mechanism for the regulation of an immune response.  Checkpoint 
modulation can either diminish an inflammatory process or escalate an immune response.  
Modulation of coinhibitory and costimulatory receptors of the immune system has become a 
proven approach for the immunotherapy of cancer (Chen and Mellman 2013).   
The development of fully human antibodies that target and modulate immune receptors in 
humans have led to the discovery of multiple validated targets for the immunotherapy of cancer 
(Chen and Mellman 2013, Leach et al 1996).  Antibodies that engage the various checkpoint 
modulators can broadly be classified into 2 categories based on mechanism of action:  
antagonists (blocking the interaction between receptor and cognate ligand[s]) and agonists 
(inducing or facilitating receptor-forward signaling).  Clinical testing of therapeutic antibodies 
has demonstrated their ability to influence the direction and magnitude of the immune responses, 
leading to tumor eradication (Yao et al 2013).  The blocking of coinhibitory receptors such as 
CTLA-4 or PD-1 blockade are the basis of FDA-approved therapies to augment an antitumor 
immune response.  Clinical and preclinical research has demonstrated a rationale for targeting 
costimulatory receptors within the TNFSF (Schaer et al 2013). 
While single-agent activity has consistently been reported, combining immunotherapies that 
target distinct immune pathways has the potential to further enhance the depth and breadth of the 
antitumor immune response over single agents.  Multiple immune mechanisms have been shown 
to be present concurrently in the tumor microenvironment, suggesting that combination therapies 
may be required for optimal therapeutic effect (Quezada and Peggs 2013, Spranger et al 2014).   


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Blocking of immune inhibitory pathways is a proven therapeutic modality for the treatment of 
cancer, as evidenced by the clinical responses observed with antibodies to CTLA-4 and PD-1/L1.  
Following initial T-cell activation, CTLA-4 is upregulated on T cells and serves as a checkpoint 
to inhibit the pending immune response.  CTLA-4 binds to B7, an inhibitor ligand, with a higher 
affinity than the costimulatory ligand CD28.  Blocking of CTLA-4 with ipilimumab has proven 
to be an effective method to enhance active immune responses, including antitumor responses.  
As with CTLA-4, PD-1 is also an inhibitory receptor that is expressed on activated T cells and is 
the first indication of T-cell exhaustion.  Binding of PD-1 to PD-L1 expressed on tumor cells or 
other immune cells is the checkpoint by which these activated T cells are programed to die and 
diminishes any active immune response.  Blocking of PD-1 with nivolumab or pembrolizumab is 
proven to be an effective means to prolong antitumor immune responses and offer patients 
clinical benefit. 
Ipilimumab is most active during the induction of antitumor immunity and promotes 
proliferation of T-cells earlier in the immune response.  PD-1–blocking antibodies like 
nivolumab are more relevant during the effector phase within the tumor microenvironment.  
Given these unique checkpoints, it was speculated that combining these immune therapies would 
synergize and lead to a more robust antitumor immune response.  This was proven in clinical 
trials evaluating patients with metastatic melanoma, and the combination of nivolumab and 
ipilimumab has since been approved by regulatory authorities for melanoma, and this 
combination continues to be investigated in a number of additional tumor types. 
1.1.5.1. 
Combined Inhibition With Anti-OX40 and Immune Therapies 
Preclinical work with anti-OX40 antibodies have elucidated at least 2 potential antitumor 
mechanisms of action for an agonist OX40 antibody in the clinical setting.  First, effective OX40 
forward signaling through the TNF receptor-associated factor NFκB signaling axis may promote 
enhanced T cell responsiveness under conditions of suboptimal stimulation and/or decrease the 
suppressive activity of intratumoral Treg.  Secondly, optimal antitumor efficacy may require 
co-engagement of activating FcγRs on effector cells in order to selectively deplete immune 
suppressive Tregs located within the tumor.  Therefore, an anti-OX40 mAb could support or 
enhance other immune therapies.   
This hypothesis has been tested in preclinical models in combination with both anti–CTLA-4 and 
anti–PD-1.  Mouse models for prostate and sarcoma tumors were treated with agonist anti-OX40 
monotherapy, blocking anti–CTLA-4 monotherapy, and combined anti-OX40 and anti–CTLA-4.  
The combination regimen had a significant improvement in tumor regression and survival 
compared with the monotherapy regimens.  Correlative analyses demonstrated that the 
combination therapy increased the proliferation of effector CD4+ T cells and showed a 
significant increase in IL-2 and IFN-ᶌ compared to the monotherapy treatment 
(Redmond et al 2014).  Combinatorial PD-1 blockade and OX40 agonist were studied in a 
murine ovarian cancer model.  Again, combination treatment provided effective inhibition of 
tumor growth compared to each monotherapy arm.  This tumor suppression correlated with 
significantly higher ratios of effector to Tregs (Guo et al 2014).   


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The mechanism of action of INCAGN01949 suggests that it may prime the tumor 
microenvironment in a manner that may support the additional use of an anti–PD-1 mAb either 
concurrently or subsequently.  These combinations may lead to a more robust antitumor immune 
response. 
A humanized OX40 antibody (MOXR0916) has been combined with an anti–PD-L1 antibody in 
humans and results from that clinical study are discussed above in Section 1.1.4. 
1.2. 
Overview of INCAGN01949 
INCAGN01949 is an agonistic antihuman OX40 mAb, with the potential to enhance the function 
of tumor-specific T cells and promote antitumor immunity in cancer patients.  Recent clinical 
success with checkpoint inhibitors has provided rationale for investigating agonists such as 
OX40 in order to extend clinical benefit to patients. 
1.2.1. 
Pharmacology of INCAGN01949 
INCAGN01949 is a fully human IgG1κ mAb being developed for the treatment of advanced 
malignancies.  INCAGN01949 binds selectively to the extracellular domain of human OX40 and 
does not bind to related TNFR super family members.  INCAGN01949 functions as an OX40 
agonist antibody in human cells by activating NF-κB signaling and providing T-cell 
costimulation in the context of suboptimal TCR activation. 
Consistent with a human IgG1κ Fc region, INCAGN01949 binds to both recombinant and cell 
expressed FcγRs. Co-engagement of FcγRs by INCAGN01949-labeled target cells triggers 
FcγRIIA and FcγRIIIA signaling and results in FcγR-mediated effector cell activity by a NK cell 
line, as measured by antibody-dependent cellular cytotoxicity.  Also consistent with an IgG1κ Fc 
region, INCAGN01949 binds to recombinant C1q, the first subcomponent of the C1 complex of 
the classical pathway of complement activation, and shows evidence of complement-dependent 
cytotoxicity of OX40-expressing target cells.  A fresh human whole blood cytokine release assay 
was used to evaluate the potential risk of INCAGN01949 eliciting adverse proinflammatory 
infusion reactions in soluble and complexed (plate-bound) formats.  At concentrations up to 
100 μg/mL, INCAGN01949 demonstrates only modest induction of IL-6 and does not induce 
other cytokines in whole blood that in vivo would be predictive of CRS in patients.  Taken 
together, the pharmacologic properties of INCAGN01949 illustrate its suitability for clinical 
development in patients with advanced malignancies. 
Preclinical findings highlight the potential antitumor mechanisms of action of INCAGN01949:  
1) OX40 signaling in the context of TCR activation enhances effector T-cell activation, cytokine 
production, and survival, which promote memory T-cell differentiation and reactivation, and 
2) intratumoral depletion of T regulatory cells through ADCC (Gonzalez et al 2016).  Together, 
this would suggest that an agonistic OX40 mAb such as INCAGN01949 would have a focused 
effect in the human immune response leading to the proliferation and augmentation of an 
ineffectually active antitumor immune response. 




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Table 1: 
Summary of INCAGN01949 Pharmacokinetic Parameters in Cycle 1 
Cohort 
Dose (N) 
Cmax 
(ng/mL) 
Tmax 
(h)
a 
AUC0-t 
(h∙μg/mL) 
AUC0-∞(obs) 
(h∙μg/mL) 
Clobs 
(mL/h) 
Vz(obs) 
(mL) 
t½ 
(h) 
1 
 mg (4) 
1630 ± 735 
0.5 
(0.5, 4) 
178 ± 82.1 
258 ± 120 
33.0 ± 17.4 
5700 ± 1370 
140 ± 60.4 
2 
 mg (4) 
5820 ± 834 
5770 
2.25 
(0.5, 4) 
881 ± 213 
1250 ± 451 
17.2 ± 4.71 
3760 ± 1360 
149 ± 28.2 
3 
mg (10) 
14100 ± 3850 
4.0 
(0.5, 4) 
1630 ± 764 
3030 ± 1380 
26.1 ± 8.60 
6880 ± 1110 
209 ± 115 
4 
 mg (9) 
34700 ± 10800 
0.5 
(0.5, 4) 
5120 ± 2520 
8660 ± 6000 
35.9 ± 27.2 
8520 ± 5040 
208 ± 132 
5 
mg (6) 
45400 ± 11900 
0.5 
(0.5, 0.5) 
5690 ± 2620 
12400 ± 3730 30.8 ± 11.4 10500 ± 3630 
264 ± 133 
6 
mg (4) 215000 ± 38800 
2.25 
(0.5, 4) 
24300 ± 5130 
31600 ± 49 
22.5 ± 3.25 
4900 ± 1070 
150 ± 19.6 
a Values are presented as mean ± standard deviation except tmax, which is presented as median with range. 
1.2.5. 
Clinical Safety of INCAGN01949 
Study INCAGN 1949-101 is an open-label, nonrandomized, Phase 1/2 study to determine the 
safety and tolerability, define the MTD or PAD, and assess the preliminary efficacy of 
INCAGN01949 in subjects with advanced or metastatic solid tumors.  Dose escalation is 
ongoing using a traditional 3 + 3 design with cohorts of subjects sequentially enrolled at doses of 
7 mg, 20 mg, 70 mg, 200 mg, 350 mg, 700 mg, and 1400 mg.  INCAGN01949 is administered 
IV over 30 minutes on Day 1 of each 14-day cycle until disease progression or intolerable 
toxicity.  Decisions for dose escalation are based on predetermined DLTs observed during a 
28-day observation period. 
As of 05 JAN 2018, no DLTs have been observed, and the MTD/PAD has not yet been defined.  
Dose expansion is ongoing.  Treatment-related AEs occurring in more than 5% of subjects 
include events of fatigue (n = 8) and diarrhea, nausea, and rash (n = 3 each).  One CTCAE 
Grade 3 treatment-related event of arthralgia was reported.  Ten percent of subjects experienced 
SAEs.  Serious AEs occurring in more than 1 subject were nausea, small intestinal obstruction, 
and dyspnea (n = 2 each, 4%).  


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1.3. 
Overview of Standard Therapies  
1.3.1. 
Nivolumab 
1.3.1.1. 
Nivolumab Summary 
Nivolumab (OPDIVO®) is PD-1 blocking antibody that has been approved as monotherapy in 
the United States for the treatment of patients with unresectable or metastatic melanoma, 
metastatic NSCLC, advanced RCC, recurrent or metastatic SCCHN, locally advanced or 
metastatic urothelial carcinoma, classical Hodgkin lymphoma, MSI-H or dMMR metastatic 
CRC, and HCC.  Nivolumab is also approved in combination with ipilimumab in patients with 
unresectable or metastatic melanoma (Opdivo 2018).  Nivolumab is approved in the European 
Union as monotherapy or in combination with ipilimumab for advanced (unresectable or 
metastatic) melanoma, as monotherapy for locally advanced or metastatic NSCLC, for advanced 
RCC, for Hodgkin lymphoma, for SCCHN, and for urothelial carcinoma (Opdivo SmPC 2018). 
1.3.1.2. 
Risks From Nivolumab 
Due to the mechanism of action of nivolumab, immune-mediated adverse reactions have been 
seen when used as monotherapy and in combination with ipilimumab.  Guidance is provided in 
the package insert for the management of immune-mediated pneumonitis, immune-mediated 
colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated 
nephritis and renal dysfunction, immune-mediated skin adverse reactions, and immune-mediated 
encephalitis.  Infusion reactions are also possible following administration of nivolumab.  The 
most common adverse reactions seen in ≥ 20% of patients receiving nivolumab monotherapy 
were fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, 
constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, and 
pyrexia.  The most common adverse reactions seen in ≥ 20% of patients receiving nivolumab in 
combination with ipilimumab were fatigue, rash, musculoskeletal pain, pruritus, diarrhea, 
nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper 
respiratory infection, pyrexia, headache, and abdominal pain (Opdivo 2018).  Refer to the 
Opdivo prescribing information and SmPC for updated information regarding safety and risks.   
1.3.2. 
Ipilimumab 
1.3.2.1. 
Ipilimumab Summary 
Ipilimumab (YERVOY®) is a human CTLA-4–blocking antibody indicated as a monotherapy 
and in combination with nivolumab for the treatment of patients with advanced melanoma.   
1.3.2.2. 
Risks From Ipilimumab 
Ipilimumab may cause immune-mediated adverse reactions, including immune-mediated 
hepatitis, immune-mediated enterocolitis, immune-mediated dermatitis, immune-mediated 
neuropathies, immune-mediated endocrinopathies, and other immune-mediated adverse 
reactions.  Guidance for the management of these events is found in the package insert.  The 
approved dose of ipilimumab is 3 mg/kg Q3W for 4 doses.  The most common AEs (≥ 5%) seen 
at the approved dose are fatigue, diarrhea, pruritus, rash, and colitis.  Additional common 
adverse reactions (≥ 5%), seen in patients receiving a higher dose of 10 mg/kg, include nausea, 


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vomiting, headache, weight loss, pyrexia, decreased appetite, and insomnia (Yervoy 2018).  
Refer to the Yervoy prescribing information and SmPC for updated information regarding safety 
and risks (Yervoy 2018). 
The combination of nivolumab and ipilimumab was initially explored in subjects with advanced 
or metastatic melanoma using doses of 1 mg/kg nivolumab and 3 mg/kg ipilimumab given Q3W 
for 4 doses followed by 3 mg/kg nivolumab administered Q2W.  The toxicity of the combination 
was significantly higher than either agent alone with 36.4% of subjects discontinuing treatment 
due to an AE and 68.7% of subjects experiencing Grade 3 or 4 AEs (Larkin et al 2015).  More 
recent published data have demonstrated that lower doses and less frequent administration of 
ipilimumab improves the toxicity profile of the combination (Antonia al 2016, Hellmann 
et al 2016).  In a study of 3 mg/kg nivolumab administered Q2W plus 1 mg/kg ipilimumab 
administered Q6W in first-line NSCLC, only 13% of subjects discontinued due to a 
treatment-related AE, and only 33% had a Grade 3 or 4 treatment-related AE (Hellmann 
et al 2016).  The most common AEs seen in this treatment group were skin events (36%, 5% 
Grade 3 or 4), endocrine (20%, 5% Grade 3 or 4), and GI (23%, 5% Grade 3 or 4).  Due to this 
emerging data, 1 mg/kg Q6W of ipilimumab is being used in the triplet combinations 
(nivolumab, ipilimumab, and INCAGN01949).  Prior to initiating the triplet combinations, the 
safety and tolerability of ipilimumab 1 mg/kg Q6W will be tested in the doublet combination 
(ipilimumab and INCAGN01949). 
1.4. 
Potential Risks of the Combination Regimens 
The principal toxicities of administering agents that modulate the immune system are irAEs, 
including skin manifestations, pneumonitis, enterocolitis, and endocrinopathies.  Immune-related 
AEs have been reported in subjects treated with nivolumab and ipilimumab.  As the use of 
immunotherapies become more prevalent, guidelines for the management of irAEs continue to 
evolve.  Careful monitoring, early diagnosis, and treatment with corticosteroids for more severe 
events is recommended.  The time of onset of irAEs varies, with skin manifestations and GI 
toxicity seen early and elevated liver enzymes and endocrinopathies appearing later 
(Weber et al 2015).  Subjects enrolled in this study will be carefully monitored for the onset of 
irAEs, and guidelines for the management of these toxicities are provided in the Protocol and in 
the prescribing information for nivolumab and ipilimumab.   
INCAGN01949 was well-tolerated in toxicology studies in cynomolgus monkeys at several 
doses and has been well-tolerated at doses explored so far in the Phase 1 clinical study 
(INCAGN 1949-101).  No subjects discontinued due to a treatment-related toxicity.  Adverse 
events were generally mild and managed with supportive care.  However, as INCAGN01949 is 
an immune stimulator, it may enhance or exacerbate irAEs associated with any immune therapy. 
The risks of nivolumab and ipilimumab are well-characterized and described in more detail in 
Section 1.3.  Of note, a lower dose and less frequent administration of ipilimumab (1 mg/kg 
Q6W) was selected for the doublet and triplet combinations to minimize AEs based on emerging 
safety data with the nivolumab and ipilimumab combination (Antonia et al 2016, Hellmann 
et al 2016). 


