A Phase 1/2, Open-Label, Dose-Escalation, Safety and Tolerability Study of INCAGN01876 in Subjects With Advanced or Metastatic Solid Tumors
Phase: PHASE1
Conditions: Advanced Malignancies, Metastatic Cancer
Sponsor: Incyte Biosciences International Sàrl

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Protocol INCAGN 1876-101 Amendment 3 
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CONFIDENTIAL 
 
Clinical Study Protocol 
 
INCAGN 1876-101 
A Phase 1/2, Open-Label, Dose-Escalation, Safety and Tolerability 
Study of INCAGN01876 in Subjects With Advanced or Metastatic 
Solid Tumors 
 
 
 
 
 
Product: 
INCAGN01876 
IND Number: 
128,658 
Phase of Study: 
1/2 
Sponsor: 
Incyte Europe Sàrl 
rue du Pré-de-la-Bichette 1 
1202 Geneva, Switzerland 
Date of Protocol: 
16 DEC 2015 
Date of Amendment 1: 
20 JAN 2016 
Date of Amendment 2: 
24 OCT 2016 
Date of Amendment 3: 
16 MAY 2017 
 
This study will be performed in accordance with ethical principles that have their origin in the Declaration of 
Helsinki and conducted in adherence to the study Protocol, Good Clinical Practices as defined in Title 21 of the 
US Code of Federal Regulations Parts 11, 50, 54, 56, and 312, as well as ICH GCP consolidated guidelines (E6) and 
applicable regulatory requirements. 
 
The information in this document is confidential.  No part of this information may be duplicated, referenced, or 
transmitted in any form or by any means (electronic, mechanical, photocopy, recording, or otherwise) without the prior 
written consent of Incyte Europe Sàrl. 

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INVESTIGATOR'S AGREEMENT 
I have read the INCAGN 1876-101 Protocol Amendment 3 (dated 16 MAY 2017) 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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escalated if 0 of the first 3 evaluable subjects enrolled has a DLT.  If 1 of the first 3 evaluable subjects 
enrolled has a DLT, then the cohort will be expanded to include 3 additional evaluable subjects, and if no 
DLT occurs in the additional 3 subjects, then the dose will be escalated.  If a DLT occurs in one-third or 
more of the expanded cohort, then the MTD will be deemed to be exceeded and the previous dose level 
will be considered the MTD.  If a DLT occurs at the 20.0 mg/kg dose, then a dose level of 15.0 mg/kg 
may be explored pending safety review.  If only 3 subjects were treated at the MTD or PAD, then a 
minimum of 3 additional evaluable subjects will be enrolled at this dose before it is administered in Part 2 
of the study.   
If Cohort 1 (0.03 mg/kg; starting dose) exceeds the MTD, the sponsor and investigators will consider 
dosing INCAGN01876 at 0.01 mg/kg (Cohort -1), and/or investigate 0.03 mg/kg at alternate dose 
schedules, based on available safety, PK, 
 data.  If an alternate schedule is tested and 
determined to be safe, re-escalation of INCAGN01876 will proceed according to the table below. 
Throughout the treatment period, if > 33% of subjects (a minimum of 6 subjects) experience a ≥ Grade 3 
toxicity related to study drug after completing ≥ 4 cycles, then dose administration will be stopped, and 
the MNTD will be determined in conjunction with the investigators and sponsor based on all available 
safety data. 
Additional subjects will be enrolled in a cohort to achieve the minimum of 3 evaluable subjects.  Subjects 
who drop out for reasons other than a DLT (eg, events clearly associated with the underlying disease, 
disease progression, concomitant medication, or comorbidity), during the 28-day DLT observation period 
will be considered nonevaluable and will be replaced.  Dose modifications should not be made during the 
DLT observation period without discussion with the medical monitor.  Intrasubject dose escalation is not 
permitted; however, once the recommended Part 2 dose (RP2D) and schedule has been determined, 
ongoing subjects in Part 1 may be permitted to escalate to the RP2D with approval of the medical 
monitor.  The cohorts and dose levels are shown in the table below. 
Cohort 
Dose of INCAGN01876 
-1 
0.01 mg/kga 
1 (starting dose) 
0.03 mg/kg 
2 
0.1 mg/kg 
3 
0.3 mg/kg 
4 
1.0 mg/kg 
5 
3.0 mg/kg 
6 
5.0 mg/kg 
7 
10.0 mg/kg 
8 
20.0 mg/kg 
a  Subjects who require a dose reduction below 0.01 mg/kg should be discontinued from study drug. 
Part 1 – Safety Expansion 
In order to 
 confirm the preliminary safety of the 
dose escalation cohorts, Part 1 of the study may include safety expansion cohorts evaluating doses and 
schedules equivalent to or lower than the highest dose levels determined to be safe and/or doses 
determined to be pharmacologically active.  Fixed doses of INCAGN01876 (equivalent to or less than the 
MTD/PAD determined during dose escalation), may also be explored during the safety expansion.  All 
doses and schedules explored during the safety expansion will depend on PK, 
 and safety 
results. 
Approximately 36 evaluable subjects will be enrolled in the Part 1 safety expansion, with each cohort 
enrolling approximately 9 evaluable subjects.  If < 3 of 9 evaluable subjects experience a DLT, the cohort 

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will be deemed safe.  If > 1 safety expansion cohort is deemed safe, then a recommended dose and 
schedule will be determined in conjunction with the investigators and sponsor based on all available 
safety, PK, 
 results.  The safety expansion cohorts may be conducted in parallel to 
Part 2 and may be limited by the sponsor to subjects with specific tumor types to achieve a balance across 
cohorts. 
Part 2 − Dose Expansion 
Part 2 of the study will further evaluate the safety, tolerability, preliminary efficacy, PK, and 
pharmacologic activity of the RP2D of INCAGN01876 in subjects with advanced or metastatic 
adenocarcinoma of the endometrium, melanoma, NSCLC (squamous and nonsquamous), and RCC.  Each 
cohort will comprise of an individual tumor type.  A Simon 2-stage design will be utilized with a stopping 
rule to allow for early termination of a particular cohort at the end of Stage 1 if there are insufficient 
responses observed.  During Stage 1, 9 evaluable subjects will be enrolled in each cohort; if no responses 
are observed within the cohort then the cohort will be discontinued.  If at least 1 response is observed, 
8 additional evaluable subjects will be enrolled in the cohort (Stage 2), for a maximum of 17 evaluable 
subjects per cohort.   
Subjects will continue to receive INCAGN01876 at the RP2D and schedule until Protocol-defined 
withdrawal criteria are met.  Continuous evaluation of toxicity events will be performed throughout 
enrollment in Part 2 of the study.  If the cumulative incidence of DLTs occurs in ≥ 33% of subjects after 
6 subjects have been observed for at least 28 days, further enrollment may be interrupted until the sponsor 
has determined the appropriate course of action.  All AEs, regardless of the time of occurrence on study 
may be considered in determining the appropriate dose, schedule, and MNTD. 
Toxicity will continue to be monitored throughout the treatment period.  If > 33% of subjects (minimum 
of 6 subjects) experience a ≥ Grade 3 toxicity related to study drug after completing ≥ 4 cycles,  then the 
MNTD will be determined in conjunction with the investigators and sponsor based on all available safety 
data. 
Study Population: 
Key Inclusion Criteria: 
• 
Men and women, aged 18 or older. 
• 
Willingness to provide written informed consent for the study. 
• 
Locally advanced or metastatic disease; locally advanced disease must not be amenable to resection 
with curative intent. 
• 
Part 1:  Subjects with advanced or metastatic solid tumors. 
• 
Part 2:  Subjects with advanced or metastatic adenocarcinoma of endometrium, melanoma, NSCLC, 
and RCC.  
− 
For subjects with adenocarcinoma of the endometrium: should have documented microsatellite 
instability (MSI) status (eg, MSI-high, MSI-low, microsatellite stable), or consent to MSI status 
testing during the screening period.   
Note:  MSI-high is defined by instability in ≥ 30% of examined microsatellites.  MSI-low is 
defined by instability of < 30% of examined microsatellites.  Microsatellite stable is defined by 
no instability. 
− 
For subjects with melanoma: mucosal or cutaneous melanoma is acceptable; however, subjects 
with ocular melanoma are excluded.  Subjects should have documented V600E-activating BRAF 
mutation status, or consent to BRAF V600E mutation testing during the screening period. 
Note:  BRAF mutation status determined as part of a panel of genetic tests performed in a gene 
expression analysis will also satisfy the inclusion criteria for BRAF mutation testing. 
 

