Conditions: Solid Tumors Advanced Malignancies Metastatic Cancer
Keywords: Solid tumors NSCLC CRC
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 70
Healthy volunteers: no

Brief summary:
This is an open-label, Phase 1/2 study in subjects with advanced or metastatic solid tumors. The study has three separate treatment groups where separate epigenetic agents are evaluated with an immunotherapy combination. Treatment Group A will evaluate the DNA methyltransferase inhibitor azacitidine in combination with the programmed death receptor-1 (PD-1) inhibitor pembrolizumab and the indoleamine 2,3-dioxygenase (IDO-1) inhibitor epacadostat; Treatment Group B will evaluate the bromodomain and extra-terminal (BET) inhibitor INCB057643 with pembrolizumab and epacadostat; and Treatment Group C will evaluate the lysine-specific demethylase 1A (LSD1) inhibitor INCB059872 with pembrolizumab and epacadostat. The study will be divided into 2 parts (Part 1 and 2). Part 1 is a dose-escalation assessment to evaluate the safety and tolerability of the combination therapies. Once the recommended doses have been determined, subjects with previously treated NSCLC, microsatellite-stable colorectal cancer (CRC), head and neck squamous cell carcinoma, urothelial carcinoma, and melanoma will be enrolled into expansion cohorts in Part 2.

Detailed description:

Arms:
arm 1: Part 1 is an open-label 3 + 3 + 3 dose-escalation design based on observing each dose level for a period of 21 days. Part 2 will evaluate the recommended dose determined in Part 1. arm 2: Part 1 is an open-label 3 + 3 + 3 dose-escalation design based on observing each dose level for a period of 42 days. Part 1 will also contain dose-expansion cohorts in previously treated NSCLC and MSS CRC. Part 2 will evaluate the recommended dose determined in Part 1. arm 3: Part 1 is an open-label 3 + 3 + 3 dose-escalation design based on observing each dose level for a period of 42 days. Part 1 will also contain dose-expansion cohorts in previously treated NSCLC and MSS CRC. Part 2 will evaluate the recommended dose determined in Part 1.

Interventions: intervention 1: Azacitidine intervention 2: Pembrolizumab intervention 3: Epacadostat intervention 4: INCB057643 intervention 5: Pembrolizumab intervention 6: Epacadostat intervention 7: INCB059872
Intervention descriptions: intervention 1: Five doses of azacitidine will be administered by subcutaneous injection or intravenously (IV) over Days 1 to 7 in Cycles 1 through 6. intervention 2: Pembrolizumab will be administered in a 30-minute IV infusion every 3 weeks on Day 1 of each 21-day cycle. intervention 3: Epacadostat tablets will be administered orally twice daily. intervention 4: INCB057643 will be orally self- administered once daily beginning on Cycle 1 Day 1 and continuously thereafter in 21-day cycles. intervention 5: Pembrolizumab will be administered in a 30-minute IV infusion every 3 weeks of each 21-day cycle starting on Cycle 2 Day 1. intervention 6: Epacadostat tablets will be administered orally twice daily starting at Cycle 2 Day 1. intervention 7: INCB059872 will be orally self- administered once daily OR every other day beginning on Cycle 1 Day 1 and continuously thereafter in 21-day cycles.

Protocol document:
Prot_001.pdf: 
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Clinical Study  Protocol 
 
 
 
 
 
INCB 24360-206 I NCT02959437 
 
A Phase 1/2 Study Exploring the Safety, Tolerability, Effect  on the 
Tumor Microenvironment, and  Efficacy of Azacitidine in 
Combination With  Pembrolizumab and  Epacadostat in Subjects 
With  Advanced Solid Tumors and  Previously Treated Stage  IIIB or 
Stage IV Non-Small Cell Lung Cancer and  Stage IV 
Microsatellite-Stable Colorectal Cancer 
 
 
 
Product: 
Epacadostat, Pembrolizumab, Azacitidine, INCB057643, a nd 
INCB059872 
INDNumber: 
132,309 
EudraCT Number: 
2016-004289-25 
Phase of Study: 
112 
Sponsor: 
Incyte Corporation 
1801Augustine Cut-Off 
Wilmington, DE 19803 
Original Protocol (Version 0): 
30 SEP 2016 
Amendment (Version) 1: 
04 NOV2016 
Amendment (Version) 2: 
02 JUN 2017 
Amendment (Version) 3: 
20 OCT 2017 
Amendment (Version) 4: 
30 AUG 2018 
 
 
 
This study will be perf01med 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 defmed 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 docmnent is confidential.  No prut of this inf01mation may be duplicated, referenced, or 
transmitted in any f01m or by any means (electronic, mechanical, photocopy, recording, or othetwise) without the prior 
written consent oflncyte Corporation. 


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INVESTIGATOR'S AGREEMENT 
 
I have read the INCB 24360-206 Protocol Amendment 4 (Version 4 dated 30 AUG 2018) and 
agree to conduct the study as outlined.  I agree to maintain the confidentiality of all infmmation 
received or developed in connection with this Protocol. 
 
 
 
 
 
 
 
 
(P1inted Name of Investigator) 
 
 
 
 
 
 
 
(Signature of Investigator)  
(Date) 


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SYNOPSIS 
 
Name of Investigational Product:  Epacadostat, Pembrolizumab, Azacitidine,  INCB057643, and 
INCB059872 
Title of Study: A Phase 112 Study Exploring the Safety, Tolerability, Effect on the Tumor 
Microenvironment, and Efficacy of Azacitidine in Combination With Pembrolizumab and Epacadostat in 
Subjects With Advanced Solid Tumors and Previously Treated Stage IIIB or Stage IV Non-Small Cell 
Lung Cancer and Stage IV Microsatellite-Stable Colorectal Cancer 
Protocol Number: INCB 24360-206 
Study Phase:   1/2 
Indication:   Advanced or metastatic solid ntmors and previously treated Stage IV or recunent 
non-small cell lung cancer (NSCLC) and Stage IV microsatellite stable (MSS) colorectal cancer (CRC) 
Primary Objectives: 
• Prut 1: To evaluate the safety and tolerability and to detennine the maximum tolerated dose (MTD), 
maximum tested dose, or phannacologically active dose [PAD]) of the combinations  in subjects with 
advanced or metastatic solid tumors. 
• Prut 2:  To evaluate the efficacy of the combinations in subjects with previously treated Stage IV or 
recunent NSCLC, Stage IV MSS CRC, and other select solid tumors by assessing objective response 
rate (ORR) per Response Evaluation Critelia in Solid Tumors (RECIST) v1.1 at the MTD, maximum 
tested dose, or PAD. 
Secondary Objectives: 
• Prut 1:  To evaluate the efficacy ofthe combinations in subjects with advanced or metastatic solid 
tumors by assessing ORR per RECIST v1.1 at the MTD, maximum tested dose, or PAD. 
• Prut 2:  To evaluate the safety and tolerability of the combinations in subjects with previously treated 
Stage IV or recunent NSCLC, Stage IV MSS CRC, and select solid tumors at the MTD, maximum 
tested dose, or PAD. 
• Pruts 1 and 2:  To evaluate changes in T-cell infiltration in the ttlillor 1nicroenvironment with the 
combinations in subjects  with advanced or metastatic solid tumors, previously treated Stage IV or 
recunent NSCLC, and Stage IV MSS CRC. 
• Pruts 1 and 2:  To evaluate the efficacy of the combinations  in subjects with advanced or metastatic 
solid ttlillors, previously treated Stage IV or recunent NSCLC, and Stage IV MSS CRC by assessing 
progression-free survival (PFS). 
• Pruts 1 and 2:  To evaluate the efficacy of the combinations  in subjects with advanced or metastatic 
solid ttlillors, previously treated Stage IV or recunent NSCLC, and Stage IV MSS CRC by assessing 
duration of response (DOR). 


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Prima ry Endpoints: 
• Patt 1:  Safety  and tolerability will be assessed by monitoring the frequency, duration, and severity of 
adverse events (AEs); through physical examinations; by evaluating changes in vital signs and 
electrocru·diograms (ECGs); and through clinicallaborat01y blood and mine sample evaluations. 
• Patt 2:  Objective response rate, defmed as the percentage of subjects having a complete response (CR) 
or pattial response (PR), will be detennined  by investigator assessment of radiographic  disease as per 
RECIST v1.1. 
Secondary Endpoints: 
• Patt 1:  Objective response rate, defmed as the percentage of subjects  having a CR or PR, will be 
detennined by investigator assessment of radiographic disease as per RECIST v1.1. 
• Patt 2: Safety  and tolerability will be assessed by monitoring the frequency, duration, and severity of 
AEs; through physical exaininations; by evaluating changes in vital signs and ECGs; and through 
clinicallaborat01y blood and mine sample evaluations. 
• Patts 1 and 2: Percentage of responders,  where a responder is defined as an increase in the nmnber of 
tmnor-inflltrating lymphocytes (TILs) or the ratio of CD8+ lymphocytes to T regulat01y cells (Tregs) 
infiltrating ntmor post-treatment versus pretreatment with pembrolizumab and epacadostat in 
combination with azacitidine,  INCB057643, or INCB059872  (United States sites only) evaluated by 
immunohistochetnistiy, will be detemlined. 
• Patts 1 and 2: Progression-free  survival, defined as the time from date of first dose of study dmg until 
the eru·Iiest date of disease progression, will be detemlined  by investigator assessment of objective 
radiographic disease assessments as per RECIST v1.1, or death due to any cause,  if occuning sooner 
than progression. 
• Pruts 1 and 2: Duration of response detennined by radiographic disease assessment, defined as the time 
from earliest date of disease response lmtil the eru·Iiest date of disease progression per RECIST vl .1, or 
death due to any cause, if occuning sooner than progression, will be detemlined. 


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Overall Study Design: 
This is an open-label, multicenter,  Phase 112 stttdy evaluating the addition of 3 different epigenetic 
priming regimens to an immunotherapy doublet in subjects with advanced or metastatic solid tt1mors. 
Prut 1 of the study will be an open-label Phase 1 assessment to evaluate the safety and tolerability and to 
detemline the MTD, maximum tested dose, or PAD of the combinations in subjects with advanced or 
metastatic solid tt1mors. 
Prut 2 of the study will be an open-label Phase 2 assessment with Simon 2-stage design to evaluate ORR 
and TIL infiltration in previously treated NSCLC and MSS CRC.  Sepru·ate treatment sequencing tt1mor 
biopsy cohorts ru·e also included in Prut 2 to ftuther evaluate epigenetic changes and changes in the tt1mor 
nlicroenviromnent  in subjects with select solid  tt1mors. 
Treatment Group A 
In Treatment Group A, subjects will receive the DNA methyltransferase inhibitor azacitidine in 
combination with the progrrunmed death receptor-1 (PD-1) inhibitor pembrolizumab and the indoleanline 
2,3-dioxygenase (IDO) 1 inhibitor epacadostat.  Pa1t 1 of Treatment Group A will consist  of a dose- 
escalation assessment  of the safety and tolerability of the treatments in subjects with advanced or 
metastatic solid tumors. In Prut 1 of Treatment  Group A, pembrolizumab  and epacadostat will be 
administered  in 21-day cycles from Cycle 1 Day 1 in combination with azacitidine.   Subjects in 
Treatment Group A will receive up to 6 cycles of azacitidine as long as the subject is receiving benefit 
from treatment and has not met any criteria for study withdrawal (except for Expansion Coh01ts A-4 and 
A-5, which will receive up to 5 cycles).  In Pa1t 2 of Treatment Group A will consist of Simon 2-Stage 
coh01ts in previously treated NSCLC and MSS CRC.  Sepru·ate treatment sequencing tumor biopsy 
coh01ts ru·e also included in Prut 2 to ftuther evaluate epigenetic changes and changes in the nunor 
nlicroenviromnent  in subjects with select solid  tt1mors.  In Treatment Group A, subjects who have an 
initial response or stable disease (SD) for greater than 6 months but later relapse while receiving 
pembrolizumab and epacadostat  will have the opp01tunity to repeat the azacitidine epigenetic pdnling 
regimen to which they were odginally assigned with medical molliter approval.  Study treatment may 
continue as long as the subject is receiving benefit and has not met any cdteria  for study withdrawal or 
until the subject has received 35 adnlimstrations ofpembrolizumab (approximately 2 years), whichever 
occurs first. 
Treatment Groups B and C (Upon implementation of Amendment 4, these treatment groups are no longer 
applicable) 
In Treatment Group B, subjects will receive the bromodomain and extra-tenninal (BET) inhibitor 
INCB057643 as a monotherapy printing regimen for 21 days in Cycle 1 and then initiate pembrolizumab 
and epacadostat on Cycle 2 Day 1. In Treatment Group C (Umted States sites only), subjects will receive 
the lysine-specific  demethylase 1A (LSD1) inhibitor  INCB059872 as a monotherapy priming regimen for 
21 days in Cycle 1 and then initiate pembroliZllffiab and epacadostat on Cycle 2 Day 1.  Pa1t 1 of 
Treatment Groups Band C will consist of a dose-escalation assessment of the safety and tolerability of 
the treatments in subjects with advanced or metastatic solid nunors.   Prut 1 will also contain dose- 
expansion coh01ts in previously treated NSCLC and MSS CRC.  Fo- 
, there 
will be an optional stttdy hold for evaluation of safety, efficacy, and 
to 
facilitate a go/no-go decision regru·ding emolhnent of Prut 2.  Pa1t 2 of Treatment Groups Band C will 
consist of Simon 2-Stage coh01ts in previously treated NSCLC and MSS CRC.  Sepru·ate treatment 
sequencing tt1mor biopsy cohorts ru·e also included in Prut 2 to ftuther evaluate epigenetic changes and 
changes in the tt1mor Inicroenvironment in subjects with select solid tt1mors.  Emolhnent of the treatment 
sequencing tt1mor biopsy cohorts is contingent upon passing Stage 1 in 1 of the 2 coh01ts, for each 
respective treatment group. Stttdy treatment may continue as long as the subject is receiving benefit and 
has not met any criteda for stttdy withdrawal or lmtil the subject has received 35 adnlimstrations of 
pembrolizumab (approximately 2 yeru·s), whichever  occurs first. 


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Tumor biopsy samples are required at baseline and on study for subject patticipation in all dose-escalation 
coh01ts and Stage 1 of the Simon 2-stage coh01ts. Mandat01y tumor biopsies will be collected at baseline 
(before Day 1 administration) and while the subject is receiving study treatment as specified  below: 
• An additional on-treatment biopsy will be required to be collected during Week 5 or Week 6 
(Treatment Group A) or Week 8 or Week 9 (Treatment Groups Band C); the on-treatment biopsy is 
optional for Stage 2 coh01ts in Pmt 2. 
• Coh01ts A-3, A-4, A-5, B-9, B-10, C-11, and C-12:  A baseline biopsy and 2 on-treatment biopsies m·e 
required for subjects emolled in the treatment sequencing biopsy coh01ts. 
• An additional optional biopsy may be collected once the subject meets the requirements for SD, 
response, or progression by radiographic disease assessment. 
Note:  On-treatment biopsies should  be collected  from the same tumor lesion that was biopsied at 
baseline. 
Note:  If a subject is scheduled to have a tumor biopsy for the purposes  of this study, and it is 
subsequently detennined that ntmor tissue cannot safely be obtained, then the subject may still emoll in 
the study, and an m·chived tumor specimen, if available, can be subinitted.  Such subjects may be 
replaced. 
Note:  As a quality control step, prior to subtnitting the ntmor tissue to the centrallaboratOiy vendor, all 
tumor tissue will be fonnalin-fixed and pm·affin-embedded locally.  A hematoxylin and eosin stain will be 
perfonned  and reviewed by a local pathologist to verify the adequacy of the tumor biopsy.  Additionally, 
a quality control f01m will be signed and dated by the reviewing pathologist.  For the screening biopsy, 
this fonn will ideally be subtnitted to the sponsor at the same time the registration fonn is subinitted for 
emollment. 
 
 
 
 
criteria. 
•  
• 
• 
• •  
3 
Dose-Escalation Phase CAll Treatment Groups) 
A 3 + 3 + 3 design will be used to assess the MTD, maximum tested dose or PAD of the triplet 
combination of azacitidine,  INCB057643, or INCB059872 with pembrolizumab  and epacadostat in 
21-day treatment cycles.  The MTD will be defmed as the highest dose at which less than one-third of the 
subjects (with a tninimum of 6 subjects) have a dose-liiniting toxicity (DLT). When the MTD, maximum 
tested dose, or PAD has been detetmined  or reached, the dose will be recommended for Pmt 2.  The 
Pmt 2 expansion will begin after the detetmination of the MTD, maximum tested dose, or PAD; however, 
emolhnent priodty will be given to the open Pmt 1 dose-escalation coh01t. 
A minimum of 3 subjects will initially be emolled in Coh01t 1, and each subject will be observed for 
21 days from the strut oftdplet combination therapy before emollment in the next coh01t begins.  The 
dose of azacitidine, INCB057643, or INCB059872 (or epacadostat) will be escalated if O of the first 
3 evaluable subjects emolled has a DLT.  If 1 of 3 subjects in Coh01t 1 has a DLT, the coh01t will be 
expanded to 6 subjects. If 1 of 6 subjects in Coh01t 1 has a DLT, a new coh01t of 3 subjects will be 
treated at the next higher dose level (Coh01t 2).  If2 of 6 subjects in Coh01t 1 have a DLT, that coh01t 
will be fmther expanded to a total of9 subjects.   If2/9 subjects has a DLT, 3 subjects will be treated at 
the next higher dose level.  If2/3, 3/6, or 3/9 subjects have DLTs within a coh01t, dose de-escalation 
will be required, and Coh01t -1 or -2 will be tested. The MTD is defined as the highest dose level at 
which1/6 or2/9 subjects expedence a DLT. 
Subjects must have received75% of planned doses of study dmg during the 21-day DLT (Treatment 
Group A) or 42-day DLT (Treatment Groups Band C) observation pedod or have had a DLT to be 
evaluable  for dose tolerability (Treatment Group A:  azacitidine [4 doses], epacadostat [32 doses], and 
embrolizurnab   1 dose ; Treatment Grou   B:  INCB057643   32 doses , e  acadostat   32 doses , and 


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pembrolizumab [1 dose]; Treatment Group C:  INCB059872  [once daily (QD) dosing, 32 doses; eve1y 
other day (QoD) dosing, 16 doses], epacadostat [32 doses], and pembrolizumab [1 dose]). 
It is recognized that certain toxicities due to the combination agent (eg, including but not limited to 
gastrointestinal toxicity, including dianhea; renal insufficiency; high-grade laborat01y abn01malities; 
rash) may initially be clinically indistinguishable from toxicities due to immunotherapy. Epacadostat  will 
be held for these toxicities, and as a result, subjects may not receive75% of the presciibed dose during 
Cycle 1.  In these cases, the principal investigators and medical monitor may assess subjects who receive 
dose intensities somewhat below 75% for the detennination ofDLTs, and consider in the adjudication 
process the specific  toxicity encountered, the likely cause of the toxicity, and dose intensity and 
tolerability beyond Cycle 1.  Additional subjects will be emolled  in a coh01t to achieve the minimum of 
3 evaluable subjects if dropouts or dose intenuptions/reductions occur that result in a subject being 
nonevaluable for DLTs. 
Dming the study, dose intenuptions and/or dose modifications  may be implemented based on toxicity as 
described in the Protocol.  However, dose modifications should not be made dming the DLT observation 
period without discussion with the medical monitor.  Intrasubject dose escalation is not pe1mitted. 
Treatment Group A:  Azacitidine 
In Treatment Group A, dose escalation  will begin with sta1ting doses of azacitidine 75 mg subcutaneous 
(SC) or intravenous (IV) injection for 5 days (5 doses may be administered over the Day 1-7 period) of 
the first 2 cycles, pembrolizumab 200 mg IV eve1y 3 weeks (Q3W), and epacadostat 100 mg orally (PO) 
twice daily (BID) continuous  dose administration. If the sta1ting dose proves intolerable, azacitidine 
50 mg SC or IV for 5 days, pembrolizumab 200 mg IV Q3W, and epacadostat 100 mg PO BID will be 
evaluated.  The coh01ts and dose levels are shown in the following table. 
Treatment  Group A: Azacitidine 
 
Cohort 
-2· 
 
 
 
-1" 
 
 
 
1 
 
 
 
 
 
 
 
 
 
 
 
3 
 
Azacitidine  
Pembrolizumab  
Epacadostat 
50 mg SC or IV for 5 days 
200mgiVQ3W 
50mgPOBID 
(5 doses over Day 1-7 period) 
in Cycle 1 & 2 
50 mg SC or IV for 5 days 
200mgiVQ3W 
100 mg PO BID 
(5 doses over Day 1-7 period) 
in Cycle 1 & 2 
75 mg SC or IV for 5 days 
200 mg iV Q3W 
100 mg PO BID 
(5 dost>s over Day 1-7 period) 
in Cycle 12 
75 mg SC or IV for 5 days 
200mgiVQ3W 
300mgPOBID 
(5 doses over Day 1-7 period) 
in Cycle 1 & 2 
100 mg SC or IV for 5 days 
200mgiVQ3W 
100 mg PO BID 
(5 doses over Day 1-7 period) 
in Cycle 1 & 2 
100 mg SC or IV for 5 days 
200mgiVQ3W 
300mgPOBID 
(5 doses over Day 1-7 period) 
Days 1-5 in Cycle 1 & 2 
• IfCohort I proves intolerable, Coh01t -1may be evaluated.  If Coh01t -I is not tolerable, Coh01t -2 may be evaluated with 
epacadostat 50 mg PO BID.  If a de-escalation cohort  is detennined to be safe and tolerable, the dose ofazacitidine or 
epacadostat may be re-escalated  in separate,  additional coh01ts based on the review of available safety data. 
b  For Coh01t 2, escalation of azacitidine to 100 mg or epacadostat to 300 mg BID will be dependent on the obse1vation of 
Grade 3 or greater immtme-related or non- imnume-related toxicities in Cohort I (toxicities that were not considered DLTs).  If 
Grade 3 or greater immtme-related toxicities are obse ved in Coh01t 1, azacitidine will be escalated first (Cohort 2B).  If 
non- immune-related Grade 3 or greater toxicities are observed, epacadostat will be preferentially escalated (Coh01t 2A). 
Dose-escalation coh01ts 2A and 2B may be opened in parallel if no Grade 3 AEs are observed in Cohort I . 


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Treatment Group B:  INCB057643 
In Treatment Group B, dose escalation  will begin with a sta1ting dose ofiNCB057643 of 4 mg PO QD 
continuous dose administration  beginning on Cycle 1 Day 1 for the first 21-day cycle.  Beginning on 
Cycle 2 Day 1, pembrolizumab 200 mg IV Q3W and epacadostat 100 mg PO BID continuous dose 
adlninistration  will be added to INCB057643.   If the struting dose level proves intolerable, INCB057643 
4 mg PO QD in combination with pembrolizumab 200 mg IV Q3W and epacadostat  50 mg PO BID will 
be evaluated. The coho1ts and dose levels are shown in the table below. 
Treatment Group B: INCB057643 
 
Cohort 
INCB057643 
Pembrolizumab 
Epacadostat 
-1" 
4mgPOQD 
beginning C3D1 
200mgiVQ3W 
beginning C2Dl 
50mgPOBID 
beginning C2D1 
1 
4 mg PO QD 
beginning C1D1 
200mg iVQ3W 
beginning C2D1 
100 mg POBID 
beginning C2D1 
2 
8mgPOQD 
beginning C1D1 
200mgiVQ3W 
beginning C2Dl 
100 mgPOBID 
beginning C2D1 
3 
12mgPOQD 
beginning C1D1 
200mgiVQ3W 
beginning C2Dl 
100 mgPOBID 
beginning C2D1 
a  IfCohort I proves intolerable, Coh01t -I may be evaluated.  If Coh01t - I is not tolerable, lower  doses or alternative dose 
schedules ofiNCB057643 may be tested, however at this time 4mg tablets are the lowest dose fonnulation available.  Any dose 
reduction in INCB057643 would be combined with pembrolizumab 200 mg IV Q3W and epacadostat 50 mg PO BID.  If a 
de-escalation coh01t is detemrined to be safe and tolerable, the dose of iNCB057643 or epacadostat  may be re-escalated in 
separate,  additional cohorts based on the review of available safety data. 
Treatment Group C:  INCB059872 
In Treatment  Group C (United States sites only), dose escalation will begin with a starting dose of 
INCB059872  of 1 mg PO QoD continuous dose administration beginning  on Cycle 1 Day 1 for the first 
21-day cycle.  Beginning on Cycle 2 Day 1, pembrolizumab 200 mg IV Q3W and epacadostat 100 mg PO 
BID continuous  dose administration will be added to INCB059872. If the sta1ting dose level proves 
intolerable, INCB059872 1 mg PO QoD in combination with pembrolizumab 200 mg IV Q3W and 
epacadostat 50 mg PO BID will be evaluated.  The coho1ts and dose levels ru·e shown in the table below. 
Treatment Group C: INCB059872 
 
Cohort 
INCB059872 
Pembrolizumab 
Epacadostat 
-1" 
1 mgPO QoD 
beginning C1D1 
200mgiVQ3W 
beginning C2Dl 
50mgPO BID 
beginning C2D1 
1 
1 mgPOQoD 
beginning C1D1 
200mg iVQ3W 
beginning C2D1 
100 mg POBID 
beginning C2D1 
2Ah 
2 mgPO QoD 
beginning C1D1 
200mgiVQ3W 
beginning C2Dl 
100 mgPO BID 
beginning C2D1 
2Bb 
1 mgPOQD 
beginning C1D1 
200mgiVQ3W 
beginning C2Dl 
100 mgPO BID 
beginning C2D1 
3C 
3 mgPO QoD 
beginning C1D1 
200mgiVQ3W 
beginning C2Dl 
100 mgPO BID 
beginning C2D1 
a If Coh01t I proves intolerable, Coh01t -I may be evaluated. IfCohort -I is not tolerable, lower doses or altemative dose 
schedules ofiNCB059872 may be tested.  Any dose reduction in INCB059872  would be combined with pembroliztunab 
200 mg IV Q3W and epacadostat 50mg PO BID.  If a de-escalation coh01t is detennined to be safe and tolerable, the dose of 
INCB059872 or epacadostat may be re-escalated in separate,  additional coh01ts based on the review of available safety data. 
b Dose-escalation Cohorts 2A and 2B may be opened in parallel  if no Grade 3 AEs are observed in Cohort  I. 
c Cohort 3 will be emolled once Cohort 2A clears the DLT petiod.  Enrollment into Cohort 3 is not dependent upon clearing the 
DLT period from Cohort 2B. 