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1.5. 
Study Rationale 
1.5.1. 
Rationale for Phase 1 Subject Population 
Most cancers exhibit genetic heterogeneity, which often translates into enhanced tumor 
immunogenicity.  This concept of tumor immunogenicity is well-appreciated for its role in 
eliciting an adaptive immune response and determining the efficacy of immunotherapy.  
Blockade of PD-1/L1 has led to clinical responses in patients with many different types of 
cancer, including melanoma, NSCLC, RCC, SCCHN, gastric cancer, HCC, TNBC, cervical 
cancer, and bladder cancer (Hamid et al 2013, Herbst et al 2016, Powels et al 2014, 
Topalian et al 2014, Brahmer et al 2015, Ferris et al 2016, Melero et al 2016, Le et al 2015, 
Dirix et al 2016, Frenel et al 2016, Rosenberg et al 2016).  The combination of PD-1 and 
CTLA-4 blockade has shown to significantly improve ORR, PFS, and OS compared with 
monotherapy PD-1/L1 in a variety of tumors, including melanoma, NSCLC, SCLC, RCC, 
MSI-H CRC, and gastric cancer (Antonia et al 2016, Hellmann et al 2016, Hammers et al 2016, 
Overman et al 2016, Janjigian et al 2016).   
1.5.2. 
Rationale for Phase 2 Subject Population 
A major difficulty in the development of new agents to treat advanced malignancy is the need to 
identify the appropriate dose, schedule, and combination partner particularly in settings where 
the combination partner has no or limited antitumor activity.  The combination of nivolumab and 
ipilimumab has significant benefit in a number of tumor histologies, including melanoma and 
renal and lung cancer, although at the cost of significant toxicity.  Other combinations have not 
been successfully developed for a variety of reasons.  The combination of lenalidomide and 
pembrolizumab showed lower response rates and increased risk of death in patients with 
myeloma (FDA 2017), whereas the combination of Roche’s OX40 antibody and atezolizumab 
was associated both with reduced clinical activity and toxicity, suggesting a possible negative 
effect on the tumor microenvironment (Infante et al 2016).  Studies by Messeheimer et al (2016) 
and Shrimali et al (2017) in animal models suggest that simultaneous administration of 
antibodies that recognize PD-1 and OX40 provides a setting that is associated with upregulation 
of multiple checkpoint molecules that predispose tumor-specific T cells to undergo apoptosis 
upon antigen engagement.  In order to identify the appropriate dose of INCAGN01949 to 
combine with nivolumab, we propose evaluating a population of PD-1/L1 refractory patients 
with a fixed dose of nivolumab and escalating doses of INCAGN01949.  The best data available 
on response to PD-1/L1 blockade in combination with other agents in patients with no response 
or relapse following PD-1/L1 therapy comes from a small dataset of patients treated with 
nivolumab and anti-LAG3.  In this study, 48 subjects with relapsed or refractory melanoma were 
treated.  In subjects with prior response, there were 2 responses among 13 patients (15%), 
1 response among 14 patients with stable disease (7%) and 2 responses in 20 patients with 
progressive disease (10%; Ascierto et al 2017).  In this study, we will attempt to determine 
whether the response rate differs from the approximately 10% response rate observed in the 
study presented by Ascierto et al (2017).  The selection of renal cell cancer, gastric cancer, 
SCCHN, and NSCLC for investigation is based on the immune responsiveness of these 
populations, the variable expression levels of OX40 in these tumor types with renal cell cancer 
virtually devoid of OX40 expression and gastric cancer and head and neck cancer having a 
significant fraction of patients with high level expression and lung cancer showing low level 


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expression (data on file).  This will allow the assessment of a correlation between OX40 
expression in the tumor and clinical response.   
1.5.2.1. 
Renal Cell Carcinoma 
Renal cell carcinoma accounts for almost 4% of all new cancer cases, with an estimated 
62,700 new cases being diagnosed in 2016 (SEER 2017).  The 5-year survival rate has improved 
to approximately 74% from the period from 2006 to 2012 (SEER 2017).   
Sunitinib and pazopanib are kinase inhibitors against the vascular endothelial growth factor 
receptors and are commonly used for first-line treatment of metastatic clear cell RCC.  
Temsirolimus is used first-line for patients with poor-risk RCC.  Second-line options include 
axitinib, cabozantinib, lenvatinib plus everolimus, and nivolumab (Choueiri and Motzer 2017).  
Nivolumab is approved for subjects with RCC who have received prior anti-angiogenic therapy 
(Opdivo 2018).  In the pivotal study of nivolumab compared with everolimus, a statistically 
significant improvement in OS was seen in subjects randomized to nivolumab (25.0 months) 
versus everolimus (19.6 months).  The ORR was also higher in subjects receiving nivolumab 
(25%) as compared with everolimus (5%; Motzer et al 2015).  Nivolumab was also studied in 
combination with ipilimumab in subjects with metastatic RCC.  Subjects were randomized to 
different dose groups.  One group received a dose of nivolumab 3 mg/kg plus ipilimumab 
1 mg/kg every 3 weeks for 4 doses followed by nivolumab 3 mg/kg Q2W (Nivo 3 + Ipi 1).  
Another group received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for 4 doses 
followed by nivolumab 3 mg/kg Q2W (Nivo 1 + Ipi 3).  Forty-seven subjects were enrolled into 
each dose group with approximately 50% of subjects having received prior systemic therapy.  
The ORR was 40% in each dose group (Hammers et al 2016).  The combination of nivolumab 
and ipilimumab was recently approved by the US FDA for patients with intermediate- or 
poor-risk, previously untreated RCC (Opdivo 2018).  Recent advances have improved treatment 
options for patients with metastatic RCC; however, resistance develops commonly to the 
treatment regimens, and further treatment options are needed for this population.     
1.5.2.2. 
Gastric Cancer 
Cancers of the upper GI tract are highly lethal malignancies.  Locally advanced unresectable and 
metastatic gastroesophageal cancers are not curable conditions, and the goals of therapy include 
palliation of symptoms and prolongation of survival.  Despite a large number of randomized 
trials, there is no consensus as to the best regimen for initial or second-line chemotherapy for 
advanced gastroesophageal cancer.  In general, combination chemotherapy regimens provide 
higher response rates, but this translates into only modestly longer durations of disease control 
and survival. 
Clinical activity with anti–PD-1 checkpoint blockade has been seen in patients with previously 
treated advanced gastroesophageal carcinomas.  In the Checkmate-032 Phase 1/2 study, 
160 subjects with gastric, esophageal, or GEJ, irrespective of PD-L1 status, who had progressed 
on chemotherapy (≥ 2 prior regimens) were treated with standard doses of nivolumab (N3; 
n = 59), nivolumab 1 mg/kg + ipilimumab 3 mg/kg (N1 + I3; n = 49), or standard doses of 
nivolumab + ipilimumab 1 mg/kg (N3 + I1; n = 52).  The ORR was 14% (N3), 26% (N1 + I3), 
and 10% (N3 + I1), including 2 patients with a CR.  Additionally, disease control was seen in 


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38% of patients.  The median OS was 5 months (N3), 6.9 months (N1 + I3), and 4.8 months 
(N3 + I1; Kojima et al 2016, Janjigian et al 2016). 
Pembrolizumab was recently approved by the US FDA for patients with recurrent locally 
advanced or metastatic gastric or GEJ adenocarcinoma whose tumors express PD-L1 as 
determined by an approved test (Keytruda 2018).  Clinical activity and improved OS in patients 
with chemotherapy refractory disease are encouraging and further support investigation of 
combination immune therapies. 
1.5.2.3. 
Squamous Cell Carcinoma of the Head and Neck 
The prognosis of patients with recurrent or metastatic SCCHN is generally poor.  The median 
survival in most is 6 to 9 months.  Conventional cytotoxic chemotherapy, checkpoint inhibitor 
immunotherapy, and molecularly targeted compounds have activity in metastatic and recurrent 
head and neck cancer.  The most widely used agents include platinum compounds (cisplatin, 
carboplatin), taxanes (docetaxel, paclitaxel, Abraxane®), methotrexate, fluorouracil, and 
cetuximab.  More recently, pembrolizumab and nivolumab have shown clinically significant 
activity in patients who progressed on or after platinum-based chemotherapy regimens 
(Keytruda 2018, Mehra et al 2016, Ferris et al 2016). 
Pembrolizumab was approved by the US FDA in August 2016 for patients with recurrent or 
metastatic SCCHN who have had progression on or after platinum-based chemotherapy.  The 
approval was based upon results from 174 subjects in a Phase 1b study and is conditional upon 
the completion of randomized Phase 3 clinical studies.  An ORR was seen in 28 of 174 patients 
(16%), including 8 CRs (5%).  The median DOR was not reached, and 23 of 28 responses were 
longer than 6 months (Keytruda 2018).  Responses were independent of HPV status.  Updated 
results were presented at the 2016 ASCO meeting:  the median OS was 8 months, and the 6- and 
12-month OS rates were 58% and 38%, respectively (Mehra et al 2016). 
Nivolumab was approved by the US FDA in NOV 2016 for patients with recurrent or metastatic 
SCCHN with disease progression on or after a platinum-based therapy.  In the Checkmate-141 
Phase 3 study, 361 subjects with platinum refractory, recurrent or metastatic disease were 
randomly assigned to either nivolumab or a single-agent investigator's choice of therapy 
(methotrexate, docetaxel, or cetuximab; Ferris et al 2016).  With a median follow-up of 
5.1 months, OS for the entire study population was significantly longer in subjects treated with 
nivolumab (median 7.5 vs 5.1 months, 1-year OS rate 36% vs 17%).  The ORR was also 
increased with nivolumab (13% versus 6%).  In a prespecified exploratory analysis, OS was 
significantly increased with immunotherapy in patients with PD-L1 expression ≥ 1% (8.7 vs 
4.6 months).  In a post-hoc exploratory analysis, OS was significantly increased in subjects 
treated with immunotherapy with HPV positive tumors (median 9.1 vs 4.4 months).  The 
difference in OS was not statistically significant in those with HPV-negative tumors (median 
7.5 vs 5.8 months). 


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1.5.2.4. 
Non–Small Cell Lung Cancer 
The treatment landscape for patients with NSCLC has been evolving rapidly with the approval of 
immunotherapy in this disease over the past several years.  Anti–PD-1/L1 inhibitors have 
recently been approved in locally advanced and metastatic NSCLC in a variety of settings 
(Keytruda 2018, Imfinzi 2018, Opdivo 2018, Tecentriq 2018).  Unfortunately, a large number of 
patients still do not respond to treatment, and treatment options remain limited.  Recent data have 
shown that combining the PD-1 inhibitor, pembrolizumab, with chemotherapy can significantly 
improve the ORR, PFS, and OS as compared with chemotherapy alone, but the response rate was 
47.6%, leaving a majority of patients seeking additional treatment (Gandhi et al 2018).  
Immunotherapy combinations have also been tested with the combination of PD-1 and CTLA-4 
(nivolumab with ipilimumab) having been shown to improve PFS in patients with a high tumor 
mutational burden, but again, less than half of the patients treatment achieve an object response 
with an ORR of 45.3% (Hellmann et al 2018).  Clearly, there remains an unmet need for 
effective treatment for these patients who do not respond to a PD-1/L1 inhibitor. 
1.5.3. 
Rationale for Dose and Schedule of Combination Therapies 
The proposed starting dose and schedule of INCAGN01949 (7 mg IV Q2W) in the Phase 1 
portion of the study is based on preclinical data and emerging clinical data from the ongoing first 
in human monotherapy study (INCAGN 1949-101). 
To ensure safety in combination with nivolumab and ipilimumab in this study, the starting dose 
of INCAGN01949 will be defined as 1 dose level below the highest tolerated dose of 
INCAGN01949 when given as monotherapy.  Current clinical observations from study 
INCAGN 1949-101 have shown safety and tolerability of INCANG01949 when administered at 
a dose up to 1400 mg Q2W.  As data emerge from Study INCAGN 1949-101, a higher starting 
dose of INCAGN01949 may be used but will not exceed 1 dose level below the highest tolerated 
monotherapy dose of INCAGN01949. 
The current schedule of administration (Q2W) is based on both preclinical and clinical 
observations.  The Q2W schedule used in Study INCAGN 1949-101 was based on the PK of 
INCAGN01949 determined in cynomolgus monkeys following a single and weekly IV doses.  
The mean estimated terminal half-life was estimated to be 11.4 days.  These preclinical findings 
support Q2W dosing and are consistent with observations in the first-in-human study 
(INCAGN 1949-101). 
The proposed mechanism of action of INCAGN01949 is the depletion of Tregs in the tumor 
microenvironment and costimulation of recently activated Teff cells.  This suggests that 
INCAGN01949 may help prime the immune microenvironment for a more robust antitumor 
immune response.  Preclinical models have shown that the priming of the tumor 
microenvironment with monotherapy anti-OX40 prior to anti–PD-1 therapy offers greater 
antitumor activity when compared with combining concurrently with an anti–PD-1 or  
anti–PD-L1 antibody (Messenheimer et al 2016).  Clinical data evaluating the monotherapy 
activity of anti-OX40 antibodies have shown changes in the tumor microenvironment that would 
favor an antitumor immune response as evident by the rise of tumor infiltrating lymphocytes, 
T helper 1 cytokines, and a diminished Treg population (Hansen et al 2016).  However, when 
combined concurrently with an anti–PD-L1 antibody, the response rates were lower than 
expected (2 PRs of 58 subjects); of note, 1 of the responders was a subject who had previously 


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received monotherapy anti-OX40 antibodies (Infante et al 2016).  These findings suggest a 
rationale to evaluate INCAGN01949 as a monotherapy immune primer prior to subsequent 
immunotherapies as well as dosing both therapies concurrently.  As more clinical data emerge 
from Study INCAGN 1949-101, the dosing and schedule of INCAGN01949 will be re-assessed 
with investigators. 
The approved dose of nivolumab (240 mg Q2W) has been selected for the doublet combination 
(nivolumab and INCAGN01949).  The approved doses of nivolumab and ipilimumab in 
combination are nivolumab 3 mg/kg Q2W and ipilimumab 3 mg/kg Q3W for 4 doses.  
Additional combination studies of nivolumab (3 mg/kg Q2W) and ipilimumab (1 mg/kg Q6W) 
showed similar efficacy with better tolerability.  To minimize any additional risk to safety, 
INCAGN01949 will be combined with nivolumab (3 mg/kg Q2W) and ipilimumab (1 mg/kg 
Q6W) in the triplet cohorts (nivolumab, ipilimumab, and INCAGN01949; see Section 1.3 and 
Section 1.4; Antonia et al 2016, Hellmann et al 2016). 
INCAGN01949 has been generally well-tolerated at doses ranging from 7 mg to 1400 mg as 
monotherapy and up to 350 mg in combination with nivolumab or ipilimumab.  Preliminary data 
have not elucidated the appropriate pharmacologic dose for future studies.  The decision for dose 
selection will be based on results from biopsy data from the INCAGN 1949-101 study and the 
efficacy of INCAGN01949 and nivolumab combination in PD-1/L1 refractory patients. 
1.5.4. 
Rationale for the Study Endpoints 
1.5.4.1. 
Efficacy Endpoints 
Efficacy endpoints of this study include ORR, DOR, DCR, duration of disease control, and PFS 
by investigator assessment based on RECIST v1.1.   
1.5.4.1.1. Modified RECIST 
Note:  Modified RECIST was removed as an endpoint in Amendment 3 of the Protocol; 
however, mRECIST principles may still be used to guide treatment discontinuation decisions for 
disease progression.  RECIST v1.1 will be adapted to account for the unique tumor response 
characteristics seen with immunotherapy (Wolchok et al 2009).  Immunotherapeutic agents may 
produce antitumor effects by potentiating endogenous cancer-specific immune responses.  The 
response patterns seen with such an approach may extend beyond the typical time course of 
responses seen with cytotoxic agents and can manifest a clinical response after an initial increase 
in tumor burden or even the appearance of new lesions.  Standard RECIST may cause subjects 
who are clinically benefiting from treatment to be discontinued from treatment prematurely.  
Therefore, RECIST v1.1 will be used with the following adaptations to guide treatment 
discontinuation decisions for disease progression: 
If radiologic imaging shows initial progressive disease, tumor assessment should be repeated at 
least 4 weeks, but no later than 6 weeks, later in order to confirm disease progression with the 
option of continuing treatment while awaiting radiologic confirmation of progression.   


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In subjects who have initial evidence of radiological progression but are clinically stable as 
defined below, it is at the discretion of the treating physician whether to continue a subject on 
study treatment until repeat imaging is obtained.  This clinical judgment decision should be 
based on the subject's overall clinical condition, including performance status, clinical 
symptoms, and laboratory data.  Subjects may receive treatment while waiting for confirmation 
of disease progression if they are clinically stable as defined by the following criteria: 
 Absence of clinically significant signs and symptoms indicating disease progression. 
 No decline in ECOG performance status. 
 Absence of rapid progression of disease. 
 Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention. 
If repeat imaging shows < 20% tumor burden compared with nadir, stable or improved previous 
new lesion (if identified as cause for initial disease progression), and stable/improved nontarget 
disease (if identified as cause for initial disease progression), then treatment may be continued or 
resumed.  If repeat imaging confirms disease progression due to any of the scenarios listed 
below, subjects will be discontinued from study therapy.  However, if a subject has confirmed 
radiographic progression (ie, 2 scans at least 4 weeks, but no later than 6 weeks apart 
demonstrating progression) per mRECIST, but the subject is achieving a clinically meaningful 
benefit, an exception to continue treatment may be considered after consultation with the medical 
monitor.  Clinically stable subjects at the confirmatory scan should also have no further increase 
in the target lesions, no unequivocal increase in nontarget lesions, and no additional new lesions 
develop (nonworsening disease progression) to continue study treatment (see Section 7.7.1). 
In determining whether or not the tumor burden has increased or decreased, the site study team 
should consider all target lesions, as well as nontarget lesions (refer to RECIST v1.1 guidelines). 
Scenarios where disease progression is confirmed at repeat imaging include the following: 
 Tumor burden remains ≥ 20% and at least 5 mm absolute increase compared with 
nadir. 
 Nontarget disease resulting in initial disease progression is worse (qualitative). 
 New lesion resulting in initial disease progression is worse (qualitative). 
 Additional new lesion(s) since last evaluation. 
When feasible, subjects should not be discontinued until progression is confirmed.  This 
allowance to continue treatment despite initial radiologic progression takes into account the 
observation that some subjects can have a transient tumor flare in the first few months after the 
start of immunotherapy but with subsequent disease response.  Subjects who are deemed 
clinically unstable are not required to have repeat imaging for confirmation of disease 
progression. 






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3. 
SUBJECT ELIGIBILITY 
Deviations from eligibility criteria are not allowed because they can potentially jeopardize the 
scientific integrity of the study, regulatory acceptability, and/or subject safety.  Therefore, 
adherence to the criteria as specified in the Protocol is essential. 
3.1. 
Subject Inclusion Criteria 
A subject who meets all of the following criteria may be included in the study: 
1. Men and women, aged 18 or older. 
2. Willingness to provide written informed consent for the study. 
3. Locally advanced or metastatic disease; locally advanced disease must not be amenable 
to resection with curative intent. 
4. Phase 1 (Part 1 and Part 2):  Subjects with advanced or metastatic cervical cancer, 
endometrial cancer, gastric cancer (including stomach and GEJ), esophageal cancer, 
HCC, melanoma (ocular melanoma excluded), Merkel cell carcinoma, mesothelioma, 
MSI-H CRC, NSCLC, ovarian cancer, SCCHN, SCLC, RCC, TNBC, and urothelial 
carcinoma, or alternative tumor types with medical monitor approval. 
5. Phase 1 (Part 1 and Part 2):  Subjects who have disease progression after treatment with 
available therapies that are known to confer clinical benefit or who are intolerant to 
treatment.  There is no limit to the number of prior treatment regimens. 
6. Phase 2:  Subjects who have a diagnosis of advanced or metastatic gastric cancer, 
SCCHN, NSCLC, or RCC and are considered refractory to prior PD-1/L1 therapy.  
Refractory is defined as failure to achieve a CR or PR during prior treatment with an 
anti–PD-1/L1 agent administered either alone or in combination for advanced or 
metastatic disease. 
a. For subjects with gastric cancer:  Histologically confirmed adenocarcinoma of the 
GEJ or stomach. 
b. For subjects with SCCHN:  Histologically confirmed squamous cell carcinoma of 
the oral cavity, oropharynx, hypopharynx, or larynx.  Subjects with nasopharyngeal 
and salivary gland cancer are excluded. 
Note:  Should consent to have tumor evaluated for HPV status (per local institutional  
testing), or have documentation of HPV status. 
c. For subjects with RCC:  Histologically confirmed diagnosis of RCC that is 
predominantly clear cell histology. 
d. For subjects with NSCLC:  Subjects with histologically confirmed with squamous 
and nonsquamous histology may be enrolled. 
Note:  Subjects with nonsquamous carcinoma should have documentation of driver 
mutation status for EGFR, ALK fusion oncogene, ROS1 rearrangement, 
V600E-activated BRAF mutation status or consent to testing (per local institutional 
testing) for these markers during the screening period. 