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• 
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.  Subjects must 
also not require chronic use of corticosteroids and 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 sponsor approval. 
Note:  Bisphosphonates and denosumab are permitted medications. 
− 
Part 1:  ≤ 42 days for a prior immunotherapy.  
Part 2:  ≤ 28 days for prior immunotherapy or persistence of active cellular therapy (eg, chimeric 
antigen receptor T-cell therapy; other cellular therapies must be discussed with the medical 
monitor to determine eligibility). 
− 
≤ 28 days for prior a 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:  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 immunotherapy) 
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 Part 1 dose-escalation portion of the study. 
• 
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. 
• 
Active autoimmune disease that required systemic treatment in the past (ie, with use of disease-
modifying agents, corticosteroids, or immunosuppressive drugs).  Subjects who have not required 
systemic treatment in the past 2 years may be eligible with approval of the medical monitor. 
Note: Subjects with hyper/ hypothyroidism 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 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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• 
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. 
• 
Evidence of active, noninfectious pneumonitis or history of interstitial lung disease. 
• 
History or presence of an abnormal electrocardiogram (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 sponsor approval.  The JTc must be < 340 milliseconds 
if JTc is used in place of the QTc.  Subjects with left bundle branch block are excluded. 
Note:  QTc prolongation due to pacemaker may enroll if the JTc is normal or with medical monitor 
approval. 
• 
Active infection requiring systemic therapy. 
• 
Evidence of hepatitis B virus (HBV) or hepatitis C virus (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. 
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. 
• 
Known history of human immunodeficiency virus (HIV; HIV 1/2 antibodies). 
• 
Known allergy or reaction to any component of study drug or formulation components. 
• 
Prior treatment with any tumor necrosis factor super family agonist (eg, GITR, OX40, 41BB/ CD137, 
CD27, etc) for any indication. 
• 
Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration 
of the study, starting with the screening visit through 60 days after the last dose of study treatment. 
INCAGN01876 Dosage, and Mode of Administration: 
Part 1 and Part 2:  INCAGN01876 will be administered intravenously over a 30-minute period on Day 1 
of each cycle.  Subjects will continue to receive INCAGN01876, up to a defined maximum number of 
cycles, as long as the subject is deriving benefit and has not met any of the protocol defined conditions for 
treatment withdrawal. 
Duration of treatment (maximum number of cycles) will be determined based on safety during Part 1, and 
may be fewer than the absolute maximum number of cycles as outlined below: 
• 
For a 14-day cycle: maximum of 26 cycles  
• 
For a 21-day cycle: maximum of 17 cycles 
• 
For a 28-day cycle: maximum of 13 cycles  
Reference Therapy, Dosage, and Mode of Administration:  Not applicable 
Study Schedule/Procedures:   
Subjects will have regularly scheduled study visits at the clinical site on Day 1 of each cycle.  Additional 
study visits may be required during some cycles to monitor for safety, efficacy, or for PK
 evaluations.  
Study visits are as follows: 
• 
Screening:  up to 28 days before enrollment.  Screening will begin at the time that the subject signs 
the informed consent and will continue until the date the subject is enrolled in the study 
(Cycle 1 Day 1). 

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• 
Cycle 1 and Cycle 6:  Day 1, Day 2, and Day 7 (± 1 day). 
• 
Cycle 2: Day 1 (± 1 day) and Day 7 (± 1 day). 
• 
All other treatment cycles:  Day 1 (± 3 days). 
• 
Efficacy assessments:  Every 8 weeks (± 7 days) for 12 months, and then every 12 weeks (± 7 days) 
thereafter until disease progression is determined. 
• 
End of treatment: ± 3 days. 
• 
Safety follow-up: 30 days (+ 7 days) and 60 days (+ 7 days) after end of treatment. 
Safety Assessments:   
Subjects will have regularly scheduled study visits at the clinical site on Day 1 of every cycle where 
targeted physical examinations, vital sign collection, ECOG performance status, collection of concomitant 
medications, and AE assessments will be performed.  A 12-lead ECG will be performed at screening, 
Cycle 1 Day 1, Cycle 2 Day 1, and then Day 1 of every other cycle after Cycle 2 (eg, Cycle 4, Cycle 6, 
Cycle 8).  Triplicate ECG measurements will be performed at Screening, Cycle 1 Day 1, and Cycle 6 
Day 1, in conjunction with PK assessments.  Laboratory assessments will be collected on Day 1 of each 
cycle, with more frequent blood sample collection during the first and second cycles (Day 1 and Day 7) to 
evaluate for DLTs.  Toxicities will be monitored continuously and will be graded using the NCI 
CTCAE v4.03 criteria. 
On Day 1 of the first 4 cycles (Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, and Cycle 4 Day 1), 
subjects will be required to stay at the study site for at least 4 hours after infusion of study drug for safety 
observation.  It is recommended that the subject does not leave the site for any reason during the safety 
observation period.  During the safety observation period, subjects will be assessed for the onset of acute 
AEs. 
Regular telephone conferences with study investigators will be scheduled by the sponsor in order to 
review cohort-specific data and overall safety data, agree on dose escalation, adjudicate individual 
high-grade AEs as potentially dose-limiting, and guide other major study decisions. 
Efficacy Assessments: 
Disease assessments will be performed based on RECIST v1.1 and also on a modified form of 
RECIST v1.1 (referred to as mRECIST) to account for the unique tumor response characteristics seen 
with immunotherapy.  Modified RECIST will be defined as RECIST v1.1 with required confirmation of 
disease progression in the absence of clinical deterioration.  The best overall response for subjects will be 
defined as the best overall response occurring during treatment, even if this assessment occurs after an 
initial assessment of progressive disease. 
Assessment of tumor size (by magnetic resonance imaging or computed tomography scan) will be 
performed at screening or baseline (before beginning therapy) and every 8 weeks for 12 months, and then 
every 12 weeks thereafter until disease progression is determined.  Disease progression is defined as 
progression confirmed by a second, consecutive assessment at least 4 weeks, but no later than 6 weeks 
apart with the option for continuing treatment while awaiting radiographic confirmation of progression 
where feasible, provided that the subject meets the following definition of clinical stability: 
• 
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 tumors at critical anatomical sites (eg, cord compression) requiring urgent 
alternative medical intervention. 
Subjects who discontinue study drug for a reason other than disease progression will continue to be 
assessed for their disease status during the follow-up phase and should continue to have tumor 
assessments every 8 weeks for the first 12 months and then every 12 weeks thereafter until a new cancer 
therapy is started, disease progression, death, or the end of the study. 

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TABLE OF CONTENTS 
SYNOPSIS ......................................................................................................................................3 
LIST OF ABBREVIATIONS ........................................................................................................19 
1. 
INTRODUCTION ......................................................................................................22 
1.1. 
Background .................................................................................................................22 
1.1.1. 
The Role of the Immune System in Cancer ................................................................22 
1.1.2. 
Immune Modulators ....................................................................................................23 
1.1.3. 
Glucocorticoid-Induced Tumor Necrosis Factor Receptor and the Tumor 
Necrosis Factor Super Family ....................................................................................23 
1.1.4. 
Glucocorticoid-Induced Tumor Necrosis Factor Receptor and Activated T 
Cells ............................................................................................................................24 
1.1.5. 
Glucocorticoid-Induced Tumor Necrosis Factor Receptor and T Regulatory 
Cells ............................................................................................................................24 
1.2. 
Overview of INCAGN01876 ......................................................................................25 
1.2.1. 
Pharmacokinetics of INCAGN01876 .........................................................................25 
1.2.2. 
Pharmacology of INCAGN01876 ..............................................................................25 
1.2.3. 
Preclinical Safety and Potential Risks of INCAGN01876 .........................................26 
1.3. 
Study Rationale ...........................................................................................................27 
1.3.1. 
Rationale for the Safe Starting Dose of INCAGN01876 ............................................27 
1.3.2. 
Rationale for Fixed Dosing .........................................................................................29 
 
 
1.3.4. 
Rationale for the Study Endpoints ..............................................................................30 
1.3.4.1. 
Efficacy Endpoints ......................................................................................................30 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................31 
2.1. 
Study Objectives .........................................................................................................31 
2.1.1. 
Primary Objective .......................................................................................................31 
2.1.2. 
Secondary Objectives .................................................................................................31 
2.1.3. 
Exploratory Objectives ...............................................................................................32 
2.2. 
Study Endpoints ..........................................................................................................32 
2.2.1. 
Primary Endpoint ........................................................................................................32 
2.2.2. 
Secondary Endpoints ..................................................................................................32 
2.2.3. 
Exploratory Endpoints ................................................................................................32 
3. 
SUBJECT ELIGIBILITY ...........................................................................................33 

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3.1. 
Subject Inclusion Criteria ...........................................................................................33 
3.2. 
Subject Exclusion Criteria ..........................................................................................34 
4. 
INVESTIGATIONAL PLAN .....................................................................................38 
4.1. 
Overall Study Design ..................................................................................................38 
4.1.1. 
Part 1 – Dose Escalation .............................................................................................38 
4.1.2. 
Part 1 – Safety Expansion ...........................................................................................39 
4.1.3. 
Part 2 – Dose Expansion .............................................................................................40 
4.2. 
Measures Taken to Avoid Bias ...................................................................................41 
4.3. 
Number of Subjects ....................................................................................................41 
4.3.1. 
Planned Number of Subjects ......................................................................................41 
4.3.2. 
Replacement of Subjects .............................................................................................42 
4.4. 
Duration of Treatment and Subject Participation .......................................................42 
4.5. 
Overall Study Duration ...............................................................................................42 
4.6. 
Study Termination ......................................................................................................42 
5. 
TREATMENT ............................................................................................................43 
5.1. 
Treatment Assignment ................................................................................................43 
5.1.1. 
Subject Numbering and Treatment Assignment .........................................................43 
5.1.2. 
Randomization and Blinding ......................................................................................43 
5.2. 
Study Drug ..................................................................................................................43 
5.2.1. 
Description and Administration ..................................................................................43 
5.2.2. 
Supply, Packaging, and Labeling ...............................................................................44 
5.2.3. 
Storage ........................................................................................................................44 
5.3. 
Treatment Compliance ................................................................................................44 
5.4. 
Treatment Interruptions and Adjustments ..................................................................44 
5.4.1. 
Dose Modifications .....................................................................................................44 
5.4.2. 
Dose-Limiting Toxicity and Determination of a Maximum Tolerated Dose .............44 
5.4.3. 
Management of Dose-Limiting Toxicities or Other Urgent Situations ......................46 
5.4.4. 
Follow-Up of Dose-Limiting Toxicities .....................................................................46 
5.4.5. 
Procedures for Cohort Review and Dose Escalation ..................................................46 
5.4.6. 
Criteria and Procedures for Dose Interruptions and Adjustments of Study 
Drug ............................................................................................................................46 
5.4.7. 
Definition, Procedures, and Supportive Care Guidelines for Immune-Related 
Adverse Events ...........................................................................................................47 