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Dose-Expansion Phase 
Treatment Group A 
Once the safety profile of all doses tested has been charactelized and the recommended Phase 2 dose 
(RP2D) of the azacitidine combination has been defmed, the cohort expansion will be initiated at the 
RP2D.  The doses selected for expansion will not exceed the MTD or maximum tested dose in Prut 1. 
The purpose of Phase 2 is to gather additional safety,                                                       and preliminruy 
efficacy infmmation  regru·ding the t1iplet combination in select tumor types where there is substantial 
room for improvement over mono- and doublet inummotherapies.  The expansion will include: 
1.Safety/efficacy cohmts in NSCLC (A-1) and MSS CRC (A-2)  (2 tumor biopsies are required) 
2. Treatment sequencing biopsy cohmts that will initiate treatment (3 tumor biopsies ru·e required) 
a.A-3:  azacitidine monotherapy followed by the pembrolizumab/epacadostat doublet 
b.A-4:  pembrolizumab/epacadostat doublet followed by azacitidine 
c.A-5:  pembrolizumab monotherapy followed by epacadostat and azacitidine 
Note:  Only subjects with untreated (flrst-line) melanoma will be treated in the pembrolizumab 
monotherapy cohmt (A-5). 
Treatment Group A Safety/Efficacy Expansion Cohorts 
Two cohmts will be evaluated as prut of the safety/efficacy expansion.  The eligible  tumor types ru·e 
NSCLC and MSS CRC.  Subjects emolled  in the NSCLC tumor cohmt must have had disease 
progression on a prior PD-1 pathway-tru·geted agent. 
A Simon 2-stage design will be used with a stopping mle to allow for early tetmination of a pruticular 
cohmt at the end of Stage 1 if there ru·e insufficient  responses observed.  During Stage 1, 8 NSCLC 
subjects who progressed on a PD-1 pathway- targeted agent and 8 MSS CRC subjects will be enrolled.  If 
no responses ru·e observed in the NSCLC PD-1 failure and MSS CRC cohmts, the cohmt(s) will be 
discontinued.  If at least 1 response is observed in the NSCLC PD-1 failure or MSS CRC cohmt, 
19 additional NSCLC  PD-1 failure or MSS CRC subjects will be emolled  (Stage 2), for a maximum of 
27 subjects per cohmt (see the table below). 
Treatment  Group A Safety/Efficacy Expa nsion Cohorts (Pa rt 2) 
 
Cohort 
Treatment 
Tumor Type (n) 
Expansion Cohort A-1 
MTD or maximum tested dose for the 
azacitidine +pembrolizmnab + 
epacadostat combination. 
A maximum of27 subjects with 
previously treated Stage IV or recunent 
NSCLC with progression on a prior PD-1 
pathway-targeted agent. 
Expansion Cohmt A-2 
MTD or maximum tested dose for the 
azacitidine +pembrolizmnab + 
epacadostat combination. 
A maximum of27 subjects with 
previously treated Stage IV MSS CRC. 
Continuous evaluation of toxicity events will be petfmmed  throughout the expansion.  In the expansion, 
after the sixth patient in Stage 1 has been emolled, if > 40% of subjects have an AE Grade 3 that is 
attlibutable to the investigational agents, ftuther enrollment of subjects will be suspended lmtil the 
sponsor, investigators, and regulatmy authmities (if applicable) have detennined the appropliate course of 
action.  If an expansion cohort is discontinued because of toxicity, a new cohmt may be initiated at a 
previously tested lower dose level. 
Treatment Group A Treatment Sequencing Tumor Biopsy Cohorts (Part 2) 
The sequencing biopsy cohorts require 3 ntmor biopsies to identify epigenetic changes and changes in the 
nunor tnicroenvironment induced by each of the components of the regimen. All subjects will have 
nunor biopsies at baseline and 2 additional biopsies while on study treatment. 
Approximately 25 subjects will be emolled in Expansion Cohmts A-3 and A-4 and 10 subjects in 
Ex   ansion Cohmt A-5.  The eli  ·ble nunor  
es for Ex  ansion Cohmts A-3, A-4, and A-5 ru·e head and 


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neck squamous cell carcinoma (HNSCC), melanoma, urothelial carcinoma, and MSS CRC.   In Expansion 
Coho1ts A-3 and A-4, subjects with tumor  types other than MSS  CRC must have had disease progression 
on a p1ior PD-1 pathway-targeted agent. 
Five to 8 evaluable subjects per n1mor type in Expansion Coho1ts A-3 and A-4, and 10 subjects in 
Expansion Cohmt A-5 will initiate  treatment and have tumor biopsies pe1foimed as indicated in the table 
below. 
Treatment  Group A Treatment Sequencing Tumor Biopsy Cohorts (Pa rt 2) 
 
Cohort 
Treatment Sequence 
Biopsy Sequence 
Tumor Type (n) 
Expansion Cohort A-3 
Azacitidine monotherapy 
during Week -1 (5 doses), 
initiate pembrolizumab and 
epacadostat on C1D1 (window 
+ 5 days fi:om the date of the 
fifth azacitidine dose; should 
begin after biopsy #2), 5 doses 
of azacitidine will be 
administered in Cycles 2 and 3. 
Biopsy #1 at baseline. 
Biopsy #2 on ClD1 (window 
Day -5 to C1D1, biopsy before 
pembrolizumab/epacadostat 
administration). 
Biopsy #3 during Week 5 or 6. 
HNSCC (5-8) 
Melanoma (5-8) 
Urothelial 
carcinoma (5-8) 
MSS CRC (5-8) 
Expansion Coh01t A-4 
Pembrolizumab and 
epacadostat for 1 cycle, initiate 
azacitidine after biopsy #2, 
5 doses of azacitidine will be 
administered in Cycles 2 and 3. 
Biopsy #1 at baseline. 
Biopsy #2 on C2Dl (window 
C1Dl5 to C2Dl, biopsy before 
azacitidine administration). 
Biopsy #3 during Week 8 or 9. 
HNSCC (5-8) 
Melanoma (5-8) 
Urothelial 
carcinoma (5-8) 
MSS CRC (5-8) 
Expansion Coh01t A-5 
Pembrolizumab monotherapy 
for 1 cycle, initiate epacadostat 
and azacitidine after biopsy #2, 
5 doses of azacitidine will be 
administered in Cycles 2 and 3. 
Biopsy #1 at baseline. 
Biopsy #2 on C2Dl (window 
C1Dl5 to C2Dl, biopsy before 
epacadostat/azacitidine 
administration). 
Biopsy #3 during Week 8 or 9. 
First-line 
melanoma (10) 
Subjects in Expansion Coho1t A-3 will receive up to 6 cycles of azacitidine.  Subjects in Expansion 
Coho1ts A-4 and A-5 will receive up to 5 cycles of azacitidine. The sponsor will manage emolhnent so 
that there are 5 to 8 evaluable subjects for a given tumor  type. Subjects may be replaced if they have not 
completed all of the biopsy requirements. 
Treatment Group B 
Treatment Group B Part 1 Dose-Expansion  Cohorts (Part 1) 
Because higher  doses of epigenetic priming regimens may be deleterious to immune  function, expansion 
coho1ts at each dose level tested that cleared the DLT window will be opened for signal  detection. 
- 
analysis to guide an RP2D.   Once an RP2D  is dete1mined, this dose will be usecr:-Part 
stage and treatment sequencing ttllllor biopsy cohorts. Dming dose expansion, 
5 NSCLC subjects who progressed on a PD-1 pathway- targeted agent and 5 MSS CRC subjects will be 
emolled at each dose level with DLT clearance as detailed  below. 
The expansion will include: 
1. Safety/efficacy coho1ts in NSCLC (2 tumor  biopsies are required) 
a.B-1:  INCB057643 4 mg QD followed by the pembrolizumab/epacadostat doublet 
b.B-3:  INCB057643 8 mg QD followed by the pembrolizumab/epacadostat doublet 
c.B-5:  INCB057643 12mg QD followed by the pembrolizumab/epacadostat doublet 
2.Safety/efficacy coho1ts in MSS CRC (2 tumor biopsies are required) 
a.B-2:  INCB057643 4 mg QD followed by the pembrolizumab/epacadostat doublet 
b.B-4:  INCB057643 8 mg QD followed by the pembrolizumab/epacadostat doublet 
c.B-6:  INCB057643 12mg QD followed by the pembrolizumab/epacadostat doublet 


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The following coh01ts will be expanded only llllder ce1tain circumstances as listed below: 
1. Coh01ts B-1 and B-2:  Objective responses in subjects dosed with INCB057643 at 8 and 12 mg QD 
and, as such, are known PADs.  However, 4 mg QD dosing has not been evaluated in humans.  To 
ensure 4 mg QD is a PAD, Coh01ts B-1 and B-2 will only be enrolled if l/3 of the subjects in the 
dose-escalation coh01t have a 25% drop in platelet cmmt from Cycle 1 Day 1 to Cycle 2 Day 1. 
Continuous evaluation of toxicity events will be pe1f01med throughout the expansion coh01ts. After the 
dose-expansion coh01ts been emolled, beginning with the sixth patient for a specific regimen, if > 40% of 
subjects have an AEGrade 3 that is attributable to the investigational agents, fmther enrollment of 
subjects will be suspended until the sponsor,  investigators, and regulat01y authodties (if applicable) have 
dete1mined the appropriate course of action.  If an expansion coh01t is discontinued because of toxicity, a 
new cohort may be initiated at a previously tested lower dose level. 
Following completed enrollment of the safety/efficacy expansion coh01ts, there will be an optional 
8-week pause to utilize  
data for RP2D dete1mination. 
 
this time 
no 
emollment  may be allois no evidence of clinical ---···--··  
J 
the dose-expansion coh01ts, emollment  in the respective treatment group 
Treatment Group B Simon 2-Stage Cohorts (Part 2) 
Following safety, efficacy,  
data evaluation, an RP2D will be detennined. A Simon 
2-stage design will be 
mle to allow for early te1mination of a pmticular coh01t at the 
end of Stage 1 if there are insufficient responses observed.  During Stage 1, 8 NSCLC subjects who 
progressed on a PD-1 pathway-tm·geted agent and 8 MSS CRC subjects will be enrolled.  If no responses 
are observed in the NSCLC PD-1 failure and MSS CRC coh01ts, the coh01t(s) will be discontinued. If at 
least 1 response is observed in the NSCLC PD-1 failure or MSS CRC coh01t, 19 additional NSCLC PD-1 
failure or MSS CRC subjects will be enrolled (Stage 2), for a maximum of27 subjects per coh01t (see the 
table below). 
Treatment Group B Safety/Efficacy Expansion Cohorts (Part 2) 
 
Cohort 
Treatment 
Tumor Type (n) 
Expansion Cohort B-7 
MTD, maximum tested dose, or PAD for 
the INCB057643 + pembrolizumab + 
epacadostat combination. 
A maximmn of27 subjects with 
previously treated Stage IV or recmrent 
NSCLC with progression on a prior PD-1 
pathway-targeted agent. 
Expansion Cohort B-8 
MTD, maximum tested dose, or PAD for 
the INCB057643 + pembrolizumab + 
epacadostat combination. 
A maximmn of27 subjects with 
previously treated Stage IV MSS CRC. 
Treatment Group B Treatment Sequencing Tumor Biopsy Cohorts (Part 2} 
The sequencing biopsy coh01ts require 3 ntmor biopsies (except for Coh01t B-11 which requires 2 rumor 
biopsies) to identify epigenetic changes and changes in the ntmor 1nicroenviromnent induced by each of 
the components of the regimen. All subjects will have ttlillor biopsies at baseline and 2 additional 
biopsies while on sntdy treatment. 
Approximately 25 subjects will be enrolled in Expansion Coh01ts B-9, B-10, and B-11.  The eligible 
tumor types for Expansion Coh01ts B-9, B-10, and B-11 are HNSCC, melanoma,  urothelial carcinoma, 
and MSS CRC.  In Expansion Coh01ts B-9, B-10, and B-11, subjects with tumor types other than MSS 
CRC must have had disease progression on a prior PD-1 pathway-tm·geted agent. 
Five to 8 evaluable subjects per ntmor type in Expansion Coh01ts B-9, B-10, and B-11 will initiate 
treatment and have ntmor biopsies pe1fonned as indicated in the table below. 


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Treatment Group B Treatment Sequencing Tumor Biopsy Cohorts (Part 2) 
Cohort 
Treatment Sequence 
Biopsy Sequence 
Tumor Type (n) 
Expansion Cohort B-9 
INCB057643 continuous 
monotherapy dming C1, 
initiate pembrolizmnab and 
epacadostat on C2D1 after 
biopsy#2. 
Biopsy #1 at baseline. 
Biopsy #2 on C2D1 (window 
C1D15 to C2D1, biopsy 
before pembroliztunab/ 
epacadostat administration). 
Biopsy #3 dming Week 8 or 9. 
HNSCC (5-8) 
Melanoma (5-8) 
Urothelial 
carcinoma (5-8) 
MSS CRC (5-8) 
Expansion Cohort B-10 
INCB057643 and epacadostat 
for 1 cycle, initiate 
pembrolizmnab after 
biopsy#2. 
Biopsy #1 at baseline. 
Biopsy #2 on C2D1 (window 
C1D15 to C2D1, biopsy 
before pembroliztunab 
administration). 
Biopsy #3 dming Week 8 or 9. 
HNSCC (5-8) 
Melanoma (5-8) 
Urothelial 
carcinoma  (5-8) 
MSS CRC (5-8) 
Expansion Cohort B-11 
INCB057643, epacadostat, 
and pembrolizmnab 
beginning Cl. 
Biopsy #1 at baseline. 
Biopsy #2 dming Week 5 or 6. 
HNSCC (5-8) 
Melanoma (5-8) 
Urothelial 
carcinoma (5-8) 
MSS CRC (5-8) 
The sponsor will manage emolhnent so that there are 5 to 8 evaluable subjects for a given ntmor type. 
Subjects may be replaced if they have not completed all of the biopsy requirements. 
Treatment Group C 
Treatment Group C Dose-Expansion  Cohorts (Part 1; United States Sites Only) 
Because higher doses of epigenetic pdming regimens may be deleterious to immune function, expansion 
coh01ts at each dose level tested which clear the DLT window will be opened for signal detection. 
analysis to guide an RP2D.  Once an RP2D is detennined, this dose will be used in Prut 
stage and treatment sequencing ttlillor biopsy cohorts. Dming dose expansion, 
5 NSCLC subjects who progressed on a PD-1 pathway- tru·geted agent and 5 MSS CRC subjects will be 
emolled at each dose level with DLT cleru·ance as detailed below. 
The expansion will include: 
1. Safety/efficacy coh01ts in NSCLC (2 tumor biopsies ru·e required) 
a.C-1: INCB059872 1 mg QoD followed by the pembrolizumab/epacadostat doublet 
b.C-3: INCB059872 2 mg QoD followed by the pembrolizumab/epacadostat doublet 
c.C-5:  INCB059872 1 mg QD followed by the pembrolizumab/epacadostat doublet 
d.C-7:  INCB059872 3 mg QoD followed by the pembrolizumab/epacadostat doublet 
2.Safety/efficacy coh01ts in MSS CRC (2 tumor biopsies ru·e required) 
a.C-2: INCB059872 1 mg QoD followed by the pembrolizumab/epacadostat doublet 
b.C-4: INCB059872 2 mg QoD followed by the pembrolizumab/epacadostat doublet 
c.C-6: INCB059872 1 mg QD followed by the pembrolizumab/epacadostat doublet 
d.C-8:  INCB059872 3 mg QoD followed by the pembrolizumab/epacadostat doublet 
The following coh01ts will be expanded only under cettain circumstances as listed below: 
1. Coh01ts C-1, C-2, C-5, and C-6 (United States sites only):  Objective responses have been seen in 
subjects dosed with INCB059872 2 and 3mg QoD and, as such, ru·e PADs.  However, 1 mg QoD has 
not been evaluated in hmnans, and there is no objective data to show that 1mg QD is a PAD.  To ensme 
that 1 mg QD and 1 mg QoD are PADs, Cohorts C-1, C-2, C-5, and C-6 will only be emolled  if 
.2:._1/3 of the subjects in the dose expansion coh01t have a 25% drop in platelet count from Cycle 1 Day 1 
to Cycle 2 Day 1. 


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2. Coh011s C-3 and C-4 will only be expanded if both of the following occm: 
a.The INCB059872 1 mg QD coho1t does not clear its DLT window or is deemed not tolerated for 
reasons outside ofDLT criteria. 
b.The INCB059872 2 mg QoD coho1t clears its DLT window and is deemed to have acceptable 
tolerability. 
Continuous evaluation of toxicity events will be pe1fo1med throughout the expansion cohorts. After the 
dose-expansion coho1ts have been emolled,  beginning  with the sixth subject for a specific regimen, if 
> 40% of subjects have an AE Grade 3 that is attlibutable to the investigational agents, ftuther 
enrollment of subjects will be suspended lmtil the sponsor, investigators, and regulato1y authorities (if 
applicable)  have detennined the appropriate course of action. If an expansion coho1t is discontinued 
because of toxicity, a new coho1t may be initiated at a previously tested lower dose level. 
Following  comment of the safety/efficacy expansion coho1ts there will be an optional8-week 
pause to utilize  
data for RP2D detennination. 
this time  
. 
no subject emollment 
may be allowed.  If there is no evidence of clinical  
 
 
 
in the dose- 
expansion coho1ts, emollment  in the respective treatment group  
 
 
 
 
2. 
Treatment Group C Simon 2-Stage  Cohorts (Part 2; United States Sites Only) 
Following safety, efficacy,  
data evaluation, an RP2D will be detennined. A Simon 
2-stage design will be 
mle to allow for early te1mination of a particular coho1t at the 
end of Stage 1 if there are insufficient responses observed.  Dming Stage 1, 8 NSCLC subjects who 
progressed on a PD-1 pathway-tm·geted agent and 8 MSS CRC subjects will be emolled.   If no responses 
are observed in the NSCLC PD-1 failme and MSS CRC coho1ts, the coho1t(s) will be discontinued. If at 
least 1 response is observed in the NSCLC PD-1 failme or MSS CRC coho1t, 19 additional NSCLC PD-1 
failme  or MSS CRC subjects will be enrolled (Stage 2), for a maximum of 27 subjects per coho1t (see 
table below).   Treatment  Group C with INCB059872 is only for use in the United States sites. 
Treatment Group C Safety/Efficacy Expa nsion Cohorts (Pa rt 2) 
 
Cohort 
Treatment 
Tumor Type (n) 
Expansion Cohort C-9 
MTD, maximum tested dose, or PAD 
for the INCB059872  +pembrolizmnab 
+ epa.cadostat combination. 
A maximum of27 subjects with 
previously treated Stage IV or rectuTent 
NSCLC with progression on a prior PD-1 
pathway- targeted agent. 
Expansion Cohort C-10 
MTD, maximum tested dose, or PAD 
for the INCB059872  +pembrolizmnab 
+ epa.cadostat combination. 
A maximum of27 subjects with 
previously treated Stage IV MSS CRC. 
Treatment Group C Treatment Sequencing Tumor Biopsy Cohorts (Part 2) 
The sequencing biopsy coho1ts require 3 n1mor biopsies (except for Coho1t C-13, which requires 2 n1mor 
biopsies) to identify epigenetic changes and changes in the n1mor Inicroenvironment induced by each of 
the components of the regimen. 
Approximately 25 subjects will be emolled in Expansion Coho1ts C-11, C-12, and C-13.  The eligible 
tumor types for Expansion Coho11s C-11, C-12, and C-13 are HNSCC, melanoma,  mothelial cm·cinoma, 
and MSS CRC. In Expansion Coho1ts C-11, C-12, and C-13, subjects with n1mor types other than MSS 
CRC must have had disease progression  on a prior PD-1 pathway- tm·geted agent. 
Five to 8 evaluable subjects per n1mor type in Expansion Coho1ts C-11, C-12, and C-13 will initiate 
treatment and have n1mor biopsies pe1fo1med as indicated in the table below. 


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Treatment Group C Treatment Sequencing Tumor Biopsy Cohorts 
 
Cohort 
Treatment Sequence 
Biopsy Sequence 
Tumor Type (n) 
Expansion Cohort C-11 
INCB059872 continuous 
monotherapy dming C1, 
initiate pembrolizmnab and 
epacadostat on C2D1 (after 
biopsy#2). 
Biopsy #1 at baseline. 
Biopsy #2 on C2D1 (window 
C1D15 to C2D1, biopsy 
before 
pembrolizumab/epacadostat 
administration). 
Biopsy #3 dming Week 8 or 9. 
HNSCC (5-8) 
Melanoma (5-8) 
Urothelial 
carcinoma (5-8) 
MSS CRC (5-8) 
Expansion Cohort C-12 
INCB059872 and epacadostat 
for 1 cycle, initiate 
pembrolizmnab after 
biopsy#2. 
Biopsy #1 at baseline. 
Biopsy #2 on C2D1 (window 
C1D15 to C2D1, biopsy 
before pembrolizumab 
administration). 
Biopsy #3 dming Week 8 or 9. 
HNSCC (5-8) 
Melanoma (5-8) 
Urothelial 
carcinoma (5-8) 
MSS CRC (5-8) 
Expansion Cohort C-13 
INCB059872, epacadostat 
and pembrolizmnab 
beginning Cl. 
Biopsy #1 at baseline. 
Biopsy #2 dming Week 5 or 6 
HNSCC (5-8) 
Melanoma (5-8) 
Urothelial 
carcinoma (5-8) 
MSS CRC (5-8) 
The sponsor will manage emolhnent  so that there are 5 to 8 evaluable subjects for a given tumor type. 
Subjects may be replaced if they have not completed all of the biopsy requirements. 
 
Study Population: 
Prut 1- Dose Escalation:  Subjects with advanced or metastatic solid ntmors who have failed previous 
approved available therapy (or refused therapy) will be emolled. 
Prut 2 - Safety/Efficacy Expansion Cohorts:  Subjects with Stage IV or recunent NSCLC and Stage IV 
MSS CRC who have failed previous approved available therapy (or refused therapy) will be emolled. 
Prut 2 -Treatment Sequencing  Tumor Biopsy Cohmts:  Subjects with advanced or metastatic HNSCC, 
melanoma, and urothelial carcinoma that have had disease progression on a PD-1 pathway-targeted  agent 
and subjects with Stage IV MSS CRC that have failed previous  approved available therapy (or refused 
therapy) will be emolled.   Only subjects with untreated (first-line) melanoma will be emolled in Cohmt 
A-5. 
Key Inclusion Criteria: 
Both Prut 1 and Patt 2 
• Male or female subjects, age 18 yeru·s or older on day of signing consent. 
• Willingness to provide written infmmed consent for the study. 
• Willingness to lmdergo a pretreatment and on-treatment ntmor biopsy to obtain tumor tissue. 
On-treatment biopsy is optional in Stage 2 of Prut 2. Two on-treatment biopsies ru·e mandatmy in the 
Prut 2 Treatment Sequencing Biopsy Expansion Cohmts (except for Cohmts B-11 and C-13, which 
require 1 on-treatment biopsy). 
Note:  If a subject is scheduled to have a tumor biopsy for the purposes of this sntdy, and it is 
""""'rn"""r ''"detennined that ntmor tissue cannot  
be 
· 
then the 
·ect 
still emoll in 


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• ECOG perfo1mance status of 0 to 1. 
• Presence of measureable disease per RECIST v.1.1 as dete1mined by the site study team.  Tumor 
lesions sin1ated in a previously inadiated area are considered measureable if progression has been 
demonstrated in such lesions. The lesion selected  for pre- and/or post-treatment biopsy cannot be the 
only measurable  lesion. 
Prut 1 Only 
• Subjects with histologically or cytologically confi1med advanced or metastatic solid ttllllors that have 
failed prior standru·d therapy (disease progression; subject refusal or intolerance is also allowable). 
Note:  There is no limit to the number of prior treatment regimens. 
Prut2 Only 
Note:  Subjects must have failed available therapies that ru·e known to confer clinical benefit as indicated 
below, unless they ru·e ineligible, intolerant, or refused standard treatment. 
Subjects with histologically or cytologically confi1med NSCLC: 
• Metastatic (Stage IV) or recunent NSCLC  (according  to American Joint Committee on Cancer 
7th edition guidelines) who have had disease progression after available therapies for advanced or 
metastatic  disease that are known to confer clinical benefit, been intolerant to treatment, or refused 
standard treatment. 
• Prior systemic regimens must include previously approved therapies, including a platinlllll-containing 
chemotherapy  regimen; a tyrosine kinase inhibitor for tumors with driver mutations; and checkpoint 
inhibitors where approved. 
• Must have documented  disease progression on a prior PD-1- pathway tru·geted agent (Expansion 
Coho1ts A-1, B-1, B-3, B-5, B-7, C-1, C-3, C-5, C-7, and C-9).  Progression following cessation of 
PD-1 pathway-targeted therapy is not sufficient. The baseline scan for the purposes of this sn1dy  may 
serve as the documentation of progression. 
Subjects with recunent (unresectable) or metastatic  CRC: 
• Histologically or cytologically confi1med adenocru·cinoma of the colon or recnllll. 
• Confumed MSS CRC as per local testing. 
• Stage IV CRC (according to American Joint Committee on Cancer 7th edition guidelines) who have 
had disease progression after available therapies for advanced or metastatic disease that are known to 
confer clinical benefit, been intolerant to treatment,  or refused standard treatment. 
• Prior systemic regimens must include previously approved therapies, including fluoropyrimidine-, 
oxaliplatin-, and liinotecan-based chemotherapy; an anti-vasculru·endothelial growth factor therapy (if 
no contraindication); and if negative for KRAS, NRAS, and BRAF mutations and no contraindication, 
an antipide1mal growth factor receptor therapy; and progressed after the last administration of 
approved therapy. 
Subjects with HNSCC: 
• Histologically confumed  squamous cell cru·cinoma of the oral cavity, oropharynx, hypophruynx, or 
la1ynx. 
Note:  Cru·cinomas of the nasophruynx, salivruy gland, or nonsquamous cell histology are excluded. 
• Must have received prior treatment with a platinum-based therapy.  Subjects who relapsed within 
6 months of adjuvant therapy, including a platinum-containing regimen, may enroll.  Additionally 
subjects must have had disease progression on a prior PD-1 pathway-tru·geted agent. 
• Must have documented hlllllan papilloma viius status. 
Subjects with melanoma: 
• Histologically or cytologically confmned  melanoma. 
• Unresectable Stage III or Stage IV melanoma, as per American Joint Committee on Cancer staging 
s stem not amenable to local thera 


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• Documentation ofV600-activating BRAF mutation stants or consent to BRAF. 
• V600 mutation testing during the screening pe1iod. 
• Must not have ocular melanoma. 
Subjects with urothelial carcinoma: 
• Histologically or cytologically confhmed urothelial carcinoma of the renal pelvis, ureter, urina1y 
bladder, or urethra that is transitional cell or mixed transitionaVnontransitional  (pred01ninantly 
transitional) cell type. 
• Stage IV locally advanced or metastatic urothelial carcinoma (according to American Joint Committee 
on Cancer 7th edition guidelines) with disease progression during or after PD-1 pathway-targeted 
therapy. 
Key Exclusion Criteria: 
• Laborat01y and medical hist01y parameters not within Protocol-defined range.  Cycle 1 Day 1 
laborat01y assessments for the dete1mination of eligibility do not need to be pe1f01med if the screening 
labs were pe1fonned within 7 days of Cycle 1 Day 1. If the screening lab assessments were pe1fonned 
more than 7 days before Cycle 1 Day 1, the hematology, senun chemistiy, and liver chemistiy lab 
results must be confinned on Cycle 1 Day 1 before treannent initiation. 
- Absolute neun·ophil count < 1.5 x  109/L. 
- Platelet count < 100 x  109/L. 
- Hemoglobin < 8 g/dL (n·ansfusion is acceptable to meet this crite1ion). 
- Senun creatinine1.5 
x institutional upper limit of n01mal (ULN)  OR measured or calculated 
creatinine clearance (glomemlar filn·ation rate can also be used in place of creatinine or CrCl) 
< 50 mL/min for subjects with creatinine levels > 1.5 x institutional ULN). 
- Aspartate aminon·ansferase, alanine aminon·ansferase, and alkaline phosphatase2.5 
x ULN. 
Note:  Subjects with 1) bone metastases and 2) no hepatic parenchymal metastases on screening 
radiographic examinations may emoll if the alkaline phosphatase is < 5 x ULN. Subjects with 
1) bone metastases and 2) hepatic parenchymal metastases on screening radiographic examinations 
may enroll if the alkaline  phosphatase is < 5 x ULN only with medical monitor approval. 
-Total bilimbin1.2 
 x ULN are excluded unless direct bilimbin isULN.  If there is no institutional 
ULN, then direct bilimbin must be < 40% of total bilimbin to be eligible. 
-Intemational n01malized ratio or prothrombin  time > 1.5 x ULN. 
- Activated pa1tial thromboplastin time > 1.5 x ULN. 
- Senun albmnin < 3 g/dL. 
• Receipt of anticancer medications or investigational dmgs within the following interval before the first 
adminisn·ation of study mug: 
- < 14 days for chemotherapy, targeted small-molecule therapy, or radiation therapy.  Subjects must 
also not require c01ticosteroids and must not have had pnemnonitis as a result ofn·eatment.   A 1-week 
washout is pennitted for palliative radiation to non-central nervous system (CNS) disease  with 
sponsor approval. 
Note:  The use of denosumab is pennitted. 
- < 14 days for a prior PD-1 pathway- targeted agent.  (If the subject was on pembrolizumab 
monotherapy, a wash-out is not required.) 
- < 28 days for prior monoclonal antibody used for anticancer therapy with the exception of PD-1 
pathway- targeted agents. 
- < 14 days for an immune-suppressive-based treatment for any reason (including chronic use of 
systemic cOiticosteroid at doses of prednisone equivalent to > 10 mg/day).  Use of inhaled or topical 
steroids or systemic corticosteroids10 mg is pe1mitted.  The use of physiologic doses of 
corticosteroids  may be approved after consultation  with the sponsor. 


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-< 28 days or 5 half-lives (whichever is longer) before the first dose for all other investigational study 
<hugs or devices.  For investigational agents with long half-lives (eg, > 5 days), emollment before the 
fifth half-life requires medical monitor approval. 
• Has not recovered from toxic effect(s) of ptior therapy toGrade 1. Any immune-related adverse 
events (irAEs) from plior immunotherapy must have complete resolution and must have resolved at 
least 2 weeks before C1Dl. 
Note:  Subjects withGrade 2 neuropathy or alopecia are an exception and may emoll.   Subjects with 
immune-related hypothyroidism or a<h·enal insufficiency because of prior immunotherapy who are 
medically stable and adequately  managed on a stable dose of replacement therapy may be emolled. 
• Subjects with plior ocular toxicity from plior immune therapy are excluded. 
• Subjects who have any active or inactive autoimmune disease or syn<h·ome (ie, rheumatoid artluitis, 
moderate or severe psoriasis, multiple sclerosis, inflammat01y bowel disease) that has required systemic 
treatment in the past 2 years or who are receiving systemic therapy for an autoimmune  or inflammat01y 
disease (ie, with use of disease modifying agents, c01ticosteroids, or immunosuppressive <hugs). 
Note:  Exceptions  include subjects with vitiligo  or resolved childhood asthma/atopy, hypothyroidism 
stable on h01mone replacement, controlled asthma, Type I diabetes, Graves' disease, or Hashimoto's 
disease, or with medical monitor approval. 
• Known active CNS metastases and/or carcinomatous  meningitis. 
Note:  Subjects with previously treated brain metastases may patticipate provided they m·e stable 
(without evidence of progression by imaging for at least 4 weeks before the flrst dose of study treatment 
and any neurologic symptoms have retumed to baseline), have no evidence of new or enlarging brain 
metastases, and have not required steroids for at least 7 days before study treatment. 
• Has received a live vaccine within 30 days of planned stmt of study therapy. 
Note:  Examples of live vaccines include, but m·e not limited to, the following:  measles, mumps, 
mbella, chicken pox/zoster, yellow fever, rabies, Bacillus Calmette-Guerin, and typhoid vaccine. 
Seasonal influenza vaccines for injection are generally killed vims vaccines and m·e allowed; however, 
intranasal influenza vaccines are live-attenuated vaccines and are not allowed. 
• Evidence of interstitial hmg disease or active, noninfectious  pneumonitis. 
• Inability to swallow food or any condition of the upper gastrointestinal tract that precludes 
administration of oral medications. 
• Subject has a known hist01y of or is positive for hepatitis B (hepatitis B smface antigen reactive or 
hepatitis B vims  DNA detected) or hepatitis C (hepatitis C vims [HCV] antibody positive and/or HCV 
RNA [qualitative] is detected). 
Note:  Hepatitis C antibody-positive subjects who received and completed treatment for HCV that was 
intended to eradicate the vims may patticipate ifHCV RNA levels m·e undetectable. 
Note:  In Patt 2, subjects who m·e immune to hepatitis B (hepatitis B vims [HBV] surface antibody 
and/or HBV core antibody positive) are allowed (ie, no evidence of active infection). 
• Known hist01y of human immunodeficiency vims (HIV; HIV 1/2 antibodies). 
• Active infection requiring systemic therapy. 
• Prior receipt of an IDO inllibitor. 
• Receipt of monoamine oxidase inhibitors (MAOIs) within the 21 days before the flrst dose of study 
treatment. 
• Hist01y of serotonin syn<h·ome after receiving 1 or more serotonergic dmgs. 
• Prior receipt of any fonnulation of azacitidine, decitabine, or any other hypomethylating agent 
(Treatment Group A only). 
• Subjects with bleeding associated  with tlllnors in proximity to major blood vessels m·e excluded except 
with medical monitor approval. 
• Hist01y of a prior Grade 3 or 4 irAE (Patt 1 dose escalation only). 