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f. Total bilirubin ≥ 1.2 × ULN are excluded unless conjugated bilirubin 
≤ ULN (conjugated bilirubin only needs to be tested if total bilirubin exceeds ULN).  
If there is no institutional ULN, then direct bilirubin must be < 40% of total bilirubin 
to be eligible. 
g. INR, PT, or aPTT > 1.5 × ULN. 
2. Prior treatment with any TNFSF agonist (eg, GITR, OX40, 4-1BB/CD137, CD27, etc), 
for any indication. 
3. Administration of colony-stimulating factors (including granulocyte colony–stimulating 
factor, granulocyte macrophage colony–stimulating factor, or recombinant 
erythropoietin) within 14 days before study Day 1. 
4. Receipt of anticancer medications or investigational drugs within the following intervals 
before the first administration of study drug: 
a. ≤ 14 days for chemotherapy, targeted small molecule therapy, or radiation therapy.   
Note:  Subjects must not have had radiation pneumonitis as a result of treatment.  A 
1-week washout is permitted for palliative radiation to non–CNS disease with 
medical monitor approval. 
Note:  Bisphosphonates and denosumab are permitted concomitant medications. 
b. ≤ 14 days for prior immune therapy or persistence of active cellular therapy 
(ie, chimeric antigen receptor T-cell therapy; other cellular therapies must be 
discussed with medical monitor to determine eligibility). 
c. ≤ 28 days for a prior mAb used for anticancer therapy with the exception of 
denosumab. 
d. ≤ 7 days for immune-suppressive–based treatment for any reason. 
Note:  Use of inhaled or topical steroids or corticosteroid use for radiographic 
procedures is permitted. 
Note:  Must not require chronic use of corticosteroids.  The use of physiologic 
corticosteroid replacement therapy may be approved after consultation with the 
medical monitor. 
e. ≤ 28 days or 5 half-lives (whichever is longer) before the first dose for all other 
investigational agents or devices.  For investigational agents with long half-lives 
(eg, > 5 days), enrollment before the fifth half-life requires medical monitor approval. 
5. Has not recovered to ≤ Grade 1 from toxic effects of prior therapy (including prior 
immune therapy) and/or complications from prior surgical intervention before starting 
therapy 
Note:  Subjects with stable chronic conditions (≤ Grade 2) not expected to resolve (such 
as neuropathy and alopecia) are exceptions and may enroll. 
Note:  Subjects with a history of any grade immune-related ocular AE (eg, episcleritis, 
scleritis, uveitis) will be excluded. 
Note:  Subjects with a history of a Grade 3 or higher immune-related AE from prior 
immunotherapies are excluded from the dose-escalation portion of the study. 


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6. Receipt of a live vaccine within 30 days of planned start of study therapy. 
Note:  Examples of live vaccines include, but are not limited to, the following:  measles, 
mumps, rubella, chicken pox/zoster, yellow fever, rabies, Bacillus Calmette–Guérin, and 
typhoid vaccine.  Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live 
attenuated vaccines and are not allowed. 
7. Current use of prohibited medication as described in Section 5.6.3. 
8. Active autoimmune disease that required systemic treatment in the past (ie, with use of 
disease modifying agents, corticosteroids, or immunosuppressive drugs). 
Note:  Subjects who have not required systemic treatment in the past 2 years should 
discuss their case with medical monitor to determine eligibility. 
Note:  Subjects with hyper/hypothyroidism, vitiligo, controlled asthma, Type I diabetes, 
Graves' disease, or Hashimoto's disease are eligible to participate. 
Note:  Replacement and symptomatic therapies (eg, levothyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc) 
are not considered a form of systemic treatment and are allowed. 
9. Known active CNS metastases and/or carcinomatous meningitis. 
Note:  Subjects with previously treated brain metastases may participate provided that 
they are stable (without evidence of progression by imaging for at least 28 days before 
the first dose of study drug and any neurologic symptoms have returned to baseline), 
have no evidence of new or enlarging brain metastases or CNS edema, and have not 
required steroids for at least 7 days before the first dose of study drug. 
10. Known additional malignancy that is progressing or requires active treatment, or history 
of other malignancy within 2 years of study entry with the exception of cured basal cell 
or squamous cell carcinoma of the skin, superficial bladder cancer, prostate intraepithelial 
neoplasm, carcinoma in situ of the cervix, or other noninvasive or indolent malignancy, 
or cancers from which the subject has been disease-free for > 1 year, after treatment with 
curative intent. 
11. Evidence of active, noninfectious pneumonitis or history of interstitial lung disease. 
12. Clinically significant or uncontrolled cardiac disease, including unstable angina, acute 
myocardial infarction within 6 months from Day 1 of study drug administration, New 
York Heart Association Class III or IV congestive heart failure, and arrhythmia not 
controlled with therapy unless approved by medical monitor. 
13. History or presence of an abnormal ECG that, in the investigator's opinion, is clinically 
meaningful.  Subjects with screening QTc interval > 470 milliseconds (corrected by 
Fridericia) are excluded, unless approved by the medical monitor.  In the event that a 
single QTc is > 470 milliseconds, the subject may enroll if the average QTc for the 
3 ECGs is < 470 milliseconds.  For subjects with an intraventricular conduction delay 
(QRS interval > 120 milliseconds), the JTc interval may be used in place of the QTc with 
medical monitor approval.  The JTc must be < 340 milliseconds if JTc is used in place of 
the QTc.  Subjects with left bundle branch block are excluded. 
Note:  QTc prolongation due to pacemaker may enroll if the JTc is normal or with 
medical monitor approval. 


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14. Evidence of HBV or HCV infection or risk of reactivation.  Hepatitis B virus DNA and 
HCV RNA must be undetectable.  Subjects cannot be positive for HBV DNA, HCV 
RNA, hepatitis B surface antigen, or anti–hepatitis B core antibody, without approval 
from the medical monitor. 
Note:  Subjects with no prior history of hepatitis B infection who have been vaccinated 
against hepatitis B and who have a positive antibody against hepatitis B surface antigen 
test as the only evidence of prior exposure may participate in the study. 
15. Known history of drug-induced liver injury; alcoholic liver disease; nonalcoholic 
steatohepatitis; primary biliary cirrhosis; or ongoing extrahepatic obstruction caused by 
stones, cirrhosis of the liver, or portal hypertension. 
16. Known history of HIV; HIV 1/2 antibodies. 
17. Known allergy or reaction to any component of nivolumab, ipilimumab, or study drug or 
formulation components. 
18. Inability or unlikeliness to comply with the dose schedule and study evaluations, in the 
opinion of the investigator. 
19. Women who are pregnant or breastfeeding. 
20. Any condition that would, in the investigator's judgment, interfere with full participation 
in the study, including administration of study drug and attending required study visits; 
pose a significant risk to the subject; or interfere with interpretation of study data. 


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
Based on a change in the development plan for INCAGN01949, enrollment to the study was 
stopped after 52 subjects were enrolled.  Phase 2 of this study will not open for enrollment.  
Continued study treatment will be permitted for up to 24 months at the discretion of the 
investigator for subjects who are considered to be obtaining ongoing clinical benefit. 
This is an open-label, nonrandomized, Phase 1/2 study to determine the safety, tolerability, and 
efficacy of INCAGN01949 when given in combination with immune therapies.  Phase 1 will 
consist of 2 parts.  Dose escalation (Part 1) will consist of a 3 + 3 + 3 design to determine the 
MTD, or PAD, defined as a dose that provides a maximal biochemical effect 
 
 of INCAGN01949 when given in combination with immune 
therapies.  The safety expansion (Part 2) will further explore tolerated doses of INCAGN01949 
given as a run-in of 2 doses followed by concomitant immune therapies.  Subjects with advanced 
or metastatic cervical cancer, endometrial cancer, gastric cancer (including stomach and GEJ), 
esophageal cancer, HCC, melanoma, Merkel cell carcinoma, mesothelioma, MSI-H CRC, 
NSCLC, ovarian cancer, SCCHN, SCLC, RCC, TNBC, and urothelial carcinoma who have 
progressed after treatment with available therapies that are known to confer clinical benefit or 
who are intolerant to treatment will be enrolled in both parts of Phase 1.   
The Phase 2 expansion will further evaluate the safety, tolerability, and efficacy of immune 
therapies combined with INCAGN01949 in 2 different parts.  In Phase 2 Part A, the selected 
doses of INCAGN01949 will be combined with nivolumab in PD-1/L1 refractory subjects with 
advanced or metastatic gastric cancer, SCCHN, NSCLC, and RCC to further explore the safety 
and efficacy of different doses of INCAGN01949 in combination with nivolumab in this 
population.  Phase 2 Part B will evaluate the recommended dose(s) of INCAGN01949 in 
combination with nivolumab (and ipilimumab where applicable).  PD-1/L1 refractory subjects 
with advanced or metastatic gastric cancer, SCCHN, NSCLC, or RCC will also be enrolled in 
Phase 2 Part B.  Pretreatment biopsies will be mandatory for subjects enrolled into either part of 
Phase 2.  On-treatment biopsies will be optional. 
The sponsor may elect to prioritize (or deprioritize) enrollment to specific treatment groups or 
cohorts based on emerging safety or efficacy data in collaboration with investigational sites. 
See Figure 1 for overall study design. 


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Figure 1: 
Overall Study Design 
 
4.1.1. 
Phase 1 Part 1 – Dose Escalation 
A minimum of 3 evaluable subjects will be enrolled in each treatment group beginning with 
INCAGN01949 Dose Cohort 1 (7 mg; starting dose).  A higher starting dose of INCAGN01949 
may be used if safety data are available from the monotherapy study (INCAGN 1949-101) but 
will not exceed 1 dose level below the highest tolerated dose of INCAGN01949 monotherapy.  If 
a higher starting dose is used, the new dose will be communicated to investigational sites with an 
administrative letter.  The doses of INCAGN01949 to be evaluated in each treatment group are 
summarized in Table 2. 


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Table 2: 
INCAGN01949 Dose Cohorts 
Dose Cohort 
Dose of INCAGN01949 
-1 
2 mg 
1 (Starting dose) 
7 mg
a 
2 
20 mg 
3 
70 mg 
4 
200 mg 
5 
350 mg 
6 
700 mg 
a A higher starting dose of INCAGN01949 may be used if safety data is available from the monotherapy study 
(INCAGN 1949-101) but will not exceed 1 dose level below the highest tolerated dose of INCAGN01949 
monotherapy.  If a higher starting dose is used, the dose will be communicated to investigational sites with an 
administrative letter. 
The first 3 evaluable subjects enrolled within an INCAGN01949 dose cohort will be observed 
for the specified DLT observation period before the next dose cohort begins enrollment.  If 
0 DLTs occur in a cohort of 3 evaluable subjects, a new cohort of 3 evaluable subjects will be 
treated at the next higher dose level.  If 1 of 3 evaluable subjects experiences a DLT, that cohort 
will be expanded to 6 evaluable subjects.  If 1 of 6 evaluable subjects experiences a DLT, a new 
cohort of 3 evaluable subjects will be treated at the next higher dose level.  If 2 of 6 evaluable 
subjects experience a DLT, that cohort will be expanded to 9 evaluable subjects.  If ≥ 2 of 3, 3 of 
6, or 3 of 9 evaluable subjects experience DLTs within a cohort, then that dose level will be 
determined to have exceeded the MTD, and the previous dose level will be considered the MTD.  
If only 3 evaluable subjects were treated at the MTD or PAD, then a minimum of 3 additional 
evaluable subjects will be enrolled before this dose is administered in Phase 2 of the study. 
Additional subjects will be enrolled in a dose cohort to achieve the minimum of 3 evaluable 
subjects.  Depending on treatment group, a subject must receive at least 2 doses of the 
cohort-specified dose of INCAGN01949, 2 doses of nivolumab, and 1 dose of ipilimumab, or 
must have had a DLT during the DLT observation period, to be considered evaluable.  Subjects 
who dropout for reasons other than a DLT (eg, events clearly associated with the underlying 
disease, disease progression, concomitant medication, or comorbidity), during the DLT 
observation period will result in the subject being nonevaluable and the subject being replaced.  
Dose modifications should not be made during the DLT observation period without discussion 
with the medical monitor. 
4.1.1.1. 
Doublet Immune Therapy Combinations 
Phase 1 dose escalation will begin with 2 doublet treatment groups, as outlined in Table 3, which 
will be explored in parallel. 






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4.1.2. 
Phase 1 Part 2 – Safety Expansion 
Once an INCAGN01949 dose cohort in Treatment Group A is deemed tolerable, up to 6 subjects 
will be enrolled in Treatment Group C at the same dose of INCAGN01949.  For example, if 
INCAGN01949 7 mg is tolerated in Treatment Group A, then 7 mg will be explored in up to 
6 subjects in Treatment Group C.  Likewise, once an INCAGN01949 dose in Treatment Group D 
is deemed tolerable, up to 6 subjects will be enrolled in Treatment Group E at the same dose of 
INCAGN01949.  For example, if INCAGN01949 350 mg is tolerated in Treatment Group D, 
then 350 mg will be explored in up to 6 subjects in Treatment Group E.  Doses of 
INCAGN01949 in Treatment Group C will be escalated in parallel to those explored in 
Treatment Group A but will not exceed the MTD of INCAGN01949 established in Treatment 
Group A.  The same rules will apply with Treatment Group D and E.  See Figure 2 below.  
Alternate dose administration schedules may also be explored depending on 
 
 safety results.  The sponsor may elect to prioritize (or deprioritize) enrollment to 
specific dose cohorts based on emerging safety or efficacy data in collaboration with 
investigational sites. 
Figure 2: 
Phase 1 Safety Expansion (Part 2)  
 
If the cumulative incidence of Grade 3 or Grade 4 INCAGN01949-related AEs occurs in > 40% 
of subjects in a particular treatment group, then further enrollment will be interrupted until the 
sponsor, investigators, and regulatory authorities (if applicable) determine the appropriate course 
of action (eg, lower the dose of INCAGN01949, change dose frequency, etc).   










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In Phase 2 of the study, toxicities will continue to be monitored.  If the cumulative incidence of 
Grade 3 or Grade 4 INCAGN01949-related AEs occurs in > 40% of subjects in a particular 
treatment group after 6 subjects have been enrolled, then further enrollment in that treatment 
group will be interrupted until the sponsor, investigators, and regulatory authorities (if 
applicable) determine the appropriate course of action (eg, lower the dose of INCAGN01949, 
change dose frequency, etc).  If a treatment group is discontinued due to toxicity, it may be 
re-initiated at a previously tested lower dose level and/or alternate dosing schedule.  All AEs, 
regardless of the time of occurrence on study, may be considered for DLT determination 
purposes.   
4.2. 
Measures Taken to Avoid Bias 
This is an open-label study.  Assessment of safety using CTCAE v4.03 and efficacy using 
RECIST v1.1 are objective measurements, and only comparisons with pretreatment conditions 
will be made. 
4.3. 
Number of Subjects 
4.3.1. 
Planned Number of Subjects 
Enrollment was stopped by the sponsor following a change in the development plan of 
INCAGN01949 after 52 subjects were enrolled.  Phase 2 of this study will not open for 
enrollment. 
Approximately 306 to 684 subjects may be enrolled as follows: 
 Phase 1 Dose Escalation – Approximately 54 to 162 evaluable subjects. 
Note:  The minimum number of subjects assumes that the starting dose is 7 mg; 
however, fewer subjects would be enrolled if a higher starting dose is used based on 
available safety data from the monotherapy study INCAGN 1949-101. 
Note:  The maximum number of subjects assumes that DLTs are observed in all dose 
cohorts to a maximum of 9 subjects per cohort across all treatment groups. 
 Phase 1 Safety Expansion – Approximately 72 subjects. 
 Phase 2 Part A – Stage 1 – Approximately 60 evaluable subjects. 
 Phase 2 Part A – Stage 2 – Approximately 90 evaluable subjects. 
 Phase 2 Part B – Stage 1 – Approximately 120 evaluable subjects. 
 Phase 2 Part B – Stage 2 – Approximately 180 evaluable subjects. 
Note:  Assumes that all treatment groups and all cohorts proceed to Stage 2. 




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5. 
TREATMENT 
5.1. 
Treatment Assignment 
5.1.1. 
Subject Numbering and Treatment Assignment 
Each subject will be identified in the study by a subject ID number, which is a combination of 
the site ID and subject number.  Site staff should contact the IRT to obtain the subject ID number 
and confirm a slot is available during prescreening.  This subject ID number will be maintained 
throughout the study and will not be reassigned.  Subjects who fail screening and are repeating 
the screening process due to a change in eligibility status will be assigned a new subject ID 
number.  The site staff will contact the IRT to enroll the subject and obtain the study drug and 
treatment group assignment.  All subsequent cycles will follow this process.  The IRT will also 
be contacted for ordering study drug supplies and when subjects are discontinued from treatment.  
Full details will be provided in the IRT manual. 
5.1.2. 
Randomization and Blinding 
This is an open-label nonrandomized study; therefore, randomization and blinding do not apply.   
5.2. 
Study Drugs 
5.2.1. 
INCAGN01949 
5.2.1.1. 
Description and Administration 
The study drug (INCAGN01949) is in liquid form in the formulation buffer of 20 mM histidine, 
250 mM sorbitol, pH 6.5 at a strength of 10 mg/mL to be used for IV infusion.  The infusion site 
should not be used for blood sampling.   
Study drug will be diluted in 0.9% normal saline or acceptable admixture as outlined in the 
Pharmacy Manual and will be administered by qualified personnel as an IV infusion over a 
30-minute (-5/+10 minutes) period on Day 1 of each cycle when INCAGN01949 is scheduled to 
be given.  On days when INCAGN01949 will be administered along with other agents 
administered by infusion, INCAGN01949 will be administered first, and subsequent immune 
therapy/therapies will be administered at least 30 minutes after the end of the infusion of 
INCAGN01949. 
In Phase 1, subjects will be administered study drug, according to cohort enrollment (Table 2).  
In Phase 2, subjects will be administered study drug at the recommended dose and schedule.  
Subjects can continue to receive INCAGN01949 for up to 24 months as long as the subject is 
considered to derive ongoing clinical benefit at the discretion of the investigator, and the subject 
has not met any of the Protocol-defined conditions for treatment withdrawal (see Section 5.5). 
In Treatment Groups G and K, INCAGN01949 is only administered on Day 1 of Cycles 1 and 2. 