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5.4.8. 
Management of Infusion Reactions ............................................................................48 
5.4.9. 
Criteria for Permanent Discontinuation of Study Drug ..............................................50 
5.4.10. 
Treatment After Initial Evidence of Radiologic Disease Progression ........................50 
5.5. 
Withdrawal of Subjects From Study Drug .................................................................50 
5.5.1. 
Withdrawal Criteria ....................................................................................................50 
5.5.2. 
Withdrawal Procedures ...............................................................................................51 
5.6. 
Concomitant Medications ...........................................................................................52 
5.6.1. 
Permitted Medications ................................................................................................52 
5.6.2. 
Restricted Medications ...............................................................................................52 
5.6.3. 
Prohibited Medications ...............................................................................................52 
6. 
STUDY ASSESSMENTS ..........................................................................................53 
6.1. 
Screening ....................................................................................................................58 
6.2. 
Treatment ....................................................................................................................59 
6.3. 
End of Treatment ........................................................................................................59 
6.4. 
Follow-Up ...................................................................................................................59 
6.4.1. 
Safety Follow-Up ........................................................................................................59 
6.4.2. 
Disease Status Follow-Up ...........................................................................................60 
6.5. 
End of Study ...............................................................................................................60 
6.6. 
Unscheduled Visits .....................................................................................................60 
7. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES ...........................61 
7.1. 
Administration of Informed Consent Form ................................................................61 
7.2. 
Interactive Web Response System Procedure ............................................................61 
7.3. 
Demography and Medical History ..............................................................................61 
7.3.1. 
Demographics and General Medical History .............................................................61 
7.3.2. 
Disease Characteristics and Treatment History ..........................................................61 
7.4. 
Prior and Concomitant Medications and Procedures ..................................................62 
7.5. 
Poststudy Anticancer Therapy Status .........................................................................62 
7.6. 
Safety Assessments .....................................................................................................62 
7.6.1. 
Adverse Events ...........................................................................................................62 
7.6.2. 
Physical Examinations ................................................................................................62 
7.6.2.1. 
Comprehensive Physical Examination .......................................................................62 
7.6.2.2. 
Targeted Physical Examination ..................................................................................63 
7.6.3. 
Vital Signs and Weight ...............................................................................................63 

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7.6.4. 
Electrocardiograms .....................................................................................................63 
7.6.5. 
Laboratory Assessments .............................................................................................64 
7.6.5.1. 
Pregnancy Testing ......................................................................................................64 
7.6.5.2. 
Hepatitis Screening Tests ...........................................................................................64 
7.7. 
Efficacy Assessments .................................................................................................65 
7.7.1. 
Modified RECIST v1.1 Assessment of Disease .........................................................65 
7.7.1.1. 
Tumor Imaging ...........................................................................................................66 
7.8. 
Pharmacokinetic Assessments ....................................................................................67 
7.8.1. 
Blood Sample Collection ............................................................................................67 
7.8.2. 
Pharmacokinetic Analysis ..........................................................................................68 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.10. 
Other Study Procedures ..............................................................................................72 
7.10.1. 
Distribution of Subject Reminder Cards .....................................................................72 
8. 
SAFETY MONITORING AND REPORTING .........................................................72 
8.1. 
Adverse Events ...........................................................................................................72 
8.1.1. 
Definitions ..................................................................................................................72 
8.1.2. 
Reporting ....................................................................................................................72 
8.2. 
Laboratory Test Abnormalities ...................................................................................74 
8.3. 
Serious Adverse Events ..............................................................................................74 
8.3.1. 
Definitions ..................................................................................................................74 
8.3.2. 
Reporting ....................................................................................................................75 
8.4. 
Emergency Unblinding of Treatment Assignment .....................................................75 
8.5. 
Pregnancy ...................................................................................................................76 

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8.6. 
Warnings and Precautions ..........................................................................................76 
8.7. 
Data Monitoring Committee .......................................................................................76 
8.8. 
Immune-Related Adverse Events ...............................................................................77 
8.9. 
Product Complaints ....................................................................................................77 
9. 
STATISTICS ..............................................................................................................77 
9.1. 
Study Populations .......................................................................................................77 
9.2. 
Selection of Sample Size ............................................................................................78 
9.2.1. 
Sample Size for Part 1 ................................................................................................78 
9.2.2. 
Sample Size for Part 2 ................................................................................................78 
9.3. 
Level of Significance ..................................................................................................79 
9.4. 
Statistical Analyses .....................................................................................................79 
9.4.1. 
Efficacy Analyses .......................................................................................................79 
9.4.1.1. 
Primary Efficacy Analyses .........................................................................................79 
9.4.1.2. 
Secondary Efficacy Analyses .....................................................................................79 
9.4.1.3. 
Other Efficacy Analyses .............................................................................................80 
9.4.2. 
Safety Analyses ..........................................................................................................80 
9.4.2.1. 
Adverse Events ...........................................................................................................80 
9.4.2.2. 
Clinical Laboratory Tests ...........................................................................................80 
9.4.2.3. 
Vital Signs ..................................................................................................................80 
9.4.2.4. 
Electrocardiograms .....................................................................................................81 
9.4.3. 
Pharmacokinetic Analysis ..........................................................................................81 
 
 
9.5. 
Analyses for the Data Monitoring Committee ............................................................82 
9.6. 
Interim Analysis ..........................................................................................................82 
10. 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES ..........................................................................................................83 
10.1. 
Investigator Responsibilities .......................................................................................83 
10.2. 
Accountability, Handling, and Disposal of Study Drug .............................................84 
10.3. 
Data Management .......................................................................................................85 
10.4. 
Data Privacy and Confidentiality of Study Records ...................................................85 
10.5. 
Financial Disclosure ...................................................................................................86 
10.6. 
Publication Policy .......................................................................................................86 
11. 
REFERENCES ...........................................................................................................87 

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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 
AGM 
African green monkey 
ALK 
anaplastic lymphoma kinase 
aPTT 
activated partial thromboplastin time 
CFR 
Code of Federal Regulations 
CNS 
central nervous system 
CR 
complete response 
CRS 
cytokine release syndrome 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T-lymphocyte−associated protein 4 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
EC10 
effective concentration at 10% inhibition  
EC50 
half maximal effective concentration 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ECOG 
Eastern Cooperative Oncology Group  
EGFR 
epidermal growth factor receptor 
EOT 
end of treatment 
Fc 
fragment, crystallizable 
FcγR 
Fc-gamma receptor 
FDA 
Food and Drug Administration 
Foxp3 
forkhead box P3 
GCP 
Good Clinical Practice 
GITR 
glucocorticoid-induced tumor necrosis factor receptor 

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Abbreviation 
Definition 
GITRL 
glucocorticoid-induced tumor necrosis factor receptor ligand 
GLP 
Good Laboratory Practice 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
human immunodeficiency virus 
ICF 
informed consent form  
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
IgG1 
immunoglobulin G1 
IL 
interleukin 
IN 
Investigator Notification 
INR 
international normalized ratio 
irAE 
immune-related adverse event 
IRB 
institutional review board 
IV 
intravenous 
IWRS 
Interactive Web Response System  
LTBR 
lymphotoxin beta receptor 
mAb 
monoclonal antibody 
MABEL 
minimum anticipated biological effect level 
MedDRA 
Medical Dictionary for Regulatory Activities 
MNTD 
maximum number of tolerated doses 
mRECIST 
modified Response Evaluation Criteria in Solid Tumors 
MRI 
magnetic resonance imaging 
MSI 
microsatellite instability 
MTD 
maximum tolerated dose 
NFκB 
nuclear factor kappa-light-chain-enhancer of activated B cells 
NOEL 
no-observed-effect level  
NSCLC 
non−small cell lung cancer 
PAD 
pharmacologically active dose 
PBMC 
peripheral blood mononuclear cells 
 
  

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Abbreviation 
Definition 
PD1 
programmed cell death protein 1 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PR 
partial response 
PT 
prothrombin time 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
NSAID 
nonsteroidal anti-inflammatory drug 
RNA 
ribonucleic acid 
RP2D 
recommended Part 2 dose 
SAE 
serious adverse event 
SD 
stable disease 
SSD 
safe starting dose 
SUSAR 
suspected unexpected serious adverse reaction 
TCR 
T-cell receptor 
TNF 
tumor necrosis factor 
TNFR 
tumor necrosis factor receptor 
TNFRSF 
tumor necrosis factor receptor super family 
TNFSF 
tumor necrosis factor super family 
Treg 
regulatory T cell 
TWEAK 
tumor necrosis factor−related weak inducer of apoptosis 
ULN 
upper limit of normal 

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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, 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: 
• 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 that are deemed 
clinically unstable are not required to have repeat imaging for confirmation of disease 
progression.  
2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objective 
• To evaluate the safety, tolerability, and dose-limiting toxicities (DLTs) of 
INCAGN01876, and to define a MTD or PAD of INCAGN01876 in subjects with 
advanced or metastatic solid tumors. 
2.1.2. 
Secondary Objectives 
• To evaluate the PK of INCAGN01876 in subjects with advanced or metastatic solid 
tumors. 
• To evaluate the preliminary efficacy of INCAGN01876 by assessing the objective 
response rate, duration of response, and rate of disease control per RECIST v1.1 and 
modified RECIST v1.1 (further referred to as mRECIST v1.1). 
• To evaluate the preliminary efficacy of INCAGN01876 by assessing PFS per 
RECIST v1.1 and mRECIST v1.1. 

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d. Serum creatinine > 1.5 × institutional upper limit of normal (ULN) OR measured or 
calculated creatinine clearance (glomerular filtration rate can also be used in place of 
creatinine or creatinine clearance) < 50 mL/min for subjects with creatinine levels 
> 1.5 × institutional ULN. 
e. Aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase ≥ 2.5 
× ULN. 
Note:  Subjects with 1) bone metastases and 2) no hepatic parenchymal metastases on 
screening radiographic examinations may enroll if the alkaline phosphatase is 
≤ 5 × ULN.  Subjects with 1) bone metastases and/or 2) hepatic parenchymal 
metastases on screening radiographic examinations may enroll if the alkaline 
phosphatase is ≤ 5 × ULN only with medical monitor approval. 
f. Total bilirubin ≥ 1.2 × ULN 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. 
g. International normalized ratio (INR) or prothrombin time (PT) > 1.5 × ULN. 
h. Activated partial thromboplastin time (aPTT) > 1.5 × ULN. 
2. Transfusion of blood products (including platelets or red blood cells) or 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. 
3. 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.  
Subjects must also not require chronic use of corticosteroids and 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 sponsor 
approval. 
Note:  Bisphosphonates and denosumab are permitted medications. 
b. Part 1:  ≤ 42 days for a prior immunotherapy. 
Part 2:  ≤ 28 days for prior immunotherapy or persistence of active cellular therapy 
(eg, chimeric antigen receptor T-cell therapy; other cellular therapies must be 
discussed with the 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:  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 study drugs or devices.  For investigational agents with long half-lives 
(eg, > 5 days), enrollment before the fifth half-life requires medical monitor approval.  