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• Subjects with uncontrolled  type I or type II diabetes mellitus (defined as HgbAlc > 8). 
• Prior receipt of a BET inhibitor (Treatment Group B only). 
• Subjects with a histo1y of bleeding related to cancer under stt1dy requiring a medical intervention (eg, 
embolization procedure, RBC transfusion, or hospitalization) within 30 days of stt1dy emollment 
(Treatment Groups Band Conly). 
• Clinically significant bleeding within 14 days of Cycle 1 Day 1 (Treatment Groups Band Conly). 
• Subjects cunently receiving warfarin therapy (Treatment Group B only). 
• Prior receipt of an LSD1 inhibitor including INCB059872 (Treatment Group Conly). 
Epacadosta t, Dosage, a nd Mode of Administration: 
Epacadostat will be orally self-administered BID beginning on Cycle 1 Day 1 (or Cycle 2 Day 1 in 
Treatment Groups Band C) and continuously thereafter in 21-day cycles.  All BID doses will be taken in 
the moming and evening, approximately 12 hours apa1t without regard to food. If a dose is missed by 
more than 4 hours, then that dose should be skipped, and the next scheduled dose should be taken at the 
usual time. Details for stt1dy dmg administration in the treatment sequencing rumor biopsy coho1ts 
(Coho1ts A-3 through A-5, B-9 through B-11, and C-11 through C-13) ru·e presented in the Overall Srudy 
Design section of the Synopsis and in the Protocol. 
INCB057643, Dosage, and Mode of Administration: 
INCB057643 will be orally self-administered QD beginning on Cycle 1 Day 1 and continuously 
thereafter in 21-day cycles. All daily doses will be taken in the moming at the same time as the moming 
dose of epacadostat,  approximately 24 houprior and 1 hour following dose administration, except 
on days when serial  
srunpling is conducted, then 
subjects will fast at least 8 hours before and 1 hour after stt1dy dmg or as indicated in the Protocol.   If a 
dose is missed by more than 8 hours, then that dose should be skipped,  and the next scheduled  dose 
should be taken at the usual time. Details for srudy dmg administration  in the treatment sequencing 
ttimor biopsy coho1ts (Cohorts B-9 through  B-11) ru·e presented in the Overall Srudy Design section of 
the Synopsis and in the Protocol. 
INCB059872, Dosage, and Mode of Administration: 
INCB059872  (United States sites only) will be orally self-administered either QD or QoD beginning on 
Cycle 1 Day 1 and continuously thereafter in 21-day cycles.  All daily doses will be taken in the moming 
at the same time as the moming dose of epacadostat, approximately 24 hom 
prior and 1 hour following dose administration, except on days when selial 
sampling is conducted, then subjects will fast at least 8 hours before and 1 hour after srudy dmg or as 
indicated in the Protocol.  If a dose is missed by more than 8 hours, then that dose should be skipped,  and 
the next scheduled dose should be taken at the usual time.  Details for srudy dmg administration in the 
treatment sequencing tt1mor biopsy coho1ts (Coho1ts C-11 through C-13) are presented in the Overall 
Srudy Design section of the Synopsis and in the Protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Reference Therapies, Dosage, a nd Mode of Administration: 
Pembrolizumab will be administered as a 200 mg, 30-minute IV infusion Q3W on Day 1 of each 21-day 
cycle. Details for study dmg administration in the treatment sequencing tumor biopsy coh011s (Coh011s 
A-3 through A-5, B-9 through B-11, and C-11 through C-13) are presented in the Overall Stttdy Design 
section in the Synopsis and in the Protocol. 
Azacitidine will be administered as a SC injection or IV infusion for 5 days in Cycles 1 through 3 (in the 
European Union, it will be administered SC only).  Details for study dmg administration  in the treatment 
sequencing tumor biopsy cohmts (Cohmts A-3 through A-5) are presented in the Overall Study Design 
section of the Synopsis and in the Protocol.  Subjects who remain on treatment beyond the Week 9 scan 
should continue to receive azacitidine until the second on-study scan (up to the Week 18 scan, for a 
maximum of3 additional cycles).  Five doses should be administered over the Day 1-7 period. 
Re-treatment with azacitidine (based on original treatment assignment) along with pembrolizumab and 
epacadostat may be administered for subjects who had a CR, PR, or SD (for > 6 months) and later had 
evidence of progressive disease while receiving pembrolizumab and epacadostat with medical monitor 
approval.  Three additional cycles of azacitidine are pennitted. 
Study Schedule/Procedures: 
Subjects will have regularly scheduled study visits at the clinical site on Day 1 of each cycle.  Additional 
study visits will be required during Cycles 1 through 3 (or Cycle 6 for subjects continuing azacitidine 
treatment beyond the first scan) while subjects are receiving priining doses of azacitidine, INCB057643, 
or INCB059872  
ted States sites only) and throughout the study to monitor for safety, efficacy, or for 
. Study visits will be as follows: 
• Screening: up to 28 days before enrollment.   Screening will begin at the time that the subject signs the 
llfmmed consent fmm and will continue until the date the subject is enrolled in the study (Cycle 1 Day 
1 or Day 1 of Week -1 for Expansion Coho1t A-3). 
• Treatment (Pa1t 1 Cohotts): 
- Cycle 1 (Treatment Group A):  Day 1, 4 additional  visits between Day 2 and Day 7, and Day 15 
(± 3 days). 
- Cycle 2 (Treatment Group A):  Day 1, 4 additional  visits between Day 2 and Day 7, and Day 15 
(± 3 days). 
- Cycle 1 (Treatment Groups Band C):  Days 1, 8 (± 3 days), and 15 (± 3 days). 
- Cycle 2 (Treatment Groups Band C):  Days 1, 8 (± 3 days), and 15 (± 3 days). For subjects receiving 
INCB059872  QoD, an additional visit will be perfmmed on Cycle 2 Day 2 or 4 so that the. 
- 
and ECG assessments occur on the day ofiNCB059872 administration. 
- All other treatment cycles:  Day 1 (± 3 days). 
Note:  Visit schedules for the Part 2 Cohmts are specified in the Protocol. 
• Efficacy assessments:  Eve1y 9 weeks(± 7 days) for 12 months, and then eve1y 12 weeks(± 7 days) 
thereafter until disease progression is dete1mined. 
• End of treatment (+ 5 days). 
• Safety follow-up:  42 to 49 days after end of treatment. 
• Disease status follow-up:  Eve1y 9 weeks (63 ± 7 days) lmtil the sta1t of new antineoplastic therapy, 
disease progression, death, or the end of the study.  Upon implementation of Amendment 4, follow-up 
for disease status will no longer be requii·ed. 
• Survival follow-up: Eve1y 12 weeks (+ 7 days) following disease progression or start of new anticancer 
therapy.  Upon implementation of Amendment 4, follow-up for survival statt1s will no longer be 
requii·ed. 


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Estimated Duration  of Pa rticipation: 
Up to 28 days for screening, continuous treatment in consecutive 21-day cycles as long as subjects are 
receiving  benefit and have not met any clitelia for stttdy withdrawal, and 42 to 49 days(+ 7 days) for 
safety follow-up. A survival follow-up period will continue evety 12 weeks(+ 7 days) after study 
treatment discontinuation. It is estimated that an individual subject will patticipate for approximately 
18 months (screening/study treatment for 6 months and follow-up for an additional12 months).  Upon 
implementation of Amendment 4, survival follow-up will no longer be required. 
 
Estimated Number  of Subjects: 
Up to approximately 531 subjects will be enrolled in the stttdy: 
• Part 1 (Treatment Group A):  15 to 45 subjects. 
• Patt 2 (Treatment Group A):  76 to 114 subjects. 
• Patt 1 (Treatment Group B):  39 to 57 subjects. 
• Patt 2 (Treatment Group B):  0 to 129 subjects. 
• Patt 1 (Treatment Group C):  39 to 57 subjects. 
• Patt2 
0 to 129 
 
 
Statistical Methods: 
, United States 
This is an open-label, multicenter, nonrandomized, dose-escalation Phase 1/2 stttdy. In Patt 1, dose 
escalation (all treatment groups), the primmy objective of the study is to detennine the MTD, maximum 
tested dose, or PAD ofazacitidine, INCB057643, or INCB059872  administered in combination with 
pembrolizumab and epacadostat  in subjects with advanced or metastatic solid tumors.  Dose-escalation 
will follow a 3 + 3 + 3 design algorithm.   The total number of subjects will depend on the frequency of 
DLTs and the number of dose levels tested before the MTD, maximum tested dose, or PAD is reached. 
In addition, Pa1t 1 dose expansion coh01ts for Treatment Groups Band C in 5 NSCLC subjects who 
progressed on a PD-1 pathway- targeted agent and 5 MSS CRC  
· 
will be opened at each dose level 
tested that clears the DLT window for signal  
 
 analysis to guide an RP2D. 
The safety/efficacy expansion in Pa1t 2 will include 2 
m 
3 treatment groups, subjects 
with NSCLC who have had disease progression on a prior PD-1 pathway-targeted agent and subjects with 
MSS CRC.  A Simon 2-stage design  will be used for each of the coh01ts. The response rates for histolical 
control (po), desired response rates for the combination (p1), number of subjects needed in Stage 1 (n1) 
and Stage 2 (n2), total number of subjects (n), first stage threshold declm·ing coh01t undesirable (n), and 
the upper lhnit of the number of responses inn subjects such that futility ofthe dmg is concluded (r) m·e 
provided in the table below. Detailed calculation is based on a 1-sided Type   enor of0.05 and power of 
80%. 


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Simon 2-Stage Design 
 
Cohort 
Tumor Type 
Po 
Pt 
n1 n2 
n 
rt 
r 
Expansion Cohort A-1 
NSCLC subjects who have had 
disease progression on a prior PD-1 
pathway-targeted agent 
3% 
20% 
8 
19 
27 
0 
2 
Expansion Coh01t A-2 
MSSCRC 
3% 
20% 
8 
19 
27 
0 
2 
Expansion Coh01t B-7 
NSCLC subjects who have had 
disease progression on a prior PD-1 
pathway-targeted agent 
3% 
20% 
8 
19 
27 
0 
2 
Expansion Coh01t B-8 
MSSCRC 
3% 
20% 
8 
19 
27 
0 
2 
Expansion Coh01t C-9 
NSCLC subjects who have had 
disease progression on a prior PD-1 
pathway-targeted agent 
3% 
20% 
8 
19 
27 
0 
2 
Expansion Coh01t C-10 
MSSCRC 
3% 
20% 
8 
19 
27 
0 
2 
In addition to the 6 Simon 2-stage  safety/efficacy expansion coho1ts, another 9 treatment sequencing 
tumor biopsy coho1ts will be emolled to evaluate epigenetic and tumor microenvironment  changes. A 
total of25 subjects will be emolled in each Expansion Cohorts A-3, A-4, B-9 through B-11 and C-11 
through C-13, and 10 first-line melanoma subjects will be emolled  in Expansion Cohort A-5. 
In the Part 2 treatment sequencing tumor biopsy cohorts, assuming the true rate of subjects positive for 
the biomarker is 70%, the probability of observing 16 or more subjects out of 25 subjects with the 
biomarker is 81% for Expansion Coho1ts A-3, A-4, B-9 through B-11, and C-11 through C-13 and the 
probability of observing 6 or more subjects out of 10 subjects with the biomarker is 85% for Expansion 
Coh01t A-5. 
All statistical analyses are descdptive in nature. Descriptive statistics will be dedved  where appropriate. 
Continuous endpoints will be summarized with number of subjects, mean, standard deviation, minimum, 
median, and maximum for each coho1t. Catego1ical endpoints will be summarized with frequency and 
percent for each coho1t. 
If data wanants, ORR will be estimated with 95% exact confidence interval.  Time to event endpoints 
such as DOR, PFS, and OS will be summarized  with Kaplan-Meier estimates by cohort. 


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- 
- 
 
TABLE OF CONTENTS 
 
SYNOPSIS ......................................................................................................................................3 
 
LIST OF ABBREVIATIONS........................................................................................................31 
 
1.  
INTRODUCTION ......................................................................................................36 
 
1.1. 
 
1.2. 
 
1.3. 
 
1.4. 
 
1.5. 
 
1.6. 
 
1.7. 
 
1.7.1. 
 
1.7.2. 
 
1.7.3. 
 
1.7.3.1. 
 
1.7.3.2. 
 
1.7.3.3. 
 
1.8. 
 
 
 
1.8.2. 
 
1.8.3. 
 
1.8.4. 
 
1.8.5. 
 
1.8.6. 
 
2. 
 
2.1. 
 
2.1.1. 
 
2.1.2. 
 
 
 
2.2. 
 
2.2.1. 
 
2.2.2. 
 
Innnunotherapy in Cancer ..........................................................................................36 
 
Overview of Pembrolizumab......................................................................................38 
 
Overview of Epacadostat ............................................................................................38 
 
Overview of Azacitidine.............................................................................................40 
 
Overview of iNCB057643..........................................................................................41 
 
Overview of iNCB059872..........................................................................................44 
 
Study Rationale...........................................................................................................46 
 
Rationale for Combining Epigenetic Therapy With Innnunotherapy ........................46 
 
Justification for the Treatment  Regimen ....................................................................48 
 
Rationale for Phase 2 Subject Populations .................................................................52 
 
Non-Small Cell Lung Cancer.....................................................................................52 
 
Microsatellite Stable Colorectal Cancer .....................................................................54 
 
Treatment Sequencing Tumor Biopsy Cohmt Indications .........................................55 
 
Potential Risks and Benefits of the Treatment Regimen ............................................55 
 55 
Risks From Pembrolizumab .......................................................................................57 
 
Risks From Azacitidine ..............................................................................................57 
 
Risks From INCB057643 ...........................................................................................57 
 
Risks From INCB059872 ...........................................................................................58 
 
Risks From Combination Therapy..............................................................................58 
 
STUDY OBJECTIVES AND ENDPOINTS..............................................................59 
 
Study Objectives .........................................................................................................59 
 
Prima1y Objectives .....................................................................................................59 
Seconda1y Objectives .................................................................................................59 
 59 
Study Endpoints..........................................................................................................60 
 
Prima1y Endpoints ......................................................................................................60 
 
Seconda1y Endpoints ..................................................................................................60 


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61 
3. 
 
3.1. 
 
3.2. 
 
4. 
 
4.1. 
 
4.1.1. 
 
4.1.1.1. 
 
4.1.1.2. 
 
4.1.1.3. 
 
4.1.2. 
 
4.1.2.1. 
 
4.1.2.2. 
 
4.1.2.3. 
 
4.2. 
 
4.3. 
 
4.3.1. 
 
4.3.2. 
 
4.4. 
 
4.5. 
 
4.6. 
 
5. 
 
5.1. 
 
5.1.1. 
 
5.1.2. 
 
5.2. 
 
5.2.1. 
 
5.2.1.1. 
 
5.2.1.2. 
 
5.2.1.3. 
 
5.2.1.4. 
 
5.2.2. 
 
5.2.2.1. 
SUBJECT ELIGIBILITY ...........................................................................................62 
 
Subject Inclusion Criteria ...........................................................................................62 
 
Subject Exclusion Criteria ..........................................................................................64 
 
INVESTIGATIONAL PLAN.....................................................................................68 
 
Overall Study  Design..................................................................................................68 
 
Dose-Escalation Phase (All Treatment Groups).........................................................70 
 
Treatment Group  A:  Azacitidine ...............................................................................71 
 
Treatment Group  B:  INCB057643 ............................................................................71 
 
Treatment  Group C:  INCB059872 ............................................................................72 
 
Dose-Expansion Phase................................................................................................73 
 
Treatment  Group A.....................................................................................................73 
 
Treatment  Group B .....................................................................................................75 
 
Treatment Group  C .....................................................................................................77 
 
Measures Taken to Avoid Bias...................................................................................83 
 
Number  of Subjects ....................................................................................................83 
 
Planned Number of Subjects ......................................................................................83 
 
Replacement of Subjects.............................................................................................83 
 
Duration of Treatment and Subject Participation .......................................................83 
 
Overall Study  Duration...............................................................................................84 
 
Study Terrnination ......................................................................................................84 
 
TREATMENT ............................................................................................................84 
 
Treatment  Assignment................................................................................................84 
 
Subject Numbering and Treatment Assignment.........................................................84 
 
Randomization and Blinding ......................................................................................85 
 
Study Drugs ................................................................................................................85 
 
Epacadostat .................................................................................................................85 
 
Description and Administration..................................................................................85 
 
Supply, Packaging, and Labeling ...............................................................................85 
 
Storage ........................................................................................................................85 
 
Instruction to Subjects  for Handling Epacadostat ......................................................85 
 
Pembrolizumab ...........................................................................................................86 
 
Description and Administration..................................................................................86 


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5.2.2.2. 
 
5.2.2.3. 
 
5.2.3. 
 
5.2.3.1. 
 
5.2.3.2. 
 
5.2.3.3. 
 
5.2.4. 
 
5.2.4.1. 
 
5.2.4.2. 
 
5.2.4.3. 
 
5.2.4.4. 
 
5.2.5. 
 
5.2.5.1. 
 
5.2.5.2. 
 
5.2.5.3. 
 
5.2.5.4. 
 
5.3. 
 
5.4. 
 
5.4.1. 
 
5.4.1.1. 
 
5.4.1.2. 
 
 
5.4.1.3. 
 
5.4.2. 
 
5.4.3. 
 
5.4.4. 
 
5.5. 
 
5.5.1. 
 
5.5.2. 
 
5.6. 
 
5.6.1. 
 
5.6.2. 
 
5.6.3. 
Supply, Packaging, and Labeling ...............................................................................86 
 
Storage ........................................................................................................................86 
 
Azacitidine ..................................................................................................................86 
 
Description and Administration..................................................................................86 
 
Supply,  Packaging, and Labeling ...............................................................................87 
 
Storage ........................................................................................................................87 
 
INCB057643...............................................................................................................87 
 
Description and Administration..................................................................................87 
 
Supply, Packaging, and Labeling ...............................................................................87 
 
Storage ........................................................................................................................87 
 
Instmction to Subjects  for Handling INCB057643 ....................................................88 
 
INCB059872...............................................................................................................88 
 
Description and Administration..................................................................................88 
 
Supply, Packaging, and Labeling ...............................................................................88 
 
Storage ........................................................................................................................89 
 
Instmction to Subjects  for Handling INCB059872 ....................................................89 
 
Treatment  Compliance................................................................................................89 
 
Treatment  futenuptions and Adjustments ..................................................................90 
 
Dose Modifications.....................................................................................................90 
 
Dose-Limiting Toxicity and Detennination of Maximum  Tolerated  Dose................90 
 
Criteria and Procedures for Dose futenuptions and Adjustments of Study 
Diug ............................................................................................................................92 
 
Procedures for Subjects Exhibiting Immune-Related Adverse Events ....................100 
 
Treatment  After fuitial Evidence of Radiographic Disease Progression..................l08 
 
Procedures  for Subjects Exhibiting Serotonin Syndrome ........................................109 
 
Criteria for Pe1manent Discontinuation of Study Dmg ............................................110 
 
Withdrawal of Subjects From Study Treatment .......................................................I l l 
Withdrawal Crite1ia ..................................................................................................I l l 
Withdrawal Procedures.............................................................................................I l l 
Concomitant Medications .........................................................................................112 
Pe1mitted Medications ..............................................................................................112 
 
Restricted Medications .............................................................................................112 
 
Prohibited Medications .............................................................................................113 


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6. 
 
6.1. 
 
6.2. 
 
6.3. 
 
6.4. 
 
6.4.1. 
 
6.4.2. 
 
6.4.3. 
 
6.5. 
 
6.6. 
 
7. 
 
7.1. 
 
7.2. 
 
7.3. 
 
7.3.1. 
 
7.3.2. 
 
7.4. 
 
7.5. 
 
7.5.1. 
 
7.5.2. 
 
7.5.2.1. 
 
7.5.2.2. 
 
7.5.3. 
 
7.5.4. 
 
7.5.4.1. 
 
7.5.5. 
 
7.5.5.1. 
 
7.5.5.2. 
 
7.5.5.3. 
 
7.5.5.4. 
 
7.5.5.5. 
 
 
 
7.6. 
STUDY ASSESSMENTS ........................................................................................114 
 
Screening ..................................................................................................................170 
 
Treatment ..................................................................................................................170 
 
End of Treatment ......................................................................................................171 
 
Follow-Up.................................................................................................................171 
 
Safety Follow-Up......................................................................................................171 
 
Disease Status Follow-Up.........................................................................................171 
 
Survival Follow-Up ..................................................................................................171 
 
End of Study .............................................................................................................172 
 
Unscheduled Visits ...................................................................................................172 
 
CONDUCT OF STUDY  ASSESSMENTS AND PROCEDURES .........................173 
 
Administration of fufmmed Consent Fmm ..............................................................173 
futeractive Response Technology Procedure............................................................173 
Demography and Medical Histmy............................................................................173 
 
Demographics and General Medical  History ...........................................................173 
 
Disease Characteristics and Treatment Histmy........................................................173 
 
Prior and Concomitant  Medications and Procedures................................................173 
 
Safety  Assessments...................................................................................................174 
 
Adverse Events .........................................................................................................174 
 
Physical  Examinations..............................................................................................174 
 
Comprehensive Physical  Examination .....................................................................174 
 
Targeted  Physical Examination ................................................................................174 
 
Vital Signs ................................................................................................................174 
 
Electrocardiograms ...................................................................................................174 
 
Timed Electrocardiograms........................................................................................175 
 
Laboratory Assessments ...........................................................................................175 
 
Senun Chemistry Tests.............................................................................................175 
 
Endocrine  Function Testing......................................................................................175 
 
Pregnancy Testing ....................................................................................................175 
 
Hepatitis Screening Tests .........................................................................................176 
 
CA 19-9 Testing .......................................................................................................176 
 176 
Efficacy Assessments ...............................................................................................176 


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176 
7.6.1.1. 
 
7.6.1.2. 
 
7.6.2. 
 
7.7. 
I-
I -
II 
-- 
7.10. 
 
7.10.1. 
 
7.10.2. 
 
8. 
 
8.1. 
 
8.1.1. 
 
8.1.2. 
 
8.2. 
 
8.3. 
 
8.3.1. 
 
8.3.2. 
 
8.4. 
 
8.5. 
 
8.6. 
 
8.7. 
 
8.8. 
 
8.9. 
 
9. 
 
9.1. 
 
9.2. 
Initial Tumor  hnaging...............................................................................................177 
 
Tumor hnaging Dming the Study.............................................................................177 
 
Tumor Biopsy ...........................................................................................................178 
 
Perfmmance  and Quality-of-Life Assessments ........................................................178 
 
178 
 
178 
 
181 
 
181 
 
181 
 
181 
 
181 
 
181 
 
Other Study Procedures ............................................................................................182 
 
Distribution of Subject Reminder Cards  and Subject  Diaries ..................................182 
 
Data Collection for Survival Follow-Up ..................................................................182 
 
SAFETY MONITORING AND REPORTING .......................................................183 
 
Adverse Events .........................................................................................................183 
 
Definitions ................................................................................................................183 
 
Reporting ..................................................................................................................183 
 
Laboratory Test Abnmmalities.................................................................................184 
 
Serious Adverse Events ............................................................................................185 
 
Definitions ................................................................................................................185 
 
Reporting ..................................................................................................................185 
 
Adverse Events of Special Interest ...........................................................................186 
 
Emergency Unblinding of Treatment Assignment ...................................................187 
 
Pregnancy .................................................................................................................187 
 
Wamings  and Precautions ........................................................................................187 
 
Data Monitoring Committee.....................................................................................187 
 
Product Complaints ..................................................................................................187 
 
STATISTICS ............................................................................................................188 
 
Study Populations .....................................................................................................188 
 
Selection of Sample Size ..........................................................................................188 


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- 
- 
 
9.2.1. 
 
9.2.1.1. 
 
9.2.1.2. 
 
9.2.2. 
 
9.2.2.1. 
 
9.2.2.2. 
 
9.3. 
 
9.4. 
 
9.4.1. 
 
9.4.2. 
 
 
 
9.4.4. 
 
9.4.4.1. 
 
9.4.4.2. 
 
9.4.4.3. 
 
9.4.4.4. 
 
9.4.4.5. 
 
 
 
 
 
9.5. 
 
9.6. 
 
10. 
 
 
10.1. 
 
10.2. 
 
10.3. 
 
10.4. 
 
10.5. 
 
10.6. 
 