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5.2.1.2. 
Supply, Packaging, and Labeling 
Study drug will be supplied as 5 mL of aqueous solution in 10 mL glass vials with 10 mg/mL of 
INCAGN01949.  Study drug will be packaged as open-labeled supplies, and each vial will be 
labeled and placed in a carton.  The Pharmacy Manual contains additional information regarding 
supply, packaging, and labeling of study drug. 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study drug in 
accordance with the Protocol and any applicable laws and regulations. 
All Incyte investigational product labels will be in the local language and will comply with the 
legal requirements of each country. 
5.2.1.3. 
INCAGN01949 Storage 
Study drug must be stored refrigerated (2°C-8°C) and protected from light, in a secure, limited 
access location.  Receipt and dispensing of study drug must be recorded by an authorized person 
at the study site.  Study drug may not be used for any purpose other than that stated in the 
Protocol.  The Pharmacy Manual contains additional information regarding storage of study 
drug. 
5.2.2. 
Standard Immune Therapies 
5.2.2.1. 
Nivolumab 
Nivolumab will be administered IV per instructions in the package insert at the site, at a dose that 
is dependent on the assigned treatment group as follows: 
 Doublet Treatment Groups A and F:  240 mg on Day 1 of every 2-week (ie, 14-day) 
cycle. 
 Doublet Treatment Groups C, G, and H:  240 mg on Day 1 of every 2-week 
(ie, 14-day) cycle beginning on Cycle 3 Day 1. 
 Triplet Treatment Groups D and J:  3 mg/kg on Day 1 of every 2-week (ie, 14-day) 
cycle. 
 Triplet Treatment Groups E, K, and L: 3 mg/kg on Day of every 2-week (ie, 14-day) 
cycle beginning on Cycle 3 Day 1. 
Alternate dose administration schedules may also be explored depending on 
 
 safety results. 
Nivolumab will be administered at least 30 minutes after the end of the infusion of 
INCAGN01949 (when applicable), and subjects will continue to receive nivolumab for up to 
24 months as long as the subject is considered to derive ongoing clinical benefit at the discretion 
of the investigator, and the subject has not met any of the Protocol-defined conditions for 
treatment withdrawal. 


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Nivolumab is commercially available.  Investigators are responsible for ensuring that subjects 
receive commercially available supplies of nivolumab for the entire duration of study 
participation.  Incyte may provide certain standard-of-care medications such as nivolumab where 
required by applicable law or specific regulation or under other circumstances when subjects 
may not otherwise have access to them.  Nivolumab must be used in accordance with the storage 
conditions and shelf life in the manufacturer's approved label. 
5.2.2.2. 
Ipilimumab 
Ipilimumab will be administered IV per instructions provided in the package insert at the site, at 
a dose that is dependent on the assigned treatment group as follows: 
 Doublet Treatment Group B and Triplet Treatment Group D:  1 mg/kg administered 
every 6 weeks (eg, 42 days) beginning on Cycle 1 Day 1. 
 Triplet Treatment Group J:  1 mg/kg administered every 6 weeks (eg, 42 days) 
beginning on Cycle 1 Day 1. 
 Triplet Treatment Groups E, K, and L:  1 mg/kg administered every 6 weeks 
(eg, 42 days) beginning on Cycle 3 Day 1. 
Alternate dose administration schedules may also be explored depending on 
 
 safety results.   
Ipilimumab will be administered at least 30 minutes after the end of the infusion of 
INCAGN01949 (when administered on the same day).  Ipilimumab will always be administered 
after INCAGN01949 and nivolumab.  Subjects will continue to receive ipilimumab for up to 24 
months as long as the subject is considered to derive ongoing clinical benefit at the discretion of 
the investigator, and the subject has not met any of the Protocol-defined conditions for treatment 
withdrawal. 
At the sponsor's discretion, once the MTD or PAD of INCAGN01949 has been established with 
ipilimumab at 1 mg/kg Q6W, a higher dose of ipilimumab at 3 mg/kg Q6W and/or 3 mg/kg 
Q3W for 4 doses may be tested. 
Ipilimumab is commercially available.  Investigators are responsible for ensuring that subjects 
receive commercially available supplies of ipilimumab for the entire duration of study 
participation.  Incyte may provide certain standard-of-care medications such as ipilimumab 
where required by applicable law or specific regulation or under other circumstances when 
subjects may not otherwise have access to them.  Ipilimumab must be used in accordance with 
the storage conditions and shelf life in the manufacturer's approved label.  
5.3. 
Treatment Compliance  
5.3.1. 
Treatment Compliance of INCAGN01949, Nivolumab, and Ipilimumab 
INCAGN01949, nivolumab, and ipilimumab are administered as an IV infusion by site 
personnel.  Receipt of infusions will be documented by the site staff and monitored by the 
sponsor/designee. 


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5.4. 
Treatment Interruptions and Adjustments 
5.4.1. 
Dose Modifications 
Selections and modifications to the study drug (INCAGN01949) are planned for dose-escalation 
cohorts (see Section 4.1.1).  Dose interruptions of study drug may also occur for individual study 
subjects.  The identification of DLTs will define the doses of INCAGN01949 used in planned 
cohorts (see Section 5.4.2).  Further, the occurrence of DLTs and other toxicities (related or 
unrelated to study drug) will guide decisions for treatment interruptions and discontinuation for 
individual subjects.  Dose interruptions of INCAGN01949 should not be made during the DLT 
observation period without discussion with the medical monitor.  Intrasubject dose escalation 
will not be permitted. 
No dose reductions of INCAGN01949, nivolumab, or ipilimumab are allowed for the 
management of toxicities of individual subjects.  Doses of INCAGN01949, nivolumab, and 
ipilimumab may be delayed for toxicity management (see Section 5.4.6).  
5.4.2. 
Dose-Limiting Toxicity and Determination of Maximum Tolerated Dose 
The evaluation period for DLTs will begin on Cycle 1 Day 1 and will continue up to and 
including study Day 28 for subjects in Phase 1 Part 1 (Treatment Groups A, B, and D).  All 
DLTs will be assessed by the investigator using CTCAE v4.03 criteria.  A DLT will be defined 
as the occurrence of any toxicity in Table 8, except those that are clearly and incontrovertibly 
due to disease progression or extraneous causes. 
Individual subject dose interruptions of study drug may be made based on events observed at any 
time during treatment; however, for the purposes of dose cohort escalation/de-escalation, 
expanding a dose cohort, and determining the MTD of INCAGN01949, decisions will be made 
based on events that are observed during the DLT evaluation period.  A lower MTD may 
subsequently be determined based on relevant toxicities that become evident after the end of the 
DLT evaluation period. 




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5.4.3. 
Management of Dose-Limiting Toxicities or Other Urgent Situations 
In all cases, investigators may employ any measures or concomitant medications, after 
discussion with the medical monitor (whenever possible), necessary to optimally treat the 
subject. 
5.4.4. 
Follow-Up of Dose-Limiting Toxicities 
Any DLT should be followed until it resolves to baseline or appears to have stabilized for a 
minimum of 4 weeks (eg, 28 days).  During follow-up, subjects should be seen as often as 
medically indicated to assure safety. 
5.4.5. 
Procedures for Cohort Review and Dose Escalation 
Telephone conferences will be scheduled by the sponsor with study investigators in order to 
review cohort-specific data and overall safety data, to agree on dose escalation, adjudicate 
individual high-grade AEs as potentially dose-limiting, and guide other major study decisions. 
5.4.6. 
Criteria and Procedures for Dose Interruptions of Study Drug 
Treatment with INCAGN01949 in combination with standard immune therapies may be delayed 
up to 4 weeks (28 days) to allow for resolution of toxicity.  If an interruption or 
discontinuation is necessary, all study treatments should be interrupted or discontinued.  
Subjects may resume treatment if no medical condition or other circumstance exists that, in the 
opinion of the investigator, would make the subject unsuitable for further participation in the 
study.  The treating investigator should contact the medical monitor to discuss the case of any 
subject whose treatment has been delayed for more than 4 weeks (28 days) before restarting 
treatment. 
Instructions for dose interruptions are outlined in Table 9.  Individual decisions regarding dose 
interruptions of study drug should be made using clinical judgment and in consultation with the 
medical monitor (whenever possible), taking into account relatedness of the AE to the study drug 
and the subject's underlying condition.  Adverse events that have a clear alternative explanation, 
or transient (≤ 72 hours) abnormal laboratory values without associated clinically significant 
signs or symptoms, may be exempt from dose-interruption rules.  
Dose interruptions are permitted in the case of medical/surgical events or logistical reasons not 
related to study therapy (eg, elective surgery, unrelated medical events, subject vacation, and/or 
holidays).  Subjects should be placed back on study therapy within 4 weeks (28 days) of the 
scheduled interruption, unless otherwise discussed with the medical monitor.  The reason for 
interruption should be documented in the subject's study record.   


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Table 9: 
Criteria for Interruption and Restarting of Study Treatment 
CTCAE  
Grade/Severity 
Hold 
Treatment 
(Y/N) 
Timing for  
Restarting 
Treatment 
Dose Level for 
Restarting  
INCAGN01949 
Dose Level for 
Restarting 
Immune 
Therapies 
Treatment 
Discontinuation 
1-2 
(Mild to moderate) 
No 
Continue treatment at 
the discretion of the 
investigator. 
N/A 
NA 
N/A 
3 
(Severe) 
Yes 
Toxicity resolves to 
Grade 0-1. 
Restart same dose 
Restart same dose 
Toxicity does not 
resolve within 
4 weeks (28 days) of 
last dose, except by 
approval of the 
medical monitor. 
OR 
Second occurrence 
of previously 
resolved Grade 3 
AE. 
4 
(Life-threatening) 
Yes 
Permanent 
discontinuation, 
except by approval of 
the medical monitor. 
If continuing, toxicity 
must resolve to 
Grade 0-1. 
Permanent 
discontinuation, 
except by approval of 
the medical monitor. 
If continuing, restart 
same dose 
Permanent 
discontinuation, 
except by 
approval of the 
medical monitor. 
If continuing, 
restart same dose. 
Permanent 
discontinuation for 
any severe or 
life-threatening 
event, except by 
approval of the 
medical monitor. 
5.4.7. 
Management of Immune-Related Adverse Events 
Nivolumab and ipilimumab are immune checkpoint inhibitors and are known to induce irAEs.  
INCAGN01949 is an immune modulator that may enhance the activity of other immunotherapies 
and therefore may also exacerbate any irAEs associated nivolumab and ipilimumab.  Adverse 
events of a potential immunologic etiology or irAEs may be defined as an AE consistent with an 
immune phenomenon associated with drug exposure after all other etiologies have been ruled 
out.  Immune-related AEs may be expected based on the nature of the study treatment, their 
mechanism of action, and reported experience with these and other immunotherapies.  Special 
attention should be paid to AEs that may be suggestive of potential irAEs.  An irAE can occur 
shortly after the first dose or several months after the last dose of treatment.  Suspected irAEs 
should be discussed with the medical monitor when possible. 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of drug-related 
AEs with potential immunologic etiology are outlined in Table 10.  Detailed supportive care 
guidelines for specific irAEs can be in found in Appendix B.  Nivolumab and ipilimumab are 
approved therapies and have specific irAE management guidelines within their package insert; 
the treating investigator may use labeled guidance or institutional guidelines for the management 
of irAEs if preferred.  For each AE, attempts should be made to rule out other causes, including 
but not limited to metastatic disease or bacterial or viral infection, which might require specific 
supportive care.   


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Table 10: 
Supportive Care Guidelines for Immune-Related Adverse Events 
CTCAE Grade/Severity 
Supportive Care
a 
1 
(Mild) 
 Monitor symptoms and provide symptomatic treatment. 
2 
(Moderate) 
 Monitor symptoms and provide symptomatic treatment. 
 Consider consultation with specialists as necessary. 
 Consider systemic corticosteroids per institutional standard of care. 
3-4 
(Severe to life-threatening) 
 Monitor symptoms and provide symptomatic treatment. 
 Consider consultation with specialists as necessary. 
 Administer corticosteroids per institutional standard of care. 
 More potent immunosuppressive therapies should be considered for events not 
responding to systemic steroids after discussing with the medical monitor. 
 Study treatment may be permanently discontinued for clinically significant or 
severe irAEs, or for events where steroid course cannot be tapered below 
7.5 mg/day prednisone or equivalent to manage symptoms. 
a Detailed supportive care guidelines for specific irAEs can be found in Appendix B. 
5.4.8. 
Management of Infusion Reactions 
Table 11 shows treatment guidelines for subjects who experience an infusion reaction associated 
with administration of study treatment.  Signs and symptoms usually develop during or shortly 
after drug infusion and generally resolve completely within 24 hours of completion of infusion.  
Nivolumab and ipilimumab are approved therapies and may have specific infusion reaction 
management guidelines within their package insert; the treating investigator may use labeled 
guidance or institutional guidelines for the management of infusion reactions if preferred. 


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Table 11: 
Infusion Reaction Treatment Guidelines 
CTCAE Grade 
Treatment 
Premedication at  
Subsequent Dose 
Administration 
Grade 1: 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated. 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator. 
None. 
Grade 2: 
Requires infusion interruption 
but responds promptly to 
symptomatic treatment  
(eg, antihistamines, NSAIDs, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤ 24 hours. 
Stop infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to the following: 
 IV fluids 
 Antihistamines 
 NSAIDs 
 Acetaminophen 
 Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator. 
If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate.  Otherwise, 
dose administration will be held until 
symptoms resolve, and the subject should be 
premedicated for the next scheduled dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be 
permanently discontinued from further study 
treatment. 
Subject may be premedicated 
1.5 hours (± 30 min) before 
infusion with the following: 
 Diphenhydramine 50 mg orally 
(or equivalent dose of 
antihistamine). 
 Acetaminophen 500-1000 mg 
orally (or equivalent dose of 
antipyretic). 
Grade 3: 
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; hospitalization 
indicated for other clinical 
sequelae (eg, renal 
impairment, pulmonary 
infiltrates). 
Stop infusion. 
Additional appropriate medical therapy may 
include but is not limited to the following: 
 IV fluids 
 Antihistamines 
 NSAIDs 
 Acetaminophen 
 Narcotics 
 Oxygen 
 Pressors 
 Corticosteroids 
 Epinephrine 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further study treatment. 
No subsequent dose. 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated. 
Note:  Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of 
drug administration. 


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5.4.9. 
Criteria for Permanent Discontinuation of Study Drug 
The occurrence of unacceptable toxicity not caused by the underlying malignancy will be 
presumed to be related to study treatment and will require that the study treatment be 
permanently discontinued.  Unacceptable toxicity is defined as follows: 
 Grade 4 or life-threatening AEs, except with approval from the medical monitor. 
 ≥ Grade 2 ocular irAE. 
 Occurrence of an AE that is related to treatment, in the judgment of the investigator 
or the medical monitor, and compromises the subject's ability to continue 
study-specific procedures or is considered to not be in the subject's best interest. 
 Persistent AE requiring a delay of treatment for more than 4 weeks (28 days) unless a 
greater delay has been approved by the sponsor. 
5.5. 
Withdrawal of Subjects From Study Treatment 
5.5.1. 
Withdrawal Criteria 
A subject may choose to withdraw from the study treatment at any time or be withdrawn from 
the study treatment by the investigator or sponsor, if the subject is noncompliant with the study 
requirements.  If a subject is withdrawn from study treatment, then every reasonable effort 
should be made to determine the reason for withdrawal, and this information should be recorded 
in the eCRF. 
Subjects must be withdrawn from study treatment for the following reasons: 
 The subject becomes pregnant. 
 Consent is withdrawn.  Subjects may choose to withdraw from the study at any time 
without penalty of jeopardizing their health care or loss of benefits to which the 
subject is otherwise entitled. 
Note:  Consent withdrawn means that the subject can no longer be followed and no 
additional data can be collected.  Subjects may choose to discontinue study treatment 
and remain in the study to be followed for safety through the safety follow-up period.  
 Further participation would be injurious to the subject's health or well-being, in the 
investigator's medical judgment. 
 Unacceptable toxicity (see Section 5.4.9).  Subjects with unacceptable toxicities must 
be withdrawn from study treatment but will continue in the follow-up phase of the 
study (see Section 6.4). 
 The study is terminated by the sponsor. 
 The study is terminated by the local health authority, IRB, or IEC. 
 The subject has received 24 months of treatment with study drug. 


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A subject may be discontinued from study treatment as follows: 
• Confirmed radiographic progression of disease per RECIST v1.1 (see Section 7.7.1).  
A subject may be granted an exception to continue on treatment with confirmed 
radiographic progression if clinically stable or clinically improved (see Section 7.7.1). 
Note:  For unconfirmed progression, see Section 7.7.1. 
• If, during the course of the study, a subject is found not to have met eligibility criteria 
(see Section 3), the medical monitor, in collaboration with the investigator, will 
determine whether the subject should be withdrawn from the study. 
• If a subject is lost-to-follow-up or noncompliant with study procedures or study 
treatment in the investigator's opinion, the sponsor should be consulted for instruction 
on handling the subject. 
5.5.2. 
Withdrawal Procedures 
In the event that the decision is made to permanently discontinue the study treatment, the subject 
will be withdrawn, and the EOT visit should be conducted.  Reasonable efforts should be made 
to have the subject return for all follow-up visits (see Section 6.4).  The last date of the last dose 
of study treatment and the reason for subject withdrawal will be recorded in the eCRF. 
If a subject is withdrawn from the study treatment: 
• The study monitor or sponsor must be notified. 
• The reason(s) for withdrawal from treatment must be documented in the subject's 
medical record and in the eCRF.   
Note:  The reason for withdrawal from treatment may be different than the reason for 
withdrawal from study.  For example, subjects can discontinue treatment for disease 
progression or toxicity but remain in the study for safety follow-up.   
• The EOT visit should be performed. 
• The date of the EOT visit should be recorded in the eCRF and IRT. 
• Subjects must be followed for safety until the time of the follow-up visit, or until 
study treatment–related toxicities resolve, return to baseline, or are deemed 
irreversible, or until the subject begins new anticancer therapy, whichever is longest. 
If the subject discontinues study treatment and actively withdraws consent for collection of 
safety follow-up data, then no additional data collection should occur; however, subjects will 
have the option of withdrawing consent for study treatment but continuing in the follow-up 
period of the study for safety assessments. 