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4. Has not recovered to ≤ Grade 1 from toxic effects of prior therapy (including prior 
immunotherapy) 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 Part 1 dose-escalation portion of the study. 
5. 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. 
6. Active autoimmune disease that required systemic treatment in the past (ie, with use of 
disease-modifying agents, corticosteroids, or immunosuppressive drugs).  Subjects who 
have not required systemic treatment in the past 2 years may be eligible with approval of 
the medical monitor. 
Note:  Subjects with hyper/ hypothyroidism 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. 
7. Known active CNS metastases and/or carcinomatous meningitis. 
Note:  Subjects with previously treated brain metastases may participate provided 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. 
8. 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. 
9. Evidence of active, noninfectious pneumonitis or history of interstitial lung disease. 
10. 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 
sponsor approval.  The JTc must be < 340 milliseconds if JTc is used in place of the QTc.  

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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. 
11. Active infection requiring systemic therapy. 
12. Evidence of hepatitis B virus (HBV) or hepatitis C virus (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. 
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. 
13. Known history of human immunodeficiency virus (HIV; HIV 1/2 antibodies). 
14. Known allergy or reaction to any component of study drug or formulation components. 
15. Prior treatment with any TNFSF agonist (eg, GITR, OX40, 41BB/ CD137, CD27, etc)  
for any indication. 
16. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through 60 days after the 
last dose of study treatment. 
17. 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. 
18. Inability to comprehend or unwilling to sign the informed consent form (ICF). 

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alternate dose schedules, based on available safety, PK, 
 data.  If an alternate 
schedule is tested and determined to be safe, re-escalation of INCAGN01876 will proceed 
according to Table 2. 
Throughout the treatment period, if > 33% of subjects (a minimum of 6 subjects) experience a 
≥ Grade 3 toxicity related to study drug after completing ≥ 4 cycles, then dose administration 
will be stopped, and the MNTD will be determined in conjunction with the investigators and 
sponsor based on all available safety data. 
Additional subjects will be enrolled in a cohort to achieve the minimum of 3 evaluable subjects.  
Subjects who drop out for reasons other than a DLT (eg, events clearly associated with the 
underlying disease, disease progression, concomitant medication, or comorbidity) during the 
28-day DLT observation period will be considered nonevaluable and will be replaced.  Dose 
modifications should not be made during the DLT observation period without discussion with 
the medical monitor.  Intrasubject dose escalation is not permitted; however, once the RP2D and 
schedule has been determined, ongoing subjects in Part 1 may be permitted to escalate to the 
RP2D with approval of the medical monitor.  The cohorts and dose levels are shown in Table 2. 
Table 2: 
INCAGN01876 Dose Levels and Cohorts 
Cohort 
Dose of INCAGN01876 
-1 
0.01 mg/kga 
1 (starting dose) 
0.03 mg/kg 
2 
0.1 mg/kg 
3 
0.3 mg/kg 
4 
1.0 mg/kg 
5 
3.0 mg/kg 
6 
5.0 mg/kg 
7 
10.0 mg/kg 
8 
20.0 mg/kg 
a Subjects who require a dose reduction below 0.01 mg/kg should be discontinued from study drug. 
4.1.2. 
Part 1 – Safety Expansion 
In order to 
 confirm the preliminary safety 
of the dose escalation cohorts, Part 1 of the study may include safety expansion cohorts 
evaluating doses and schedules equivalent to or lower than the highest dose levels determined to 
be safe and/or doses determined to be pharmacologically active.  Fixed doses of INCAGN01876 
(equivalent to or less than the MTD/PAD determined during dose escalation), may also be 
explored during the safety expansion.  All doses and schedules explored during the safety 
expansion will depend on PK, 
 and safety results. 
Approximately 36 evaluable subjects will be enrolled in the Part 1 safety expansion, with each 
cohort enrolling approximately 9 evaluable subjects.  If < 3 of 9 evaluable subjects experience a 
DLT, then the cohort will be deemed safe.  If > 1 safety expansion cohort is deemed safe, then a 
recommended dose and schedule will be determined in conjunction with the investigators and 

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sponsor based on all available safety, PK, 
 results.  The safety expansion 
cohorts may be conducted in parallel to Part 2 and may be limited by the sponsor to subjects with 
specific tumor types to achieve a balance across cohorts. 
4.1.3. 
Part 2 – Dose Expansion 
Part 2 of the study will further evaluate the safety, tolerability, preliminary efficacy, PK, and 
pharmacologic activity of the RP2D of INCAGN01876 in subjects with advanced or metastatic 
adenocarcinoma of the endometrium, melanoma, NSCLC (squamous and nonsquamous), and 
RCC.  Each cohort will comprise an individual tumor type.  A Simon 2-stage design will be 
utilized with a stopping rule to allow early termination of a particular cohort at the end of Stage 1 
if there are insufficient responses observed.  During Stage 1, 9 evaluable subjects will be 
enrolled in each cohort; if no responses are observed within the cohort, then the cohort will be 
discontinued.  If at least 1 response is observed, then 8 additional evaluable subjects will be 
enrolled in the cohort (Stage 2), for a maximum of 17 evaluable subjects per cohort.   
Subjects will continue to receive INCAGN01876 at the RP2D and schedule until 
Protocol-defined withdrawal criteria are met.  Continuous evaluation of toxicity events will be 
performed throughout enrollment in Part 2 of the study.  If the cumulative incidence of DLTs 
occurs in ≥ 33% of subjects after 6 subjects have been observed for at least 28 days, further 
enrollment may be interrupted until the sponsor has determined the appropriate course of action.  
All AEs, regardless of the time of occurrence on study, may be considered in determining the 
appropriate dose, schedule, and MNTD. 
Toxicity will continue to be monitored throughout the treatment period.  If > 33% of subjects 
(minimum of 6 subjects) experience a ≥ Grade 3 toxicity related to study drug after completing 
≥ 4 cycles, then the MNTD will be determined in conjunction with the investigators and sponsor 
based on all available safety data. 

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The sponsor may terminate the study electively, if required by regulatory decision or upon 
review of emerging data.  If the study is terminated prematurely, then the sponsor or designee 
will notify the investigators, the IRBs and IECs, and regulatory bodies of the decision and reason 
for termination of the study. 
5. 
TREATMENT 
5.1. 
Treatment Assignment 
5.1.1. 
Subject Numbering and Treatment Assignment 
All subject numbers will be 6 digits; the first 3 digits will be the site number, and the last 3 digits 
will be the subject's number.  This subject number will be maintained throughout the study and 
will not be reassigned.  Subjects who withdraw consent or discontinue from the study after being 
assigned a subject number will retain their number. 
This is a nonrandomized study, in which subjects will be enrolled into either Part 1 or Part 2 as 
described previously, with all subjects receiving INCAGN01876 (herein referred to as study 
drug).  Site staff will contact the interactive web response system (IWRS) at the time of 
screening, when enrolling subjects, and when ordering study drug for all treatment cycles, as 
well as to discontinue subjects from treatment.  Refer to the IWRS manual for detailed 
information. 
5.1.2. 
Randomization and Blinding 
This is an open-label nonrandomized study; therefore, randomization and blinding do not apply. 
5.2. 
Study Drug 
5.2.1. 
Description and Administration 
The study drug (INCAGN01876) is in liquid form in the formulation buffer of 10 mM histidine, 
7% sucrose, pH 6.0 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 and administered by qualified personnel as an 
IV infusion over a 30-minute period on Day 1 of each cycle.  In Part 1, subjects will be 
administered study drug, according to cohort enrollment (Table 2).  In Part 2, subjects will be 
administered study drug at the RP2D and schedule.  Subjects will continue to receive 
INCAGN01876, up to the defined maximum number of cycles, as long as the subject is deriving 
benefit and has not met any of the Protocol-defined conditions for treatment withdrawal (see 
Section 5.5). 
Duration of treatment (maximum number of cycles) will be determined based on safety during 
Part 1 and may be fewer than the absolute maximum number of cycles as outlined below: 
• For a 14-day cycle:  maximum of 26 cycles  
• For a 21-day cycle:  maximum of 17 cycles 
• For a 28-day cycle:  maximum of 13 cycles 

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The Pharmacy Manual contains additional information and instructions for study drug 
preparation and infusion. 
5.2.2. 
Supply, Packaging, and Labeling 
Study drug will be supplied as 5.0 mL aqueous solution in 10 mL glass vials with 10 mg/mL of 
INCAGN01876.  Study drug will be packaged as open-labelled supplies, each vial will be 
labelled 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 and will state "Caution:  New Drug--Limited by Federal (or 
United States) law to investigational use." 
5.2.3. 
Storage 
Study drug must be stored refrigerated (2-8°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.  
5.3. 
Treatment Compliance 
Compliance with study drug dosing will be calculated by the sponsor based on the drug 
accountability and infusion records documented by the site staff and monitored by the 
sponsor/designee. 
5.4. 
Treatment Interruptions and Adjustments 
5.4.1. 
Dose Modifications 
Selections and modifications to the study drug are planned for dose-escalation cohorts.  Dose 
interruptions and modifications also may occur for individual study subjects.  The identification 
of DLTs will define the doses used in planned cohorts (see Section 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.  Intrasubject dose 
escalation is not permitted; however, once the RP2D has been determined, ongoing subjects in 
Part 1 may be permitted to dose escalate to the RP2D with medical monitor approval. 
5.4.2. 
Dose-Limiting Toxicity and Determination of a 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.  All DLTs will be assessed by the investigator using CTCAE v4.03.  A 
DLT will be defined as the occurrence of any toxicity in Table 3, with the exception of events 