11. 
Sample Size in Pa1t 1................................................................................................188 
 
Dose Escalation ........................................................................................................188 
 
Dose Expansion ........................................................................................................189 
 
Sample Size in Pa1t 2................................................................................................189 
 
Safety/Efficacy Expansion  Cohmts..........................................................................189 
 
Sample Size for Treatment Sequencing Tumor  Biopsy Cohmts..............................190 
 
Level of Significance................................................................................................190 
 
Statistical Analyses ...................................................................................................191 
 
Prima1y Analyses......................................................................................................191 
Seconda1y Analyses..................................................................................................191 
 191 
Safety  Analyses ........................................................................................................192 
 
Adverse Events .........................................................................................................192 
 
Clinical Laboratmy Tests .........................................................................................192 
 
Vital Signs ................................................................................................................192 
 
Electrocardiograms ...................................................................................................193 
 
Adverse Events of Special futerest ...........................................................................193 
 
193 
 
194 
 
Analyses for the Data Monitming Committee..........................................................194 
futerim Analysis........................................................................................................194 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES ........................................................................................................195 
fuvestigator Responsibilities.....................................................................................195 
Accountability, Handling, and Disposal of Study Dmg ...........................................196 
 
Data Management .....................................................................................................197 
 
Data P1ivacy and Confidentiality of Study Records.................................................197 
 
Financial  Disclosure .................................................................................................198 
 
Publication Policy.....................................................................................................198 
 
REFERENCES .........................................................................................................199 
 
APPENDIX A.  INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS .............................................................................206 
 
 


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APPENDIX C. PROHIBITED MONOAMINE OXIDASE INHIBITORS AND DRUGS 
ASSOCIATED WITH SIGNIFICANT MONOAMINE OXIDASE INHIBITORY 
ACTIVITY .......................................................................................208 
 
APPENDIX D. EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS.....................................................................................209 
 
APPENDIX E. PROTOCOL AMENDMENT SUMMARY OF CHANGES ..........................210 
 
 
 
LIST OF TABLES 
 
Table 1: 
Dose Levels:  Treatment Group A..............................................................................71 
 
Table 2: 
Dose Levels:  Treatment Group B ..............................................................................72 
 
Table 3: 
Dose Levels:  Treatment Group C ..............................................................................72 
 
Table 4: 
Treatment Group A Safety/Efficacy Expansion Cohmts (Pa1t 2) ..............................73 
 
Table 5: 
Treatment Group A Treatment Sequencing Tumor Biopsy Cohmts (Pa1t 2).............74 
 
Table 6: 
Treatment Group B Safety/Efficacy Expansion Cohmts (Pa1t 2) ..............................76 
 
Table 7: 
Treatment Group B Treatment Sequencing Tumor Biopsy Cohmts (Part 2) .............77 
 
Table 8: 
Treatment Group C Safety/Efficacy Expansion Cohmts (Pa1t 2) ..............................78 
 
Table 9:  
Treatment Group C Treatment Sequencing Tumor Biopsy Cohmts ..........................79 
 
Table 10: Definition of Dose-Limiting Toxicity ........................................................................91 
 
Table 11: 
Epacadostat Dose Reductions.....................................................................................93 
 
Table 12: Azacitidine Dose Reductions......................................................................................93 
 
Table 13: INCB057643 Dose Reductions...................................................................................93 
 
Table 14: INCB059872 Dose Reductions...................................................................................94 
 
Table 15: Dose Modification Guidelines for Dmg-Related Adverse Events (Treatment 
Group A) .....................................................................................................................95 
 
Table 16: Dose Modification Guidelines for Dmg-Related Adverse Events (Treatment 
Group B) .....................................................................................................................96 
 
Table 17:  Dose Modification Guidelines for Dmg-Related Adverse Events (Treatment 
Group C) .....................................................................................................................98 
 
Table 18: General Approach to Handling Immune-Related Adverse Events...........................100 
 
Table 19: Recommended Approach for Handling Noninfectious Pneumonitis .......................102 
 
Table 20: Recommended Approach for Handling Enterocolitis...............................................103 
 
Table 21:  Recommended Approach for Handling Hepatitis.....................................................104 
 
Table 22: Recommended Approach for Handling De1matitis ..................................................105 
 
Table 23: Recommended Approach for Handling Neuropathies..............................................106 


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Table 24: Recommended Approach for Handling Endocrinopathies .......................................107 
 
Table 25: Recommended Approach for Handling Myocarditis................................................108 
 
Table 26: Imaging and Treatment After First Radiographic Evidence of Progressive 
Disease......................................................................................................................109 
 
Table 27: Signs and Symptoms of Serotonin Syndrome ..........................................................110 
 
Table 28: Warfa1in Dose Modifications ...................................................................................113 
 
Table 29: Schedule of Assessments (Treatment Group A:  Part 1 and Pa1t 2 Expansion 
Cohorts A-1 and A-2) ...............................................................................................115 
 
Table 30: Laboratmy Assessments (Treatment Group A:  Part 1 and Part 2 Expansion 
Cohorts A-1 and A-2) ...............................................................................................118 
 
Table 31:  Schedule of Assessments (Treatment Group A:  Part 2 Expansion 
Cohmt A-3, Azacitidine Monotherapy Lead-In) ......................................................120 
 
Table 32: Laboratmy Assessments (Treatment Group A:  Part 2 Expansion 
Cohmt A-3, Azacitidine Monotherapy Lead-In) ......................................................123 
 
Table 33: Schedule of Assessments (Treatment Group A:  Part 2 Expansion 
Cohmt A-4, Pembrolizumab/Epacadostat Lead-In) .................................................124 
 
Table 34: Laboratmy Assessments (Treatment Group A:  Part 2 Expansion 
Cohmt A-4, Pembrolizumab/Epacadostat Lead-In) .................................................127 
 
Table 35: Schedule of Assessments (Treatment Group A:  Part 2 Expansion 
Cohmt A-5, Pembrolizumab Monotherapy Lead-In) ...............................................128 
 
Table 36: Laboratory Assessments (Treatment Group A:  Part 2 Expansion 
Cohmt A-5, Pembrolizumab Monotherapy Lead-In) ...............................................131 
 
Table 37: Schedule of Assessments (Treatment Group B: Part 1 Dose-Escalation and 
Expansion Cohmts B-1 to B-6 and Pa1t 2 Expansion Cohmts B-7, B-8, and 
B-9) ...........................................................................................................................132 
 
Table 38: Laboratmy Assessments (Treatment Group B:  Part 1 Dose-Escalation and 
Expansion Cohmts B-1 to B-6 and Pa1t 2 Expansion Cohmts B-7, B-8, and 
B-9) ...........................................................................................................................137 
 
Table 39: Schedule of Assessments (Treatment Group B: Part 2 Expansion 
Cohort B-10) .............................................................................................................139 
 
Table 40: Laboratory Assessments (Treatment Group B:  Pa1t 2 Expansion 
Cohort B-10) .............................................................................................................143 
 
Table 41: Schedule of Assessments (Treatment Group B: Part 2 Expansion 
Cohort B-11) .............................................................................................................145 
 
Table 42: Laboratory Assessments (Treatment Group B:  Pa1t 2 Expansion 
Cohort B-11) .............................................................................................................149 


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Table 43: Schedule of Assessments (Treatment Group C: Pa1t 1 Dose-Escalation and 
Expansion Cohmts C-1 to C-8 and Pa1t 2 Expansion Cohmts C-9, C-10, and 
C-11) .........................................................................................................................151 
 
Table 44: Laboratmy Assessments (Treatment Group C:  Pa1t 1 Dose-Escalation and 
Expansion Cohmts C-1 to C-8 and Pa1t 2 Expansion Cohmts C-9, C-10, and 
C-11) .........................................................................................................................155 
 
Table 45: Schedule of Assessments (Treatment Group C: Pa1t 2 Expansion 
Coho1t C-12) .............................................................................................................157 
 
Table 46: Laboratory Assessments (Treatment Group C:  Pa1t 2 Expansion 
Coho1t C-12) .............................................................................................................161 
 
Table 47: Schedule of Assessments (Treatment Group C: Pa1t 2 Expansion 
Coho1t C-13) .............................................................................................................163 
 
Table 48: Laboratory Assessments (Treatment Group C:  Pa1t 2 Expansion 
Coho1t C-13) .............................................................................................................167 
 
Table 49: Local Laboratmy Tests:  Required Analytes ............................................................169 
 
 
 
79 
 
 
79 
 
 
80 
 
 
80 
 
 
80 
 
Table 55: Probability of Dose De-Escalation for Va1ious Dose-Limiting Toxicity Rates .......189 
 
Table 56: Simon 2-Stage Design ..............................................................................................190 
 
Table 57: Criteria for Clinically Notable Vital Sign Abnmmalities.........................................193 
 
Table 58: Criteria for Clinically Notable Electrocardiogram Abnmmalities ...........................193 
 
 
 
LIST OF FIGURES 
 
Figure 1:  
Study Design:  Treatment Group A ............................................................................80 
 
Figure 2: 
Study Design:  Treatment Group B ............................................................................81 
 
Figure 3: 
Study Design:  Treatment Group C ............................................................................82 


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LIST OF ABBREVIATIONS 
 
The following abbreviations and special te1ms are used in this clinical study Protocol. 
 
Abbreviation 
Definition 
 
ACTH 
 
 
AE 
adverse event 
ALK 
anaplastic lymphoma kinase 
ALT  
alanine aminotransferase 
AML  
acute myeloid leukemia 
AST 
aspmtate aminotransferase 
----+ 
 
 
 
 
 
 
 
BBB 
blood-brain bmTier 
BCRP 
breast cancer resistance protein 
BID 
twice daily 
BET 
bromodomain and extra-te1minal protein 
BRD 
bromodomain-containing protein 
BRDT 
bromodomain testis-specific protein 
-----+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
c-MYC 
cellulm·f01m of a regulator gene that can act as an oncogene (MYC) 
c-Myc 
transcription factor encoded by the c-MYC gene 
CNS 
central nervous system 
CR  
complete response 
CRC 
colorectal cancer 
CrCl 
creatinine clem·ance 
CT  
computed tomography 


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Abbreviation 
Definition 
CTCAE 
Collllllon Te1minology Criteria for Adverse Events 
CTFG 
Clinical Trial Facilitation Group 
CTLA 
cytotoxic T-lymphocyte antigen 
CYP 
cytochrome P450 
DC 
dendlitic cells 
DDI 
dmg-dmg interaction 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DNMT 
deoxyribonucleic acid methyltransferase 
DOR 
duration of response 
ECso 
half maximal effective concentration 
ECG 
electrocardiogram 
ECOG 
Eastem Cooperative Oncology Group 
eCRF 
electronic case repo1t f01m 
EDso 
median effective dose 
EDC 
electronic data capn1re 
EGFR 
epide1mal growth factor receptor 
EOT 
end of treatment 
FAD 
flavin adenine dinucleotide 
FDA 
Food and Dmg Administration 
I 
FOXP3 
forkhead box P3 
GCP 
Good Clinical Practice 
H&E 
hematoxylin and eosin 
HBV 
hepatitis B vims 
HCV 
hepatitis  C vims 
HDAC 
histone  deacetylase 
HIPAA 
Health Insurance Po1tability and Accountability Act of 1996 
HIV 
human immunodeficiency vims 
HNSCC 
head and neck squamous cell carcinoma 
IB 
Investigator's  Brochure 
ICso 
half maximal inhibito1y concentration 
lCgo 
concentration that results in 90% inhibition 
ICF 
info1med consent f01m 
ICH 
Intemational Conference on Harmonisation 
IDO 
indoleamine 2,3-dioxygenase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Abbreviation 
Definition 
IEC 
independent ethics cormnittee 
IHC 
inummohistochemist1y 
IL 
interleukin 
IMP 
investigational medicinal product 
IN 
Investigator Notification 
INR 
intemational nonnalized ratio 
irAE 
inunune-related adverse event 
IRB 
institutional review board 
IRT 
interactive voice/web  response system 
IDD 
intrauterine device 
IDS 
intrauterine  ho1mone-releasing system 
IV 
intravenous 
JAK 
Janus kinase 
LFT 
liver function test 
LSDl 
lysine-specific demethylase  lA 
LSD2 
lysine-specific demethylase 2 
MAO-A 
monoamine oxidase A 
MAO-B 
monoamine oxidase B 
MAOI 
monoamine oxidase inhibitor 
MCP 
methyl-accepting chemotaxis protein 
MDS 
myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulato1y Activities 
MM 
multiple myeloma 
MMR 
MRI 
mismatch repair 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
MSI 
microsatellite instability 
MSI-L 
microsatellite instability-low 
MSI-H 
microsatellite instability-high 
MSS 
microsatellite stable 
MTD 
maximum tolerated dose 
NCCN 
National Comprehensive  Cancer Network 
NCI 
National Cancer Institute 
NSCLC 
non- small-cell lung cancer 
OAT 
organic anion transpo1ter 


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Abbreviation 
Definition 
OATP 
organic anion t:ransp01ting polypeptide 
OCT 
organic cation transp01ter 
ORR 
objective response rate 
OS 
overall survival 
PAD 
pharmacologically active dose 
PD 
progressive disease 
PD-1 
programmed death receptor-! 
PD-Ll 
programmed death-ligand  1 
PET 
positron emission tomography 
PFS 
progression-fi·ee survival 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic 
PO 
orally 
PR 
pa1tial response 
PSA 
prostate-specific antigen 
PT 
prothrombin time 
Q3W 
evety 3 weeks 
Q9W 
evety 9 weeks 
Q12W 
evety 12 weeks 
QAM 
evety moming 
QD 
once daily 
QoD 
evety other day 
QPM 
evety evening 
RCC 
renal cell car·cinoma 
RECIST 
Response Evaluation Critelia in Solid Tumors 
RNA 
ribonucleic acid 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
sc 
subcutaneous 
SCCHN 
squamous cell carcinoma of the head and neck 
SCLC 
small-cell lung cancer 
SD 
stable disease 
SmPC 
Summa1y of Product Characteristics 
SNRI 
serotonin-norepinephrine reuptake inhibitor 
ss 
serotonin syndrome 
SSRI 
selective serotonin reuptake inhibitor 


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Abbreviation 
Definition 
 
SUSAR  
suspected unexpected serious adverse  reaction 
1-:-------+ 
 
TDLN  
tumor-draining lymph nodes 
 
TEAE 
TGA 
TGB 
TGC 
TGI 
TIL 
TKI 
Treg 
treatment-emergent adverse event 
 
Treatment Group A 
Treatment Group B 
Treatment Group C 
tumor growth inhibition 
tumor-infiltrating lymphocyte 
tyrosine kinase inhibitor 
T regulato1y cells 
 
ULN  
upper limit of nmmal 
 
VEGF 


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1- 
INTRODUCTION 
 
This is an open-label, multicenter, Phase 1/2 study evaluating the addition of 3 different 
epigenetic p1iming regimens to an immunotherapy  doublet in 
·ects with advanced or 
metastatic solid tumors.  This study will use a suite of tissue  
 
technologies to 
evaluate the immune activity of the DNA methyltransferase 
 
 
azacitidine; the 
bromodomain and extra-terminal (BET) inhibitor, INCB057643; or the lysine-specific 
demethylase  IA (LSDI) inhibitor, INCB059872, in combination with the programmed death 
receptor-I (PD-1) inhibitor pembrolizumab  and the indoleamine 2,3-deoxygenase (IDO) 1 
inhibitor epacadostat.  The first part of the study will consist of a dose-escalation  assessment of 
the safety and tolerability of the treatments in subjects with advanced or metastatic solid tumors. 
Pmt 2 of the study will be an open-label Phase 2 assessment with Simon 2-stage design to 
evaluate objective response rate (ORR) and tumor-infiltrating  lymphocyte (TIL)  infiltration in 
previously treated non-small-celllung cancer (NSCLC)  and microsatellite stable (MSS) 
colorectal cancer (CRC).  Separate treatment sequencing tumor biopsy cohorts are also included 
in the expansion to fmther evaluate epigenetic changes and changes in the tumor 
microenvironment in subjects with head and neck squamous cell carcinoma (HNSCC), 
melanoma, urothelial carcinoma, and MSS CRC. 
 
LL  
Immunotherapy  in Cancer 
 
The impmtance of intact immune smveillance in controlling outgrowth of neoplastic 
transfmmation  has been known for decades (Disis 2010).  The inability of the immune system to 
control tumor growth does not appear to result from an inability to recognize the tumor as 
foreign.  Tumor cells have been shown to evade the immune system by exploiting the immune 
checkpoint pathways that down-regulate the immune response to avoid healthy tissue damage 
(Davies 2014).  Histologic evaluation of many human cancers shows extensive infiltration by 
inflammatmy and immune cells (Galon et al2006), suggesting that the immune system responds 
to malignancy, albeit less effectively than needed to eradicate the tumors.  The presence ofTILs 
in cancer tissue among va1ious malignancies  has been shown to confer a more favorable 
prognosis (Mei et al2014, Gooden et al2011, Bremnes et al2011, Talmadge 2011).  Detailed 
analysis of CD8+ T cells and the ratio of CD8+ effector T cells/forkhead box P3 (FOXP3)+ 
T regulatmy cells (Tregs) seem to conelate  with improved prognosis and long-te1m smvival in 
many solid tumors (Nosho et al2010, Chang et al2014, Preston et al2013, Yoon et al2012, 
Kim et al2013). Although the immune system has been shown to recognize and reject a tumor, 
many tumors evade immune smveillance or develop mechanisms of resistance. 
 
Immune therapies targeting the immune checkpoint pathways have recently become an important 
therapeutic strategy for hamessing the immune system's  ability to control malignancy. 
Justification for the blockade of immune inhibitmy pathways is evidenced by the clinical 
responses obse1ved with antibodies to cytotoxic T-lymphocyte antigen (CTLA)-4  and 
PD-1/programmed death-ligand 1 (PD-Ll). Checkpoint inhibitors including ipilimumab, 
nivolumab,  pembrolizumab, and atezolizumab have shown durable antitumor activity with 
minimal toxicity in several different tumor types and have been approved as monotherapy or 
combination treatment in melanoma, NSCLC, renal cell carcinoma, classical Hodgkin 
lymphoma, urothelial carcinoma, and HNSCC (Opdivo 2017, Keytmda 2017, 


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Powles et al2014). While great advances have been made, with the exception of melanoma, 
which has shown the highest response rates in monotherapy, the majority of solid tumors do not 
respond  to checkpoint inhibitors alone.  Additionally, the greatest antitumor effect is in patients 
with the highest expression of the PD-l ligand, PD-Ll , on tumor cells (Brahmer et al2010, 
Garon et al2015). Multiple immune inhibitmy mechanisms  are present concunently within the 
tumor microenvironment, suggesting that combination therapies may be required for optimal 
therapeutic effect (Quezada and Peggs 2013).  A combination of immunotherapy agents that 
stimulate an immune response  targeted to tumor cells combined with the relief of negative 
regulation should synergize in allowing the immune system to generate a response  leading to 
enhanced tumor rejection. 
 
One mechanism of inducing tolerance for malignancy is through IDOl (Godin-Ethier et al2011). 
Indoleamine 2,3 dioxygenase 1 is a heme-containing, monomeric oxidoreductase that catalyzes 
the degradation of the essential amino acid  tryptophan to N-fmmyl-kynurenine.  Indoleamine 
2,3-dioxygenase l-d1iven oxidation of tryptophan results in a strong inhibitmy effect on the 
development ofT-cell-mediated responses by blocking T-cell activation  and inducing T-cell 
apoptosis (Mellor et al2003). Both the reduction in local tryptophan levels and the production 
of tryptophan catabolites are inhibitmy to T-cell proliferation and contribute to 
immunosuppressive effects (Fnnnento et al 2002).  Indoleamine 2,3-dioxygenase 1 activity also 
promotes the differentiation of naive T cells to cells with a regulatmy phenotype (Treg; 
Fallarino et al2006). Since increased Treg activity has been shown to promote tumor growth 
and Treg depletion has been shown to stimulate an othe1wise  ineffectual antitumor immune 
response  (Zou 2006), IDO1 expansion of Tregs may provide an additional mechanism whereby 
IDO1 could promote an immunosuppressive environment. 
 
Epigenetic therapies such as DNMT inhibitors, histone deacetylase (HDAC) inhibitors and BET 
inhibitors have recently become a suggested  combination pa1tner for immune therapies.   Over 
the last several decades, there has been a greater understanding  of the functional  implications  of 
histone modifications  and DNA methylation  pattems in regards to cell cycle regulation and 
cancer (Ahuja et al2016). Recent preclinical studies have shown evidence that epigenetic 
modulators may sensitize tumor-bearing animals to immune therapies including PD-1 blockade. 
In NSCLC cell lines, azacitidine has been shown to upregulate  genes and pathways related to 
both innate and adaptive immunity as well as genes related to immune evasion.  Of particular 
interest, azacitidine was shown to up-regulate PD-Ll  tr·anscripts and protein 
(Wrangle et al2013). In a recent study, Chiappinelli et al (2015) showed that DNMT inhibitors 
up-regulated immune signaling in cancer cell lines through a viral defense pathway.  In ova1ian 
cancer, DNTM inhibition u·iggered cytosolic sensing of double-stranded RNA and caused a 
Type I interferon response and apoptosis. 
 
Early signals of potential efficacy from combined epigenetic agents were obse1ved in solid 
tumors while evaluating a low dose regimen of the DNMT inhibitor azacitidine with the HDAC 
inhibitor entinostat.   In a heavily pretreated NSCLC population of 45 subjects, objective 
responses were obse1ved in only 4% of subjects, but 1 subject had a complete response (CR) for 
a duration of 14 months and a second subject had a pa1tial response (PR) that lasted 8 months. 
There were 10 subjects who had stable disease (SD) for at least 12 weeks.  The clinical responses 
that were obse1ved continued after the discontinuation of the epigenetic modifiers, suggesting a 
sustained  antitumoral effect (Juergens et al2011). Five NSCLC subjects from this epigenetic 
study went on to receive immune checkpoint therapy in a nivolumab Phase 1 study.  All 


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5 subjects were without progression at 6 months, and 3 of these subjects developed high-grade 
Response Evaluation C1iteria in Solid Tumors (RECIST) PRs that have been durable for over 
2.5 years (Chiappinelli  et al2016). As a result  of the preclinical and early clinical data, several 
clinical studies  have been initiated in solid tumors to dete1mine whether the combination of an 
epigenetic modifier with checkpoint inhibitors may increase response rates and prolong duration 
of response  (DOR) in tumor types that are known to respond to PD-1 pathway inhibition 
(NCT01928576, NCT02512172).  There are also investigations unde1way to dete1mine whether 
adding epigenetic therapy to checkpoint inhibitors can release the immune tolerance and generate 
responses in leukemia and solid tumors where they have not been shown to be responsive to 
checkpoint inhibition alone (Murphy et al2016, Daver et al2016). The current study will 
investigate whether generating an inte1feron response while simultaneously blocking multiple 
adaptive resistance pathways that are also interferon regulated creates benefit in subjects with 
solid tumors. 
 
1.2.  
Overview  of Pembrolizumab 
 
Pembrolizumab is a humanized immunoglobulin G4 antibody that blocks the PD-1 receptor 
expressed by T cells (Hamid et al2013). In a Phase 1 study in subjects with advanced melanoma 
and NSCLC, pembrolizumab was shown to be generally well-tolerated with no maximum 
tolerated dose (MTD) identified.  Pembrolizumab showed promising antitumor activity in 
melanoma and NSCLC with ORRs of38% and 19.4%, respectively (Hamid et al2013, 
Garon et al 2015).  A broad development program was initiated in multiple solid tumors and 
hematological malignancies, and pembrolizumab was first approved by the FDA on 04 SEP 2014 
for the treatment of patients with umesectable or metastatic melanoma and disease progression 
following ipilimumab and, ifBRAF V600 mutation-positive, a BRAF inhibitor.  Pembrolizumab 
has shown broad anticancer activity in a variety of solid tumors and has also been approved in 
subjects with metastatic  NSCLC whose tumors express PD-Ll  and had progression on or after 
platinum-based  chemotherapy and in subjects with recunent or metastatic  HNSCC that have 
disease progression on or after platinum-containing chemotherapy (Robe1t et al 2014, 
Le et al2015, Ribas et al2015, Herbst et al2016, Seiwe1i et al2016). 
 
Refer to the pembrolizumab approved label for fmther preclinical and clinical study data. 
 
1.3.  
Overview  of Epacadostat 
 
Epacadostat represents a novel, potent, and selective inhibitor of the enzyme IDO1.  In 
cell-based  assays, epacadostat potently inhibits IDOl  in both human tumor cells and human 
dendritic cells (DCs), resulting  in reduced tryptophan to kynurenine conversion (ICso 
values = 7.1-12.7 nM).  Epacadostat does not significantly inhibit other proteins that could affect 
tryptophan catabolism.  In cell culture, epacadostat reverses the strongly inhibitmy effect on the 
development ofT-cell-mediated responses that IDO1 activity impa1ts, resulting  in enhanced 
T-cell and natural killer cell proliferation, enhanced interferon-y production, reduced Treg 
differentiation, reduced DC apoptosis, and enhanced expression of DC activation markers. 
Epacadostat reversal of the IDO1-mediated suppression ofT-cell proliferation is dose-dependent, 
with a potency consistent with its inhibition of tryptophan to kynurenine conversion 
(ECso = 17.7 nM).  The in vivo data demonsti·ate that epacadostat can inhibit IDOl  systemically, 
and impmtantly, in tumors and tumor-draining lymph nodes (TDLN). Epacadostat was 


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efficacious  in mouse models of colon and pancreatic cancer, and its ability to reduce tumor 
growth was dependent on a functional immune system,  which is consistent with its proposed 
mechanism of action.  Moreover, epacadostat enhanced lymphocyte function in tumors and 
TDLN.  The combination of epacadostat  and either an antimouse  CTLA-4 or an antimouse 
PD-L1 antibody was also shown to act synergistically in significantly reducing tumor growth in a 
melanoma xenograft model.  Finally, epacadostat improved  the tumor growth control of 
cytotoxic chemotherapy when used in combination.  These data support  the evaluation of 
epacadostat  in patients with malignant diseases. 
 
As ofSEP 2016, 12 Phase 1, 2, or 3 Incyte-sponsored clinical studies  have either been completed 
or are ongoing.  Five investigator-sponsored clinical studies have either been completed or are 
ongoing.  As of 10 JUN 2016, 607 unique subjects have been exposed to epacadostat either as 
monotherapy (91 subjects) and/or in combination with checkpoint  inhibitors (anti-PD-1 targeted 
therapy:  384 subjects; anti-PD-L1 targeted therapy:  82 subjects; and anti-CTLA-4 targeted 
therapy:  50 subjects).  Epacadostat has been evaluated in a completed Phase 1 study and has 
several  ongoing Phase 1 and 2 studies in combination  with immune-targeted agents, such as a 
small molecule Janus kinase (JAK)-1 inhibitor and anti-PD-1, anti-PD-L1, and anti-CTLA-4 
antibodies. Based off of preliminary data in subjects with melanoma in the Phase 112 study 
evaluating the combination of pembrolizumab and epacadostat  (Study INCB 24360-202),  a global 
Phase 3 study has been initiated in first-line metastatic melanoma. 
 
In the Phase 1 clinical study in subjects with refractmy solid tumors (INCB 24360-101), 
epacadostat  was well-tolerated at doses  ranging from 50 mg once daily (QD) to 700 mg twice 
daily (BID).  Twenty-five (48.1%) ofthe 52 subjects administered epacadostat repmted a serious 
adverse event (SAE).  The most frequently repmted SAEs were disease progression (4 subjects, 
7.7%) followed by abdominal pain, nausea, and hypoxia (3 subjects each,  5.8%).  The most 
commonly repmted treatment-related  treatment-emergent adverse events (TEAEs) were fatigue 
and nausea (25 subjects,  48.1%). Two dose-limiting toxicities (DLTs) occUlTed: 1 DLT of 
radiation pneumonitis at the 300 mg dose level and 1 DLT of fatigue at the 400 mg BID dose 
level. 
 
In an ongoing Phase 1 open-label dose-escalation study of epacadostat with ipilimumab (3 mglkg 
intravenously [IV]), daily doses of epacadostat have been evaluated in 21-day cycles.  A total of 
48 subjects have been emolled to date in 6 cohmts:  300 mg, 100 mg, 25 mg, and 50 mg BID; 
75 mg total daily dose (50 mg eve1y moming [QAM] and 25 mg eve1y evening [QPM]); and 
50 mg BID intemlittent  doses (2 weeks on and 1 week off).  The initial evaluation of 
INCB024360 300 mg BID in combination  with ipilimumab was tenninated  due to the occunence 
of Grade 3 or 4 alanine aminotransferase (ALT)/aspaitate aminotransferase (AST) elevations  in 
5 of7 subjects treated at tills dose.  These adverse events (AEs)  were reversible in all subjects 
upon discontinuation of study therapy and institution  of corticosteroids based on an established 
protocol for the management of immune toxicities related to ipilimumab therapy.  Emollment 
was resta1ted at 25 mg BID.  Serious AEs were observed in the 300 mg BID, 25 mg BID, 75 mg 
total daily dose (50 mg QAM and 25 mg QPM), and 50 mg BID inte1mittent dose groups.  The 
system organ class with the most frequently repmted SAEs was gastrointestinal disorders 
(8 subjects,  16.7%) followed by investigations (6 subjects, 12.5%).  Treatment-emergent AEs 
were repmted in 49 subjects (98.0%). Fatigue was the most frequently repmted TEAE 
(33 subjects, 66.0%)  followed by rash (27 subjects, 54.0%; includes the prefened te1ms  rash, 
rash generalized, rash macular, rash maculopapular, and rash pmritic). As of European Society 


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for Medical Oncology 2015, 30 immunotherapy-naive subjects were emolled; 30% of those 
subjects achieved objective response, and 60% achieved disease control (both assessed by 
immune-related response c1iteria; Gibney et al2015). INCB024360 at doses up to 50 mg BID 
with ipilimumab were generally well-tolerated,  and immune-related  adverse events (irAEs) 
previously observed with ipilimumab were reversible with approp1iate management.  Tumor 
response and duration data suggest the potential for enhanced melanoma patient outcomes 
compared with ipilimumab monotherapy.  Epacadostat is also being evaluated in 2 clinical 
studies with the PD-1 inhibitors nivolumab (INCB 24360-204) and pembrolizumab 
(INCB 24360-202) and 2 studies with anti-PD-Ll  inhibitors, atezolizumab (INCB 24360-110) 
and dmvalumab (INCB 24360-203). 
 
In a current, ongoing study (INCB 24360-202), emollment  is complete in the Phase 1 cohmts of 
epacadostat 25 mg BID, 50 mg BID, 100 mg BID, and 300 mg BID cohmts with pembrolizumab 
2 mglkg or 200 mg IV eve1y 3 weeks (Q3W).  The Phase 2 pa1t of the study is still ongoing, in 
which the recommended Phase 2 dose (RP2D) of epacadostat 100 mg BID is being evaluated in 
combination with the fixed dose ofpembrolizumab 200 mg IV Q3W.  As of28 MAR 2016, a 
total of 181 subjects have been emolled to the study (both Phase 1 and Phase 2).  Among the 
117 subjects who have received epacadostat 100 mg BID in combination with pembrolizumab, 
the most frequently reported (;::: 15%) AEs of any grade for all treatment groups combined were 
fatigue (35.0%), constipation (24.8%), dianhea (20.5%), nausea (20.5%), vomiting (18.8%), 
pyrexia (16.2%), and dyspnea (15.4%). Fatigue (13.7%) and rash (11.1%; including the 
prefened tenns rash, rash maculopapular, rash generalized, and rash macular)  were the only 
treatment-related AEs repmted in > 10% of subjects.  Treatment-related  AEs of rash were only 
repmted in the Phase 2 group. 
 
The ORR in 19 evaluable subjects with treatment-naive metastatic melanoma was 53% (10119), 
with disease control rate of74% (14119).  Median progression-free smvival (PFS) has not been 
reached, and all responses are ongoing with minimum follow-up of 31.7 weeks.  Objective 
responses were also seen in other tumor types emolled in Phase 1 (Gangadhar et al2015). Based 
off of data in Study INCB 24360-202, a Phase 3 study of epacadostat in combination with 
pembrolizumab  has been initiated in subjects with umesectable or metastatic melanoma. 
 
Refer to the epacadostat Investigator's Brochure (IB) for additional preclinical and clinical study 
data. 
 