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5.6. 
Concomitant Medications 
All concomitant medications and treatments must be recorded in the eCRF.  Any prior 
medication received up to 28 days before the first dose of study treatment and 60 days after the 
last dose of study treatment, or until the subject begins a new anticancer therapy, whichever 
occurs first, will be recorded in the eCRF.  Any addition, deletion, or change in the dose of these 
medications will also be recorded.  Concomitant medications administered after 60 days after the 
last dose of study treatment should be recorded for SAEs as defined in Section 8.  Concomitant 
treatments/procedures that are required to manage a subject's medical condition during the study 
will also be recorded in the eCRF. 
5.6.1. 
Permitted Medications 
All treatments that the investigator considers necessary for a subject's welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medications will be recorded on the eCRF, including all 
prescription, over-the-counter, herbal supplements, and IV medications and fluids.  If changes 
occur during the study period, documentation of drug regimen, frequency, route, and date may 
also be included on the eCRF.  Note:  The use of bisphosphonates and denosumab are permitted 
in this study. 
5.6.2. 
Restricted Medications 
Systemic glucocorticoids for any purpose other than prophylaxis for contrast allergies for 
radiographic procedures, or to modulate symptoms or treat an AE of suspected immunologic 
etiology, are restricted and require medical monitor approval.  The use of physiologic 
corticosteroid replacement therapy may be approved after consultation with the medical monitor. 
Note:  Inhaled and topical steroids are allowed.  A short course of steroids (prednisone or 
equivalent) ≤ 10 mg/day may be permitted with medical monitor approval. 
5.6.3. 
Prohibited Medications 
Medications or vaccinations specifically prohibited in the exclusion criteria (see Section 3.2) are 
not allowed during the study.  If there is a clinical indication for one of these medications or 
vaccinations specifically prohibited during the study, discontinuation from study treatment may 
be required.  The investigator should discuss any questions regarding this with the medical 
monitor.  The final decision on any supportive therapy or vaccination rests with the investigator 
and/or the subject's primary physician.  However, the decision to continue the subject on study 
treatment requires the mutual agreement of the investigator, the sponsor, and the subject. 


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Subjects are prohibited from receiving the following therapies during the screening and treatment 
periods of this study: 
 Any anticancer medications, including chemotherapy or biologic therapy other than study 
treatment. 
 Any immunological-based treatment for any reason from screening through the safety 
follow-up visit is prohibited. 
Note:  Completed adjuvant therapy (eg, vaccines) with medical monitor approval, inhaled 
or topical steroids, systemic steroids at doses ≤ 10 mg/day prednisone or equivalents, and 
immune suppressants are allowed for treatment for immune toxicities as described in 
Section 5.4.7 and Appendix B, or as prophylaxis for contrast allergy for imaging 
procedures. 
Note:  Allergy shots may be permitted after consultation with the medical monitor. 
 Investigational agents other than study treatment.  Use of such medications from 
screening through the safety follow-up visit is prohibited. 
 Concomitant 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 the medical 
monitor.  The subject must have clear measurable disease outside the radiated field.  
Administration of palliative radiation therapy will be considered clinical progression for 
the purposes of determining PFS. 
 Live vaccines within 30 days before the first dose of study treatment and while 
participating in the study.  Examples of live vaccines include, but are not limited to, the 
following:  measles, mumps, rubella, chicken pox, yellow fever, rabies, Bacillus 
Calmette–Guérin, and typhoid (oral) vaccine.  Seasonal influenza vaccines for injection 
are generally killed virus vaccines and are allowed.  However, intranasal influenza 
vaccines are live attenuated vaccines and are not allowed. 
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the study.  Subjects may receive 
other medications that the investigator deems to be medically necessary.  The exclusion criteria 
describe other medications that are prohibited in this study.  There are no prohibited therapies 
during the post-treatment follow-up period. 
6. 
STUDY ASSESSMENTS 
All study assessments will be performed as indicated in the schedule of clinical assessments 
(Table 12), and all laboratory assessments will be performed as indicated in Table 13.  Table 14 
presents a summary of clinical laboratory analytes to be assessed.  The order of assessments is 
suggested by the order of mention within the schedule.  See Section 7 for instructions on each 
assessment.  Further details of study procedures and assessments can be found in the study 
reference manual or applicable procedural documentation. 


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Table 12: 
Schedule of Clinical Assessments 
Visit Day (Range) 
Protocol 
Section 
Screening 
Treatment
a 
Post-Treatment
b 
Cycles 1 and 6 
Cycles ≥ 10 
Weeks 
All Other 
Cycles 
Every 8 Weeks 
EOT 
Safety 
Follow-Up 
Visit 1 
Safety 
Follow-Up 
Visit 2 
Day 1 
Day 8 
Day 1 
Day 1 
Disease Status 
Evaluation/Window 
Day -28 
to -1 
 
± 1 day 
± 3 days 
± 3 days 
± 7 days 
± 3 days 
30 days 
(+ 7 days) 
60 days 
(+ 7 days) 
Administrative procedures 
Informed consent 
7.1 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
3.1, 3.2 
X 
X
c 
 
 
 
 
 
 
 
Contact IRT 
7.2 
X 
X 
 
X 
X 
 
X 
 
 
Medical and cancer history 
7.3.1, 7.3.2 
X 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
7.4 
X 
X 
X 
X 
X 
 
X 
X 
X 
Administer INCAGN01949 
5.2.1.1 
 
X
d 
 
Xd 
Xd 
 
 
 
 
Administer nivolumab 
5.2.2.1 
 
X
e 
 
Xe 
Xe 
 
 
 
 
Administer ipilimumab 
5.2.2.2 
 
X
f 
 
Xf 
Xf 
 
 
 
 
Poststudy anticancer therapy status 
7.5 
 
 
 
 
 
 
 
X 
X 
Clinical procedures/assessments 
Comprehensive physical 
examination (including height) 
7.6.2.1 
X 
 
 
 
 
 
 
 
 
Targeted physical assessment 
7.6.2.2 
 
X 
X
g 
X 
X 
 
X 
X 
X 
Vital signs and weight  
7.6.3 
X 
X 
Xg 
X 
X 
 
X 
X 
X 
ECOG performance status 
7.8.1 
X 
X 
Xg 
 
X 
 
 
 
 
Laboratory assessments 
7.6.5 
X 
X 
X 
X 
X 
 
X 
X 
X 
12-lead ECG
h 
7.6.4 
X 
 
 
 
 
 
 
 
 
AE assessment 
7.6.1 
X 
X 
Xg 
X 
X 
 
X 
X 
X 
Efficacy measurements 
Radiologic tumor assessments 
7.7 
X
i 
 
 
 
 
X
j 
X
k 
 
 
a Treatment cycles will be Q2W (14 days ± 3 days). 
b The safety follow-up visits should be conducted approximately 30 days and 60 days after the EOT visit (or after the last dose of study treatment if the EOT visit was not 
performed) or before the initiation of a new anticancer treatment, whichever comes first. 
c Assessment of inclusion/exclusion criteria is only required at Cycle 1 Day 1. 
d In Treatment Groups G and K, INCAGN01949 is only administered on Day 1 of Cycles 1 and 2. 
e In Treatment Groups C, E, G, H, K, and L, nivolumab administration begins at Cycle 3 Day 1. 
f For subjects enrolled into Treatment Group B (INCAGN01949 + ipilimumab) and Treatment Groups D and J (INCAGN01949 + nivolumab + ipilimumab), ipilimumab will be 
administered on Cycle 1 Day 1 and then  Day 1 of every third cycle (Cycle 1, Cycle 4, Cycle 7, etc).  In Treatment Groups E, K, and L, ipilimumab administration begins at 
Cycle 3 Day 1 and then continues on Day 1 of every third cycle.  If higher doses of ipilimumab are tested (eg, 3 mg/kg every 3 weeks [21 days] for 4 doses), then ipilimumab 
will be administered every 3 weeks for a total of 4 doses.  If the scheduled ipilimumab doses fall on days other than Day 1 of a cycle, the subjects will need to be present in clinic 
for the infusion, and any standard procedures required by the site should be performed. 


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g Only required for Cycle 6 Day 8 if subject is experiencing AEs > Grade 2. 
h All 12-lead ECGs will be performed with the subject in a recumbent or semirecumbent position after 5 minutes of rest and should not be performed within 15 minutes after a 
blood collection. 
i The initial tumor imaging will be performed within 28 days before the first dose of study treatment.  Images of the chest, abdomen, and pelvis are required for all subjects.  Scans 
performed as part of routine clinical management are acceptable for use as the screening scan if they are of diagnostic quality and performed within 28 days before the first dose 
of study treatment.  The same imaging technique should be used for a subject throughout the study.  Local reading (investigator assessment with site radiology reading) will be 
used to determine eligibility and for subject management. 
j On-study imaging will be performed at Week 8 and then every 8 weeks (± 7 days) for the first 12 months (until the Week 56 scan) and then every 12 weeks (± 7 days) thereafter.  
Imaging should follow calendar days starting with Day 1 of INCAGN01949 treatment and should NOT be adjusted for delays in cycle starts.  If imaging shows disease 
progression, then another imaging assessment should be performed at a minimum of 4 weeks but no later than 6 weeks later to confirm progression per mRECIST. 
k If scan was obtained within 4 weeks before the date of treatment discontinuation, then a scan at treatment discontinuation (EOT) is not mandatory.  For subjects who discontinue 
study therapy without confirmed disease progression, a radiologic evaluation should be repeated at the time of treatment discontinuation (ie, date of discontinuation ± 4 week 
window). 


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Table 13: 
Schedule of Laboratory Assessments 
Visit Day (Range) 
Protocol 
Section 
Timing of 
Assessment 
Screening 
Treatment 
Post-Treatment 
C1 
C2 
C4 
C6 
C7 
Every 4th 
Cycle (C8, 
C12) 
All Other 
Cycles 
EOT 
Safety 
Follow-Up 
Visit 1 
Safety 
Follow-Up 
Visit 2 
D1 
D8 
D1 
D1 
D1 
D8 
D1 
D1 
D1 
Evaluation/Window 
Day -28 to 
-1 
 
± 1 
day 
± 3 
days 
± 3 
days 
± 3 
days 
± 3 
days 
± 3 
days 
± 3 days 
± 3 days 
± 3 
days 
30 days  
(+ 7 days) 
60 days  
(+ 7 days) 
Local laboratory tests
a 
Comprehensive serum 
chemistries
b 
7.6.5 
N/A 
X
c 
X
d 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Hematology with differential 
7.6.5 
N/A 
Xc 
Xd 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Coagulation panel
e 
7.6.5 
N/A 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
7.6.5 
N/A 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
Endocrine function tests 
7.6.5 
N/A 
Xc 
 
 
 
X 
 
 
 
X 
 
X 
X 
 
Hepatitis B and C 
7.6.5.2 
N/A 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
(childbearing females only)
f 
7.6.5.1 
N/A 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Urine pregnancy test 
(childbearing females only) 
7.6.5.1 
N/A 
 
X
g 
 
 
 
a All safety laboratory assessments will be performed locally. 
b If liver chemistry tests increase in grade from baseline or are ≥ Grade 3, then liver chemistry monitoring should increase to once per week  until resolved to baseline or 
≤ Grade 1.  Liver chemistry does not need to be monitored once per week indefinitely for persistent low grade abnormalities.  Appropriate liver chemistry monitoring intervals 
should be discussed with the medical monitor for these circumstances. 




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Table 14: 
Local Laboratory Tests:  Required Analytes 
Serum Chemistries 
Hematology 
Urinalysis 
Hepatitis Screening 
Coagulation 
Albumin 
Alkaline phosphatase 
ALT 
AST  
Bicarbonate 
Blood urea nitrogen  
Calcium 
Chloride  
Creatinine 
Glucose 
Lactate dehydrogenase 
Phosphate 
Potassium 
Sodium 
Total bilirubin 
Direct bilirubin (if total bilirubin is 
elevated above ULN) 
Total protein 
Uric acid 
Amylase 
Lipase 
Complete blood count, 
including: 
 Hemoglobin 
 Hematocrit 
 Platelet count 
 Red blood cell count 
 White blood cell count 
 
Differential count, including: 
 Basophils 
 Eosinophils 
 Lymphocytes 
 Monocytes 
 Neutrophils 
 
Absolute values must be 
provided for:  
White blood cell differential 
laboratory results: 
 Lymphocytes 
 Neutrophils 
Color and appearance 
pH and specific gravity 
Bilirubin 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Occult blood 
Protein 
Hepatitis B surface antigen 
Hepatitis B core antibody 
HBV-DNA 
HCV antibody 
HCV-RNA 
PT 
aPTT 
INR 
Pregnancy Testing 
Endocrine Monitoring 
Female subjects of 
childbearing potential only 
require a serum test at 
screening and EOT 
Pregnancy tests (serum or 
urine) should be repeated if 
required by local 
regulations. 
Thyroid-stimulating hormone 
(TSH) 
Free thyroxine (T4) 
Total triiodothyronine (T3)/FT3
a 
a If considered standard by your region. 


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6.1. 
Screening 
Screening is the interval between signing the ICF and the day the subject is enrolled in the study 
(eg, Cycle 1 Day 1).  Screening may not exceed 28 days.  Informed consent must be obtained 
before performing any study-specific procedures that are not considered standard of care; 
however, procedures conducted as part of the subject's routine clinical management obtained 
before signing of informed consent may be used for screening or baseline purposes with approval 
of the medical monitor, provided that the procedure meets the Protocol-defined criteria and has 
been performed in the timeframe of the study.  Assessments that are required to demonstrate 
eligibility may be performed over the course of 1 or more days during the screening process. 
Results from the screening visit evaluations will be reviewed to confirm subject eligibility before 
enrollment.  Tests with results that fail eligibility requirements may be repeated once during 
screening if the investigator believes the results to be in error.  For screening assessments that are 
repeated, the most recent available result before enrollment will be used to determine subject 
eligibility.  Additionally, a subject who fails screening may repeat the screening process 1 time if 
the investigator believes there has been a change in eligibility status (eg, after recovery from an 
infection).  Treatment should start as soon as possible after the date of enrollment. 
6.2. 
Treatment 
The treatment period begins on the day the subject receives the first dose of study treatment 
(Cycle 1 Day 1) through the point at which the investigator determines that the subject will be 
permanently discontinued from study treatment.  Cycle 1 Day 1 must be no more than 28 days 
after the subject has signed the ICF and should be within 3 days of enrollment in the study.  
Subjects will have regularly scheduled study visits as outlined in Table 12, and toxicities will be 
monitored continuously and will be graded using the NCI CTCAE v4.03 criteria. 
6.3. 
End of Treatment 
When the subject permanently discontinues study treatment, the EOT visit should be conducted.  
If the EOT visit coincides with a regular study visit, the EOT evaluations will supersede those of 
that scheduled visit, and the data should be entered in the EOT visit in the eCRF.  The subject 
should be encouraged to return for the safety follow-up visits. 
6.4. 
Safety Follow-Up 
The safety follow-up period is the interval between the EOT visit and the scheduled follow-up 
visit, which should occur 30 days (+ 7 days) and 60 days (+ 7 days) after the last dose of study 
treatment.  Monitoring for the occurrence of new AEs should be continued for at least 60 days 
after the last dose of study treatment or until the start of new anticancer therapy, whichever 
occurs first.  Reasonable efforts should be made to have the subject return for the follow-up 
visits and report any AEs that may occur during this period.  If a subject is scheduled to begin a 
new anticancer therapy before the end of the 30-day or 60-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, AEs and SAEs will no longer be collected and the subject 
will be considered to have completed the study. 


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6.5. 
End of Study 
The end of the study will occur when all subjects have completed the last study follow-up visit or 
have discontinued study treatment and have completed applicable follow-up assessments.  
Additionally, subjects will be considered as having completed the study if they meet any of the 
following criteria: 
 Subject dies and a date of death is available. 
 Subject is known to have died; however, the date of death cannot be obtained.  
(NOTE: Every effort must be made to obtain the date of death.) 
 Consent is withdrawn for any further contact related to this study. 
 Every reasonable effort should be made to determine the reason a subject 
withdraws prematurely, and this information should be recorded in the eCRF. 
 The study is terminated by the sponsor. 
 The study is terminated by the local health authority or IRB or IEC. 
6.6. 
Unscheduled Visits 
Unscheduled study visits may occur at any time if medically warranted.  Any assessments 
performed at those visits should be recorded in the eCRF. 


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7. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES 
Individual study procedures are described in detail below.  It may be necessary to perform these 
procedures at unscheduled timepoints if deemed clinically necessary by the investigator.  
Furthermore, additional evaluations/testing may be deemed necessary for reasons related to 
subject safety.  In some cases, such evaluation/testing may be potentially sensitive in nature 
(eg, HIV, HCV), and thus local regulations may require that additional informed consent be 
obtained from the subject.  In these cases, such evaluations/testing will be performed in 
accordance with those regulations.  Subjects of childbearing potential must agree to take 
appropriate measures to avoid pregnancy in order to participate in the study (Appendix A). 
7.1. 
Administration of Informed Consent Form 
Valid informed consent must be obtained from the study subject before conducting any 
study-specific procedures using an ICF approved by the local IRB/IEC that contains all elements 
required by ICH E6 and describes the nature, scope, and possible consequences of the study in a 
form understandable to the study subject.  Local and institutional guidelines for ICF content and 
administration must be followed; the original signed ICF must be retained by the investigator, 
and a copy of the signed ICF must be provided to the study subject.  The informed consent 
process for each subject must be documented in writing within the subject source documentation. 
7.2. 
Interactive Response Technology System Procedure 
The site will contact the IRT to obtain a subject identification number when a subject enters the 
prescreening phase.  Upon determining that the subject is eligible for study entry, the IRT will be 
contacted to obtain the subject number and treatment group assignment.  Additionally, the IRT 
will be contacted to update the subject's disposition and disease response and for study drug 
resupply.  Refer to the IRT manual for detailed instructions.   
7.3. 
Demography and Medical History 
7.3.1. 
Demographics and General Medical History 
Demographic data and a complete medical and medication history will be collected at screening 
by the investigator or qualified designee and will include date of birth, race, ethnicity, medical 
and surgical history, and current illnesses.  Medical history will include relevant medical or 
surgical treatment within the last 10 years that are considered to be clinically significant by 
the investigator. 
7.3.2. 
Disease Characteristics and Treatment History 
A disease-targeted medical and medication history will be collected at screening.  Details 
regarding the subject's malignancy under study including date of diagnosis, initial and current 
cancer stage, tumor histology, relevant disease characteristics, and prior treatments including 
systemic, radiation, and surgical procedures will be recorded. 