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clearly associated with the underlying disease, disease progression, a concomitant medication, or 
comorbidity. 
Individual subject dose reductions may be made based on events observed at any time during 
treatment with study drug; however, for the purposes of dose cohort escalation/de-escalation, 
expanding a dose cohort, and determining the MTD/PAD of study drug, decisions will be made 
based on events that are observed from the first day of study drug administration through and 
including study Day 28.  A lower MTD may subsequently be determined based on relevant 
toxicities that become evident after study Day 28. 
Table 3: 
Definition of Dose-Limiting Toxicity 
Nonhematologic toxicity 
• Any ≥ Grade 3 nonhematologic toxicity EXCEPT the following: 
- Transient (≤ 72 hours) abnormal laboratory values without associated clinically significant signs or symptoms.  
- Nausea, vomiting, and diarrhea adequately controlled with supportive care within 48 hours. 
- Changes in cholesterol and triglycerides. 
- An event clearly associated with the underlying disease, disease progression, a concomitant medication, or 
comorbidity. 
- Asymptomatic changes in lipid profiles. 
- Asymptomatic changes in amylase and lipase. 
- Single or nonfasting elevations in blood glucose (ie, blood glucose excursions will be considered toxicities if 
fasting blood glucose is elevated on 2 separate occasions). 
Hematologic toxicity 
• Grade 3 thrombocytopenia with clinically significant bleeding (ie, requires hospitalization, transfusion of blood 
products, or other urgent medical intervention). 
• Grade 4 thrombocytopenia. 
• ≥ Grade 3 febrile neutropenia (absolute neutrophil count < 1.0 × 109/L and fever > 101°F/38.3°C).  
• Grade 4 neutropenia that does not recover to ≤ Grade 2 in ≤ 3 days after interrupting study drug. 
• Grade 4 anemia not explained by underlying disease or some other concomitant disorder. 
Immune-related toxicitya  
• ≥ Grade 2 ocular irAEs will be considered a DLT. 
• Grade 3 irAEs that do not improve to baseline or at least Grade 1 in < 5 days with appropriate care or with 
corticosteroid therapy will be considered a DLT.   
• Grade 4 irAEs will be considered a DLT regardless of duration.   
General  
• Inability to receive the planned number of doses within the 28-day DLT period due to toxicity, regardless of grade, 
will be considered a DLT. 

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Table 3: 
Definition of Dose-Limiting Toxicity (Continued) 
MTD 
• In Part 1 of the study, the MTD will be defined as 1 dose level below that at which ≥ one-third of subjects in a 
particular cohort have DLTs. 
• In Part 2 of the study, toxicities will continue to be monitored.  If the cumulative incidence of DLTs occurs in 
> 33% of subjects after 6 subjects have been observed for at least 28 days, then further enrollment may be 
interrupted, and the investigators and sponsor will meet and reassess the MTD.  All AEs, regardless of the time of 
occurrence on study, may be considered in determining the appropriate dose, schedule, and MNTD.  
MNTD 
• Throughout the treatment period, if > 33% of subjects (minimum of 6 subjects) experience a ≥ Grade 3 toxicity 
related to study drug after completing ≥ 4 cycles, then dose administration will be stopped, and the MNTD will be 
determined in conjunction with the investigators and sponsor based on all available safety data. 
 
a Immune-related AEs are a diagnosis of exclusion, after alternative etiologies have been ruled out. 
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 sponsor (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 and Adjustments of Study Drug 
Treatment with study drug may be delayed to allow for resolution of toxicity.  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.  For 
toxicities that occur outside of the 28-day DLT period, 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 with study drug. 
Instructions for dose modifications and interruptions are outlined in Table 4.  Individual 
decisions regarding dose interruptions and reductions should be made using appropriate clinical 
judgment in consultation with the medical monitor, 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-reduction 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 

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holidays).  Subjects should be placed back on study therapy within 4 weeks (28 days) of the 
scheduled interruption, unless otherwise discussed with the sponsor.  The reason for interruption 
should be documented in the subject's study record. 
Table 4: 
Rules for Interruption and Restarting of Study Drug 
CTCAE  
Grade or Severity 
Timing for  
Restarting Treatment 
Dose Level for 
Restarting Treatment 
Treatment Discontinuation 
1-2 (mild-moderate) 
Continue treatment at the 
discretion of the investigator. 
N/A 
N/A 
3 (severe) 
Toxicity resolves to Grade 0-1. 
Reduce by 1 dose level.a 
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) 
Permanently discontinue. 
N/A 
Permanently discontinue. 
Note:  Permanently discontinue for any severe or Grade 3 AE that recurs or any life-threatening event. 
a No more than 2 dose reductions of study drug are permitted, or 1 dose reduction of study drug if the starting dose is 0.03 mg/kg 
(see Table 2).  Subjects should be permanently discontinued from study drug if they have AEs requiring more than 2 dose 
reductions of study drug. 
5.4.7. 
Definition, Procedures, and Supportive Care Guidelines for Immune-Related 
Adverse Events 
INCAGN01876 is an immune modulator, and although no toxicities were identified in 
preclinical models, it is possible that irAEs (both nonserious and serious) similar to those 
described with approved immunotherapies may occur.  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 eliminated.  
Immune-related AEs may be expected based on the nature of INCAGN01876, its mechanism of 
action, and based on reported experience with 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 5.  Detailed supportive care 
guidelines for specific irAEs can be in found in Appendix B.  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 5: 
Supportive Care Guidelines for Subjects Exhibiting Immune-Related 
Adverse Events 
CTCAE Grade/Severity 
Supportive Carea 
Grade 1 (mild) 
• Monitor symptoms and provide symptomatic treatment. 
Grade 2 (moderate) 
• Monitor symptoms and provide symptomatic treatment. 
• Consider consultation with specialists as necessary. 
• Consider systemic corticosteroids per institutional standard of care. 
Grade 3-4  
(severe–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 drug should 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 in found in Appendix B. 
5.4.8. 
Management of Infusion Reactions 
Table 6 shows treatment guidelines for subjects who experience an infusion reaction associated 
with administration of study drug.  Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 

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Table 6: 
INCAGN01876 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 interrupted 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 drug administration. 
Subject may be premedicated 1.5 h 
(± 30 min) prior to 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: 
• 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 drug administration. 
No subsequent dose. 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated. 
NSAID = nonsteroidal anti-inflammatory drug. 
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 an unacceptable toxicity not caused by the underlying malignancy will be 
presumed to be related to study drug and will require that the study drug be permanently 
discontinued.  Unacceptable toxicity is defined as follows: 
• Grade 4 or life-threatening AEs (see Table 4 and Table 6). 
• ≥ Grade 2 ocular irAE. 
• Occurrence of an AE that is related to treatment with the study drug that, in the 
judgment of the investigator or the sponsor's medical monitor, compromises the 
subject's ability to continue study-specific procedures, or is considered to not be in 
the subject's best interest. 
• An AE requiring more than 2 dose reductions of study drug, or more than 1 dose 
reduction of study drug if the starting dose is 0.03 mg/kg (see Table 2). 
• Persistent AE requiring a delay of study drug beyond 4 weeks (28 days), unless the 
delay has been approved by the sponsor. 
5.4.10. 
Treatment After Initial Evidence of Radiologic Disease Progression 
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 may manifest 
as a clinical response after an initial increase in tumor burden or even the appearance of new 
lesions. 
If radiologic imaging shows disease progression, then subjects have the option to continue 
treatment while awaiting radiographic confirmation of progression as outlined in Section 7.7.1.1. 
5.5. 
Withdrawal of Subjects From Study Drug 
5.5.1. 
Withdrawal Criteria 
A subject may choose to withdraw from the study at any time or be withdrawn from the study by 
the investigator or sponsor, if the subject is noncompliant with the study requirements.  Subjects 
may also be withdrawn at the discretion of the FDA or health authorities.  If a subject is 
withdrawn, then every reasonable effort should be made to determine the reason for withdrawal, 
and this information should be recorded in the electronic case report form (eCRF). 
Subjects must be withdrawn from study drug 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. 
• Further participation would be injurious to the subject's health or well-being, in the 
investigator's medical judgment. 
• The subject is lost to follow-up. 