1.4.  
Overview  of Azacitidine 
 
Azacitidine is a cytidine nucleoside  analog that incorporates with DNA and RNA.  Once 
azacitidine is incorporated in the DNA, this leads to the depletion of DNMTs, hypomethylation 
of DNA, and the induction of DNA damage (Hollenbach 2010).  There are 2 main mechanisms 
that result in antitumor activity for azacitidine, cytotoxicity, which is the result of its 
incorporation into RNA and DNA, and DNA hypomethylation, which restores nmmal growth 
control and the differentiation in hematopoietic cells.  Clinical investigation  of azacitidine as a 
standard cytotoxic agent began in the late 1960s and 1970s in various hematologic and solid 
tumor indications.   Early studies  evaluated doses ranging from 150 to 750 mg/m2  and showed 
activity in myeloid malignancies.  In subsequent studies in subjects with relapsed leukemia, an 
obse1vation was made that higher remission rates occmTed with treatment at lower doses 
(Vigil et al2010). Azacitidine was evaluated in subjects with myelodysplastic syndrome (MDS) 


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in a Phase 3 randomized controlled study using a subcutaneous (SC) dose of 75 mg/m2  for 7 days 
every 4 weeks.  In this study, 60% of patients randomized to azacitidine had a response (7% CR, 
16% PR, and 37% had hematologic improvement),  compared with 5% improved in the 
supportive care aim.  The median time to leukemic transfmmation or death was 21 months on 
the azacitidine aim, compared with 13 months on the best suppmtive care aim (Silve1man 
et al2002). In a separate randomized overall survival (OS) study in high-risk MDS, azacitidine 
showed a median OS of24.5 months, compared with 15.0 months for subjects receiving 
conventional care (Fenaux et al2009). Azacitidine was approved by the FDA in 2004 for the 
treatment MDS, defmed by French-American-British criteria.  In the European Union, 
azacitidine is indicated for the treatment of adult patients who are not eligible for hematopoietic 
stem cell transplantation with inteimediate-2  and high-1isk MDS according to the Intemational 
Prognostic Scoring System, chronic myelomonocytic leukemia with 10% to 29% manow blasts 
without myeloproliferative disorder,  acute myeloid leukemia (AML) with 20% to 30% blasts and 
multilineage dysplasia (according to WHO classification, and AML with > 30% manow blasts 
according to the WHO classification. 
 
In the United States, azacitidine may be administered by SC injection or IV infusion  with a 
recommended staiting dose of 75 mg/m2  daily for 7 days.  In the European Union, azacitidine is 
approved with the same dose with administration by the SC route only.  Cycles should be 
repeated every 4 weeks, and after 2 cycles, the dose may be increased to 100 mg/m2  if no 
beneficial effect has been observed and no toxicity other than nausea and vomiting has occmTed. 
By SC injection, azacitidine is rapidly absorbed with a maximum plasma concentration observed 
at 30 minutes and a mean plasma half-life of approximately 41 minutes.   Due to the 
inconvenience of a 7-day schedule, a randomized study evaluated altemative dose schedules 
(with a maximum of 5 consecutive days) and showed them to be similarly safe and efficacious 
compared with the approved regimen.  Results suggested that a azacitidine regimen of75 mg/m2 
daily for 5 days may be better tolerated and more convenient (Lyons et al 2009). 
 
Evidence of efficacy from azacitidine treatment in solid tumors has recently been shown in 
several preclinical and clinical studies (Juergens et al2011, Tsai et al2012, Wrangle et al2013, 
Li et al2014). When given in low doses, on-target effects have been maintained, and off-target 
effects have been avoided.  In solid tumor cell lines, it has been shown  that low doses of 
azacitidine alter several key pathways related to cancer, including cell cycle and mitotic 
pathways, mRNA splicing and translation, and transcription and DNA replication.  Treatment 
with azacitidine has shown  strong upregulation of immunomodulatmy pathways and suggests  the 
possibility that epigenetic therapy may be able to sensitize patients  to immunotherapy (Wrangle 
et al2013, Li et al2014, Chiappinelli et al2015, Peng et al2015, Chiappinelli et al2016). 
 
Refer to the azacitidine local label for fmther preclinical and clinical study data. 
 
L5- 
Overview of INCB057643 
 
INCB057643 is a selective inhibitor of BET proteins that is proposed for the treatment of 
advanced cancer.  The BET family ofbromodomain-containing proteins (BRDs) function as 
transcriptional regulators binding to acetylation marks in chromatin at gene promoter and 
enhancer elements and recmiting transcription initiation and elongation complexes.  In tumor 
cells, abenant  patte1ns of epigenetic marks, including acetylation, underlie abnmmal 
transcriptional regulation of genes involved in cellular proliferation, smvival, differentiation, and 


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migration, thereby promoting an oncogenic program.   Bromodomain  and extra-te1minal proteins 
are essential for the transcription of many of these genes; thus, inhibition of BET binding to 
chromatin may suppress oncogenic transcription in cancer cells.  Suppression of these oncogenic 
factors has the potential to inhibit the growth of a va1iety of tumor cell types and may be 
effective in the treatment of advanced malignancies. 
 
In vitro, INCB057643  inhibited binding of BET proteins to acetylated histone H4 peptide.  The 
ICso values for BRD4BD1 and BRD4BD2 are 39 ± 6 and 6 ± 1 nM (mean ± standard deviation), 
respectively. INCB057643 also inhibited BRD2, BRD3, and with lower potency, bromodomain 
testis-specific protein (BRDT),  in biochemical assays.  When evaluated against 32 distinct 
bromodomains from 25 human proteins, INCB057643 exhibited selectivity for BET family BDs. 
In cellular  assays, INCB057643 suppressed  the c-MYC protein, a BRD4 target, in KMS12BM 
multiple myeloma (MM) cells, with an ICso value of 111 ± 41 nM.  Many cancer cells derived 
from hematologic malignancies showed sensitivity to INCB057643 in viability assays, and cells 
treated with INCB057643 exhibited G1 cell cycle anest and, in some examples, apoptotic cell 
death.  Multiple myeloma and AML cell lines showed the greatest sensitivity,  in general, with 
ICso values for growth inhibition generally < 200 nM. In contrast, INCB057643 inhibited the 
proliferation of interleukin (IL)-2-stimulated T cells from nmmal donors with a potency of 
494 ± 118 nM (mean± standard deviation). The growth of a number of solid tumor cell lines 
from colon, lung, and breast cancer were also inhibited by INCB057643. In an assay to estimate 
potency in the presence of human semm proteins, INCB057643 suppressed c-Myc protein levels 
in myeloma cells spiked into human whole blood, with an ICso value of 55 nM.  INCB057643 
also suppressed the induction of endogenous methyl-accepting chemotaxis protein (MCP)-1 and 
MCP-3 from human whole blood that was stimulated ex vivo with lipopolysaccharide. The ICso 
values of 40 nM and 39 nM for MCP-1 and MCP-3, respectively, are similar to the c-Myc whole 
blood ICso value.  These data demonstrate that INCB057643 inhibits BET proteins in vitro and in 
cellular assays, and that inhibition of BET proteins results in the anest  and, in some models, 
death of cancer cells. 
 
In vivo, INCB057643 inhibited the growth of several tumor models in mice at tolerated, oral 
doses.  In the MMl.S model ofMM, a single dose of iNCB057643 suppressed c-Myc protein 
levels in tumor cells in a dose-dependent manner.  Tumor pha1macokinetic (PK)- 
phaimacodynamic analysis revealed an in vivo ICso value of 367 nM for c-Myc suppression  in 
the MM1.S MM model.  The growth of established human tumors was suppressed significantly 
by INCB057643 when administered as a single agent in the MMl.S MM, MOLM-16 AML, 
WILL2 lymphoma, H526 small-celllung cancer (SCLC), and RKO colon cancer SC xenograft 
models in immunocompromised mice at 3 
to 20  
administered  
or 1 to 3 
administered BID 
 
 
 
The absorption, distiibution,  metabolism, and excretion of iNCB057643 have been characterized 
in rats, dogs, and monkeys.  Following IV administration,  the systemic clearance was moderate in 
rats (36% hepatic blood flow) and low in dogs and monkeys (4.1% and 13% of hepatic blood 
flow, respectively). The steady-state volume of disti·ibution was moderate in rats and monkeys 
(2.6 and 2.8 L/kg, respectively), but low in dogs (0.66 L/kg).  The te1minal elimination half-life 
was moderate, estimated  to be approximately 4.3 hours in rats, 7.1 hours in dogs, and 7.0 hours 
in monkeys.  INCB057643 has low to moderate renal excretion; the administered dose excreted 


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in mine as parent  varied  from 12.5% in monkeys, to 17.6% in rats, and to 26.1% in dogs. After 
oral administration, oral bioavailability was low in dogs (21%), but moderate in rats (58%) and 
monkeys (39%-78%).  Based on 2-species allometric scaling from  rats and monkeys, the 
temlinal elimination half-life in humans is projected to be approximately 17 hours, and the oral 
bioavailability is projected to be approximately 40%.  At a clinical  dose of 12 mg QD,  which is 
expected to provide plasma concentration exceeding ICso (55 nM based on whole blood  c-Myc 
inhibition) for 12 hours, the total steady-state plasma AUCo-24 and Cmax are estimated to be 
approximately 1.5 JlM·h and 0.1 JlM, respectively. 
 
INCB057643 exhibits low in vitro pe1meability across  Caco-2 monolayers and low aqueous 
solubility. In vitro transpmt studies indicate that INCB057643 is a substrate of both 
P-glycoprotein (P-gp) and breast cancer resistant protein  (BCRP) efflux transpmters, and neither 
efflux  transpmter was saturated up to 300 JlM.  INCB057643 has limited penetration across  the 
rat blood-brain banier (BBB), with a steady-state brain to plasma concentration ratio of 0.11. 
In vitro human protein binding of INCB057643 was low (unbound fraction of 49.1%), similar to 
that in preclirucal species. 
 
The interactions of iNCB057643 with uptake and efflux  transpmters were evaluated using  in 
vitro systems. Though INCB057643 is a moderate inhibitor of P-gp, organic cation transpmter 
(OCT)2, organic anion transpmter (OAT)3, orgaruc  aruon transpmting polypeptide (OATP)1B3, 
and OATP1B1, no dmg-dmg interactions (DDis) are expected based on the projected steady-
state human plasma Cmax and concentrations in the gut.  Reaction phenotyping using 
recombinant human cytochrome P450s  (CYPs) indicated that INCB057643 was primarily 
metabolized by CYP3A4/5, and therefore, it is possible that the PK ofiNCB057643 might be 
affected by coadministration of potent CYP3A4 inhibitors or inducers.  INCB057643 is not an 
inhibitor of the major  CYPs evaluated. The metabolism profiles of iNCB057643 in rat, monkey, 
and human in vitro liver preparations were qualitatively similar.  Analysis of plasma samples 
identified M3 (INCB070378) to be a major metabolite in rats and M2 (INCB057228) to be a 
major metabolite in monkeys in vivo.  There was no evidence of a human-specific metabolite. 
Metabolite M2 (INCB057228) is an active metabolite with an ICso of 29 nM (whole blood 
c-MYC inhibition) while M3 (INCB070378) was not active.  The metabolites observed in vitro 
in human  liver  microsomes were also observed in vivo in preclinical species.  No glutathione 
adducts  were detected upon  incubation of iNCB057643 in human liver microsomes, suggesting 
that INCB057643 does not generate any reactive metabolites. 
 
Recent  studies have shown that BET protein inhibition may have effects  beyond the direct 
inhibition of malignant cell growth. Using genetic knockdown and small  molecule inhibitors, 
BET protein inhibition altered the expression of pro-inflammatory cytokine genes 
(Belkina et al2013) and (Ceribelli et al2014). Inhibition of BET protein  activity may have 
utility in a setting where there is an altered expression of growth-promoting, proinflammatory, 
and survival genes contiibuting to the establishment and persistence of the oncogenic phenotype. 
 
INCB057643 is cunently being evaluated in an ongoing Phase 1 study (INCB 57643-101) in 
subjects with advanced solid tumors or hematologic malignancies.  A total of 32 subjects have 
been dosed with INCB057643 as of 17 MAY 2017. See Section 1.7.2 for fmther details. For  a 
thorough discussion of the pha1macology of iNCB057643, refer to the INCB057643 
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L6- 
Overview of INCB059872 
 
INCB059872 is a covalent flavin adenine dinucleotide (FAD)-directed inhibitor ofLSD1 that is 
proposed  for the treatment of advanced malignancies. Lysine-specific demethylase 1 regulates 
gene expression epigenetically by removing methylation marks from lysine 4 or 9 of histone  H3. 
Target genes of LSD1 are involved in many biological processes including cell growth, survival, 
differentiation, and stem cell homeostasis. Studies have shown that deregulated LSD1 activity is 
associated with human diseases, including cancer, where overexpression of LSD1 is frequently 
associated with poor clinical outcomes.  These data suggest that INCB059872 may be 
therapeutic for the treatment of a variety of malignancies. 
 
In enzyme-based assays, INCB059872  potently inhibited LSD1, with half maximal inhibition 
(ICso) values of 18 ± 3 nM (mean ± standard deviation), while INCB059872 did not inhibit 
lysine-specific demethylase 2 (LSD2)  and monoamine oxidase AlB (MAO-A, MAO-B).  Both 
biochemical and in vitro phatmacodynamic assays consistently demonstrated that INCB059872 
was a FAD-directed inhibitor ofLSD1. In cellular assays, INCB059872 inhibition resulted in 
the up-regulated expression of the differentiation markers, CD86 and CD11b, in multiple AML 
cell lines and human primaty AML cells across the different French-American-British subtypes. 
Using the human acute monocytic leukemia cell line, THP-1, spiked into human whole blood to 
estimate potency in the presence of human semm proteins, INCB059872 induced CD86 protein 
with an ECso value of 23 ± 8 nM.  Human AML cell lines showed various degrees of sensitivity 
to INCB059872  in cell proliferation assays, with ECso values ranging from 17 to 314 nM, and 
treated cells undetwent G1 cell cycle anest. The antitumor activity of INCB059872 was fmther 
evaluated in human ptimaty AML cells ex vivo.  INCB059872 as a single agent or in 
combination with all-trans retinoic acid induced cellular differentiation (CD86 and CD11b 
induction) and reduced ptimary AML cell viability ex vivo. 
 
The proliferation of a number of SCLC cell lines was also inhibited by INCB059872, with ECso 
values ranging from 47 to 377 nM.  Non-tumorigenic cells, by contrast, were significantly less 
sensitive to INCB059872, with ICso values > 10 11M in IL-2-stimulated T cells from nmmal 
donors.  INCB059872  also demonstrated no significant effects on cellular proliferation or 
survival  in HEK293 human embtyonic kidney cells at concentrations up to 20 JlM. These data 
demonstrate that INCB059872 inhibits LSD1 activity in vitro, and that inhibition ofLSD1 results 
in the growth anest  and differentiation of cancer cells compared to nmmal cells.  In vitro 
phatmacodynamic assays for LSD1 inhibition in AML cells showed that induction of the CD86 
myeloid differentiation marker by INCB059872 was sustained for 5 days after removal of 
INCB059872 in culture.  These results confitm that INCB059872 is a covalent FAD-directed 
inhibitor of LSD1 in cells. 
 
In vivo, oral administration of INCB059872 demonstrated phatmacodynamic activity and efficacy 
in several models of human and murine AML and in human SCLC xenograft models in mice.  
Tumor phatmacodynamic analyses conducted in both the Molm-13 human AML systemic 
xenograft model and the THP-1 human AML SC xenograft model demonstrated induction of 
CD86 and CD11b expression, consistent with in vitro data. In these models, the 
phatmacodynamic activity ofiNCB059872 was marginal at a dose of0.1 mg/kg and maximal at 
doses 2:: 0.5 mg/kg, demonstrating an in vivo EDso for CD86 induction of approximately 
0.3 mg/kg.  In addition, tumor phatmacodynamic responses were sustained for over 48 to 
72 hours after administration, consistent with the inhibition of LSD1 by covalent modification of 


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FAD.  Consistent with in vivo phatmacodynamic studies, QD doses ofiNCB059872 greater than 
the in vivo EDso showed significant and comparable antitumor effects in human AML xenograft 
models, while doses less than the in vivo EDso exhibited either no efficacy or marginal TGI in 
these tumor xenograft models.  Similar effects of QD administration regimens on TGI were 
observed  in human SCLC tumor xenograft models (NCI-H562 and NCI-H1417), with a marked 
reduction in plasma pro-gastrin-releasing peptide levels in INCB059872-treated NCI-H1417 
tumor-bearing mice relative to vehicle controls.  Altemative oral administration regimens of 
INCB059872, including every other day (QoD), generally were comparably efficacious as a QD 
administration regimen in these AML and SCLC xenograft models, consistent with the 
prolonged phatmacodynamic effects associated with INCB059872. 
 
In the MLL-AF9 murine leukemia engraftment model in C57BL/6 mice, the median survival of 
leukemic animals was significantly prolonged in mice receiving doses greater than or equal to a 
phatmacodynamically active oral dose ofiNCB059872 over a 14-day administration  period. 
These survival effects ofiNCB059872 in the MLL-AF9 murine AML model were associated 
with an expansion of the percentage  of nmmal bone manow cells, a reduction in leukemic stem 
cells, a decrease in the number of AML blast cells, the induction of myeloid differentiation, and 
a nmmalization  of hematological parameters to those of non-leukemic mice. 
 
The absorption, distiibution, metabolism, and excretion ofiNCB059872, a covalent 
FAD-directed inhibitor of LSD1, have been characterized in rats, dogs, and monkeys.  After IV 
administi·ation, the systemic clearance was low in monkeys and dogs (23% and 29% of hepatic 
blood flow, respectively), and moderate in rats (37% of hepatic blood flow).  The clearance 
mechanisms ofiNCB059872 include both CYP-dependent  metabolism  and non-enzyme 
dependent catabolism. The administered dose excreted in urine as intact INCB059872 varied 
from approximately 9.9% in rats to 7.8%  in dogs and 3.5% in monkeys, indicating renal 
clearance as minor elimination pathways.  INCB059872 exhibited a moderate steady-state 
volume of distribution  in all3 species (0.9-1.5  L/kg), suggesting moderate disti·ibution. After 
oral administration, oral bioavailability was moderate in monkeys (37%), but high in rats (70%) 
and dogs (100%).  The tetminal elimination half-life was 1.0 hour in rats, 1.2 hours in dogs, and 
3.3 hours in monkeys.  Despite a shmt half-life, sustained  phatmacological activity was observed 
in vitro and in vivo, presumably a result of covalent binding ofFAD, the cofactor ofLSD1 
(resulting in LSD1 inhibition, ie, a PK-phatmacodynamic divergence is expected for this mode of 
inhibition by INCB059872).  Based on allometiic scaling,  the tetminal elimination  half-life in 
humans is projected to be approximately 3 hours, and the oral bioavailability is projected to be 
70%.  Significant antitumor effects were observed in mice when peak plasma concentration 
exceeded the ECso in the whole blood assay with either QD or QoD administi·ation. Based on 
preclinical PK-phatmacodynamic relationship, the projected clinical dose for efficacy is 2 mg 
QoD, which is expected to provide plasma concenti·ations exceeding the ECso of0.023 JlM 
(based on THP-1 spiked whole blood assay with CD86 induction) for 2 hours, the total 
steady-state plasma AUCo-48 and Cmax are estimated to be approximately  0.2 J.1M·h and 0.05 J.l.M, 
respectively. 
 
INCB059872 exhibits moderate in vitro petmeability across Caco-2 monolayers 
(3.8 x I0-6  em/sec) and high aqueous solubility (20 mg/mL).  In vitro tt·anspmt studies indicate 
that INCB059872  is a weak substrate  of efflux transpmter P-gp, but not ofBCRP. INCB059872 
has limited peneti·ation across the rat BBB, with a steady-state brain to plasma ratio of 0.1. 


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In vitro human protein binding ofiNCB059872 was low (unbound  fraction of73.5%), similar to 
that in preclinical species. 
 
INCB059872 did not inhibit hepatic uptake transporters (OATP1B1 and OATP1B3).  While 
INCB059872 was a weak inhibitor of renal uptake transpmters (OCT2, OAT1 and OAT3), no 
DDis are expected based on inhibitmy activities of the INCB059872 uptake transpmter at 
phatmacologically relevant exposures. Moreover, INCB059872 did not inhibit P-gp or BCRP 
efflux transpmters.  Reaction phenotyping using recombinant human CYPs indicated that 
INCB059872 was metabolized by CYP2D6 and CYP3A4, and therefore it is possible that the PK 
of INCB059872 will be affected by co-administration of potent CYP2D6 inhibitors or CYP3A4 
inhibitors/inducers. INCB059872 is not an inhibitor of the 6 CYPs evaluated and therefore no 
DDis are expected based on INCB059872 CYP inhibitmy activities at pha1macologically 
relevant exposures of INCB059872.  The metabolism profile of INCB059872 in rat, dog, 
monkey, and human in vitro liver preparations was qualitatively similar,  with M1 (INCB061984) 
generated at levels greater than 10% ofiNCB059872 across all species. However,  M1 was also 
generated in buffer or buffer fmtified with rat bile, bilimbin and FAD, indicating that 
nonenzymatic mechanisms  are also involved in the fmmation ofM1. There was no evidence of 
any human specific metabolites. In vivo, parent INCB059872 was the most abundant component 
in rat and dog plasma and M1 (INCB061984) was identified in rat plasma (-4% of 
INCB059872) and dog plasma (-40% ofiNCB059872). 
 
INCB059872 is cunently being evaluated in an ongoing Phase 1 study (INCB 59872-101) in 
subjects with advanced solid tumors or hematologic malignancies. A total of 39 patients have 
been dosed with INCB059872 as of 10 mL 2017.  See Section 1.7.2 for further details.  For a 
thorough discussion of the pha1macology ofiNCB059872, refer to the INCB059872 
Investigator's Brochure (IB). 
 
L7- 
Study Rationale 
 
1.7.1. 
Rationale for Combining Epigenetic Therapy With Immunotherapy 
 
Blockade of immune inhibitmy pathways is emerging as an important therapeutic modality for 
the treatment of cancer as evidenced by the clinical responses observed with antibodies to 
CTLA-4 and PD-1/PD-Ll. Pembrolizumab  has shown broad antitumor activity and has 
produced durable objective responses in patients with melanoma, NSCLC, urothelial cancer, 
gastric cancer, triple-negative breast cancer, and classical Hodgkin lymphoma (Robe1t et al2015, 
Plimack et al2015, Herbst et al2016, Muro et al2016, Nanda et al 2016, Almand et al 2016). 
Although checkpoint inhibitors as single agents have significant  antitumor activity in several 
areas of unmet need, there are many patients that do not respond  to this immune therapy. 
Multiple immune inhibitmy mechanisms are present  concurrently within the tumor 
microenvironment, suggesting that combination therapies may be required for optimal 
therapeutic effect (Quezada and Peggs 2013).  There are many clinical studies in all phases of 
development evaluating checkpoint inhibitors with chemotherapy, radiotherapy, molecularly 
targeted agents, vaccines, and other novel immunotherapies. 
 
In recent years, there have been many discoveries related to the understanding of the nmmal and 
cancer "epigenome" and how it is regulated.  The knowledgebase of epigenetics continues to 
expand as more is leamed about the functional significance of histone modifications and DNA 


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methylation pattems in relation to malignancy (Chiappinelli  et al2016). Recent preclinical 
studies have shown evidence that epigenetic therapy may be able to sensitize tumor-bearing 
animals to immune therapies including PD-1 blockade.  fu NSCLC cell lines, the DNMT 
inhibitor azacitidine has been shown to upregulate genes and pathways related to both the innate 
and adaptive immunity as well as genes related to immune evasion.  Of particular interest, 
azacitidine was shown to up-regulate PD-L1 transcripts and protein (Wrangle et al 2013).  fu a 
recent study, Chiappinelli et al (2015)  showed that DNMT inhibitors up-regulated immune 
signaling in cancer cell lines through a viral defense pathway.  fu ova1ian cancer, DNTM 
inhibition triggered cytosolic sensing  of double-stranded RNA and caused a Type I interferon 
response  and apoptosis.  Early signals of potential efficacy to epigenetic agents were observed in 
solid tumors while evaluating a low-dose regimen of azacitidine with the HDAC inhibitor 
entinostat.  fu a heavily pretreated NSCLC population of 45 subjects, objective responses were 
observed in only 4% of subjects, but 1 subject had a CR for a duration of 14 months, and a 
second subject had aPR that lasted 8 months.  There were 10 subjects  that had SD for at least 
12 weeks.  Additionally, the clinical responses that were observed continued after the 
discontinuation of the epigenetic therapy, suggesting a sustained effect (Juergens et al 2011). 
Five NSCLC subjects from this epigenetic study went on to receive immune checkpoint therapy 
in a nivolumab Phase 1 study.  All 5 subjects were without progression at 6 months and 3 of 
these subjects developed high-grade RECIST PRs that have been durable for over 2.5 years 
(Chiappinelli  et al2016). 
 
As noted in Section 1.4, early studies of azacitidine used much higher doses that were associated 
with more toxicity compared with the cunently approved dose of azacitidine (Vigil et al2010). 
Lower doses of azacitidine are also required for the induction of DNA hypomethylation 
compared with direct cytotoxicity (Tsimberidou  et al 2015).  Utilizing a lower dose of 
azacitidine should permit hypomethylating  and minimize toxicity allowing it to be combined 
with immune therapies. 
 
Recent studies  of BET inhibitors have demonstrated the ability to potently alter the tumor 
microenvironment resulting in improved tumor immunologic response. fu a syngeneic xenograft 
mouse model of pancreatic cancer, BET inhibition led to an increase in CD3+, CD4+, and CD8+ 
T-cells while simultaneously decreasing M2 macrophage infiltration (Koblish et al 2016).  fu this 
same study BET inhibition in combination with either epacadostat or anti-PD-L1 therapy 
synergistically  led to decreased xenograft tumor growth.  BET inhibitors were independently 
shown to decrease expression ofPD-L1 on both tumor cells and DCs with a conesponding 
increase in number of IFNy- and granzyme B-positive cytolytic T cells in the tumor 
microenvironment of a syngeneic mouse model of ovarian cancer (Zhu et al2016). fu addition 
to altering the immune milieu, BET inhibitors have been shown  to improve T-cell persistence 
and anti-tumor effects in vivo (Kagoya et al 2016).  Fmthe1more, BET inhibition alters the 
expression ofpro-inflammatmy cytokine genes (Belkina et al2013, Ceribelli et al2014).  As 
such, BET inhibition has the potential to remodel the tumor microenvironment and improve 
Immune responses. 
 
Multiple recent reports demonstrate a potential role for LSD1 inhibition in checkpoint inhibitor 
priming strategies.  Small interfe1ing RNA inhibition of LSD1 led to an increase in genes 
associated with interferon signaling as well as major histocompatibility complex Class I 
expression (Jin et al2017). Fmthe1more, LSD1 inhibition by INCB059872  led to increased 
effector T-cell and macrophage infiltration and a concomitant decreased myeloid-deprived 


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In summa1y, epigenetic priming with DNMT, BET, or LSD1 inhibitors alone or in combination 
has been shown to alter the expression of growth-promoting, pro-inflammatmy, and survival 
genes, which contributes to the establishment  and persistence of the oncogenic phenotype. 
Azacitidine, as well as BET or LSD1 inhibition, has the ability to modulate the immune system 
and may potentially serve as a priming method for immunotherapy combinations.  Adding 
epigenetic p1iming and complimenta1y IDO1 inhibition to checkpoint inhibition may lead to 
increasing response rates in tumor types that have shown benefit to monotherapy checkpoint 
inhibition and may sensitize tumors that have been immune tolerant through the expression of 
silenced genes. 
 
1.7.2.  
Justification for the Treatment Regimen 
 
The safety and tolerability of the pembrolizumab  and epacadostat combination is cunently being 
evaluated in the ongoing Phase 1/2 INCB 24360-202 study.  In Phase 1 of the study, the 
established regimen of pembrolizumab 2 mglkg Q3W and 200 mg Q3W was evaluated with 
epacadostat  doses ranging from 25 mg BID to 300 mg BID.  Prelimina1y data suggest that doses 
up to 300 mg BID of epacadostat in combination with 2 mglkg or 200 mg IV infusion Q3W are 
generally well-tolerated.  In the Phase 1 portion of the study, the 50 mg BID cohort had 2 DLTs 
in 18 subjects (Grade 3 rash and Grade 3 arthralgia); the 100 mg BID cohmt had 2 DLTs in 
15 subjects (Grade 3 increased AST and Grade 3 nervous system disorder); and the 300 mg BID 
cohmt had 4 DLTs in 16 subjects (Grade 1 skin e1ythema, 2 Grade 3 rash, and Grade 2 nervous 
system disorder).  The MTD was not exceeded at any dose evaluated.  There were no treatment- 
related Grade 4 AEs or deaths.  In a safety-evaluable cohmt of 60 subjects, the most frequent 
treatment-related AEs were rash (27%), fatigue (23%), and a1thralgia (15%).  An epacadostat 
dose of 100 mg BID with pembrolizumab 200 mg Q3W were selected as the Phase 2 doses 
(Hamid et al 2015). 
 
The epacadostat  sta1ting dose selected for the cunent  study was dete1mined on the basis of having 
a well-tolerated safety profile as monotherapy and in combination with pembrolizumab, as well 
as providing nearly maximum target inhibition of IDO1.  In general, as single agents, epacadostat 
and pembrolizumab have been well-tolerated in this study population that has significant  
comorbidities.  As monotherapy, maximally effective epacadostat doses in preclinical models 
result in exposures that are comparable to doses of 50 to 100 mg BID in humans.  Doses of 
epacadostat  of up to 700 mg BID as monotherapy have been well-tolerated,  and the 100 mg BID 
dose of epacadostat in combination  with pembrolizumab  is cunently being evaluated as the 
RP2D. 
 