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7.4. 
Prior and Concomitant Medications and Procedures 
Prior and concomitant medications and procedures will be reviewed to determine subject 
eligibility.  Any medication received or procedure performed within 28 days before the first dose 
of study treatment, up to the end of the safety follow-up phase, or until the subject starts a new 
anticancer therapy, whichever occurs first, will be recorded in the eCRF.  The medication record 
will be maintained after signing the ICF to document concomitant medications, including any 
changes to the dose or regimen.  Concomitant medications include any prescription, 
over-the-counter, or natural/herbal preparations taken or administered during the study period.  
Concomitant treatments and/or procedures that are required to manage a subject's medical 
condition during the study will also be recorded in the eCRF.  See Section 5.6  for details 
regarding restricted and prohibited medications. 
7.5. 
Poststudy Anticancer Therapy Status 
The investigator or qualified designee will review all new anticancer therapy initiated after the 
last dose of study treatment.  If a subject initiates a new anticancer therapy within 30 to 60 days 
after the last dose of study treatment, the 30-day or 60-day safety follow-up visit should occur 
before the first dose of the new anticancer therapy. 
7.6. 
Safety Assessments 
7.6.1. 
Adverse Events 
Adverse events will be monitored from the time the subject signs the ICF.  Subjects will be 
instructed to report all AEs during the study and will be assessed for the occurrence of AEs 
throughout the study.  In order to avoid bias in eliciting AEs, subjects will be asked general, 
nonleading questions such as "How are you feeling?"  All AEs (serious and nonserious) must be 
recorded on the source documents and eCRFs regardless of the assumption of a causal 
relationship with the study drug.  The definition, reporting, and recording requirements for AEs 
are described in Section 8. 
7.6.2. 
Physical Examinations 
Physical examinations must be performed by a medically qualified individual such as a licensed 
physician, physician's assistant, or an advanced registered nurse practitioner, as local law 
permits.  Clinically notable abnormalities that are considered clinically significant in the 
judgement of the investigator are to be reported as AEs. 
7.6.2.1. 
Comprehensive Physical Examination 
The comprehensive physical examination will include assessment(s) of the following organ or 
body systems:  skin; head, eyes, ears, nose, and throat; thyroid; lungs; cardiovascular system; 
abdomen (liver, spleen); extremities; and lymph nodes, as well as a brief neurological 
examination.  The screening physical examination should also include a measurement of height. 


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7.6.2.2. 
Targeted Physical Examination 
The targeted physical examination will be a symptom-directed evaluation conducted by the 
investigator or a medically qualified designee.  The targeted physical examination will include 
assessment(s) of the body systems or organs, as indicated by subject symptoms, AEs, or other 
findings.   
7.6.3. 
Vital Signs 
Vital sign measurements include blood pressure, pulse, respiratory rate, and body temperature.  
Blood pressure and pulse will be taken with the subject in the recumbent, semirecumbent, or 
sitting position after 5 minutes of rest.  Weight will also be assessed at each study visit.  
Clinically notable abnormalities that are considered clinically significant in the judgment of the 
investigator are to be reported as AEs. 
7.6.4. 
Electrocardiograms 
All 12-lead ECGs will be performed at the study site with the subject in a recumbent or 
semirecumbent position after 5 minutes of rest. 
The 12-lead ECG readings will be interpreted by the investigator at the site to be used for 
immediate subject management.  The decision to include or exclude a subject or withdraw a 
subject from the study treatment based on an ECG flagged as "Abnormal, Clinically Significant" 
is the responsibility of the investigator, in consultation with the medical monitor, as appropriate.  
Clinically notable abnormalities that are considered clinically significant in the judgment of the 
investigator are to be reported as AEs.  In the event that a single QTc is > 470 milliseconds at 
screening, the subject may enroll if the average QTc for the 3 ECGs is < 470 milliseconds or 
with approval from the medical monitor.  For subjects with an intraventricular conduction delay 
(QRS interval > 120 milliseconds) at screening, the JTc interval may be used in place of the QTc 
with medical monitor approval.  In addition, the JTc interval should be used for all subsequent 
assessments. 
7.6.5. 
Laboratory Assessments 
A certified laboratory local to the study site and subject will perform all clinical laboratory 
assessments for safety (ie, blood chemistries, hematology assessments, coagulation tests, 
endocrine function, and urinalysis).  The investigative site will enter the laboratory results and 
laboratory normal ranges into the eCRF.  All local laboratory assessments should be performed 
using standard procedures on the days indicated in Table 13.  Table 14 lists the specific 
laboratory analytes required for each test.  Additional testing may be required by the sponsor 
based on emerging safety data.  Additional tests may also be performed if clinically indicated. 
Screening laboratory assessments must be performed within 7 days of Cycle 1 Day 1.  If 
performed more than 7 days before Cycle 1 Day 1, then the tests must be repeated and eligibility 
confirmed before study drug administration on Cycle 1 Day 1.  Laboratory samples collected on 
study Day 1 must be performed before study drug administration.  After Cycle 1, predose 
laboratory procedures can be conducted up to 72 hours before study drug administration (within 
the 3-day study window), and results should be reviewed by the investigator or qualified 
designee and found to be acceptable before a new cycle of treatment is initiated. 


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7.6.5.1. 
Pregnancy Testing 
A local laboratory serum pregnancy test will be required for all women of childbearing potential 
during screening and at EOT.  The serum pregnancy test performed at screening must be 
performed within 72 hours before the first dose of study drug.  Urine pregnancy tests will be 
performed locally as outlined in Table 13, 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. 
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. 
7.6.5.2. 
Hepatitis Screening Tests 
Hepatitis screening assessments will be performed at the screening visit (Table 13) to rule out 
hepatitis infection; required analytes are shown in Table 14.  Generally, hepatitis tests should be 
performed early in the screening process due to the length of time needed to obtain the results.  
Additional tests may be performed if clinically indicated. 
7.7. 
Efficacy Assessments 
7.7.1. 
Modified RECIST Assessment Disease 
Modified RECIST will be applied by the site as a basis for Protocol guidelines related to disease 
status (eg, discontinuation of study therapy).  As noted in Section 1.5.4.1, RECIST v1.1 has been 
adapted to account for the unique tumor responses seen with immunotherapy 
(Wolchok et al 2009). 
If radiologic imaging shows progressive disease, tumor assessment may be repeated at a 
minimum of 4 weeks, but no later than 6 weeks later to confirm progression, with the option of 
continuing treatment while awaiting radiologic confirmation of progression.  Table 15 provides 
instructions on how to proceed with treatment based on the subject's clinical status once the 
initial scan showing radiologic evidence of progression is observed. 
Subjects may receive treatment while waiting for confirmation of progression if they are 
clinically stable as defined by the following criteria: 
 Absence of clinically significant signs and symptoms (including worsening of 
laboratory values) indicating disease progression. 
 No decline in ECOG performance status. 
 Absence of rapid progression of disease. 
 Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention. 


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Table 15: 
Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease 
 
Clinically Stable 
Clinically Unstable 
Tumor Imaging 
Treatment 
Tumor Imaging 
Treatment 
First radiologic 
evidence of 
progression 
Repeat imaging 
4-6 weeks to confirm 
progression 
May continue study 
treatment at the 
investigator's discretion 
while awaiting 
confirmatory tumor 
imaging  
Repeat tumor imaging 
4-6 weeks to confirm 
progression per 
physician discretion 
only 
Discontinue 
treatment 
Repeat scan  
confirms 
progression 
No additional tumor 
imaging required 
Discontinue treatment 
No additional tumor 
imaging required 
N/A 
Repeat scan 
shows SD, PR, or 
CR 
Continue regularly 
scheduled tumor 
imaging assessments 
Continue study treatment 
at the investigator's 
discretion 
Continue regularly 
scheduled tumor 
imaging assessments 
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable per 
investigator's 
discretion 
As noted above, if disease progression is observed, the study site may elect to continue 
treatment, repeat imaging at a minimum of 4 weeks, but no later than 6 weeks later, and assess 
tumor response or confirmed progression per mRECIST. 
In determining whether or not the tumor burden has increased or decreased, study site 
investigators should consider all target lesions as well as nontarget lesions.  Subjects who are 
deemed clinically unstable are not required to have repeat tumor imaging for confirmation.  If 
radiologic progression is confirmed by subsequent scan, then the subject should be discontinued 
from study treatment.  If radiologic progression is not confirmed, then the subject should resume 
or continue study treatment and have the next tumor imaging according to the Protocol schedule 
(see Table 12).  If progression is not confirmed and the subject continues on treatment, then the 
next scan that documents disease progression (and is confirmed by a second scan at least 
4 weeks, but no later than 6 weeks later) will be considered the date of disease progression. 
If a subject has confirmed radiographic progression (ie, 2 scans at least 4 weeks, but no later than 
6 weeks, apart demonstrating progression) per mRECIST, but the subject is achieving a 
clinically meaningful benefit, an exception to continue treatment may be considered after 
consultation with the medical monitor.  Clinically stable subjects at the confirmatory scan should 
also have no further increase in the target lesions, no unequivocal increase in nontarget lesions, 
and no additional new lesions develop (nonworsening disease progression) to continue study 
treatment. 












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7.11. 
Other Study Procedures 
7.11.1. 
Distribution of Subject Reminder Cards 
Subjects will be provided with a reminder card at each visit.  The subject reminder cards will 
remind the subject of the date/time of the next visit, as well as any necessary instructions.   


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8. 
SAFETY MONITORING AND REPORTING 
8.1. 
Adverse Events 
8.1.1. 
Definitions 
For the purposes of this Protocol, an 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 drug(s). 
8.1.2. 
Reporting 
Adverse events that begin or worsen after informed consent should be recorded on the Adverse 
Events form of the eCRF.  Conditions that were already present at the time of informed consent 
should be recorded on the Medical History form in the eCRF.  Monitoring for the occurrence of 
new AEs should be continued for at least 60 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.   
The term "disease progression" should be recorded as an AE/SAE only if there are no other 
identifiable AEs/SAEs associated with the disease progression at the time of reporting.  For 
events associated with disease progression, the relevant signs and symptoms should be reported 
using a diagnosis whenever possible rather than individual underlying signs and symptoms.  
When a clear diagnosis cannot be identified, each sign or symptom should be reported as a 
separate AE.  If the events resulting from disease progression meet the criteria for an SAE 
(eg, resulted in hospitalization, a life-threatening event, or death), the specific event(s) should be 
reported as an SAE(s) as described in Section 8.3.2.  In both cases (ie, AEs or SAEs related to 
disease progression), it should be indicated that each event (reported as a diagnosis or as signs 
and symptoms) is related to disease progression on the Adverse Events form of the eCRF. 
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 
Death due to AE. 


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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). 
 Note: causality assessment for each agent administered per study must be 
indicated. 
 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 SAE definition provided in Section 8.3.1. 
Unlike routine safety assessments, SAEs are monitored continuously and have special reporting 
requirements (see Section 8.3.2). 
All AEs should be treated appropriately.  If an AE is treated with a concomitant medication or 
nondrug therapy, this action should be recorded on Adverse Event form and the treatment should 
be specified on the Prior/Concomitant Medications or Procedures and Non-Drug Therapy form 
in the eCRF. 
Once an AE is detected, it should be followed until it has resolved or until it is judged to be 
permanent; assessment should be made at each visit (or more frequently if necessary) of any 
changes in severity, the suspected relationship to the study 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. 


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8.2. 
Laboratory Test Abnormalities 
Laboratory abnormalities that constitute an AE in their own right (considered clinically 
meaningful, induce clinical signs or symptoms, require concomitant therapy, or require changes 
in study 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. 
Laboratory abnormalities that do not meet the definition of an AE should not be reported as AEs.  
A Grade 3 or 4 AE does not automatically indicate an SAE unless it meets the definition of 
serious, as defined in Section 8.3.1.  A dose modification for the laboratory abnormality may be 
required (see Section 5.4) and should not contribute to the designation of a laboratory test 
abnormality as an SAE. 
8.3. 
Serious Adverse Events 
8.3.1. 
Definitions 
An SAE is defined as an event that meets at least 1 of the following criteria: 
 Is fatal or life-threatening. 
 Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is a result of: 
 A routine treatment or monitoring of the studied indication not associated with 
any deterioration in condition.  
 An elective surgery or preplanned treatment for a pre-existing condition that is 
unrelated to the indication under study and has not worsened since signing the 
ICF. 
 A treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE and not resulting in hospital admission. 
 Any social reasons and respite care, in the absence of any deterioration in the 
subject's general condition. 
 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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8.3.2. 
Reporting 
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 the last 
study visit (or 60 days after the last dose of study treatment, or until the subject receives a new 
anticancer therapy whichever occurs earlier) must be reported to the sponsor (or designee) within 
24 hours of learning of its occurrence, unless otherwise specified by the Protocol.  Any SAEs 
occurring more than 60 days after the last dose of study treatment should be reported to the 
sponsor or its designee only if the investigator suspects a causal relationship to the study 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 each specific 
study treatment.  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 
specific 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, 
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 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 IB for the study drug (new occurrence) and is thought to be 
related to the sponsor's study drug, 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 to inform all investigators involved in any study 
with the same drug that this SAE has been reported.  Suspected Unexpected Serious Adverse 
Reactions will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with Directive 2001/20/EC, or as per national regulatory requirements 
in participating countries. 
8.4. 
Emergency Unblinding of Treatment Assignment 
Not applicable. 


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8.5. 
Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that study drug may 
have interfered with the effectiveness of a contraceptive medication or method.  When a 
pregnancy has been confirmed in a subject during maternal or paternal exposure to study drug, 
the following procedures should be followed in order to ensure subject safety: 
 The study treatment must be discontinued immediately (female subjects only). 
 The investigator must complete and submit the Incyte Clinical Trial Pregnancy form 
to the sponsor or its designee within 24 hours of learning of the pregnancy. 
 A serum pregnancy test must be performed to confirm the urine pregnancy test result.  
If a negative serum test does not confirm the urine pregnancy result, then: 
 The investigator will use his or her expert judgment, based on an assessment of 
the potential benefit/risk to the subject, to determine whether it is in the subject's 
best interest to resume study treatment and continue participation in the study. 
 The EOT visit evaluations must be performed. 
Data on fetal outcome and breastfeeding are collected for regulatory reporting and drug safety 
evaluation.  Follow-up should be conducted for each pregnancy to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence of any 
birth defects, congenital abnormalities, or maternal and/or newborn complications, by following 
until the first well-baby visit.  Pregnancy should be recorded on a Clinical Trial Pregnancy form 
and reported by the investigator to the sponsor or its designee.  Pregnancy follow-up information 
should be recorded on the same form and should include an assessment of the possible causal 
relationship to the sponsor's study drug to any pregnancy outcome, as well as follow-up to the 
first well-baby visit or the duration specified in local regulations, whichever is later.  Refer to the 
Incyte Reference Guide for Completing the Clinical Trial Pregnancy Form. 
Any SAE occurring during pregnancy must be recorded on the SAE report form and 
submitted to the sponsor or designee. 
8.6. 
Warnings and Precautions 
Special warnings or precautions for the study drug, derived from safety information collected by 
the sponsor or its designee, are presented in the Investigator's Brochure (INCAGN01949 IB).  
Additional safety information collected between IB updates will be communicated in the form of 
Investigator Notifications.  Any important new safety information should be discussed with the 
subject during the study, as necessary.  If new significant risks are identified, they will be added 
to the ICF. 
8.7. 
Data Monitoring Committee 
Formal safety reviews will be conducted by the study team and an independent internal review 
committee, at least every 6 months during Phase 2, to review safety data.  Details regarding 
internal data monitoring will be addressed in the Data Monitoring Charter.  


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8.8. 
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 8.1.2 of this Protocol. 
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint communication with the product. 




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Table 20: 
Probability of Dose Escalation for Various DLT Rates 
True DLT Rate 
Probability of Dose Escalation 
20% 
78.4% 
30% 
56.1% 
40% 
35.0% 
50% 
18.9% 
60% 
8.8% 
For example, if the true DLT rate is 50% at a given dose level, there is an 18.9% chance that the 
dose would be escalated.  Further, if the true DLT rate is 20%, there is a 78.4% chance that the 
dose would be escalated.  If the MTD is not determined at the highest dose level tested during 
the study, then the MTD is at or above the highest dose level.  The MTD is below the lowest 
dose level of INCAGN01949 if the Cohort 1 dose is not well-tolerated. 
9.2.1.2. 
Sample Size for Phase 1 Part 2 
Once an INCAGN01949 dose cohort in Treatment Group A is deemed tolerable, 6 subjects will 
be enrolled in Treatment Group C at the same dose of INCAGN01949.  For example, if 
INCAGN01949 7 mg is tolerated in Treatment Group A, then 7 mg will be explored in 6 subjects 
in Treatment Group C.  Likewise, once an INCAGN01949 dose cohort in Treatment Group D is 
deemed tolerable, 6 subjects will be enrolled in Treatment Group E at the same dose of 
INCAGN01949.  For example, if 350 mg of INCAGN01949 is tolerated in Treatment Group D 
then 350 mg will be explored in 6 subjects in Treatment Group E. 
9.2.2. 
Sample Size for Phase 2 
Phase 2 will further evaluate the safety, tolerability, preliminary efficacy,
 and 
 
 of the recommended dose of INCAGN01949 in combination with immune therapies as 
part of doublet and triplet drug expansion cohorts.  In Phase 2 Part A, a Simon 2-stage design 
will be run for each dose expansion cohort.  In Phase 2 Part B, a Simon 2-stage design will be 
run for each cohort within a given doublet or triplet drug expansion cohort.   
The sample size for each cohort within a given doublet or triplet expansion cohort will be guided 
by the Simon 2-stage design.  The planned Simon 2-stage designs are summarized in Table 21.  
Each Simon 2-stage design will have a stopping rule to allow early termination of a cohort within 
the given treatment combination at the end of Stage 1 if there is insufficient response observed 
(calculated response rate < p0%), while enrolling enough subjects to predict possible target 
responses (≥ p1%) worthy of cohort expansion and potentially further evaluation in future 
studies.  The Simon 2-stage designs run for each cohort within each doublet or triplet expansion 
cohort will have design parameters that are determined by historical response rates.  As all 
cohorts are being run in subjects determined to be PD-1/L1 refractory, the same Simon 2-stage 
parameters will be used for all cohorts. 