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• Unacceptable toxicity (see Section 5.4).  Subjects with unacceptable toxicities must 
be withdrawn from study drug but will continue to be followed during the safety 
follow-up visits as specified in Section 6.4. 
• The study is terminated by the sponsor. 
• The study is terminated by the local health authority, IRB, or IEC. 
A subject may be discontinued from study drug as follows: 
• Confirmed radiographic progression of disease per mRECIST v1.1.  See 
Section 7.7.1. 
Note:  For unconfirmed progression, see Section 7.7.1. 
Note:  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. 
• If, during the course of the study, a subject is found not to have met eligibility criteria 
(see Section 3), then the medical monitor, in collaboration with the investigator, will 
determine whether the subject should be withdrawn from the study. 
• If a subject is noncompliant with study procedures or study drug administration in the 
investigator's opinion, then 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 drug, the subject will 
be withdrawn from the study, and the end-of-treatment (EOT) visit should be conducted.  
Reasonable efforts should be made to have the subject return for follow-up visits.  These visits 
are described in Section 6.  The last date of the last dose of study drug and the reason for subject 
withdrawal will be recorded in the eCRF. 
If a subject is withdrawn from the study: 
• The study monitor or sponsor must be notified. 
• The reason(s) for withdrawal must be documented in the subject's medical record and 
in the eCRF. 
• The EOT visit should be performed. 
• The date of the EOT visit should be recorded in the IWRS. 
• Subjects must be followed for safety until the time of the follow-up visit or until 
study drug–related toxicities resolve, return to baseline, or are deemed irreversible, 
whichever is longest. 
If the subject discontinues study drug and actively withdraws consent for collection of follow-up 
data (safety follow-up or disease assessment), then no additional data collection should occur; 
however, subjects will have the option of withdrawing consent for study drug but continuing in 
the follow-up period of the study for safety/efficacy 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 drug and 60 days after the last 
dose of study drug 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 drug 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 
Use of systemic glucocorticoids is restricted to prophylaxis for contrast allergies for radiographic 
procedures, or to modulate symptoms or treat an AE of suspected immunologic etiology.  The 
use of physiologic corticosteroid replacement therapy may be approved after consultation with 
the sponsor. 
Note:  Inhaled and topical steroids are allowed.  A short course of steroids (prednisone or 
equivalent) ≤ 10 mg/day may be permitted with sponsor approval. 
• Acetaminophen and nonsteroidal anti-inflammatory agents (NSAIDs; eg, ibuprofen) 
may be used.  Due to the risk of liver injury with the use of high doses of 
acetaminophen, subjects should be advised to stay within the recommended daily 
dose of acetaminophen. 
5.6.3. 
Prohibited Medications 
Medications or vaccinations specifically prohibited in the exclusion criteria (see Section 3.2) are 
not allowed during the ongoing study.  If there is a clinical indication for one of these 
medications or vaccinations specifically prohibited during the study, discontinuation from study 
drug or vaccination may be required.  The investigator should discuss any questions regarding 
this with the sponsor.  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 drug or vaccination schedule 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 
the study drug. 
• Any immunological-based treatment for any reason from screening through follow-up 
visit. 
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 of immune toxicities 
as described in Section 5.4.7 and Appendix B. 
Note:  Allergy shots may be permitted after consultation with the medical monitor. 
• Investigational agents other than the study drug from screening through the follow-up 
visits. 
• 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 drug 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 (eg, FluMist®) 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 assessments (see 
Table 7) and all laboratory assessments will be performed as indicated in Table 8 and Table 9.  
Table 10 presents a summary of clinical laboratory analytes to be assessed.  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 7: 
Schedule of Assessments 
Visit Day (Range) 
Protocol 
Section 
Screening 
Treatmenta 
Post-Treatmentb 
Cycle 1 and Cycle 2 
All Subsequent 
Cycles 
Every 8 weeks 
EOT 
Safety 
Follow-Up  
Visit 1 
Safety 
Follow-Up 
Visit 2 
Day 1 
Day 7 
Day 1 
Disease Status 
Evaluation/Window 
Day -28 
to -1 
 
± 1 day 
± 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 
 
 
 
 
 
 
Contact IWRS 
7.2 
X 
X 
 
X 
 
X 
 
 
Medical and cancer history 
7.3 
X 
 
 
 
 
 
 
 
Prior/concomitant 
medications 
7.4 
X 
X 
X 
X 
 
X 
X 
X 
Administer INCAGN01876 
5.2.1 
 
X 
 
X 
 
 
 
 
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 
X 
 
X 
X 
X 
Vital signs and weight  
7.6.3 
X 
Xc 
X 
X 
 
X 
X 
X 
ECOG performance status 
Appendix D 
X 
X 
X 
X 
 
X 
X 
X 
Laboratory assessments 
7.6.5 
X 
Xd 
X 
X 
 
X 
X 
X 
12-lead ECGe 
7.6.4 
Xf,g 
Xg 
 
Xg,h 
 
X 
X 
 
AE assessment 
7.6.1 
X 
X 
X 
X 
 
X 
X 
X 
Efficacy measurements 
 
Radiologic tumor 
assessments 
7.7 
Xi 
 
 
 
Xj 
Xk 
Xk 
a Treatment cycles will begin every 14 days (± 3 days).  Alternate dosing schedules may also be explored based on emerging safety, PK
 data. 
b The mandatory safety follow-up visits should be conducted approximately 30 days and 60 days after the last dose of study drug or before the initiation of a new anticancer 
treatment, whichever comes first. 
c On Day 1 of the first 4 cycles (C1D1, C2D1, C3D1, and C4D1), subjects will be required to stay at the study site for safety observation for up to 4 hours postinfusion.  It is 
recommended that the subject does not leave the site for any reason during the safety observation period.  During the safety observation period, vital signs (blood pressure, pulse, 
respiratory rate, and body temperature) will be assessed every 60 minutes ± 10 minutes (eg, 1 hour postinfusion, 2 hours postinfusion, 3 hours postinfusion, etc).  Subjects will 
also be assessed for the onset of acute AEs. 

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d Laboratory assessments may also be required on additional visit days as described in Table 8 and Table 9. 
e 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. 
f 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 or with approval from the medical monitor. 
g Triplicate ECG measurements are required at screening, C1D1 (in conjunction with PK samples), and C6D1 (in conjunction with PK samples).  Subsequent ECGs only 
need to be performed in triplicate if there has been a QT prolongation on study or if the ECG shows a clinically significant abnormality not present at baseline.  See Table 11 for 
information regarding timing of triplicate ECGs. 
h A 12-lead ECG should be performed on Day 1 of every other cycle after Cycle 2 (eg, Cycle 4, Cycle 6, Cycle 8, Cycle 10). 
i The initial tumor imaging will be performed within 28 days before the first dose of study drug.  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 drug.  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 and then every 12 weeks (± 7 days) thereafter.  Imaging should follow 
calendar days 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 prior to the date of 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).  
For subjects who discontinue treatment for reasons other than disease progression, every effort should be made to continue monitoring their disease status every 8 weeks 
(± 7 days) by radiographic imaging until 1) start of new antineoplastic therapy, 2) documented disease progression, 3) death, or 4) the end of the study, whichever occurs first. 

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Table 8: 
Schedule of Laboratory Assessments 
 
 
 
Treatment 
Post-Treatment 
Visit Day (Range) 
Protocol 
Section 
Screening 
C1 and C2 
Odd Numbered Cycles 
(C3, C5, C7, C9, etc) 
Even Numbered Cycles 
(C4, C6, C8, etc) 
EOT 
Safety 
Follow-Up 
Visit 1 
Safety 
Follow-Up 
Visit 2 
D1 
D7 
D1  
D1 
Evaluation/Window 
 
Day 
-28 to -1 
Predose 
± 1 day 
± 3 days 
± 3 days 
± 3 days 
30 days  
(+ 7 days) 
60 days  
(+ 7 days) 
Local Laboratory Testsa 
Comprehensive serum chemistriesb 
7.6.5 
Xc 
X 
X 
X 
X 
X 
X 
X 
Hematology with differential 
7.6.5 
Xc 
X 
X 
X 
X 
X 
X 
X 
Coagulation panel  
7.6.5 
Xc 
X 
X 
X 
 
X 
X 
X 
Urinalysis 
7.6.5 
Xc 
X 
X 
X 
 
X 
 
 
Endocrine function tests 
7.6.5 
Xc 
X 
X 
X 
 
X 
X 
X 
Hepatitis B and C 
7.6.5.2 
Xc 
 
 
 
 
 
 
 
Serum pregnancy test 
(childbearing females only)d 
7.6.5.1 
Xc 
 
 
 
 
X 
 
 
Urine pregnancy test (childbearing 
females only)e 
7.6.5.1 
 
 
 
X 
X 
 
 
 
a All safety laboratory assessments will be performed locally. 
b If liver chemistry tests are abnormal (eg, change in grade from baseline), then liver chemistry monitoring should increase to once per week until resolved to baseline.  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. 
c 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. 
d A serum pregnancy test will be required for all women of childbearing potential during screening and must be within 72 hours before the first dose of study drug. 
e Urine pregnancy tests will be conducted as medically indicated or per country-specific requirements. 

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Table 9: 
Schedule of Pharmacokinetic 
 Assessments 
Visit Day (Range) 
Protocol 
Section 
Timing of 
Assessment 
Screening 
Treatment 
Post-
Treatment 
C1  
C2 
C3 
C4 
C6 
C7 
C8 & 
C12 
Safety 
Follow-Up 
Visit 1 
D1 
D2 
D7 
D1 
D1 
D1 
D1 
D2 
D7 
D1  
D1 
Evaluation/Window 
 
 
Day 
-28 to -1 
 
24 h 
± 1 
day 
± 1 
day 
± 3 
days 
± 3 
days 
± 3 
days 
24 h 
± 1 
day 
± 3 
days 
± 3 
days 
30 days  
(+ 7 days) 
Pharmacokinetic Assessmentsa 
Serum sample for PK 
7.8 
Table 13 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
a All PK assessments will be performed by a central laboratory.  Details regarding PK samples including specimen handling, processing, and shipping will be outlined in the 
laboratory manual.  