Pha1macokinetic and pha1macodynamic obse1vations from Studies INCB 24360-101 and INCB 
24360-201 in cancer subjects suppmt the 25 mg BID to 300 mg BID dose levels, which provide a 
differential pha1macologic effect.  Based on a 6-hour obse1vation pe1iod at steady state on Day 15 
after administration of epacadostat and using a standardized  whole blood assay, 


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kynurenine levels are incompletely  inhibited (66%), compared with baseline levels in subjects 
treated with 25 mg BID, but are nearly maximally inhibited (89%) in subjects treated with 
100 mg BID.  Complete inhibition of the IDOl  target is not required for maximally effective 
activity in preclinical models; however, maximally effective doses in nonclinical models result in 
exposures that are comparable to monotherapy doses of 50 mg BID to 100 mg BID in humans. 
 
Doses of epacadostat of up to 700 mg BID as monotherapy have been well-tolerated, and the 
100 mg BID dose as well as 300 mg BID of epacadostat in combination with pembrolizumab and 
nivolumab is cunently being evaluated in multiple ongoing Phase 2 studies.  In Study 
INCB 24360-101, among 43 subjects treated with epacadostat  monotherapy at doses of up to 
700 mg BID, there was 1 report of Grade 3 liver function test (LFT) elevations in a subject with 
bilia1y obstruction from progressive cancer.  The initial evaluation of epacadostat 300 mg BID in 
combination with ipilimumab was terminated because of the occmTence of Grade 3 or 4 
ALT/AST elevation in 5 of7 subjects  n·eated at this dose level.  These AEs were reversible in all 
subjects upon discontinuation  of study therapy and institution  of corticosteroids based on an 
established protocol for the management of immune toxicities related to ipilimumab  therapy. 
 
The safety profile for the 300 mg BID dose of epacadostat in combination with pembrolizumab 
in a Phase 112 study (INCB 24360-202) did not exceed the MTD in that study.  While there was 
a higher incidence of Grade 3 rash in the 300 mg BID cohort compared to the 100 mg BID 
cohmt, these did not qualify as Protocol-specified DLTs.  The dose of epacadostat 300 mg BID 
in combination with pembrolizumab is cunently under study in other studies of epacadostat plus 
checkpoint inhibitors. 
 
The dose combination of epacadostat 100 mg BID plus pembrolizumab 200 mg Q3W for the 
Phase 3 melanoma study (INCB 24360-301) was chosen based on a benefit/risk assessment 
made specifically in melanoma in collaboration with Merck.  In INCB 24360-202, there was 
evidence of improved efficacy in melanoma subjects at all doses of epacadostat from 50 to 
300 mg BID.  Given that melanoma is an immunotherapy-responsive tumor, and lower doses of 
epacadostat  appeared to have similar activity, the decision was made to take the 100 mg BID 
dose combination fmward because of the lower incidence of dose intenuptions and dose 
reductions compared to the 300 mg BID dose. 
 
However,  in other tumor types that appear to demonst:I·ate more resistance to known 
immunotherapies, greater target coverage for inhibition of IDO1 may be necessary. 
Pharmacokinetic/pharmacodynamic modelling suggests that doses of epacadostat 100 mg BID 
achieve an average ICso at n·ough in most patients.  At 300 mg BID, epacadostat achieves target 
inhibition above the IC9o at trough.  Incyte believes that greater target inhibition may be 
necessary in more resistant tumors, and potentially balances benefit/risk  in favor of the higher 
epacadostat dose combination given that the dose does not exceed the MTD. 
 
The azacitidine sta1ting dose of 75 mg per day on Days 1 to 5 for 2 cycles was selected  based off 
of previous studies evaluating the combination of azacitidine and entinostat as a stand-alone 
regimen or as a priming regimen before the receipt of nivolumab. In a Phase 1/2 study 
evaluating azacitidine and entinostat in subjects with recmTent metastatic  NSCLC, the 
combination of 40 mg/m2  azacitidine administered on Days 1 to 6 and 8 to 10 and 7 mg of 
entinostat administered on Days 3 and 10 of each cycle was generally well-tolerated  and no 
DLTs were observed (Juergens et al2011). This dose regimen was chosen as RP2D, and a 
randomized Phase 2 study in subjects with recunent  metastatic NSCLC was initiated evaluating 


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this combination as a priming regimen for 2 cycles before beginning nivolumab monotherapy 
versus nivolumab without epigenetic p1iming (NCT01928576).  For the cunent  study, a flat dose 
of azacitidine has been chosen to be adininistered in the clinic for 5 days per cycle and the 
starting dose of75 mg for 5 days represents  approximately 40% of the dose adininistered per 
cycle for subjects receiving the MDS approved dose of 75 mg/m2  for 7 days to be repeated in 
28-day cycles.  There is 1 planned dose-escalation of azacitidine to 100 mg, and this fmal dose 
will then be approximately half of the MDS-approved dose, which should minimize hematologic 
toxicity. 
 
INCB057643 is cunently being evaluated in a Phase 1 dose-escalation and dose-expansion study, 
INCB 57643-101, in subjects with advanced solid and hematologic malignancies. The first 
subject was enrolled in this study on 18 MAY 2016.  The following data were derived from the 
clinical database, and ce1tain data were not cleaned or confi1med at the data cutoff date; thus, they 
should be considered preliininaiy/subject to change. 
 
As of the data cutoff date of 17 MAY 2017, 16 subjects each in Part 1 (solid tumors, n = 13; 
lymphoma, n = 3) and Pa1t 2 (solid tumors, n = 14; lymphoma, n = 2) have been emolled.  Doses 
of 8, 12, and 16 mg QD were explored in Pmt 1/TGA.  Pmt 1/TGB and TGC are cunently open 
for emollment at 8 mg QD (no subjects have emolled as of the data cutoff date).  Pa1t 2/TGA 
expanded at a sta1ting dose of 12 mg QD. 
The emollment sta1ted in Pa1t 1/TGA dose escalation with a 3 + 3 design, using a sta1ting dose 
of 8 mg QD.  Four subjects were emolled in Cohmt 1.  During the DLT evaluation period 
(Cycle 1), no DLTs were observed in Cohmt 1.  Cohmt 2 had a sta1ting dose of 16 mg QD.  One 
DLT of increased intemational nmmalized ratio (INR; Grade 3) was observed in Cohmt 2 in the 
initial3 subjects.  Cohmt 2 was then expanded to emoll a total of 6 DLT-evaluable subjects 
(n = 8; 2 subjects were not evaluable due to early disease progression).  Five subjects (5/8) 
required dose intenuption due to AEs dming Cycle 1 or 2 in Cohmt 2 (due to Grade 3 INR 
increased,  Grade 3 thrombocytopenia, eye pain, Grade 4 hyperglycemia, and Grade 2 total 
bilimbin increased/Grade 3 direct bilimbin increased, respectively).  Even though there was only 
1 protocol-defmed  DLT in Cohmt 2, because of the extent of dose intenuption due to other 
Grade 3/4 AEs, 16 mg QD was deemed to be not tolerated by the investigators and the sponsor. 
Cohmt 3 emolled 4 subjects at the stmting dose of 12 mg QD.  Three of the 4 subjects were 
deemed evaluable, and no DLT was repmted.  One subject was not evaluable due to early 
clinical progression.  The MTD was thus dete1mined to be 12 mg QD in Part 1/TGA and was 
also selected as the RP2D for fmther exploration in Pmt 2/TGA. 
 
As of the data cutoff date, dose levels of 8, 12, and 16 mg QD have been administered over an 
average of 174.5, 59.5, and 54 days, respectively, in various solid tumors and lymphomas in 
Pmt 1/TGA. 
 
In Pa1t 1/TGA,  there were 5 deaths that occmTed after study dmg discontinuation and during 
survival follow-up; all of which were caused by disease progression and umelated to study dmg. 
Of these 5 deaths, 3 were due to fatal AEs (hepatic failure, pneumonia, and new metastasis of the 
central nervous system [CNS; brain metastasis; n = 1 each]) that occmTed 14, 22, and 0 days post 
study dmg discontinuation, respectively, and the subjects died 25, 8, and 41 days after the onset 
of the fatal AE, respectively.   All of the fatal AEs were umelated to study treatment based on 
investigator opinion.  All of the 16 subjects (100%) emolled in Pa1t 1/TGA repmted at least 
1 TEAE; 10 ofwhich (62.5%) repmted aGrade 3 TEAE.  Fomteen of the 16 subjects (88%) 


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repmted1 treatment-related TEAE, and 4 of those subjects (25%) repmted aGrade 3 
treatment-related TEAE.  Additionally, 2 treatment-related TEAEs occuned in 1 subject each: 
Grade 3 increased  conjugated bilimbin and Grade 3 increased INR, respectively. Eight subjects 
(50%)  reported SAEs; 2 subjects (12.5%) had SAEs that were considered by the investigator  to 
be treatment-related  (Grade 4 hyperglycemia and Grade 3 INR increased, respectively). 
Treatment-related  TEAEs led to dose intenuption in 5 subjects, primarily due to increased 
conjugated bilimbin, increased INR, thrombocytopenia, decreased appetite, and decreased 
platelet count (n = 1 each [6%]) and led to dose reduction in 1 subject (increased conjugated 
bilimbin [6%]).   In total, 13 ofthe 16 subjects (81%) have discontinued treatment (4 because of 
TEAEs [upper abdominal pain and confusional state, perfmmance  status decreased, 
hyperglycemia, and increased INR, respectively], 8 because of progressive disease, and 1lost to 
follow-up).  In Pa1t IITGA, the median exposure  of the study dmg was 59.5 days 
(range, 6-282 days). 
 
In Part IITGA,  11 of the subjects with solid tumors were evaluable for efficacy; 1 subject had 
SD lasting6 months (cholangiocarcinoma, ongoing at 9 months), 2 subjects had SD lasting 
< 6 months (discontinued at 3 months  due to decreased  perfmmance  status and progressed at 
2 months, respectively), 6 subjects had radiographic progression as best response, and 2 subjects 
had clinical progression. Two subjects were not evaluable for efficacy (both subjects 
discontinued  treatment due to AEs before the first assessment). The 3 subjects with 
non-Hodgkin's lymphoma were evaluable for efficacy; 1 subject with follicular lymphoma had a 
CR (CR based on positron emission  tomography [PET], ongoing at 8 months), and 2 subjects 
had SD lasting < 6 months (ongoing at 5.5 months and progressed at 4 months, respectively). 
 
These data indicate that INCB057643 is safe and well tolerated as a single agent at 8 and 12 mg 
QD.  To mitigate any potential AEs of INCB057643 in combination with epacadostat and 
pembrolizumab,  as well as avoid any potential deleterious cytotoxic effects on effector T-cells, 
dose escalation ofiNCB057643 will be started at 1 dose level (4 mg QD) below the lowest tested 
dose in humans, 8 mg QD.  Dose escalation will proceed in cohmts including 8 and 12 mg QD 
until an MTD or maximum tested dose is reached. 
 
INCB059872 is being evaluated in a Phase 1 dose-escalation and dose-expansion study, 
INCB 59872-101, in subjects with advanced solid tumors and hematological malignancies. 
Patt 1 (dose escalation) to determine the sta1ting dose(s) ofiNCB059872 for dose expansion, 
based on the MTD and/or a tolerated phatmacologically active dose (PAD), has been open and 
emolling since MAY 2016.  Both QoD and QD schedules have been explored  to collect safety, 
PK, and pharmacodynamic data to establish the optimal dose and schedule for subjects with solid 
tumor and hematological  malignancies. 
 
In Part 1, the initial2 mg QoD dose was well-tolerated by subjects in both treatment groups, 
TGA (AML/MDS) and TGB (solid tumors).  As AMLIMDS is a rapidly proliferating disease, it 
was decided in discussion with the pa1ticipating investigators to use a QD dosing schedule for 
TGA.  A total of 17 subjects have been treated in 4 different cohmts (3 at 2 mg QoD; 6 at 2 mg 
QD; 5 at 3mg QD; and 3 at 4 mg QD) in TGA.  The treatment was generally well-tolerated 
without any DLTs. 4 mg QD is determined as the monotherapy RP2D for AMLIMDS subjects. 
 
In TGB, a total of22 subjects have been treated in 6 different cohmts.  The QoD schedules 
included 16 of those subjects (3 at 2 mg QoD; 6 at 3 mg QoD; and 7 at 4 mg QoD) in 3 different 
cohmts.  The QoD schedule was generally well-tolerated.  There was 1 DLT of Grade 4 


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thrombocytopenia at 4 mg QoD.  Further dose escalation was stopped, and the next lower dose 
cohmt of 3 mg QoD was expanded to treat a total of 6 subjects.  No DLTs or Grade 3/4 
thrombocytopenias were reported at 3 mg QoD, and this dose is the RP2D for solid tumors. 
Dose escalation of the QD schedule  in TGB has been halted due to 2 DLTs in the 3 mg QD 
cohmt and 1 DLT in the 2 mg QD cohmt.  A cohmt of 3 subjects has completed emollment, and 
there were no DLTs seen in the DLT window. 
 
Prelimina1y, unaudited data as of 10 JUL 2017 is summarized for 39 subjects who have been 
treated with INCB059872 doses of 1 mg QD, 2 mg (QoD or QD), 3 mg (QoD or QD), and 4 mg 
(QoD or QD).  Eight subjects were receiving treatment  as of the data cutoff date.  Of the 
39 subjects, 12 subjects have received INCB059872 for > 20 days, 14 subjects have received 
INCB059872 for > 30 days, and 6 subjects have received INCB059872 for > 90 days. 
 
The most frequent TEAE among all dose cohmts in TGA was fatigue and nausea (6 subjects 
each).  The most frequent TEAE among all dose cohmts in TGB was thrombocytopenia and 
dysgeusia (9 subjects each). 
 
Based on preclinical data generated to date, there is reason to believe that subjects may develop 
some level of thrombocytopenia. As of the data cutoff date, 6 DLTs of 2:: Grade 3 
thrombocytopenia or platelet count decrease have been repmted in the 2 mg QD, 3 mg QD, and 
4 mg QoD cohmts in TGB (1, 2, and 3 DLTs respectively).  Treatment intenuption occurred in 
the subjects with DLTs, and following recove1y, 4 of these subjects resumed study treatment at a 
reduced dose (3 mg QoD). 
 
Four treatment-emergent SAEs resulted in discontinuation of study treatment: thrombocytopenia, 
bile duct obstmction, epistaxis, and hypotension. With the exception of thrombocytopenia, none 
of these treatment-emergent SAEs leading to INCB059872  discontinuation  were considered 
related to study treatment.  Five treatment-emergent SAEs have resulted in death, none of which 
were considered  related to study treatment  by the investigators: leukocytosis, sepsis, pulmona1y 
alveolar hemonhage, respiratmy failure, and gastrointestinal hemonhage. 
 
These data indicate that INCB059872 is safe and well-tolerated in advanced solid tumors as a 
single agent at 2 mg QoD, 3 mg QoD, and 1 mg QD.  To mitigate any potential AEs of 
INCB059872 in combination with epacadostat and pembrolizumab, as well as avoid any 
potential delete1ious cytotoxic effects on effector immune cells, dose escalation of INCB059872 
will be sta1ted 1 dose level (I mg QoD) below the lowest tested dose in humans, 2 mg QoD. 
Dose escalation will proceed in cohmts including  2 mg QoD, 1 mg QD, and 3 mg QoD until an 
MTD or maximum tested dose is reached. 
 
1.7.3. 
Rationale for Phase 2 Subject Populations 
 
1.7.3.1.  
Non-Small Cell Lung Cancer 
 
Lung cancer is the most common cause of death from cancer worldwide, and the majority of 
subjects present  with advanced NSCLC, where the 5-year survival is less than 15% 
(Siegel et al2016).  Non-small cell lung cancer accounts for approximately 80% to 85% of all 
cases of lung cancer (D'Adda1io et al2010). 


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The standard of care in first-line for patients with non-oncogenic-driven advanced NSCLC is 
platinum-based doublet chemotherapy (Rizvi et al2016). Therapy should be individualized 
based on molecular  and histologic features of the tumor.  Whenever possible, patients should 
have tumor tissue assessed for the presence of a driver mutation  that stimulates tumor growth. 
These mutations define subsets of patients likely to respond to specific inhibitors 
(NCCN Guidelines).  Patients with a known driver mutation in the epidetmal growth factor 
receptor (EGFR) are initially managed with an EGFR tyrosine kinase inhibitor (TKI; Moran and 
Sequist 2012, Gridelli et al2012). Those with an anaplastic lymphoma kinase (ALK) fusion 
oncogene in their tumor are preferentially treated with crizotinib (Kwak et al2010, 
Camidge et al2012, Shaw et al2013). Patients without a driver mutation are generally treated 
with chemotherapy. 
 
Phase 1 studies of anti-PD-1 agents have demonstrated promising results.  In 2015, the FDA 
granted approval for both pembrolizumab  and nivolumab for the treatment of metastatic NSCLC 
after progression on or after platinum-based chemotherapy.  Pembrolizumab was approved for 
patients whose tumors express PD-L1 as dete1mined by an FDA-approved test and who have 
disease progression on or after platinum-containing regimens (Garon et al2015). Patients with 
EGFR or ALK genomic tumor abenations should have disease progression on an FDA-approved 
therapy for these abenations before receiving pembrolizumab.  In the Phase 1 study by 
Garon et al (2015), an ORR of 19.4% was repmted in the 495 NSCLC patients who received 
monotherapy pembrolizumab.  Median DOR was 12.5 months, median PFS was 3.7 months, and 
OS was 12 months.  Nivolumab was also approved in 2015 for patients with metastatic NSCLC 
with progression on or after platinum-based chemotherapy.  Patients with EGFR or ALK 
genomic tumor aberrations should also have disease progression on an FDA-approved therapy 
for these agents.  The Phase 3 study comparing nivolumab to docetaxel resulted in an OS of 
12.2 months (95% confidence interval [CI], 9.7 to 15.0) among 292 subjects in the nivolumab 
group and 9.4 months among the 290 subjects in the docetaxel group (hazard ratio, 0.73; 96% CI, 
0.59 to 0.89; p = 0.002).  The response rate with nivolumab was 19% as compared with 12% in 
the docetaxel group (p = 0.02; Borghaei et al2015). Based on results in second-line advanced 
NSCLC, investigation of PD-1 pathway inhibitors moved to the first-line setting, evaluating 
PD-1-targeting antibodies  as monotherapy as well as in combination  with other 
immunotherapies and chemotherapy (Gettinger et al2016, Rizvi et al2016). On 05 AUG 2016, 
Bristol-Myers Squibb announced top-line results from the Phase 3 CheckMate-026 study 
evaluating nivolumab monotherapy versus investigator's choice chemotherapy in a first-line 
advanced NSCLC population.  In the open-label, randomized study, nivolumab did not meet the 
primaty endpoint of PFS in subjects with at least 5% PD-L1 expression on their tumors 
(Bristol-Myers Squibb 2016). 
 
While PD-1 inhibition in NSCLC has demonstrated durable antitumor activity that has the 
potential for long-te1m survival, a significant number of patients do not receive benefit, 
demonstrated by the failure of nivolumab in the first-line setting.  Patients with advanced and 
metastatic NSCLC represent a population with a large unmet medical need.  Therefore, 
combinations with other immunotherapies, chemotherapy, and targeted agents are being pursued. 


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1.7.3.2.  
Microsatellite Stable Colorectal Cancer 
 
Colorectal cancer is the third most common diagnosis worldwide with almost 1.4 million  new 
cases diagnosed in 2012.  Survival is highly dependent upon the stage at the time of diagnosis; 
unfortunately only 40% ofCRC cases have an early stage diagnosis, and approximately 50% of 
patients who are recently  diagnosed will progress  to have metastatic disease  (Jacobs et al2015). 
Systemic chemotherapy with fluorop)'limidine-based regimens combined with oxaliplatin or 
irinotecan is the primary  treatment for subjects with metastatic CRC.  Targeted therapies  are also 
routinely used to manage  metastatic disease.  Agents  targeting EGFR and vascular endothelial 
growth  factor (VEGF)  have become standard of care and have demonstrated survival benefit  in 
combination with chemotherapy (Verdaguer et al2016). 
 
Checkpoint inhibitors have been evaluated across a broad auay of tumor types and have been 
shown  to be effective in several specific tumor types. Many studies have emolled subjects with 
CRC, and they have been generally umesponsive to anti-PD-1 or anti-PD-L1 therapies 
(Brahmer et al2010, Topalian et al2012). A subset ofCRC subjects, primarily subjects with 
microsatellite instability-high (MSI-H) CRC, have been shown to have high expression ofPD-L1 
and a high density of tumor-infiltrating immune  cells.  Therefore, subjects with a MSI-H 
phenotype have been expected to be responsive to PD-1 targeted  therapies (Kim  et al2016). A 
Phase 2 clinical study evaluated pembrolizumab in 41 subjects with treatment refractmy 
progressive metastatic cancer.   Subjects were categorized based on mismatch repair (MMR) 
status; cohmts were MMR-deficient CRC, MMR-proficient CRC, and cancers  of other types 
who were MMR-deficient. An ORR of 40% was observed in subjects with MMR-deficient CRC 
and 0% for MMR-proficient CRC.  Subjects with other tumor types that were MMR-deficient 
had similar  responses with 5 of7 subjects (71%) responding to pembrolizumab. Whole exome 
sequences revealed a high number  of somatic mutations in MMR-deficient tumors  compared 
with MMR-proficient tumors  (Le et al2015). 
 
Alterations to the DNA MMR pathway affect 4 key human proteins; MLH1,  MSH2, MSH6,  and 
PMS2.   This  leads to an accumulation of mutations in microsatellite regions of DNA that affect 
DNA repair, cell signaling, and apoptosis, which  leads to the development of malignancy 
(Lee et al2016).  Immunohistochemistry (IHC) and PCR are used  to screen  patients  for MMR  or 
microsatellite instability (MSI), as the fmmer identifies underlying protein  abnmmalities and the 
latter is useful in determining functional abnmmalities in DNA. The 2 testing platfmms are 
considered complimentary, but PCR is considered the gold standard for identifying CRC subjects 
with MSI, as it is more reproducible across laboratories, and it can detect nontluncating protein 
mutations in the 4 MMR proteins  that are tested and can also identify MSI caused  by other 
defects.  In PCR testing for MSI,  subjects who have no sites with MSI are considered MSS, 
subjects with 1 site are MSI-low (MSI-L), and subjects that have 2 or more sites ofMSI are 
considered MSI-H (Lee et al 2016).  Approximately 15% of subjects with CRC have MSI 
disease  (Vilar and Gruber  2010, Xiao and Freeman 2015), and so a large population of subjects 
who are MSS are not expected to respond  to checkpoint inhibitors alone.  Therefore, the 
evaluation of combined immunotherapy with epigenetic therapy that has the potential to increase 
the immunogenicity of CRC tumors  and synergistically generate an immune response is 
wauanted in this indication with significant unmet need. 


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1.7.3.3.  
Treatment Sequencing Tumor Biopsy Cohort Indications 
 
Subjects with 3 additional tumor types (HNSCC, melanoma, and urothelial carcinoma) will be 
emolled in the treatment sequencing tumor biopsy cohmts.   All 3 tumor types have been 
demonstrated to be immunotherapy-responsive, and checkpoint inhibitors including ipilimumab, 
nivolumab, pembrolizumab,  atezolizumab, durvalumab, and avelumab have shown durable 
antitumor activity and have been approved for treatment in either a first-line setting (melanoma) 
or following progression on chemotherapy (Opdivo 2017, Keytmda 2017, Tecentiiq 2017). 
While substantial benefit has been observed, the majority of solid tumors do not respond to 
checkpoint inhibitors alone, and combination therapy with anti-PD-1 agents is being investigated 
to dete1mine if additional subjects are able to obtain an immune response. 
 
Response data for subjects  with metastatic HNSCC, melanoma, NSCLC, renal cell carcinoma 
(RCC), and urothelial carcinoma from the ongoing Phase 1/2 study INCB 24360-202 
(KEYNOTE-037) are encouraging, with high ORRs observed for the pembrolizumab + 
epacadostat combination that exceed historic monotherapy data with PD-1 and PD-L1 inhibitors. 
Recently presented data from Phase 1 and Phase 2 subjects showed ORRs and disease conti·ol 
rates, respectively, of35% and 63% in 40 NSCLC subjects (Gangadhar et al2017); 33% and 
50% in 30 RCC subjects (Lara et al2017); 35% and 53% in 40 urothelial carcinoma subjects 
(Sinith et al2017); and 34% and 61% in 38 squamous  cell carcinoma of the head and neck 
(SCCHN) subjects (Hamid et al2017a). An update on the melanoma cohort was presented at the 
European Society for Medical Oncology Annual Meeting 2017.  Across all subjects with 
treatment-naive or treatment-experienced advanced melanoma, an ORR of 56% was observed; 
median PFS was 12.4 months, with PFS rates of 65% at 6 months, 52% at 12 months, and 49% 
at 18 months (Hamid et al2017b). Data from the INCB 24360-202 study demonstrate that 
combination treatment with epacadostat and pembrolizumab  across multiple tumor types shows 
improved  response  rates and durability compared  with pembrolizumab alone, thus wananting 
finther study in controlled randomized studies.  The addition of epigenetic p1iming to the 
pembrolizumab  and epacadostat combination may increase response rates in immunotherapy- 
sensitive tumor types that have shown  benefit from monotherapy and combination therapy 
checkpoint inhibition.  Another focus of the investigation in the ti·eatment sequencing expansion 
cohmt is to dete1mine whether the addition of epigenetic priining regimens can sensitize tumors 
that were primarily refractmy to PD-1/PD-L1 inhibition or re-sensitize tumors that were initially 
sensitive to checkpoint inhibition but progressed while on a PD-11PD-L1 inhibitor. 
 
1.8. 
Potential Risks and Benefits of the Treatment Regimen 
 
 


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1.8.2. 
Risks From Pembrolizumab 
 
Potential safety concems and recommended management guidelines regarding pulmona1y 
toxicity, gastrointestinal toxicity, hepatotoxicity,  endocrinopathies, nephritis and renal 
dysfunction, infusion-related reactions, and other immune-mediated toxicities of concem are 
summa1ized in the pembrolizumab  approved label. 
 
The overall safety experience with pembrolizumab is based on experience in subjects as either a 
monotherapy or in combination with other therapeutics.  In general for monotherapy, the safety 
profile is similar  across tumor types.  The 1 exception is AEs of pulmonaty inflammation, which 
may be numerically greater in subjects with NSCLC,  possibly because in some cases it can be 
difficult  to distinguish between pembrolizumab-related and umelated causes of pulmonary 
symptoms and radiographic changes.  The most frequently repmted treatment-related AE is 
fatigue, which is almost always low grade. 
 
1.8.3. 
Risks From Azacitidine 
 
Azacitidine is known to be associated to cytopenias including,  anemia, neutropenia, and 
thrombocytopenias. Subjects will have complete blood counts perfmmed at baseline and 
2 additional times per cycle in Cycle 1 and 2 in Pa1t 1 dose escalation. Potential safety concems 
and recommended management guidelines regarding hematologic toxicities, hepatotoxicity, renal 
abnmmalities, and other toxicities of concem are summarized in the azacitidine approved label. 
 
1.8.4. 
Risks From INCB057643 
 
Data from the INCB 57643-101 Phase  1 clinical trial indicate that INCB057643 is overall 
well-tolerated. Overall, only 1 DLT was noted out of8 subjects repmted at 16mg QD, which is 
1 dose level higher than the RP2D of 12 mg QD, the highest dose proposed  to be tested in this 
study.   Eight subjects were emolled at 16 mg QD, and 5 of those 8 subjects required dose 
inten11ption due to AEs during Cycle 1 or 2 (due to Grade 3 INR increased,  Grade 3 
thrombocytopenia, eye pain, Grade 4 hyperglycemia, Grade 2 total bilimbin  increased/Grade 3 
direct bilirubin increased, respectively). Nine of the 16 subjects (56%) in the dose-expansion 
cohmt of Study  INCB 57643-101 repmted at least 1 treatment-related TEAE.  Subjects repmted 
4 TEAEs;::: Grade 3 (abdominal pain, appendicitis, sepsis,  and thrombocytopenia [n = 1 each 
[6.3%]); all of which were also repmted as SAEs, and of those,  only thrombocytopenia was 
considered  treatment-related by the investigator.  Treatment-related TEAEs led to dose 
inten11ption in 2 subjects, p1imarily due to decreased appetite (n = 2 [13%]), and no dose 
reductions due to treatment-related TEAEs were repmted as of the data cut-off date.  Three of 
the 16 subjects (19%) discontinued  treatment (disease progression, n = 2 [13%]; other, n = 1 
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1.8.5.  
Risks From INCB059872 
 
Data from the Phase 1 clinical study INCB 59872-101 indicate that INCB059872 is generally 
well-tolerated. Overall, only 1 DLT was noted in subjects dosed  at 4 mg QoD, which is 1 dose 
level higher than the RP2D of 3 mg QoD, the highest dose proposed  to be tested in this study.  In 
the dose-escalation cohort of Study INCB 59872-101, 6 DLTs of 2: Grade 3 thrombocytopenia  or 
platelet count decreased have been reported in the 2 mg QD, 3 mg QD, and 4 mg QoD cohmts in 
TGB (1, 2, and 3 DLTs respectively), none of which are being evaluated in this study. 
Treatment intenuption occmTed in the subjects with DLTs, and, following  recovery, 4 of these 
subjects resumed study treatment at a reduced dose (3 mg QoD).  Four treatment-emergent SAEs 
resulted in discontinuation of study treatment:  thrombocytopenia, bile duct obstruction, 
epistaxis, and hypotension. With the exception of thrombocytopenia, none of these treatment- 
emergent SAEs leading to INCB059872 discontinuation were considered related to study 
u·eatment. Five treatment-emergent SAEs have resulted in death, none of which were considered 
related to study treatment by the investigators: leukocytosis, sepsis, pulmona1y alveolar 
hemonhage, respiratmy failure, and gastr·ointestinal hemonhage. 
 