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In order to determine whether the target response rate (p1%) is likely, an initial number of 
evaluable subjects (n1 subjects) treated at the MTD or PAD and schedule of INCAGN01949 
within the corresponding doublet or triplet expansion cohort will be enrolled in a cohort 
(Stage 1).  If there are r1 or fewer responses in the cohort, it will be concluded that the true 
response rate is unlikely to be greater than or equal to the target rate, and no more subjects will 
be enrolled in that cohort in Stage 2.  In the cohorts in which greater than r1 responses are 
observed among the Stage 1 subjects, n2 additional evaluable subjects will be treated in Stage 2 
to estimate the response rate.  At the end of Stage 2, if ≤ r subjects have responded among the 
n evaluable subjects, the doublet or triplet schedule will be declared nonpromising for that 
cohort.  In other words, after the study is finished, if there is a sufficient number of responses in 
the 2 stages combined, the study doublet or triplet is considered promising; otherwise it is 
considered nonpromising.  The detailed calculations for each cohort are based on a 1-sided 
Type I error of 0.05 and power of 85%.  The individual p0 and p1 values for the tumor types 
within doublet or triplet expansion cohorts are listed in Table 21. 
Formal quarterly safety reviews will be conducted to review efficacy and safety data with the 
obligation to hold a safety review meeting every 6 months during Phase 2.  
Table 21: 
Planned Simon 2-Stage Designs for Phase 2 
Indication 
Combination 
r1 
n1 
r 
n2 
n 
p0 
p1 
Refractory to 
anti–PD-1/L1 
OX40 + Nivo 
2 
20 
8 
30 
50 
10% 
25% 
Refractory to 
anti–PD-1/L1  
OX40 + Nivo + Ipi 
2 
20 
8 
30 
50 
10% 
25% 
9.3. 
Level of Significance 
This is an exploratory study and no formal statistical tests will be performed.  All confidence 
intervals will be 95%. 


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9.4. 
Statistical Analyses 
9.4.1. 
Efficacy Analyses 
9.4.1.1. 
Primary Efficacy Analyses 
In Phase 2, the proportion of subjects who meet the objective response criteria (CR + PR) per 
RECIST v1.1 will be summarized by dose and tumor type. 
If there are ≤ r1 responses in each doublet or triplet expansion out of the  n1 evaluable subjects 
specific to that cohort (consistent with a calculated response rate < p0%) at Stage 1, then the 
study will be stopped for futility, and the null hypothesis is not rejected.  Otherwise, in the 
cohorts in which greater than r1 responses among the evaluable Stage 1 subjects is observed, 
where r1 is also specific to the doublet or triplet expansion cohort, an additional n2 evaluable 
subjects will be treated in Stage 2.  If there are ≤ r responders among the evaluable subjects at 
the end of Stage 2, then the drug will be declared nonpromising for that cohort within the given 
doublet or triplet expansion cohort, and the null hypothesis is not rejected.  Further investigation 
of the study drug will be considered interesting (predictive of ≥ p1% response rate) if 
> r responses are observed in the first n evaluable subjects.  For the hypothesis tests in the Simon 
2-stage design, the null response rate is p0% and alternative response rate is p1%, where p0 and p1 
are specific to the cohort within a given doublet or triplet expansion cohort and are determined 
from historical response rates. 
9.4.1.2. 
Secondary Efficacy Analyses 
Disease control rate, defined as the proportion of subjects who have disease control (CR + PR + 
SD), as per RECIST v1.1 will be summarized. 
Progression-free survival, DOR, and duration of disease control will be estimated using the 
Kaplan-Meier method as per RECIST v1.1.   
In Phase 2, the proportion of subjects who meet the objective response criteria (CR + PR) per 
RECIST v1.1 will be summarized by tumor type. 
9.4.2. 
Safety Analyses 
9.4.2.1. 
Adverse Events 
A TEAE is any AE either reported for the first time or worsening of a pre-existing event after 
first dose of study drug.  Analysis of AEs will be limited to TEAEs, but data listings will include 
all AEs regardless of their timing to study drug administration.  Adverse events will be tabulated 
by the MedDRA preferred term and system organ class.  Severity of AEs will be based on the 
NCI CTCAE v4.03 using Grades 1 through 5. 
The subset of AEs considered by the investigator to have a relationship to study drug will be 
considered to be treatment-related AEs.  If the investigator does not specify the relationship of 
the AE to study drug, the AE will be considered treatment-related.  The incidence of AEs and 
treatment-related AEs will be tabulated. 


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9.4.2.2. 
Clinical Laboratory Tests 
Laboratory test values outside the normal range will be assessed for severity based on the normal 
ranges for the clinical reference laboratory.  The incidence of abnormal laboratory values and 
shift tables relative to baseline will be tabulated. 
Laboratory data will be classified into Grades 1 through 4 using CTCAE v4.03.  The following 
summaries will be produced for the laboratory data: 
 Number and percentage of subjects with worst postbaseline CTCAE grade (regardless 
of baseline value).  Each subject will be counted only for the worst grade observed 
postbaseline. 
 Shift tables from baseline to the worst postbaseline value using CTCAE grade. 
 For laboratory parameters where CTCAE grades are not defined, shift tables to the 
worst postbaseline value using the low/normal/high classifications based on 
laboratory reference ranges. 
9.4.2.3. 
Vital Signs 
Descriptive statistics and mean change from baseline will be determined for vital signs (blood 
pressure, pulse, respiratory rate, and body temperature) at each assessment time.  Vital sign 
results will be reviewed for clinically notable abnormalities (see Table 22), and subjects 
exhibiting clinically notable vital sign abnormalities will be listed.  A value will be considered an 
"alert" value if it is outside the established range and shows a > 25% change from baseline. 
Table 22: 
Criteria for Clinically Notable Vital Sign Abnormalities 
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure 
> 155 mmHg 
< 85 mmHg 
Diastolic blood pressure 
> 100 mmHg 
< 40 mmHg 
Pulse 
> 100 bpm 
< 45 bpm 
Temperature 
> 38ºC 
< 35.5ºC 
Respiratory rate 
> 24/min 
< 8/min 
9.4.2.4. 
Electrocardiograms 
Descriptive statistics and mean change from baseline will be determined for each ECG parameter 
at each assessment time.  Electrocardiogram results will be reviewed for clinically notable 
abnormalities according to predefined criteria (Table 23).  Subjects exhibiting clinically notable 
ECG abnormalities will be listed. 
Table 23: 
Criteria for Clinically Notable Electrocardiogram Abnormalities 
Parameter 
High Threshold 
Low Threshold 
QTcF 
> 460 msec 
< 295 msec 
PR 
> 220 msec 
< 75 msec 
QRS 
> 120 msec 
< 50 msec 
QT 
> 500 msec 
< 300 msec 
RR 
> 1330 msec 
< 600 msec 
QTcF = Fridericia correction. 




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10. 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES 
10.1. 
Investigator Responsibilities 
This study will be performed in accordance with ethical principles that originate in the 
Declaration of Helsinki and conducted in adherence to the study Protocol; GCPs as defined in 
Title 21 of the US CFR Parts 11, 50, 54, 56, and 312; ICH E6 GCP consolidated guidelines; and 
local regulatory requirements as applicable to the study locations. 
The investigator will be responsible for: 
 Permitting study-related monitoring, sponsor audits, IRB/IEC review, and regulatory 
inspections by providing direct access to source data and other relevant clinical study 
documents. 
 Monitoring:  Qualified representatives of the sponsor or its designee, study 
monitors, will monitor the study according to a predetermined plan.  The 
investigator must allow the study monitors to review any study materials and 
subject records at each monitoring visit. 
 Auditing:  Qualified representatives of the sponsor or its designee may audit the 
clinical study site and study data to evaluate compliance with the Protocol, 
applicable local clinical study regulations, and overall study conduct.  The 
investigator must allow the auditors to review original source records and study 
documentation for all subjects. 
 Regulatory inspection:  Regulatory authorities may conduct an inspection of the 
study and the site at any time during the development of an investigational 
product.  The investigator and staff are expected to cooperate with the inspectors 
and allow access to all source documents supporting the eCRFs and other 
study-related documents.  The investigator must immediately notify the sponsor 
when contacted by any regulatory authority for the purposes of conducting an 
inspection. 
 Obtaining informed consent and ensuring that the study subjects' questions have been 
answered and the subjects fully understand study procedures: 
 Informed consent must be obtained before any study-related procedures are 
conducted, unless otherwise specified by the Protocol. 
 Informed consent must be obtained using the IRB/IEC-approved version in a 
language that is native and understandable to the subject.  A template will be 
provided by the sponsor or its designee.  The sponsor or its designee must review 
and acknowledge the site-specific changes to the ICF template.  The ICF must 
include a statement that the sponsor or its designee and regulatory authorities have 
direct access to subject records. 


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 Obtaining approval from the IRB/IEC before the start of the study and for any 
changes to the clinical study Protocol, important Protocol deviations, routine updates, 
and safety information in accordance with institutional requirements and local law. 
 The investigator is responsible for ensuring that the safety reports provided by the 
sponsor are reviewed and processed in accordance with regulatory requirements 
and with the policies and procedures established by the IRB/IEC. 
 Adhering to the Protocol as described in this document and agreeing that changes to 
the Protocol procedures, with the exception of medical emergencies, must be 
discussed and approved, first, by the sponsor or its designee and, second, by the 
IRB/IEC.  Each investigator is responsible for enrolling subjects who have met the 
specified eligibility criteria. 
 Retaining records in accordance with all local, national, and regulatory laws, but for a 
minimum period of at least 2 years after the last marketing application approval in an 
ICH region and until there are no pending or contemplated marketing applications in 
an ICH region, or if not approved, 2 years after the termination of the test article for 
investigation to ensure the availability of study documentation should it become 
necessary for the sponsor or a regulatory authority to review. 
 The investigator must not destroy any records associated with the study without 
receiving approval from the sponsor.  The investigator must notify the sponsor or 
its designee in the event of accidental loss or destruction of any study records.  If 
the investigator leaves the institution where the study was conducted, the sponsor 
or its designee must be contacted to arrange alternative record storage options. 
 All eCRF data entered by the site (including audit trail), as well as computer 
hardware and software (for accessing the data), will be maintained or made 
available at the site in compliance with applicable record retention regulations.  
The sponsor will retain the original eCRF data and audit trail. 
10.2. 
Accountability, Handling, and Disposal of Study 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 drug to the study site. 
 Inventory of study drug at the site. 
 Lot numbers and/or vial numbers (as applicable) of study drug used to prepare the 
infusion solution 
 Subject use of the study drug including pill or unit counts from each supply 
dispensed. 
 Return of study drug to the investigator or designee by subjects. 


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The investigational product must be used only in accordance with the Protocol.  The investigator 
will also maintain records adequately documenting that the subjects were provided the specified 
study drug.  These records should include dates, quantities, and any available batch or serial 
numbers or unique code numbers assigned to the investigational product and study subjects. 
Completed accountability records will be archived by the site.  The investigator or designee will 
be expected to collect and retain all used, unused, and partially used containers of study drug 
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 drug 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 drug is destroyed before 
monitor inspection, the monitors rely on documentation of destruction per the site SOP. 
10.3. 
Data Management 
Data management will be performed in a validated database via an EDC system.  All data entry, 
verification, and validation will be performed in accordance with the current standard operating 
procedures of the Data Management Department at the sponsor or its designee.  The database 
will be authorized for lock once all defined procedures are completed. 
The investigator will be provided with access to an EDC system so that an eCRF can be 
completed for each subject.  Entries made in the eCRF must be verifiable against source 
documents; if updates to the database are not possible, any discrepancies should be explained 
and documented.  The investigator will be responsible for reviewing all data and eCRF entries, 
and will sign and date the designated forms in each subject's eCRF, verifying that the 
information is true and correct.  The investigator is responsible for the review and approval of all 
query responses. 
Protocol deviations will be identified and recorded in the Protocol Deviation form of the eCRF.  
The study monitor will reference the Monitoring Plan in order to ensure that each issue identified 
is appropriately documented, reported, and resolved in a timely manner in accordance with the 
plan's requirements. 
10.4. 
Data Privacy and Confidentiality of Study Records 
The investigator and the sponsor or its designee must adhere to applicable data privacy laws and 
regulations.  The investigator and the sponsor or its designee are responsible for ensuring that 
sensitive information is handled in accordance with local requirements (eg, HIPAA).  
Appropriate consent and authorizations for use and disclosure and/or transfer (if applicable) of 
protected information must be obtained. 


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Subject names will not be supplied to the sponsor or its designee, if applicable.  Only the subject 
number and subject's initials (subject's initials will only be recorded if allowable by local 
regulations) will be recorded in the eCRF, where permitted; if the subject's name appears on any 
other document (eg, laboratory report), it must be obliterated on the copy of the document to be 
supplied to the sponsor or its designee.  Study findings stored on a computer will be stored in 
accordance with local data protection laws.  The subjects will be informed that representatives of 
the sponsor or its designee, IRB or IEC, or regulatory authorities may inspect their medical 
records to verify the information collected, and that all personal information made available for 
inspection will be handled in strictest confidence and in accordance with local data protection 
laws. 
10.5. 
Financial Disclosure 
Before study initiation, all clinical investigators participating in clinical studies subject to FDA 
Regulation Title 21 CFR Part 54 – Financial Disclosure by Clinical Investigators (ie, "covered 
studies") are required to submit a completed Clinical Investigator Financial Disclosure form that 
sufficiently details any financial interests and arrangements that apply.  For the purpose of this 
regulation, "clinical investigator" is defined as any investigator or subinvestigator who is directly 
involved in the treatment or evaluation of research subjects, including the spouse and each 
dependent child of the clinical investigator or subinvestigator.  These requirements apply to both 
US and foreign clinical investigators conducting covered clinical studies. 
Any new clinical investigators added to the covered clinical study during its conduct must also 
submit a completed Investigator Financial Disclosure Form.  During a covered clinical study, 
any changes to the financial information previously reported by a clinical investigator must be 
reported to the sponsor or its designee.  At the conclusion of the covered clinical study, the 
clinical investigators will be reminded of their obligations.  In the event that the clinical 
investigator is not reminded, they nevertheless will remain obligated to report to the sponsor or 
its designee any changes to the financial information previously reported, as well as any changes 
in their financial information for a period of 1 year after completion of the covered clinical study. 
10.6. 
Publication Policy 
By signing the study Protocol, the investigator and his or her institution agree that the results of 
the study may be used by the sponsor, Incyte Biosciences International Sàrl (Incyte), for the 
purposes of national and international registration, publication, and information for medical and 
pharmaceutical professionals.  Study results will be published in accordance with applicable 
local and national regulations.  If necessary, the authorities will be notified of the investigator's 
name, address, qualifications, and extent of involvement.  The terms regarding the publication of 
study results are contained in the agreement signed with the sponsor or its designee.  A signed 
agreement will be retained by the sponsor or its designee. 


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combination with ipilimumab in metastatic renal cell carcinoma: the CheckMate 016 study. Ann 
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OX40 agonist MOXR0916 in patients with refractory solid tumors. Cancer Res 
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INCAGN01949 Investigator's Brochure (IB). Wilmington, DE: Incyte Corporation. 
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APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS 
For Subjects Participating in the Study: 
The following methods that can achieve a failure rate of less than 1% per year when used 
consistently and correctly are considered as highly effective birth control methods.  
Such methods include: 
 Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation1 
 oral 
 intravaginal 
 transdermal 
 Progestogen-only hormonal contraception associated with inhibition of ovulation1 
 oral 
 injectable 
 implantable2 
 Intrauterine device (IUD)2 
 Intrauterine hormone-releasing system (IUS)2 
 Bilateral tubal occlusion2 
 Vasectomized partner2,3 
 Sexual abstinence4 
 
1  Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the 
contraception method. 
2  Contraception methods that in the context of this guidance are considered to have low user dependency. 
3  Vasectomised partner is a highly effective method provided of avoiding pregnancy that partner is the sole sexual 
partner of the WOCBP trial participant and that the vasectomized partner has received medical assessment of the 
surgical success.  
4  In the context of this guidance, sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments.  The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the subject. 
Source:  CTFG 2014. 


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APPENDIX B. PROCEDURES AND SUPPORTIVE CARE GUIDELINES 
FOR SUBJECTS EXHIBITING IMMUNE-RELATED 
ADVERSE EVENTS  
irAE 
Supportive Care 
Pneumonitis 
For Grade 2 (mild to moderate new symptoms): 
 Monitor symptoms daily and consider hospitalization.  
 Promptly start systemic steroids per institutional standard of care. 
 Consider adding prophylactic antibiotics for opportunistic infections in the case 
of prolonged steroid administration. 
 Reimaging as clinically indicated. 
 If no improvement within 3 to 5 days, additional work-up should be considered 
and prompt treatment with IV methylprednisolone should be started. 
 If still no improvement within 3 to 5 days despite IV methylprednisone, consider 
starting immunosuppressive therapy (eg, infliximab), after discussing with the 
medical monitor. 
Caution:  Important to rule out sepsis and refer to infliximab label for general 
guidance before using infliximab.  
 Once improving, gradually taper steroids over ≥ 4 weeks and consider 
prophylactic antibiotics, antifungal, or anti-PCP treatment (refer to current 
NCCN 2017 for treatment of cancer-related infections 
(Category 2B recommendation).  
 Consider pulmonary and infectious disease consult.  
For Grade 3 or 4 (severe or new symptoms, new/worsening pneumonitis, life 
threatening): 
 Promptly initiate empiric IV methylprednisolone or equivalent.  
 Carefully monitor subject, and institute medical intervention as appropriate for 
the management of symptoms.  Consider obtaining pulmonary and infectious 
disease consult.  
 If no improvement within 3-5 days, additional work-up should be considered and 
prompt treatment with additional immunosuppressive therapy (eg, infliximab), 
after discussing with the medical monitor. 
Caution:  Rule out sepsis and refer to infliximab label for general guidance 
before using infliximab.  
 Once improving, gradually taper steroids over ≥ 4 weeks and consider 
prophylactic antibiotics, antifungals, and in particular, anti-PCP treatment (refer 
to current NCCN 2017 for treatment of cancer-related infections (Category 2B 
recommendation). 