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Table 10: 
Local Laboratory Tests:  Required Analytes 
Serum Chemistry 
Hematology 
Other 
Albumin  
Alkaline phosphatase 
Alanine aminotransferase 
Aspartate aminotransferase 
Bicarbonate 
Blood urea nitrogen  
Calcium 
Chloride 
Creatinine 
Glucose 
Lactate dehydrogenase 
Phosphorus 
Potassium 
Sodium 
Total bilirubin 
Direct bilirubin (If total 
bilirubin is elevated above 
ULN) 
Total protein 
Uric acid 
Amylase 
Lipase 
 
 
Complete blood count, 
including:  
• Hematocrit 
• Hemoglobin 
• Mean corpuscular volume 
• Platelet count 
• Red blood cell count 
• White blood cell count 
 
Differential count, including: 
• Basophils 
• Eosinophils 
• Lymphocytes 
• Monocytes 
• Neutrophils 
 
Absolute values must be 
provided for the following 
WBC differential laboratory 
results:   
• White blood cells 
• Lymphocytes 
• Neutrophils 
Hepatitis 
Hepatitis B surface antigen 
Hepatitis B core antibody 
HBV-DNA 
Hepatitis C virus antibody 
HCV-RNA 
Pregnancy Testa 
Female subjects of childbearing potential only 
require a serum test at screening.  
Pregnancy tests (serum or urine) should be 
repeated if required by local regulations. 
Urinalysis  
Color and appearance 
pH and specific gravity 
Bilirubin 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Occult blood 
Protein 
Urobilinogen 
Coagulation 
PT  
aPTT 
INR 
 
Endocrine Monitoring 
 
Thyroid-stimulating hormone 
Free thyroxine 
Total triiodothyronine/free triiodothyronineb 
Note:  Additional tests may be required, as agreed by investigator and sponsor, based on emerging safety data. 
a Urine pregnancy tests are only required if medically indicated or a country-specific requirement. 
b If considered standard by your region. 
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 

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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 or administration of study drug.  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 drug (Cycle 1 
Day 1) through the point at which the investigator determines that the subject will be 
permanently discontinued from study drug.  Cycle 1 Day 1 must be no more than 28 days after 
the subject has signed the ICF. 
Subjects will have regularly scheduled study visits on Day 1 of every cycle ± 3 days.  Additional 
visits will be required on Day 2 of Cycles 1 and 6, and Day 7 of Cycles 1, 2, and 6.  During study 
visits, the subject will have clinical and laboratory assessments as outlined in Table 7 and 
Table 8.  At certain study visits as indicated in Section 7.8 and Section 7.9, subjects will have 
PK, 
 samples obtained (see Table 9).  Toxicities will be monitored 
continuously and will be graded using the NCI CTCAE v4.03 criteria. 
On Day 1 of the first 4 cycles (Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, and Cycle 4 
Day 1), subjects will be required to stay at the study site for safety observation for up to 
4 hours postinfusion.  It is recommended that the subject does not leave the site for any reason 
during the safety observation period.  During the safety observation period, subjects will be 
assessed for the onset of acute AEs. 
6.3. 
End of Treatment 
When the subject permanently discontinues study drug, the EOT visit should be conducted.  If 
the EOT visit coincides with a regular study visit, then 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 follow-up visit(s). 
6.4. 
Follow-Up 
6.4.1. 
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 EOT visit (or after 
the last dose of study drug if the EOT visit was not performed).  Adverse events and SAEs must 
be reported up until at least 60 days after the last dose of study drug, the date of the follow-up 
visit, or until toxicities resolve, return to baseline, or are deemed irreversible, whichever is 

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longer.  If a subject is scheduled to begin a new anticancer therapy before the end of the 30-day 
or the 60-day safety follow-up period, then the safety follow-up visit should be performed before 
new anticancer therapy is started. 
6.4.2. 
Disease Status Follow-Up 
Subjects who discontinue study drug for a reason other than disease progression will move into 
the disease status follow-up period and should continue to be assessed every 8 weeks (± 7 days) 
for the first 12 months and then every 12 weeks (± 7 days) thereafter, by radiologic imaging to 
monitor disease status.  Every effort should be made to collect information regarding disease 
status until the earliest of the following: 
• The start of new anticancer therapy. 
• Disease progression. 
• Death. 
• The end of the study. 
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 drug 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 subject before conducting any study-specific 
procedures using an ICF approved by the local IRB/IEC.  The ICF should contain all elements 
required by ICH E6 and describe the nature, scope, and possible consequences of the study in a 
manner that the subject can understand.  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 Web Response System Procedure 
The investigator or designee will assign a subject number when a subject enters the screening 
phase.  Upon determining that the subject is eligible for the study (see Section 3.1 and 
Section 3.2), the subject will be entered into the IWRS.  The IWRS will be contacted to update 
the subject's status and for study drug supply.  Refer to the IWRS 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, primary tumor histology, 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.  All concomitant medications and measures must be recorded in the eCRF, and any 
medication received or procedure performed within 28 days before the first dose of study drug 
and up to the end of the follow-up phase of the study 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 drug.  If a subject initiates a new anticancer therapy within 30 to 60 days after 
the last dose of study drug, 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 
7.6.2.1. 
Comprehensive Physical Examination 
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. 
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.  
Clinically notable abnormalities that are considered clinically significant in the judgment of the 
investigator are to be reported as AEs. 

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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.  Clinically notable abnormalities that are considered clinically significant in the 
judgment of the investigator are to be reported as AEs. 
7.6.3. 
Vital Signs and Weight 
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.  On Day 1 of the first 4 cycles (C1D1, C2D1, C3D1, and 
C4D1), subjects will be required to stay at the study site for safety observation for up to 4 hours 
postinfusion.  It is recommended that the subject does not leave the site for any reason during the 
safety observation period.  During the safety observation period, vital signs (blood pressure, 
pulse, respiratory rate, and body temperature) will be assessed every 60 minutes ± 10 minutes 
(eg, 1 hour postinfusion, 2 hours postinfusion, 3 hours postinfusion, etc). 
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 with the subject in a recumbent or semirecumbent position 
after 5 minutes of rest and should not be performed within 15 minutes of a blood collection.  All 
12-lead ECGs will be acquired using an ECG analysis system with analysis and printing 
capabilities, as well as digital transmission capabilities to a central capture module at the central 
ECG laboratory. 
Timed triplicate ECGs (separated by 5 minutes) will be conducted at screening and in 
conjunction with the pre- and postinfusion PK timepoints on C1D1 and C6D1 (see Table 11).  
The specified postdose timepoint may be adjusted based on emerging PK data. 
A 12-lead ECG should be performed on Day 1 of every other cycle after Cycle 2 (eg, Cycle 4, 
Cycle 6, Cycle 8, Cycle 10, etc).  Subsequent ECGs only need to be performed in triplicate if 
there has been a QT prolongation on study or the ECG shows a clinically significant abnormality 
not present at baseline. 
The automated 12-lead ECGs readings will be interpreted by the investigator, or qualified 
designee at the site to be used for immediate subject management.  The decision to include or 
exclude a subject or withdraw a subject from the study based on a centrally analyzed ECG 
flagged as "Abnormal, Clinically Significant" is the responsibility of the investigator, in 
consultation with the medical monitor, as appropriate.  Clinically significant abnormal findings 
before signing consent should be recorded as medical history.  Clinically significant abnormal 
findings after signing consent should be recorded as an AE.  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 

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interval may be used in place of the QTc with sponsor approval.  In addition, the JTc interval 
should be used for all subsequent assessments. 
Table 11: 
Timing of Triplicate Electrocardiograms 
Study Visit 
Timing of Sample 
Any Time 
Preinfusion 
Postinfusion 
PK Timepoint 
4-Hr Postinfusion 
PK Timepoint 
Screening 
X 
 
 
 
C1D1 
 
Xa 
Xb 
Xa 
C6D1 
 
Xa 
Xb 
Xa 
a Electrocardiograms should be conducted before but within 30 minutes of the PK blood draw at the corresponding timepoint. 
b Electrocardiograms should be performed 15 to 30 minutes after the corresponding PK sample is drawn. 
7.6.5. 
Laboratory Assessments 
A 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 8.  Table 10 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. 
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 the EOT visit.  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 8, 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 drug and continue participation in the study. 
7.6.5.2. 
Hepatitis Screening Tests 
Hepatitis screening assessments will be performed at the screening visit (Table 8) to rule out 
hepatitis infection; required analytes are shown in Table 10.  Generally, hepatitis tests should be 

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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 v1.1 Assessment of Disease 
Modified RECIST will be applied by the site as the primary measure for assessment of tumor 
response and as a basis for Protocol guidelines related to disease status (eg, discontinuation of 
study therapy).  As noted in Section 1.3.4, 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, then tumor assessments should 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 12 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. 
Table 12: 
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 

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7.7.1.1.2. Tumor Imaging During the Study 
The first imaging assessment should be performed 8 weeks after the first dose of study drug and 
then every 8 weeks (56 days ± 7 days) for 12 months and then every 12 weeks thereafter until 
disease progression is determined.  Imaging assessments may be done more frequently if 
clinically indicated.  Imaging should not be delayed for delays in cycle starts. 
Per mRECIST v1.1, response should be confirmed by a repeat radiographic assessment not less 
than 4 weeks from the date that the response was first documented.  The scan for confirmation of 
response may be performed at the earliest 4 weeks after the first indication of response or at the 
next scheduled scan, whichever is clinically indicated. 
Imaging should continue to be performed until documented disease progression, the start of new 
anticancer treatment, withdrawal of consent, death, or the end of the study, whichever occurs 
first.  Disease progression should be confirmed at least 4 weeks, but no later than 6 weeks after 
the first scan indicating progression in clinically stable subjects.  Subjects who have unconfirmed 
disease progression may continue on treatment until progression is confirmed, provided that they 
have met the conditions detailed in Section 7.7.1.  A central imaging vendor will not be used in 
this study. 
7.7.1.1.3. Imaging During Follow-Up 
If the subject discontinues study drug for reasons other than disease progression, imaging 
assessments should continue at the Protocol-specified interval until documented disease 
progression, the start of new anticancer treatment, withdrawal of consent, death, or the end of the 
study, whichever occurs first.   
7.8. 
Pharmacokinetic Assessments 
7.8.1. 
Blood Sample Collection 
Pharmacokinetic 
 samples will be obtained at the visits indicated in Table 9.  Timing of 
PK 
 assessments are outlined in Table 13.  After the predose PK sample is drawn, 
subjects will begin the study drug infusion.  Predose is defined as within 24 hours before 
administration of study drug.  Adjustments to the timing of blood sampling may be made based 
on emerging PK data.  The exact date and time of each PK blood draw will be recorded in the 
eCRF.  Instructions for sample preparation and shipping will be provided in the Laboratory 
Manual. 

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7.10. 
Other Study Procedures 
7.10.1. 
Distribution of Subject Reminder Cards 
Subjects will be provided with a reminder card at each visit.  The subject reminder card will 
remind the subject of the date/time of the next visit. 
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 drug.  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 4.  The CTCAE 
v4.03 severity of Grade 5 will not be used; AEs resulting in death will be graded accordingly 
using Grades 1 through 4 and have the outcome noted as fatal.   