1.8.6. 
Risks From Combination Therapy 
 
The combination of the immunotherapies epacadostat and pembrolizumab have the potential to 
precipitate more frequent, more severe, and/or new immune-related toxicities as compared with 
each individually. The addition of azacitidine, INCB057643, or INCB059872 to the epacadostat 
and pembrolizumab regimen may have the potential to increase irAEs due to their ability to 
re-express and up-regulate genes related to diverse immune pathways.  The combination of 
azacitidine with pembrolizumab and epacadostat has been well-tolerated in Cohmts 1, 2A, 2B, 
and 3 with no DLTs observed to date in Pa1t 1. 


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2- 
STUDY  OBJECTIVES AND ENDPOINTS 
 
2-L  
Study  Objectives 
 
2.1.1. 
Primary Objectives 
 
• Pa1t 1:  To evaluate the safety and tolerability and to determine the MTD, maximum 
tested dose, or PAD of the combinations in subjects with advanced or metastatic solid 
tumors. 
 
• Pa1t 2:  To evaluate the efficacy of the combinations in subjects with previously 
treated Stage IV or recunent  NSCLC, Stage IV MSS CRC, and select solid tumors by 
assessing ORR per RECIST v1.1 at the MTD, maximum tested dose, or PAD. 
 
2.1.2. 
Secondary Objectives 
 
• Pa1t 1:  To evaluate the efficacy of the combinations in subjects with advanced or 
metastatic solid tumors by assessing ORR per RECIST v1.1 at the MTD, maximum 
tested dose, or PAD. 
 
• Pa1t 2:  To evaluate the safety and tolerability of the combinations  in subjects with 
previously treated Stage IV or recurrent NSCLC, Stage IV MSS CRC, and select 
solid tumors at the MTD, maximum tested dose, or PAD. 
 
• Pa1ts 1 and 2:  To evaluate changes in T-cell infiltration in the tumor 
microenvironment  with the combinations in subjects with advanced or metastatic 
solid tumors, previously  treated Stage IV or recunent NSCLC, and Stage IV MSS 
CRC. 
 
• Pa1ts 1 and 2:  To evaluate the efficacy of the combinations in subjects with advanced 
or metastatic solid tumors, previously treated Stage IV or recunent NSCLC, and 
Stage IV MSS CRC by assessing PFS. 
 
• Pa1ts 1 and 2:  To evaluate the efficacy of the combinations in subjects with advanced 
or metastatic solid tumors, previously treated Stage IV or recunent NSCLC, and 
Stage IV MSS CRC by assessing DOR. 
 
 


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2-2- 
Study Endpoints 
 
2.2.1. 
 Primary Endpoints 
 
• Pa1t 1: Safety and tolerability will be assessed by monitoring the frequency, duration, 
and severity of AEs; through physical examinations; by evaluating changes in vital 
signs and electrocardiograms (ECGs); and through clinicallaboratmy blood and urine 
sample evaluations. 
 
• Pa1t 2:  Objective response rate, defined as the percentage of subjects having a CR or 
PR, will be dete1mined by investigator  assessment of radiographic disease  as per 
RECIST vl.l. 
 
2.2.2. 
 Secondary Endpoints 
 
• Pa1t 1:  Objective response rate, defined as the percentage of subjects having a CR or 
PR, will be dete1mined by investigator  assessment of radiographic disease  as per 
RECIST vl.l. 
 
• Pa1t 2: Safety and tolerability will be assessed by monitoring the frequency, duration, 
and severity of AEs; through physical examinations; by evaluating changes in vital 
signs and ECGs; and through clinicallaboratmy blood and urine sample evaluations. 
 
• Pa1ts 1 and 2:  Percentage of responders, where a responder is defined as an increase 
in the number of TILs or the ratio of CD8+ lymphocytes to Tregs infiltrating tumor 
post-treatment versus pretreatment with pembrolizumab and epacadostat in 
combination with azacitidine, INCB057643, or INCB059872 evaluated by IHC, will 
be dete1mined. 
 
• Pa1ts 1 and 2:  Progression-free smvival, defmed as the time from date of first dose of 
study dmg until the earliest date of disease progression, will be dete1mined by 
investigator  assessment of objective radiographic disease assessments per 
RECIST v1.1, or death due to any cause, if occmTing sooner than progression. 
 
• Pa1ts 1 and 2:  Duration of response dete1mined by radiographic  disease assessment, 
defined as the time from earliest date of disease response until the earliest date of 
disease progression as per RECIST v1.1, or death due to any cause, if occmTing 
sooner than progression, will be dete1mined. 


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3_ 
SUBJECT ELIGIBILITY 
 
Deviations from eligibility crite1ia are not allowed because they can potentially jeopardize the 
scientific integrity of the study, regulatmy acceptability, and/or subject safety.  Therefore, 
adherence to the crite1ia as specified in the Protocol is essential. 
 
3-L 
Subject Inclusion Criteria 
 
A subject who meets all of the following criteria may be included in the study: 
Both Part 1 and 2 
1.   Male or female subjects, age 18 years or older on day of signing consent. 
 
2.   Willingness to provide written infmmed consent  for the study. 
 
3.   Willingness to undergo a pretreatment and on-treatment tumor biopsy to obtain tumor 
tissue.  On-treatment biopsy is optional in Stage 2 of Pa1t 2.  Two on-treatment biopsies 
are mandatmy in the Pa1t 2 treatment sequencing biopsy expansion cohmts (except for 
Cohmts B-11 and C-13, which require 1 on-treatment biopsy). 
 
Note:  If a subject is scheduled to have a tumor biopsy for the purposes of this study, and 
it is subsequently dete1mined that tumor tissue cannot s 
be 
· 
then the 
·ect 
still emoll in the 
 
 
 
 
 
 
 
 
4.   Life expectancy >12 weeks. 
 
5.   ECOG perfmmance status of 0 to 1. 
 
6.   Presence of measureable disease per RECIST v.1.1 as dete1mined by the site study team. 
Tumor lesions situated in a previously inadiated area are considered measureable if 
progression has been demonstrated in such lesions. The lesion selected for pre- and/or 
post-treatment biopsy cannot be the only measurable lesion. 
 
7.   Willingness to avoid pregnancy or fathe1ing children based on the c1iteria below: 
 
a.   Woman of nonchildbearing potential (ie, surgically sterile with a hysterectomy and/or 
bilateral oophorectomy OR ;::: 12 months of amenonhea and at least 50 years of age.) 
b.   Woman of childbearing potential who has a negative semm pregnancy test at 
screening (must be perfmmed within 72 hours before the first dose of study dmg) and 
who agrees to take appropriate precautions to avoid pregnancy (with at least 99% 
ce1tainty) from screening through 120 days after the last dose of study dmg. 
Pe1mitted methods that are at least 99% effective in preventing pregnancy (see 
Appendix A) should be communicated  to the subject and their understanding 
confi1med. 


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c.   Man who agrees to take appropriate precautions to avoid fathe1ing children (with at 
least 99% certainty) from screening through 120 days after the last dose of study 
dmg.  Pe1mitted methods that are at least 99% effective in preventing pregnancy (see 
Appendix A) should be communicated  to the subject and their understanding 
confi1med. 
 
Part 1 Only 
 
8.   Subjects with histologically or cytologically confi1med advanced or metastatic solid 
tumors that have failed prior standard therapy (disease progression; subject refusal or 
intolerance is also allowable). 
 
Note:  There is no limit to the number of prior treatment  regimens. 
Part 2 Only 
Note:  Subjects must have failed available  therapies that are known to confer clinical benefit as 
indicated below, unless they are ineligible, intolerant, or refused standard treatment. 
Subjects with histologically or cytologically confi1med NSCLC: 
9.   Metastatic (Stage IV) or recunent NSCLC (according to American Joint Committee on 
Cancer 7th edition guidelines)  who have had disease progression after available therapies 
for advanced or metastatic disease that are known to confer clinical benefit, been 
intolerant to treatment, or refused  standard treatment. 
 
10. Prior systemic regimens must include previously  approved therapies, including a 
platinum-containing chemotherapy regimen; a TKI for tumors with driver mutations; and 
checkpoint inhibitors where approved. 
 
11. Must have documented disease progression while on a prior PD-1 pathway-targeted 
agent (Expansion Cohmts A-1, B-1, B-3, B-5, B-7, C-1, C-3, C-5, C-7, and C-9). 
Progression following cessation of PD-1 pathway-targeted therapy is not sufficient.  The 
baseline scan for the purposes of this study may se1ve as the documentation of 
progressiOn. 
 
Subjects with recunent (umesectable) or metastatic CRC: 
 
12. Histologically or cytologically confnmed  adenocarcinoma of the colon or rectum. 
 
13. Confnmed MSS CRC as per local testing. 
 
14. Stage IV CRC (according to American Joint Committee on Cancer 7th edition guidelines) 
who have had disease progression after available therapies for advanced or metastatic 
disease that are known to confer clinical benefit, been intolerant to treatment, or refused 
standard treatment. 
 
15. Prior systemic regimens must include previously  approved therapies, including 
fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; an anti-VEGF 
therapy (if no contraindication); and if negative for KRAS, NRAS, and BRAF mutations 
and no contraindication, an anti-EGFR therapy; and progressed  after the last 
administration of approved therapy. 


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Subjects with HNSCC: 
 
16. Histologically confnmed squamous  cell carcinoma of the oral cavity, oropharynx, 
hypopharynx, or larynx. 
 
Note:  Carcinomas of the nasopharynx, salivary gland, or nonsquamous cell histology  are 
excluded. 
17. Must have received p1ior treatment with a platinum-based therapy.  Subjects who 
relapsed within 6 months of adjuvant therapy, including a platinum-containing regimen, 
may emoll.  Additionally, subjects must have had documented disease progression while 
on a prior PD-1 pathway-targeted agent.  Progression following cessation of PD-1 
pathway-targeted therapy is not sufficient. 
 
18. Must have documented human papilloma vims status. 
Subjects with melanoma: 
19. Histologically or cytologically  confnmed melanoma. 
 
20. Umesectable Stage III or Stage IV melanoma, as per American Joint Committee on 
Cancer staging system not amenable to local therapy. 
 
21. Documentation  ofV600-activating BRAF mutation status or consent to BRAF. 
 
22. V600 mutation testing during the screening period. 
 
23. Must not have ocular melanoma. 
Subjects with urothelial carcinoma: 
24. Histologically or cytologically  confnmed urothelial carcinoma of the renal pelvis, ureter, 
urina1y bladder, or urethra that is transitional cell or mixed transitionaVnontransitional 
(predominantly transitional) cell type. 
 
25. Stage IV locally advanced or metastatic  urothelial carcinoma (according to American 
Joint Committee on Cancer 7th edition guidelines) with documented disease progression 
while on a PD-1 pathway-targeted  therapy.  Progression following cessation of PD-1 
pathway-targeted therapy is not sufficient. 
 
3-2- 
Subject Exclusion Criteria 
 
A subject who meets any of the following criteria will be excluded from the study: 
 
1.   Laboratory and medical histmy parameters not within Protocol-defined  range.  Cycle 1 
Day 1 laboratmy assessments for the dete1mination of eligibility do not need to be 
perfmmed if the screening labs were perfmmed within 7 days of Cycle 1 Day 1.  If the 
screening lab assessments were pe1fmmed more than 7 days before Cycle 1 Day 1, the 
hematology, semm chemistry,  and liver chemistry lab results must be confi1med on 
Cycle 1 Day 1 before tr·eatment initiation. 
 
a.   Absolute neutr·ophil count < 1.5 x 109/L. 
b.   Platelet count < 100 x 109/L. 
c.   Hemoglobin < 8 g/dL (transfusion is acceptable to meet this criterion). 


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d.   Semm creatinine 2:: 1.5 x institutional upper limit of nmmal (ULN) OR 
measured or calculated creatinine clearance (glomemlar filtration rate can also 
be used in place of creatinine or CrCl) < 50 mL!min for subjects with creatinine 
levels > 1.5 x institutional ULN). 
e.   Aspartate aminotransferase,  ALT, and alkaline phosphatase 2::2.5 x ULN. 
Note:  Subjects with 1) bone metastases and 2) no hepatic parenchymal metastases on 
screening radiographic examinations may emoll if the alkaline phosphatase is 
< 5 x ULN.  Subjects with 1) bone metastases and 2) hepatic parenchymal metastases 
on screening radiographic examinations may emoll if the alkaline phosphatase is 
< 5 x ULN only with medical monitor approval. 
f. Total bilimbin 2:: 1.2 x ULN are excluded unless direct bilimbin is:::; ULN.  If there is 
no institutional ULN, then direct bilimbin must be < 40% of total bilimbin to be 
eligible. 
g.   Intemational nmmalized ratio or prothrombin time (PT) > 1.5 x ULN. 
h.   Activated pa1tial thromboplastin time > 1.5 x ULN. 
1. 
Semm albumin < 3 g/dL. 
 
2.   Receipt of anticancer medications or investigational dmgs within the following interval 
before the first administration of study dmg: 
 
a.   < 14 days for chemotherapy, targeted small-molecule  therapy, or radiation therapy. 
Subjects must also not require cmticosteroids  and must not have had pneumonitis as a 
result of treatment.  A 1-week washout is pe1mitted for palliative radiation to 
non-CNS disease with sponsor approval. 
Note:  The use of denosumab is pe1mitted. 
b.   < 14 days for a p1ior PD-1 pathway-targeted agent.  (If the subject was on 
pembrolizumab monotherapy, a wash-out is not required.) 
c.   < 28 days for prior monoclonal antibody used for anticancer therapy with the 
exception of PD-1 pathway-targeted agents. 
d.   < 14 days for an immune-suppressive-based treatment for any reason (including 
chronic use of systemic cmticosteroid at doses of prednisone equivalent 
to > 10 mg/day).  Use of inhaled or topical steroids, or systemic cmticosteroids 
to :::; 10 mg is pe1mitted. The use of physiologic doses of corticosteroids may be 
approved after consultation with the sponsor. 
e.   < 28 days or 5 half-lives (whichever  is longer) before the first dose for all other 
investigational study dmgs or devices.  For investigational agents with long half-lives 
(eg, > 5 days), emollment  before the fifth half-life requires medical monitor approval. 
 
3.   Has not recovered from toxic effect(s) ofp1ior therapy to:::; Grade 1.  Any irAEs from 
prior immunotherapy must have complete resolution and must have resolved  at least 
2 weeks before Cycle 1 Day 1. 
 
Note:  Subjects  with:::; Grade 2 neuropathy or alopecia are an exception and may emoll. 
Subjects  with immune-related hypothyroidism or adrenal insufficiency because of prior 
immunotherapy who are medically stable and adequately managed on a stable dose of 
replacement therapy may be emolled. 
 
4.   Subjects  with p1ior ocular toxicity from p1ior immune therapy are excluded. 


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5.   Subjects who have not recovered adequately from toxicity and/or complications from 
surgical intervention before sta1ting therapy. 
 
6.   Subjects who have any active or inactive autoimmune disease or syndrome  (ie, 
rheumatoid arthritis, moderate or severe psmiasis, multiple sclerosis,  inflammatmy  bowel 
disease) that has required systemic treatment in the past 2 years or who are receiving 
systemic therapy for an autoimmune or inflammatmy disease (ie, with use of disease 
modifying agents, cmticosteroids, or immunosuppressive dmgs). 
 
Note:  Exceptions include subjects with vitiligo or resolved  childhood asthma/atopy, 
hypothyroidism stable on hmmone replacement, controlled asthma, Type I diabetes, 
Graves' disease, or Hashimoto's disease, or with medical monitor approval. 
 
7.   Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg [> 10 mg] daily of prednisone equivalent) or any other fmm of 
immunosuppressive therapy within 7 days before the first dose of study treatment.  Use 
of inhaled or topical steroids or systemic cmticosteroids10 mg is pe1mitted. 
 
8.   Known active CNS metastases and/or carcinomatous meningitis. 
 
Note:  Subjects with previously treated brain metastases may pa1ticipate provided they 
are stable (without evidence of progression by imaging for at least 4 weeks before the 
first dose of study treatment and any neurologic symptoms have retumed to baseline), 
have no evidence of new or enlarging brain metastases, and have not required steroids for 
at least 7 days before study treatment. 
 
9.   Has received a live vaccine within 30 days of planned sta1t of study therapy. 
 
Note:  Examples of live vaccines include, but are not limited to, the following:  measles, 
mumps, mbella, chicken pox/zoster,  yellow fever, rabies, Bacillus Calmette-Guerin, and 
typhoid vaccine.  Seasonal influenza vaccines for injection are generally killed vims 
vaccines and are allowed; however, intranasal  influenza vaccines (eg, FluMisat re 
live-attenuated  vaccines and are not allowed. 
 
10. Evidence of interstitial  lung disease or active, noninfectious pneumonitis. 
 
11. Histmy or presence of an abnmmal ECG that, in the investigator's opinion, is clinically 
meaningful.  Screening QTc interval > 480 milliseconds is excluded (corrected  by 
Fridericia).  In the event that a single QTc is > 480 milliseconds, the subject may emoll if 
the average QTc for the 3 ECGs is < 480 milliseconds. For subjects with an 
intraventricular conduction delay (QRS interval > 120 Insec), 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 JT is nmmal or with medical 
monitor approval. 
 
12. Clinically significant cardiac disease,  including unstable angina, acute myocardial 
infarction within 6 months from Day 1 of study dmg administration, New York Hea1t 
Association Class III or IV congestive hea1t failure, and arrhythmia requiring therapy. 
 
Note:  A subject with an arrhythmia may emoll if the subject is on anti-arrhythmic 
medication and is in sinus rhythm on the screening ECG. 


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13. fuability to swallow food or any condition of the upper gastrointestinal tract that 
precludes administration  of oral medications. 
 
14. Subject has a known histmy of or is positive for hepatitis B (hepatitis B virus [HBV] 
smface  antigen reactive or HBV DNA detected) or hepatitis C (hepatitis C virus [HCV] 
antibody positive and/or HCV RNA [qualitative] is detected). 
 
Note:  Hepatitis C antibody-positive subjects who received and completed treatment for 
hepatitis C that was intended to eradicate the virus may participate if HCV RNA levels 
are undetectable. 
 
Note:  fu Patt 2, subjects who are immune to hepatitis B (HBV surface antibody and/or 
HBV core antibody positive) are allowed (ie, no evidence of active infection). 
 
15. Known histmy of human immunodeficiency virus (HIV; HIV 112 antibodies). 
 
16. Active infection requiring systemic therapy. 
 
17. Known allergy, hypersensitivity, or reaction to any component of the study drugs, 
fmmulation  components, or excipients, including mannitol. 
 
18. Women who are pregnant or breastfeeding. 
 
19. Known additional malignancy that is progressing or requires active treatment. 
Exceptions  include basal cell carcinoma of the skin, squamous cell carcinoma of the skin 
that has undergone potentially curative therapy, in situ cervical cancer, or early stage 
endometrial cancer. 
 
20. Prior receipt of an IDO inhibitor. 
 
21. Receipt ofMAOis within the 21 days before the first dose of study treatment. 
 
22. Use of any UGT1A9 inhibitor from screening through the safety follow-up period, 
including the following:  diclofenac, imipramine, ketoconazole, mefenamic acid, and 
probenecid.  See Section 5.6.3 for more details. 
 
23. Histmy ofSS after receiving 1 or more serotonergic  drugs. 
 
24. fuability or unlikeliness to comply with the dose schedule and study evaluations, in the 
opinion of the investigator. 
 
25. Any condition that would, in the investigator's judgment, interfere with full patticipation 
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. 
 
26. Prior receipt of any fmmulation  of azacitidine, decitabine, or any other hypomethylating 
agent (Treatment  Group A only). 
 
27. Exclusion  criterion removed as of Protocol Amendment 3. 
 
28. Subjects with bleeding associated with tumors in proximity to major blood vessels are 
excluded except with medical monitor approval. 
 
29. Histmy of a prior Grade 3 or 4 irAE (Part 1 dose escalation only). 
 
30. Subjects  with uncontrolled type I or type II diabetes mellitus (defined as HgbA1c > 8). 


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31. Prior receipt of a BET inhibitor (Treatment Group B only). 
 
32. Subjects  with a histmy of bleeding related to cancer under study requiring a medical 
intervention (eg, embolization  procedure, RBC transfusion, or hospitalization) within 
30 days of study emollment (Treatment  Groups B and C only). 
 
33. Clinically significant bleeding within 14 days of Cycle 1 Day 1 (Treatment  Groups B and 
Conly). 
 
34. Subjects cunently receiving warfarin therapy (Treatment  Group B only). 
 
35. Prior receipt of an LSD1 inhibitor, including INCB059872 (Treatment  Group Conly). 
 
 
 
4- 
INVESTIGATIONAL  PLAN 
 
4-L 
Overall Study Design 
 
This is an open-label, multicenter, Phase 1/2 study evaluating the addition of 3 different 
epigenetic p1iming regimens to an immunotherapy  doublet in subjects with advanced  or 
metastatic solid tumors. 
 
Part 1 of the study will be an open-label Phase 1 assessment to evaluate the safety and 
tolerability and to dete1mine the MTD, maximum tested dose, or PAD of the combinations in 
subjects with advanced or metastatic solid tumors. 
 
Part 2 of the study will be an open-label Phase 2 assessment with Simon 2-stage design to 
evaluate ORR and TIL infiltration in previously  treated NSCLC and MSS CRC.  Separate 
treatment sequencing tumor biopsy cohmts are also included in Pa112 to further evaluate 
epigenetic changes  and changes in the tumor microenvironment in subjects with select solid 
tumors. 
 
Tumor biopsy samples are required at baseline and on study for subject pa1ticipation in all 
dose-escalation cohmts and Stage 1 of the Simon 2-stage cohmts.  Mandatmy tumor biopsies 
will be collected at baseline (before Day 1 administration) and while the subject is receiving 
study treatment as specified below: 
 
• An additional on-treatment biopsy will be required to be collected  during Week 5 or 
Week 6 (Treatment Group A) or Week 8 or Week 9 (Treatment Groups Band C); the 
on-treatment biopsy is optional for Stage 2 cohmts in Pai12.  On-treatment biopsy 
requirements for the treatment sequencing biopsy cohmts are presented  in Table 5, 
Table 7, and Table 9. 
 
• An additional optional biopsy may be collected once the subject meets the 
requirements for SD, response, or progression by radiographic disease assessment. 
 
Note:  On-treatment biopsies should be collected  from the same tumor lesion  that was biopsied at 
baseline. 
Note:  If a subject is scheduled to have a tumor biopsy for the purposes of this study, and it is 
subsequently dete1mined that tumor tissue cannot safely be obtained, then the subject may still 
emoll in the study, and an archived tumor specimen,  if available,  can be submitted.  Such 
subjects may be replaced. 


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Note:  As a quality control step, prior to submitting the tumor tissue to the centrallaboratmy 
vendor, all tumor tissue will be fmmalin-fixed  and paraffin-embedded locally.  A hematoxylin 
and eosin (H&E) stain will be perfmmed and reviewed by a local pathologist to vetify the 
adequacy of the tumor biopsy.  Additionally, a quality control fmm will be signed and dated by 
the reviewing pathologist.   For the screening biopsy, this fmm will ideally be submitted to the 
sponsor at the same time that the registration fmm is submitted for emollment. 
 
 
 
Treatment Group A 
 
In Treatment Group A, subjects will receive the DNMT inhibitor azacitidine in combination with 
the PD-1 inhibitor pembrolizumab and the IDO1 inhibitor epacadostat.   Part 1 of Treatment Group 
A will consist of a dose-escalation assessment of the safety and tolerability of the treatments in 
subjects with advanced or metastatic solid tumors.  In Part 1 of Treatment Group A, 
pembrolizumab  and epacadostat will be administered  in 21-day cycles from Cycle 1 Day 1 in 
combination with azacitidine.  Subjects in Treatment Group A will receive  up to 6 cycles of 
azacitidine as long as the subject  is receiving benefit from treatment and has not met any critetia 
for study withdrawal (except for Expansion Cohmts A-4 and A-5 which, will receive  up to 
5 cycles). In Pat12 of Treatment Group A will consist of Simon 2-Stage cohmts in previously 
treated NSCLC and MSS CRC.  Separate treatment sequencing tumor biopsy cohmts  are also 
included in Part 2 to finther evaluate epigenetic changes and changes in the tumor 
microenvironment in subjects with select solid tumors.  In Treatment Group A, subjects who 
have an initial response or SD for greater than 6 months but later relapse while receiving 
pembrolizumab  and epacadostat will have the opportunity to repeat the epigenetic priming 
regimen to which they were originally assigned with medical monitor approval.  Study treatment 
may continue as long as the subject  is receiving benefit and has not met any criteria for study 
withdrawal or until the subject has received  35 administrations ofpembrolizumab (approximately 
2 years), whichever occurs first.  See Figure 1 for study design illustration. 
 
Treatment Groups B and C  (NOTE: Upon implementation  of Amendment 4, Treatment 
Groups Band Care no longer applicable.) 
 
In Treatment Group B, subjects will receive the BET inhibitor INCB057643 as a monotherapy 
priming regimen in Cycle 1 and then will add pembrolizumab and epacadostat on Cycle 2 Day 1. 
In Treatment Group C, subjects will receive the LSD1 inhibitor INCB059872 as a monotherapy 
priming regimen in Cycle 1 and then will add pembrolizumab and epacadostat on Cycle 2 Day 1. 
Pa111 of Treatment Groups B and C will consist of a dose-escalation assessment of the safety 
and tolerability of the treatments in subjects with advanced or metastatic solid tumors.  Pa111 
will also contain dose-expansion cohmts in previously treated NSCLC and MSS CRC. 
nn T .Tl,n emollment of Pai11 there will be an optional study hold for evaluation of safety, 
to facilitate a go/no-go decision regarding emollment of 
Patt 2. 
and C will consist of Simon 2-Stage cohmts in previously 
treated NSCLC and MSS CRC.  Separate treatment sequencing tumor biopsy cohmts  are also 
included in Part 2 to finther evaluate epigenetic changes and changes in the tumor 
microenvironment in subjects with select solid tumors.  Emollment of the treatment sequencing 


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tumor biopsy cohmts is contingent upon passing Stage I in I of the 2 cohorts, for each respective 
treatment group.  Study treatment may continue as long as the subject is receiving benefit and 
has not met any criteria for study withdrawal or until the subject has received 35 administrations 
ofpembrolizumab (approximately 2 years), whichever occurs first.  See Figure 2 and Figure 3 
for study design illustration for Treatment Group B and C. 
 
4.1.1.  
Dose-Escalation Phase (All Treatment Groups) 
 
A 3 + 3 + 3 design will be used to assess the MTD, maximum tested dose, or PAD of the t1iplet 
combination of azacitidine, INCB057643, or INCB059872 with pembrolizumab  and epacadostat 
in 2I-day treatment cycles.  The MTD will be defined as the highest dose at which less than 
one-third of the subjects (with a minimum of 6 subjects) have a DLT.  When the MTD, 
maximum tested dose, or PAD has been dete1mined or reached, the dose will be recommended 
for Pa1t 2.  The Pa1t 2 expansion will begin after the dete1mination of the MTD, maximum tested 
dose, or PAD; however,  emollment p1iority will be given to the open Pa1t I dose-escalation 
cohmt. 
 
A minimum of 3 subjects will initially be emolled in Cohmt I, and each subject will be observed 
for 2I  days from the sta1t of triplet combination therapy before emollment in the next cohmt 
begins.  The dose of azacitidine, INCB057643, or INCB059872 (or epacadostat) will be 
escalated  if 0 of the first 3 evaluable subjects emolled has a DLT.  If I of 3 subjects in Cohmt I 
has a DLT, the cohmt will be expanded to 6 subjects.  If I of 6 subjects in Cohmt I has a DLT, a 
new cohmt of3 subjects will be treated at the next higher dose level (Cohort 2).  If2 of 
6 subjects in Cohmt I have a DLT, that cohmt will be fu1ther expanded to a total of9 subjects. 
If :::; 2/9 subjects have a DLT, 3 subjects will be treated at the next higher dose level.  If 2: 2/3, 
3/6, or 3/9 subjects have a DLT within a cohmt, dose de-escalation will be required, and 
Cohmts -I or -2 will be tested.  The MTD is defined as the highest dose level at which :::;  I/6 or 
:::; 2/9 subjects expe1ience a DLT. 
 
Subjects must have received 2:75% of planned doses of study dmg during the 2I-day DLT 
(Treatment Group A) or 42-day DLT (Treatment Groups Band C) obse1vation period or have 
had a DLT to be evaluable for dose tolerability (Treatment  Group A:  azacitidine [4 doses], 
epacadostat [32 doses], and pembrolizumab [I dose]; Treatment Group B:  INCB057643 
[32 doses], epacadostat [32 doses], and pembrolizumab [I dose]; Treatment Group C: 
INCB059872 [QD dosing, 32 doses; QoD dosing, I6 doses], epacadostat [32 doses], and 
pembrolizumab  [I dose]). 
 