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irAE 
Supportive Care 
Diarrhea/Colitis 
(continued) 
Note:  Subjects should be carefully monitored for signs and symptoms of 
enterocolitis (such as diarrhea, abdominal pain, blood or mucus in stool, with or 
without fever) and of bowel perforation (such as peritoneal signs and ileus). 
For Grade 2 (mild to moderate new symptoms): 
 Consider symptomatic treatment, including hydration, electrolyte replacement, 
dietary changes (eg, American Dietetic Association colitis diet), and loperamide 
and/or budesonide. 
 Promptly start systemic steroids per institutional standard of care. 
 If event is not responsive within 3 to 5 days or worsens, gastrointestinal (GI) 
consult should be obtained for consideration of further work-up, and prompt 
treatment with IV methylprednisolone started. 
 If still no improvement within 3 to 5 days, consider starting immunosuppressives 
(eg, infliximab) after discussing with the medical monitor. 
Caution:  Important to rule out bowel perforation and refer to infliximab label 
for general guidance before using infliximab. 
 Consult medical monitor if no resolution to ≤ Grade 1 in 3 to 4 days. 
 Once improving, gradually taper steroids over ≥ 4 weeks and consider 
prophylactic antibiotics, antifungals, and anti-PCP treatment (refer to current 
NCCN 2017 for treatment of cancer-related infections [Category 2B 
recommendation]). 
For Grade 3 or 4 (severe or new symptoms, new/worsening diarrhea/colitis, 
life threatening): 
 Treatment with systemic corticosteroids should be initiated per institutional 
standard of care. 
 Manage symptoms and consider GI consult for further work-up as appropriate. 
 If still no improvement within 3 to 5 days, consider starting immunosuppressives 
(eg, infliximab), after discussing with the medical monitor. 
Caution:  Ensure GI consult to rule out bowel perforation and refer to infliximab 
label for general guidance before using infliximab. 
 Once improving, gradually taper steroids over ≥ 4 weeks and consider 
prophylactic antibiotics, antifungals, and anti-PCP treatment (refer to current 
NCCN 2017 for treatment of cancer-related infections [Category 2B 
recommendation]). 


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irAE 
Supportive Care 
Hepatitis 
For Grade 2 (mild to moderate new symptoms): 
 Observe subject with regular and frequent checking of liver chemistries until 
improving or resolved. 
 Rule out non-irAE etiologies. 
 If event is persistent (> 3-5 days) or worsens, consider starting systemic steroids 
per institutional standard of care. 
 If still no improvement within 3 to 5 days, consider additional work-up and 
prompt treatment with IV methylprednisolone. 
 If still no improvement within 3 to 5 days, consider starting immunosuppressives 
(eg, mycophenolate mofetil), after discussing with the medical monitor. 
 Infliximab should NOT be used. 
 Once improving, gradually taper steroids over ≥ 4 weeks and consider 
prophylactic antibiotics, antifungals, and anti-PCP treatment (refer to current 
NCCN 2017 for treatment of cancer-related infections [Category 2B 
recommendation]). 
For Grade 3 or 4 (severe or new symptoms, new/worsening hepatitis, life 
threatening): 
 Promptly initiate empiric IV methylprednisolone or equivalent. 
 If still no improvement within 3 to 5 days, consider starting treatment with 
immunosuppressive therapy (eg, mycophenolate mofetil), after discussing with 
the medical monitor. 
 Infliximab should NOT be used. 
 Consider hepatology consult for additional work-up, as appropriate. 
 Once improving, gradually taper steroids over ≥ 4 weeks and consider 
prophylactic antibiotics, antifungals, and anti-PCP treatment (refer to current 
NCCN 2017 for treatment of cancer-related infections [Category 2B 
recommendation]). 


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irAE 
Supportive Care 
Dermatitis 
Note:  Monitor subjects for signs and symptoms of dermatitis such as rash and 
pruritus.  Unless an alternate etiology has been identified, signs or symptoms of 
dermatitis should be considered immune-mediated.  If there is any bullous 
formation, the medical monitor should be contacted, and study treatment should be 
discontinued. 
For Grade 2 (mild to moderate new symptoms): 
 Consider dermatology consult. 
 Consider symptomatic treatment per institutional standard of care. 
 Consider moderate-strength topical steroid. 
 If no improvement of rash/skin lesions occurs within 3 to 5 days or is worsening 
despite symptomatic treatment and/or use of moderate strength topical steroid, 
discuss with medical monitor and promptly start systemic steroids. 
For Grade 3 or 4 (severe or new symptoms, new/worsening dermatitis, life 
threatening): 
 Consider dermatology consult. 
 Promptly initiate empiric IV methylprednisolone or equivalent. 
 Carefully monitor subject, and institute medical intervention as appropriate for 
the management of symptoms.   
 Consider hospitalization. 
 Once improving, gradually taper steroids over ≥ 4 weeks and consider 
prophylactic antibiotics, antifungals, and anti-PCP treatment (refer to current 
NCCN 2017 for treatment of cancer-related infections [Category 2B 
recommendation]). 
 Discuss with medical monitor. 
Renal Failure or 
Nephritis 
Note:  Subjects should be monitored for signs and symptoms that may be related to 
changes in renal function.  Subjects should be thoroughly evaluated to rule out any 
alternative etiology.  Steroids should be considered in the absence of clear 
alternative etiology even for low-grade events (Grade 2) in order to prevent 
potential progression to higher grade event. 
For Grades 2 to 4:  
 Carefully monitor subject, and institute medical intervention as appropriate for 
the management of symptoms.  Consider consult with nephrologist, if clinically 
indicated.   
 If event is persistent (> 3-5 days) or worsens, promptly start systemic steroids per 
institutional standard of care. 
 If event is not responsive within 3-5 days or worsens despite steroids, additional 
work-up should be considered, and prompt treatment with IV methylprednisolone 
started. 
 Once improving, gradually taper steroids over ≥ 4 weeks and consider 
prophylactic antibiotics, antifungals, and anti-PCP treatment (refer to current 
NCCN 2017 for treatment of cancer-related infections [Category 2B 
recommendation]). 


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irAE 
Supportive Care 
Endocrinopathies 
Note:  Subjects should be monitored for clinical signs and symptoms of 
hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or 
hypothyroidism.  Subjects may present with fatigue, headache, mental status 
changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific 
symptoms which may resemble other causes such as brain metastasis or underlying 
disease.  Unless an alternate etiology has been identified, signs or symptoms of 
endocrinopathies should be considered immune-mediated. 
For Grade 2 (mild to moderate new symptoms):  
 In hypophysitis, treat with systemic corticosteroids, per institutional standard of 
care.  When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks.  Replacement of appropriate hormones 
may be required as the steroid dose is tapered. 
Note: These suggested supportive care measures also apply to Grade 3 
hypophysitis  
 In hyperthyroidism, nonselective beta-blockers (eg, propranolol) are suggested as 
initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyronine, is indicated per standard of care. 
Note: Isolated hypothyroidism may be treated with replacement therapy without 
treatment interruption and without corticosteroids. 
 Evaluate endocrine function and, as clinically indicated, consider pituitary scan. 
 For subjects with abnormal endocrine work-up, except for those with isolated 
hypothyroidism, consider short-term, high-dose corticosteroids (eg, 
methylprednisolone or IV equivalent) and initiate appropriate hormone 
replacement therapy. 
 For subjects with normal endocrine work-up (labs or MRI), repeat labs/MRI as 
clinically indicated. 
For Grade 3 or 4 (severe or new symptoms, new/worsening endocrinopathies, 
life threatening): 
 Hypothyroidism may be treated with replacement therapy without treatment 
interruption and without corticosteroids. 
 In hyperthyroidism, treat with an initial dose of IV corticosteroid followed by 
oral corticosteroids.  Consider initiation of systemic corticosteroids at a dose of 
1-2 mg/kg per day of prednisone or equivalent, and initiate appropriate hormone 
replacement therapy.  Once improving, gradually taper immunosuppressive 
steroids over ≥ 4 weeks. 
 In hypophysitis, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids.  When symptoms improve to Grade 1 or less, steroid taper should 
be started and continued over no less than 4 weeks.  Replacement of appropriate 
hormones may be required as the steroid dose is tapered. 
 For adrenal crisis, severe dehydration, hypotension, or shock:  immediately 
initiate intravenous corticosteroids with mineralocorticoid activity. 
 Consult endocrinologist. 
 Consult medical monitor. 


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irAE 
Supportive Care 
Neuropathies 
Note:  Monitor subjects for symptoms of motor or sensory neuropathy such as 
unilateral or bilateral weakness, sensory alterations, or paresthesia. 
For Grade 2 (mild to moderate new symptoms):  
 Consider systemic corticosteroids per institutional standard of care in addition to 
appropriate symptomatic treatment. 
 If no improvement within 3-5 days, consider additional work-up and consider 
treating with additional immunosuppressive therapy (eg, IV IgG), after 
discussing with the medical monitor. 
For Grade 3 or 4 (severe or new symptoms, new/worsening neuropathies, life 
threatening): 
 Consider initiation of systemic corticosteroids (IV administration should be 
strongly considered) for severe neuropathies. 
 Institute medical intervention as appropriate for management of severe 
neuropathy. 
 If no improvement within 3-5 days despite IV corticosteroids, consider additional 
workup and consider treating with additional immunosuppressants (eg, IV IgG) 
after discussing with the medical monitor. 
 Once stable, gradually taper steroids over ≥ 4 weeks. 
 


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APPENDIX C. PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document 
Date 
Amendment (Version) 1: 
14 JUN 2017 
Amendment (Version) 2: 
29 MAY 2018 
Amendment (Version) 3: 
05 DEC 2018 
Amendment 3 (05 DEC 2018) 
Overall Rationale for the Amendment:  The primary purpose of the amendment is to decrease 
procedures, including the removal of disease and survival follow-up, for subjects remaining on 
the study. 
1. Synopsis; Section 1.5.4.1, Efficacy Endpoints; Section 2.1.2, Secondary Objectives; 
Section 2.2.2, Secondary Endpoints; Section 5.5.1, Withdrawal Criteria; 
Section 5.5.2, Withdrawal Procedures; Section 6, Study Assessments (Table 12 and 
Table 13); Section 6.3, End of Treatment; Section 6.4, Safety Follow-Up; 
Section 7.9.1.1, Blood Sample Collection (Table 17and Table 18); Section 9.4.1.2, 
Secondary Efficacy Analyses 
Description of change:  The disease follow-up and survival follow-up periods, as well as 
some study procedures and laboratory assessments during the EOT and safety follow-up 
visits, were removed.  Overall survival was removed as an endpoint for the study. 
Rationale for change:  Enrollment to the study was stopped due to changes in the 
development plan of INCAGN01949.  Therefore, disease and survival follow-up data 
would not add significant value to the study at this point in the clinical development 
program. 
2. Synopsis; Section 5.2.1.1, Description and Administration; Section 5.2.2.1, 
Nivolumab; Section 5.2.2.2, Ipilimumab; Section 5.5.1, Withdrawal Criteria 
Description of change:  Study treatment (including INCAGN01949, nivolumab, and 
ipilimumab) will be limited to 24 months of treatment with INCAGN01949. 
Rationale for change:  There have been several reports that continued treatment with 
immunotherapy does not provide additional benefit. 
Another approved anti–PD-1 agent, pembrolizumab, is administered for a maximum of 
2 years for all FDA-approved indications with the exception of melanoma 
(Keytruda 2018).  Recent follow-up data were published for subjects with NSCLC who 
received nivolumab.  This study limited nivolumab treatment to 96 weeks and the 5-year 
OS was reported to be 16%.  Of the subjects who survived for 5 years, 75% received no 
further cancer treatment after discontinuing nivolumab and had no evidence of 
progressive disease at the time the data were prepared for publishing. 


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The authors concluded that these data suggest that long-term survival may be achieved 
after nivolumab treatment of 2 years or less (Gettinger S, Horn L, Jackman D, et al. 
Five-year follow-up of nivolumab in previously treated advanced non-small-cell lung 
cancer: results from the CA209-003 study. J Clin Oncol 2018;17:1675-1684.). 
Additional studies have come to similar conclusions.  Hodi et al presented data that 
compared OS in subjects who discontinued nivolumab + ipilimumab combination 
treatment due to toxicity versus the overall combination treatment group.  The OS at 
18 months in the group that discontinued due to toxicity was 79.5 months compared with 
73.2 months in the overall population.  These data also suggest that a shorter treatment 
duration of immunotherapy may be sufficient to provide an OS benefit (Hodi F, 
Postow M, Chesney J, et al. Overall survival in patients with advanced melanoma [MEL] 
who discontinued treatment with nivolumab [NIVO] plus ipilimumab [IPI] due to 
toxicity in a phase II trial [CHECKMATE 069]. J Clin Oncol 
2016;34[suppl]:Abstract 9518.). 
Another recent data update provides long-term information on the KEYNOTE-010 study, 
in which subjects were treated for up to 2 years with pembrolizumab.  Most of the 
subjects had a durable response even after discontinuing therapy after the 2-year 
treatment period, with the response ongoing in 64% of those subjects at a median 
follow-up of 43.4 months (Herbst RS, Garon EB, Kim D-W, et al. Long-term survival in 
patients with advanced NSCLC in the KEYNOTE-010 study overall and in patients who 
completed 2 years of pembrolizumab. Ann Oncol 2018;29[suppl 8]:Abstract LBA63.).  
These data collectively suggest that treatment beyond 24 months with an immunotherapy 
may not provide additional benefit to oncology patients. 
3. Synopsis; Section 4.1, Overall Study Design; Section 4.3.1, Planned Number of 
Subjects; Section 9, Statistics 
Description of change:  Text was revised to indicate that enrollment was stopped at 
52 subjects. 
Rationale for change:  Enrollment to the study was stopped after 52 subjects were 
enrolled in Phase 1 due to changes in the development plan of INCAGN01949.  No 
subjects were enrolled in Phase 2; therefore, only Phase 1 statistical analyses will be 
performed. 


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4. Synopsis; Section 1.5.4.1, Efficacy Endpoints; Section 2.1.2, Secondary Objectives; 
Section 2.2.2, Secondary Endpoints; Section 4.2, Measures Taken to Avoid Bias; 
Section 7.7.1, Modified RECIST Assessment Disease; Section 7.7.1.12, Tumor 
Imaging During the Study; Section 9.4.1.2, Secondary Efficacy Analyses 
Description of change:  Efficacy evaluation per modified RECIST (mRECIST) was 
removed as an endpoint for the study.  mRECIST may continue to be used guide 
treatment decisions for disease progression. 
Rationale for change:  Efficacy will continue to be analyzed using RECIST v1.1.  The 
additional analysis of mRECIST would not add significant value to the study at this point 
in the clinical development program. 
5. 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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4. Section 1.2.4, Clinical Pharmacokinetics; Section 1.2.5, Clinical Safety of 
INCAGN01949; Section 1.4, Potential Risks of the Combination Regimens; 
Section 1.5.3, Rationale for Dose and Schedule of Combination Therapies 
Description of change:  Added preliminary data from the INCAGN 1949-101 study. 
Rationale for change:  Provide available information to investigators. 
5. Section 1.3, Overview of Standard Therapies; Section 1.5.2.1, Renal Cell 
Carcinoma; Section 11, References 
Description of change:  Included updated information on nivolumab and ipilimumab 
from package inserts. 
Rationale for change:  Provide updated information on nivolumab and ipilimumab so 
that the information in the Protocol was consistent with the currently approved package 
inserts. 
6. Synopsis; Section 3.2, Subject Exclusion Criteria (Exclusion Criterion #3) 
Description of change:  Removed transfusion of blood products within 14 days of 
Cycle 1 Day 1 from exclusion criterion. 
Rationale for change:  Early safety data have shown that INCAGN01949 does not cause 
myelosuppression, and therefore, the removal of this exclusion criterion will allow 
subjects to receive transfusions as necessary to address chemotherapy-induced 
hematologic abnormalities without delaying the start of study treatment. 
7. Synopsis; Section 3.2, Subject Exclusion Criteria (Exclusion Criterion #4) 
Description of change:  Adjusted washout period for prior immune therapies from 
28 days to 14 days of Cycle 1 Day 1. 
Rationale for change:  Treatment with immune therapies including PD-1/L1 antibodies 
have become standard of care in a number of indications.  Subjects in Phase 2 will be 
required to have received these therapies and will receive INCAN01949 in combination 
with nivolumab, therefore, a 14-day washout period is sufficient and will allow subjects 
to start study therapy as soon as possible. 
8. Section 5.4.1, Dose Modifications; Section 5.4.2, Dose-Limiting Toxicity and 
Determination of Maximum Tolerated Dose; Section 5.4.6, Criteria and Procedures 
for Dose Interruptions and Adjustments of Study Drug; Section 5.4.9, Criteria for 
Permanent Discontinuation of Study Drug; Section 8.3.2, Reporting 
Description of change:  Requirement for dose reduction of INCAGN01949 was 
eliminated. 
Rationale for change:  Dose reduction is not a common method of managing toxicities 
in patients treated with immune therapies, and dose interruption or treatment 
discontinuation is felt to be a more appropriate method of managing treatment-related 
toxicities.  Dose reductions have not been required to manage toxicity so far in the 
INCAGN01949 development program. 




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Amendment 1 (14 JUN 2017) 
Overall Rationale for the Amendment:  The primary purpose of this amendment is to address 
comments from the United States FDA review and to update the sponsor name and address to 
Incyte Biosciences International Sarl. 
1. Synopsis; Section 3.1, Subject Inclusion Criteria 
Description of change:  The definition for platinum-ineligible was provided in the 
inclusion criteria for subjects with urothelial carcinoma. 
Rationale for change:  To provide additional guidance to the sites. 
2. Synopsis; Section 3.1, Subject Inclusion Criteria 
Description of change:  Subjects who refuse standard treatment will no longer be 
eligible for participation in Phase 1 (Parts 1 and 2) of the study.   
Rationale for change:  Change was made upon request from the FDA.  The concern is 
that patients will forgo standard therapy with a proven clinical benefit to participate in an 
investigational study. 
3. Section 5.4.2, Dose-Limiting Toxicity and Determination of Maximum Tolerated 
Dose 
Description of change: The definition of dose-limiting toxicity has been updated in 
Table 8 of the protocol.    
Rationale for change: To incorporate requested changes from the FDA. 
4. Title Page; Synopsis; Document Headers; Section 10.6, Publication Policy 
Description of change:  The name and address of the Sponsor were updated from Incyte 
Europe Sàrl to Incyte Biosciences International Sàrl. 
Rationale for change: The corporate entity Incyte Europe Sàrl will be merged into 
Incyte Biosciences International Sàrl.