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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. 
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 4). 
• Whether there is at least a reasonable possibility that the AE is related to the study 
treatment:  suspected (yes) or not suspected (no). 
• 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 (severe) 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 drug, whichever is later) 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 
drug should be reported to the sponsor or its designee only if the investigator suspects a causal 
relationship to the study drug.   
Information about all SAEs is collected and recorded on the Adverse Event form of the eCRF.  
The investigator must assess and record the causal relationship of each SAE to the study 
treatment.   
The investigator must also complete the Incyte Serious Adverse Event Report Form, in English, 
and send the completed and signed form to the sponsor or designee within 24 hours of becoming 
aware of the SAE.  The investigator must provide a causality assessment, that is, assess whether 
there is at least a reasonable possibility that the SAE is related to the study treatment:  suspected 
(yes) or not suspected (no).  Refer to the Incyte Reference Guide for Completing the Serious 
Adverse Event Report Form. 
The contact information of the sponsor's study-specific representatives is listed in the 
investigator manual provided to each site.  The original copy of the SAE Report Form and the 
confirmation sheet must be kept at the study site. 
Investigational site personnel must report any new information regarding the SAE within 
24 hours of becoming aware of the information in the same manner that the initial SAE Report 
Form was sent.  Follow-up information is recorded on an amended or new SAE Report Form, 
with an indication that it is follow-up to the previously reported SAE and the date of the original 
report.  The follow-up report should include information that was not provided on the previous 
SAE Report Form, such as the outcome of the event (eg, resolved or ongoing), treatment 
provided, action taken with study drug because of the SAE (eg, dose reduced, interrupted, or 
discontinued), or subject disposition (eg, continued or withdrew from study participation).  Each 
recurrence, complication, or progression of the original event should be reported as follow-up to 
that event, regardless of when it occurs. 
If the SAE is not documented in the 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 (IN) to inform all investigators involved in any 
study with the same drug that this SAE has been reported.  Suspected Unexpected Serious 
Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and 
relevant ethics committees in accordance with Directive 2001/20/EC, or as per national 
regulatory requirements in participating countries. 
8.4. 
Emergency Unblinding of Treatment Assignment 
Not applicable.  

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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, 
within 60 days of the last dose of study drug or within 30 days after cessation of treatment if the 
subject initiates new anticancer therapy, the following procedures should be followed in order to 
ensure subject safety: 
• The study drug must be discontinued immediately (female subjects only). 
• The investigator must complete and submit the Incyte Clinical Trial Pregnancy form 
to the sponsor or its designee within 24 hours of learning of the pregnancy. 
• 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 test 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 drug 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.  Additional safety 
information collected between IB updates will be communicated in the form of Investigator 
Notifications (INs).  Any important new safety information should be discussed with the subject 
during the study, as necessary.  If new significant risks are identified, they will be added to the 
ICF. 
8.7. 
Data Monitoring Committee 
There will be no formal Data Monitoring Committee for this open-label study.  For Part 1, the 
sponsor will conduct telephone conferences with investigators in order to review cohort-specific 
data, to review overall safety data from prior cohorts (if applicable), and to agree on dose 

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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 Code of Federal Regulations (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. 
• 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. 
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 

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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 Electronic Data Capture 
(EDC) system.  All data entry, verification, and validation will be performed in accordance with 
the current standard operating procedures of the Data Management Department at the sponsor or 
its designee.  The database will be authorized for lock once all defined procedures are completed. 
The investigator will be provided with access to an EDC system so that an eCRF can be 
completed for each subject.  Entries made in the eCRF must be verifiable against source 
documents; if updates to the database are not possible, any discrepancies should be explained 
and documented.  The investigator will be responsible for reviewing all data and eCRF entries, 
and will sign and date the designated forms in each subject's eCRF, verifying that the 
information is true and correct.  The investigator is responsible for the review and approval of all 
query responses. 
Protocol deviations will be identified and recorded in the Protocol Deviation form of the eCRF.  
The study monitor will reference the Monitoring Plan in order to ensure that each issue identified 
is appropriately documented, reported, and resolved in a timely manner in accordance with the 
plan's requirements. 
10.4. 
Data Privacy and Confidentiality of Study Records 
The investigator and the sponsor or its designee must adhere to applicable data privacy laws and 
regulations.  The investigator and the sponsor or their designees are responsible for ensuring that 
sensitive information is handled in accordance with local requirements (eg, HIPAA).  
Appropriate consent and authorizations for use and disclosure and/or transfer (if applicable) of 
protected information must be obtained. 
Subject names will not be supplied to the sponsor or its designee, if applicable.  Only the subject 
number and subject's initials (subject's initials will only be recorded if allowable by local 
regulations) will be recorded in the eCRF, where permitted; if the subject's name appears on any 
other document (eg, laboratory report), it must be obliterated on the copy of the document to be 
supplied to the sponsor or its designee.  Study findings stored on a computer will be stored in 
accordance with local data protection laws.  The subjects will be informed that representatives of 
the sponsor or its designee, IRB or IEC, or regulatory authorities may inspect their medical 

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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 Europe 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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11. 
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Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within 
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Gurney AL, Marsters SA, Huang RM, et al. Identification of a new member of the tumor 
necrosis factor family and its receptor, a human ortholog of mouse GITR. Curr Biol 
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protein co-stimulation facilitates tumor regression by inducing IL-9-producing helper T cells. 
Nat Med 2015;21:1010-1017. 
Kim ST, Jeong H, Woo OH, et al. Tumor-infiltrating lymphocytes, tumor characteristics, and 
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Matsushita H, Vesely MD, Koboldt DC, et al. Cancer exome analysis reveals a T-cell-dependent 
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systematic review and meta-analysis. Br J Cancer 2014;110:1595-1605. 
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APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS 
For Subjects Participating in the Study: 
The following methods that can achieve a failure rate of less than 1% per year when used 
consistently and correctly are considered as highly effective birth control methods.  
Such methods include: 
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation1 
− oral 
− intravaginal 
− transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation1 
− oral 
− injectable 
− implantable2 
• Intrauterine device (IUD)2 
• Intrauterine hormone-releasing system (IUS)2 
• Bilateral tubal occlusion2 
• Vasectomised partner2,3 
• Sexual abstinence4 
 
1  Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the 
contraception method. 
2  Contraception methods that in the context of this guidance are considered to have low user dependency. 
3  Vasectomised partner is a highly effective method provided of avoiding pregnancy that partner is the sole sexual 
partner of the WOCBP trial participant and that the vasectomised partner has received medical assessment of the 
surgical success.  
4  In the context of this guidance, sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments.  The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the subject. 
Source:  CTFG 2014. 

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APPENDIX B. 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 Guidelines 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 hypoxia, 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 Guidelines for treatment of cancer-related infections 
(Category 2B recommendation).  

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irAE 
Supportive Care 
Diarrhea/Colitis 
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 Guidelines for treatment of cancer-related infections [Category 2B 
recommendation]). 
For Grade 3 or 4 (severe or new symptoms, new/worsening hypoxia, 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 Guidelines 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 Guidelines for treatment of cancer-related infections [Category 2B 
recommendation]). 
For Grade 3 or 4 (severe or new symptoms, new/worsening hypoxia, 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 Guidelines 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 the study drug 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 hypoxia, 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 Guidelines 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 Guidelines 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 report 
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 hypoxia, 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 
treateating with additional immunosuppressive therapy (eg, IV IgG), after 
discussing with the medical monitor. 
For Grade 3 or 4 (severe or new symptoms, new/worsening hypoxia, 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. PHARMACOKINETIC ANALYTICAL PARAMETERS 
Cave 
Average steady-state plasma concentration (AUC0-12h/12h or 
AUC0-24h/24h) 
Cmax 
Maximum observed plasma concentration 
Cmin 
Minimum observed plasma concentration during the dosing interval 
Tmax 
Time to maximum plasma concentration 
AUC0-t 
Area under the single-dose plasma concentration-time curve from Hour 0 
to the last quantifiable measurable plasma concentration, calculated by the 
linear trapezoidal rule for increasing concentrations and the log 
trapezoidal rule for decreasing concentrations 
AUC0-τ (ie, 
AUC0-12h or 
AUC0-24h) 
Area under the steady-state plasma concentration-time curve over 
1 dosing interval (ie, from Hour 0 to 12 for BID administration or from 
Hour 0 to 24 for QD administration), calculated by the linear trapezoidal 
rule for increasing concentrations and the log trapezoidal rule for 
decreasing concentrations 
λz 
Apparent terminal phase disposition rate constant, where λz is the 
magnitude of the slope of the linear regression of the log concentration 
versus time profile during the terminal phase 
t½ 
Apparent plasma terminal phase disposition half-life (whenever possible), 
where t½ = (ln2) / λz 
Cl/F 
Oral dose clearance 
Vz/F 
Apparent oral dose volume of distribution 
Fluctuation 
Steady-state fluctuation ([Cmax – Cmin]/Cave) 
In addition, the following PK parameters may be calculated, whenever possible, for each subject: 
Ae 
Amount of drug excreted in the urine over sampling interval 
Clr 
Renal clearance, where Clr = Ae/AUC 
% Excreted or fe 
percent excreted in the urine, where % Excreted = 100 (Ae/dose) 
Pharmacokinetic calculations will be performed, if appropriate, using commercial software such 
as WinNonlin® (Pharsight Corporation, Cary, NC).  Additional details of analyses will be 
described in the statistical analysis plan. 

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APPENDIX D. EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS 
Grade 
Performance Status 
0 
Fully active, able to carry on all predisease performance without restriction  
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, eg, light house work, office work  
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities.  Up and 
about more than 50% of waking hours  
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours  
4 
Completely disabled.  Cannot carry on any selfcare. Totally confined to bed or chair  
5 
Dead  
Source:  Oken et al 1982.