It is recognized that ce1tain toxicities due to the combination agent (eg, including but not limited 
to gastrointestinal toxicity, including dianhea; renal insufficiency; high-grade laboratory 
abnmmalities; and rash) may initially be clinically indistinguishable from toxicities due to 
immunotherapy. Epacadostat will be held for these toxicities, and as a result, subjects may not 
receive 2: 75% of the prescribed  dose during Cycle I . In these cases, the p1incipal investigators 
and medical monitor may assess subjects who receive dose intensities somewhat below 75% for 
the dete1mination ofDLTs, and consider in the adjudication process the specific toxicity 
encountered, the likely cause of the toxicity, and dose intensity and tolerability beyond Cycle I. 
Additional subjects will be emolled in a cohmt to achieve the minimum of 3 evaluable subjects if 
dropouts or dose intenuptions/reductions occur that result in a subject being nonevaluable for 
DLTs. 


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During the study, dose intenuptions and/or dose modifications  may be implemented based on 
toxicity as described in Section 5.4.  However,  dose modifications should  not be made during the 
DLT observation pe1iod without  discussion with the medical monitor. Intrasubject  dose 
escalation is not pennitted. 
 
4.1.1.1. 
Treatment Group A: Azacitidine 
 
Dose escalation will begin with sta1ting doses of azacitidine 75 mg SC or IV for 5 days (5 doses 
may be administered over the Day 1-7 period) of the first 2 cycles, pembrolizumab 200 mg IV 
Q3W, and epacadostat 100 mg orally (PO) BID continuous  dose adininistration.  If the staiting 
dose proves intolerable, then azacitidine  50 mg SC or IV for 5 days, pembrolizurnab 200 mg IV 
Q3W, and epacadostat 100 mg PO BID will be evaluated. The cohmts  and dose levels are 
shown in Table 1. 
 
Table 1:  
Dose Levels: Treatment Group A 
 
Cohort 
Azacitidine 
Pembrolizumab 
Epacadostat 
-2·  
50 mg SC or IV for 5 days (5 doses 
over Day 1-7 period) in Cycle 1 & 2 
200mgiVQ3W 
50 mgPOBID 
-1" 
50 mg SC or IV for 5 days (5 doses 
over Day 1-7 period) in Cycle 1 & 2 
200mgiVQ3W 
100mgPOBID 
1 
75 mg SC or IV for 5 days (5 doses 
over Day 1-7 period) in Cycle 1& 2 
200 mgiVQ3W 
100 mg POBID 
2Ab 
75 mg SC or IV for 5 days (5 doses 
over Day 1-7 period) in Cycle 1 & 2 
200mgiVQ3W 
300mgPOBID 
2Bb 
100 mg SC or IV for 5 days (5 doses 
over Day 1-7 period) in Cycle 1 & 2 
200mgiVQ3W 
100mgPOBID 
3 
100 mg SC or IV for 5 days (5 doses 
over Day 1-7 period) in Cycle 1 & 2 
200mgiVQ3W 
300mgPOBID 
• IfCohort I proves mtolerable, Coh01t -I may be evaluated.  If Cohort -I ts not tolerable, Cohort  -2 may be evaluated wtth 
epacadostat 50 mg PO BID.  If a de-escalation cohort  is detennined to be safe and tolerable, the dose of azacitidine or 
epacadostat may be re-escalated in separate,  additional coh01ts based on the review of available safety data. 
b  For Coh01t 2, escalation of azacitidine to IOO mg or epacadostat to 300 mg BID will be dependent on the observation of 
Grade 3 or greater immtme-related or non- immune-related toxicities in Cohort I (toxicities that were not considered DLTs).  If 
Grade 3 or greater immtme-related toxicities are obsetved in Coh01t I, azacitidine will be escalated  first (Cohort 2B). If 
non- immtme-related Grade 3 or greater toxicities are observed, epacadostat  will be preferentially escalated (Coh01t 2A). 
Dose-escalation Coh01ts 2A and 2B may be opened in parallel if no Grade 3 AEs are observed in Cohort I. 
 
4.1.1.2. 
Treatment Group B: INCB057643 
 
In Treatment  Group B, dose escalation will begin with a sta1ting dose of iNCB057643 of 4 mg 
PO QD continuous  dose adininistration beginning on Cycle 1 Day 1 for the first 21-day cycle. 
Beginning on Cycle 2 Day 1, pembrolizumab 200 mg IV Q3W and epacadostat 100 mg PO BID 
continuous dose administration will be added to INCB057643. If the sta1ting dose level proves 
intolerable, INCB057643 4 mg PO QD in combination with pembrolizurnab 200 mg IV Q3W 
and epacadostat  50 mg PO BID will be evaluated. The cohmts and dose levels are shown in 
Table 2. 


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Table 2: 
Dose Levels: Treatment Group  B 
 
Cohort 
INCB057643 
Pembrolizumab 
Epacadostat 
-I" 
4mgPOQD 
beginning C3D1 
200mgiVQ3W 
beginning C2Dl 
50 mgPO BID 
beginning C2D1 
1 
4 mg PO QD 
beginning C1D1 
200mgiVQ3W 
beginning C2D1 
100 mgPOBID 
beginning C2D1 
2 
8mgPOQD 
beginning C1D1 
200mgiVQ3W 
beginning C2Dl 
100mgPOBID 
beginning C2D1 
3 
12mgPO QD 
beginning C1D1 
200mgiVQ3W 
beginning C2Dl 
100mgPOBID 
beginning C2D1 
a  IfCohort I proves mtolerable, Coh01t -I may be evaluated.  If Cohort -I IS not tolerable, lower doses or altemative dose 
schedules ofiNCB057643 may be tested; however, at this time, 4 mg tablets are the lowest dose fonnulation available.  Any 
dose reduction in INCB057643 would be combined  with pembroliztunab 200 mg IV Q3W and epacadostat 50 mg PO BID.  If 
a de-escalation coh01t is detennined to be safe and tolerable, the dose of iNCB057643 or epacadostat  may be re-escalated in 
separate,  additional cohorts based on the review of available safety data. 
 
4.1.1.3. 
Treatment Group  C: INCB059872 
 
In Treatment  Group C, dose escalation will begin with a sta1ting dose of iNCB059872 of 1 mg 
PO QoD continuous dose administration beginning on Cycle 1 Day 1 for the first 21-day cycle. 
Beginning on Cycle 2 Day 1, pembrolizumab 200 mg IV Q3W and epacadostat 100 mg PO BID 
continuous dose administration will be added to INCB059872.  If the sta1ting dose level proves 
intolerable, INCB059872 1 mg PO QoD in combination with pembrolizumab 200 mg IV Q3W 
and epacadostat  50 mg PO BID will be evaluated.  The cohmts and dose levels are shown in 
Table 3. 
 
Table 3: Dose Levels:  Treatment Group C 
 
Cohort 
INCB059872 
Pembrolizumab 
Epacadostat 
-I" 
1 mgPO QoD 
beginning C1D1 
200mgiVQ3W 
beginning C2Dl 
50 mgPO BID 
beginning C2D1 
1 
1 mgPOQoD 
beginning C1D1 
200mgiVQ3W 
beginning C2D1 
100 mgPOBID 
beginning C2D1 
2Ab 
2 mgPO QoD 
beginning C1D1 
200mgiVQ3W 
beginning C2Dl 
100mgPO BID 
beginning C2D1 
2Bb 
1 mgPO QD 
beginning C1D1 
200mgiVQ3W 
beginning C2Dl 
100mgPOBID 
beginning C2D1 
3c 
3 mgPO QoD 
beginning C1D1 
200mgiVQ3W 
beginning C2Dl 
100mgPO BID 
beginning C2D1 
a  IfCohort I proves mtolerable, Coh01t -I may be evaluated.  If Cohort -I IS not tolerable, lower doses or altemative dose 
schedules ofiNCB059872 may be tested.   Any dose reduction in INCB059872  would be combined with pembroli.ztunab 
200 mg IV Q3W and epacadostat  50 mg PO BID.  If a de-escalation cohort  is detennined to be safe and tolerable, the dose of 
INCB059872 or epacadostat  may be re-escalated in separate,  additional coh01ts based on the review of available safety data. 
b  Dose-escalation Coh01ts 2A and 2B may be opened in parallel if no Grade 3 AEs are observed in Cohort I. 
c  Cohort 3 will be enrolled once Coh01t 2A clears the DLT period.   Enrollment  into Cohort 3 is not dependent upon clearing the 
DLT period from Cohort 2B. 


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4.1.2. 
Dose-Expansion Phase 
 
4.1.2.1. 
Treatment Group  A 
 
Once the safety profile of all doses tested has been characterized and the RP2D of the 
combination has been defmed, the cohort expansion will be initiated at the RP2D.  The doses 
selected for expansion will not exceed the MTD or maximum tested dose in Pa1t 1. 
 
The purpose of Phase 2 is to gather additional safety,  
and 
prelimina1y efficacy infmmation regarding the triplet combination in select tumor types where 
there is substantial room for improvement over mono- and doublet immunotherapies.   The 
expansion will include: 
 
1.   Safety/efficacy cohorts in NSCLC (A-1)  and MSS CRC (A-2) (2 tumor biopsies are 
required) 
 
2.   Treatment sequencing biopsy cohorts (3 tumor biopsies are required) 
 
a.   A-3:  azacitidine monotherapy followed by the pembrolizumab/epacadostat doublet 
b.   A-4:  pembrolizumab/epacadostat doublet followed by azacitidine 
c.   A-5:  pembrolizumab  monotherapy followed by epacadostat and azacitidine 
 
Note:  Only subjects with untreated (first-line) melanoma will be treated in the 
pembrolizumab  monotherapy cohmt (A-5). 
 
4.1.2.1.1.   Treatment Group  A Safety/Efficacy Expansion Cohorts (Part  2) 
 
Two cohmts will be evaluated as part of the safety/efficacy expansion.  The eligible tumor types 
are NSCLC and MSS CRC.  Subjects emolled in the NSCLC tumor cohmt must have had 
disease progression on a prior PD-1 pathway-targeted agent. 
 
A Simon 2-stage design will be used with a stopping rule to allow for early termination of a 
pa1ticular cohmt at the end of Stage 1 if there are insufficient responses observed.  During 
Stage 1, 8 NSCLC subjects who progressed  on a PD-1 pathway-targeted agent and 8 MSS CRC 
subjects will be emolled. If no responses are observed in the NSCLC PD-1 failure and MSS 
CRC cohmts, the cohmt(s) will be discontinued.  If at least 1 response is observed in the NSCLC 
PD-1 failure or MSS CRC cohmt, 19 additional NSCLC PD-1 failure or MSS CRC subjects will 
be emolled (Stage 2), for a maximum of27 subjects per cohmt (see Table 4). 
 
Table  4: 
Treatment Group  A Safety/Efficacy Expansion Cohorts (Part  2) 
 
Cohort 
Treatment 
Tumor Type (n) 
Expansion Coh01t A-1 
MTD or maximum tested dose for the 
azacitidine +pembrolizumab + 
epacadostat combination. 
A maximtun of27 subjects with 
previously treated Stage IV or recmrent 
NSCLC with progression on a prior PD-1 
pathway-targeted agent. 
Expansion Coh01t A-2 
MTD or maximum tested dose for the 
azacitidine +pembrolizumab + 
epacadostat combination. 
A maximum of27 subjects with 
previously treated Stage IV MSS CRC. 


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Continuous evaluation of toxicity events will be pe1fmmed throughout  the expansion. In the 
expansion, after the sixth subject in Stage 1 has been emolled, if > 40% of subjects have an AE 
2: Grade 3 that is attributable  to the investigational agents, further emollment of subjects will be 
suspended  until the sponsor, investigators, and regulatmy authorities (if applicable) have 
dete1mined the appropriate course of action. If an expansion cohmt is discontinued because of 
toxicity, a new cohmt may be initiated at a previously tested lower dose level. 
 
4.1.2.1.2.   Treatment Group A Treatment Sequencing Tumor Biopsy Cohorts (Part 2) 
 
The sequencing biopsy cohmts require 3 tumor biopsies  to identify epigenetic changes and 
changes  in the tumor microenvironment induced by each of the components of the regimen.  All 
subjects will have tumor biopsies at baseline and 2 additional biopsies while on study treatment. 
 
Approximately 25 subjects will be emolled in Expansion Cohmts A-3 and A-4, and 
approximately 10 subjects will be emolled in Expansion Cohmt A-5. The eligible tumor types 
for Expansion Cohmts A-3, A-4, and A-5 are HNSCC, melanoma, urothelial carcinoma,  and 
MSS CRC.  In Expansion Cohmts A-3 and A-4, subjects with tumor types other than MSS CRC 
must have had disease progression on a prior PD-1 pathway-targeted agent. 
 
Five to 8 evaluable subjects per tumor type in Expansion Cohmts A-3 and A-4, and 10 subjects 
in Expansion Cohmt A-5 will initiate treatment and have tumor biopsies perfmmed as indicated 
in Table 5. 
 
Table 5: 
Treatment Group  A Treatment Sequencing Tumor  Biopsy Cohorts (Part  2) 
 
Cohort 
Treatment Sequence 
Biopsy Sequence 
Tu mor Type (n) 
Expansion Cohort A-3 
Azacitidine monotherapy during 
Week -1 (5 doses), initiate 
pembrolizmnab and epacadostat 
on C1D1 (window+ 5 days 
fi:om the date of the fifth 
azacitidine dose; should begin 
after biopsy #2), 5 doses of 
azacitidine  will be administered 
in Cycles 2 and 3. 
Biopsy #1 at baseline. 
Biopsy #2 on ClD1 (window 
Day -5 to C1D1, biopsy before 
pembrolizumab/epacadostat 
administration). 
Biopsy #3 during Week 5 or 6. 
HNSCC (5-8) 
Melanoma  (5-8) 
Urothelial 
carcinoma (5-8) 
MSS CRC (5-8) 
Expansion Coh01t A-4 
Pembrolizmnab and epacadostat 
for 1 cycle, initiate azacitidine 
after biopsy #2, 5 doses of 
azacitidine  will be administered 
in Cycles 2 and 3. 
Biopsy #1 at baseline. 
Biopsy #2 on C2Dl  (window 
C1Dl5 to C2Dl , biopsy before 
azacitidine administration). 
Biopsy #3 during Week 8 or 9. 
HNSCC (5-8) 
Melanoma (5-8) 
Urothelial 
carcinoma (5-8) 
MSS CRC (5-8) 
Expansion Coh01t A-5 
Pembrolizmnab  monotherapy 
for 1 cycle, initiate epacadostat 
and azacitidine after biopsy #2, 
5 doses of azacitidine will be 
administered  in Cycles 2 and 3. 
Biopsy #1 at baseline. 
Biopsy #2 on C2Dl  (window 
C1Dl5 to C2Dl , biopsy before 
epacadostat/azacitidine 
administration). 
Biopsy #3 during Week 8 or 9. 
First-line melanoma 
(10) 


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I
 
Subjects in Expansion Cohort A-3 will receive up to 6 cycles of azacitidine.  Subjects in 
Expansion Cohmts A-4 and A-5 will receive up to 5 cycles of azacitidine.  The sponsor will 
manage emollment so that there are approximately 5 to 8 evaluable subjects for a given tumor 
type. Subjects may be replaced if they have not completed all of the biopsy requirements. 
 
4.1.2.2. 
Treatment Group B 
 
4.1.2.2.1.   Treatment Group B Dose Expansion Cohorts  (Pa rt 1) 
 
Because higher doses of epigenetic priming regimens may be deleterious to immune function, 
expansion cohmts at each dose level tested that cleared the DLT window will be opened for 
signal detection 
 
 
 analysis to guide an RP2D.  Once an RP2D is detennined, 
this dose will be 
m 
m 
Simon 2-stage and treatment sequencing tumor biopsy 
cohmts.  During dose expansion, 5 NSCLC subjects who progressed on a PD-1 pathway- 
targeted agent and 5 MSS CRC subjects will be emolled at each dose level with DLT clearance 
as detailed below. 
 
The expansion will include: 
 
1.  Safety/efficacy cohmts in NSCLC (2 tumor biopsies are required) 
 
a.   B-1:  INCB057643 4 mg QD followed by the pembrolizumab/epacadostat doublet 
b.   B-3:  INCB057643 8 mg QD followed by the pembrolizumab/epacadostat doublet 
c.   B-5:  INCB057643 12 mg QD followed by the pembrolizumab/epacadostat doublet 
 
2.   Safety/efficacy cohorts in MSS CRC (2 tumor biopsies are required) 
 
a.   B-2:  INCB057643 4 mg QD followed by the pembrolizumab/epacadostat doublet 
b.   B-4:  INCB057643 8 mg QD followed by the pembrolizumab/epacadostat doublet 
c.   B-6:  INCB057643 12 mg QD followed by the pembrolizumab/epacadostat doublet 
 
The following cohorts will be expanded only under ce1tain circumstances, as listed below: 
 
1.  Cohmts B-1 and B-2:  Objective responses have been seen in subjects dosed with 
INCB057643 at 8 and 12 mg QD and, as such, are known PADs.  However, 4 mg QD 
dosing has not been evaluated in humans.  To ensure 4 mg QD is a PAD, Cohmts B-1 
and B-2 will only be emolled if2,_1/3 of the subjects in the dose-escalation cohmt have a 
25% drop in platelet count from Cycle 1 Day 1 to Cycle 2 Day 1. 
 
Continuous evaluation of toxicity events will be pe1fmmed throughout the expansion cohmts. 
After the dose-expansion cohmts have been emolled, beginning with the sixth patient for a 
specific regimen, if > 40% of subjects have an AE 2: Grade 3 that is attributable to the 
investigational agents, fmther emollment of subjects will be suspended until the sponsor, 
investigators, and regulatmy authorities (if applicable)  have dete1mined the appropriate course of 
action.  If an expansion cohmt is discontinued because of toxicity, a new cohmt may be initiated 
at a previously tested lower dose level. 
 
Following completed emollmen/efficacy expansion cohmts, there will be an 
optional 8-week pause to utilize 
data for RP2D dete1mination. During this time 
· 
no 
·ect emollment may be allowed. If there is no evidence of clinical efficacy 
in the dose-expansion cohorts, emollment in the respective treatment 
ct-A·nn•f1   pnor to Pa.It 2. 


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4.1.2.2.2.   Treatment Group  B Simon 2-Stage Cohorts  (Part  2) 
 
Following safety, efficacy,  
 
evaluation, an RP2D will be determined. A 
Simon 2-stage design will 
a stoppmg rule to allow for early termination of a 
particular cohmt at the end of Stage 1 if there are insufficient responses observed. During 
Stage 1, 8 NSCLC subjects who progressed on a PD-1 pathway-targeted agent and 8 MSS CRC 
subjects will be emolled. If no responses are observed in the NSCLC PD-1 failure and MSS 
CRC cohmts, the cohmt(s) will be discontinued. If at least 1 response is observed in the NSCLC 
PD-1 failure or MSS CRC cohmt, 19 additional NSCLC PD-1 failure or MSS CRC subjects will 
be emolled (Stage 2), for a maximum of 27 subjects per cohmt (see Table 6). 
 
Table 6: 
Treatment Group B Safety/Efficacy Expansion Cohorts  (Part  2) 
 
Cohort 
Treatment 
Tumor Type (n) 
Expansion Coh01t B-7 
MTD, maximum tested dose, or PAD for 
the INCB057643 + pembrolizumab  + 
epacadostat combination. 
A maximum of27 subjects with 
previously treated Stage IV or rectuTent 
NSCLC with progression on a prior PD-1 
pathway-targeted agent. 
Expansion Coh01t B-8 
MTD, maximum tested dose, or PAD for 
the INCB057643 + pembrolizumab  + 
epacadostat combination. 
A maximum of27 subjects with 
previously treated Stage IV MSS CRC. 
 
4.1.2.2.3.   Treatment Group  B Treatment Sequencing Tumor  Biopsy Cohorts  (Part  2) 
 
The sequencing biopsy cohmts require 3 tumor  biopsies (except for Cohmt B-11, which requires 
2 tumor biopsies) to identify epigenetic changes and changes in the tumor microenvironment 
induced by each of the components of the regimen.  All subjects will have tumor biopsies at 
baseline and 2 additional biopsies while on study treatment. 
 
If Stage 1 is passed in Cohmt B-7 or C-8, approximately 25 subjects will be emolled in 
Expansion Cohmts B-9, B-10, and B-11.  The eligible  tumor types for Expansion  Cohmts B-9, 
B-10, and B-11 are HNSCC, melanoma, urothelial carcinoma, and MSS CRC.  In Expansion 
Cohmts B-9, B-10, and B-11, subjects with tumor types other than MSS CRC must have had 
disease progression on a prior  PD-1 pathway-targeted agent. 
 
Five to 8 evaluable subjects per tumor type in Expansion Cohmts B-9, B-10, and B-11 will 
initiate treatment and have tumor  biopsies perfmmed as indicated in Table 7. 


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Table 7: 
Treatment Group B Treatment Sequencing Tumor Biopsy Cohorts (Part 2) 
 
Cohort 
Treatment Sequence 
Biopsy Sequence 
Tumor Type (n) 
Expansion Cohort B-9 
INCB057643 continuous 
monotherapy dming C1, 
initiate pembrolizumab and 
epacadostat  on C2D1 after 
biopsy#2. 
Biopsy #1 at baseline. 
Biopsy #2 on C2D1 (window 
ClD15 to C2D1, biopsy before 
pembrolizumab/ epacadostat 
administration). 
Biopsy #3 dming Week 8 or 9. 
HNSCC (5-8) 
Melanoma (5-8) 
Urothelial carcinoma 
(5-8) 
MSS CRC (5-8) 
Expansion Coh01t B-10 
INCB057643 and epacadostat 
for 1 cycle, initiate 
pembrolizumab after 
biopsy#2. 
Biopsy #1 at baseline. 
Biopsy #2 on C2D1 (window 
ClD15 to C2D1, biopsy before 
pembrolizumab 
administration). 
Biopsy #3 dming Week 8 or 9. 
HNSCC (5-8) 
Melanoma (5-8) 
Urothelial carcinoma 
(5-8) 
MSS CRC (5-8) 
Expansion Coh01t B-11 
INCB057643, epacadostat, 
and pembrolizumab beginning 
Cl. 
Biopsy #1 at baseline. 
Biopsy #2 dming Week 5 or 6. 
HNSCC (5-8) 
Melanoma (5-8) 
Urothelial carcinoma 
(5-8) 
MSS CRC (5-8) 
The sponsor will manage emollment so that there are 5 to 8 evaluable subjects for a given tumor 
type. Subjects may be replaced if they have not completed all of the biopsy requirements. 
 
4.1.2.3. 
Treatment Group C 
 
4.1.2.3.1. Treatment Group C Dose Expansion Cohorts (Part 1) 
 
Because higher doses of epigenetic priming regimens may be deleterious to immune function, 
expansion cohmts at each dose level tested that clear the DLT window will be opened for signal 
detection 
 
 
analysis to guide an RP2D. Once an RP2D is detennined, this 
dose will 
ill 
ill 
 Simon 2-stage and treatment sequencing tumor biopsy cohmts. 
During dose expansion, 5 NSCLC subjects who progressed on a PD-1 pathway-targeted agent 
and 5 MSS CRC subjects will be emolled at each dose level with DLT clearance as detailed 
below. 
 
The expansion will include: 
 
1.  Safety/efficacy cohorts in NSCLC (2 tumor biopsies are required) 
 
a.   C-1: INCB059872 1 mg QoD followed by the pembrolizumab/epacadostat doublet 
b.   C-3: INCB059872 2 mg QoD followed by the pembrolizumab/epacadostat doublet 
c.   C-5: INCB059872 1 mg QD followed by the pembrolizumab/epacadostat doublet 
d.   C-7: INCB059872 3 mg QoD followed by the pembrolizumab/epacadostat doublet 
 
2.   Safety/efficacy cohmts in MSS CRC (2 tumor biopsies are required) 
 
a.   C-2: INCB059872 1 mg QoD followed by the pembrolizumab/epacadostat doublet 
b.   C-4: INCB059872 2 mg QoD followed by the pembrolizumab/epacadostat doublet 
c.   C-6: INCB059872 1 mg QD followed by the pembrolizumab/epacadostat doublet 
d.   C-8: INCB059872 3 mg QoD followed by the pembrolizumab/epacadostat doublet 


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I
 
The following cohorts will be expanded only under ce1tain circumstances,  as listed below: 
 
1.   Cohmts C-1, C-2, C-5, and C-6: Objective responses have been seen in subjects dosed 
with INCB059872 2 and 3 mg QoD and above and, as such, are PADs.  However, 1 mg 
QoD has not been evaluated in humans, and there is no objective data to show that 1 mg 
QD is a PAD.  To ensure that 1 mg QD and 1 mg QoD are PADs, Cohmts C-1, C-2, C-5, 
and C-6 will only be emolled ifl/3 of the subjects in the dose-escalation cohmts have a 
25% drop in platelet count from Cycle 1 Day 1 to Cycle 2 Day 1. 
 
2.   Cohmts C-3 and C-4 will only be expanded ifboth of the following occur: 
 
a.   The INCB059872 1 mg QD cohmt does not clear its DLT window or is deemed not 
tolerated for reasons outside of strict DLT criteria. 
b.   The INCB059872 2 mg QoD cohmt clears its DLT window and is deemed to have 
acceptable tolerability. 
 
Continuous evaluation of toxicity events will be pe1fmmed throughout the expansion cohmts. 
After the dose-expansion cohorts have been emolled, beginning with the sixth patient for a 
specific regimen, if > 40% of subjects have an AE 2: Grade 3 that is attributable to the 
investigational agents, fmther emollment of subjects will be suspended until the sponsor, 
investigators, and regulatmy authorities (if applicable)  have dete1mined the appropriate course of 
action.  If an expansion cohmt is discontinued because of toxicity, a new cohmt may be initiated 
at a previously tested lower dose level. 
 
Following completed emollment of the safety/efficacy expansion cohmts, there will be an 
optional 8-week pause to utilize 
data for RP2D dete1mination. During this time 
· 
no 
·ect emollment md.  If there is no evidence of clinical efficacy 
in the dose-expansion cohmts, emollment in the respective treatment 
pnor to Part 2. 
 
4.1.2.3.2.  Treatment Group C Simon 2-Stage Cohorts (Part 2) 
 
Following safety, efficacy, 
 
 data evaluation, an RP2D will be dete1mined. A 
Simon 2-stage design will 
a stopping mle to allow for early te1mination of a 
pa1ticular cohmt at the end of Stage 1 if there are insufficient  responses observed.  During 
Stage 1, 8 NSCLC subjects who progressed on a PD-1 pathway-targeted agent and 8 MSS CRC 
subjects will be emolled.  If no responses are observed in the NSCLC PD-1 failure and MSS 
CRC cohmts, the cohmt(s) will be discontinued.  If at least 1 response is observed in the NSCLC 
PD-1 failure or MSS CRC cohmt, 19 additional NSCLC PD-1 failure or MSS CRC subjects will 
be emolled (Stage 2), for a maximum of 27 subjects per cohmt (see Table 8). 
 
Table 8: 
Treatment Group  C Safety/Efficacy  Expansion Cohorts (Part 2) 
 
Cohort 
Treatment 
Tumor Type (n) 
Expansion Coh01t C-9 
MTD, maximum tested dose, or PAD for 
the INCB059872 + pembrolizumab + 
epacadostat combination. 
A maximum of 27 subjects with 
previously treated Stage IV or rectuTent 
NSCLC with progression on a prior PD-1 
pathway-targeted agent. 
Expansion Coh01t C-10 
MTD, maximum tested dose, or PAD for 
the INCB059872 + pembrolizumab + 
epacadostat combination. 
A maximum of 27 subjects with 
previously treated Stage IV MSS CRC. 


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4.1.2.3.3.  Treatment Group C Treatment Sequencing Tumor Biopsy Cohorts (Part  2) 
 
The sequencing biopsy cohmts require 3 tumor biopsies  (except for Cohmt C-13, which requires 
2 tumor biopsies) to identify epigenetic changes  and changes in the tumor microenvironment 
induced by each of the components of the regimen. 
 
If Stage 1 is passed in Cohmt C-9 or C-10, approximately 25 subjects will be emolled in 
Expansion Cohmts C-11, C-12, and C-13.  The eligible tumor types for Expansion Cohmts C-11, 
C-12, and C-13 are HNSCC, melanoma, urothelial carcinoma,  and MSS CRC.  In Expansion 
Cohmts C-11, C-12, and C-13, subjects with tumor types other than MSS CRC must have had 
disease progression on a prior PD-1 pathway-targeted agent. 
 
Five to 8 evaluable subjects per tumor type in Expansion Cohmts C-11, C-12, and C-13 will 
initiate treatment and have tumor biopsies perfmmed as indicated in Table 9. 
 
Table 9: 
Treatment Group C Treatment Sequencing Tumor Biopsy Cohorts 
 
Cohort 
Treatment Sequence 
Biopsy Sequence 
Tumor Type (n) 
Expansion Coh01t C-11 
INCB059872 continuous 
monotherapy dming C1, 
initiate pembrolizumab and 
epacadostat on C2D1 (after 
biopsy#2). 
Biopsy #1 at baseline. 
Biopsy #2 on C2D1 (window 
ClD15 to C2D1, biopsy before 
pembrolizumab/epacadostat 
administration). 
Biopsy #3 dming Week 8 or 9. 
HNSCC (5-8) 
Melanoma (5-8) 
Urothelial carcinoma 
(5-8) 
MSS CRC (5-8) 
Expansion Coh01t C-12 
INCB059872 and epacadostat 
for 1 cycle, initiate 
pembrolizumab after 
biopsy#2. 
Biopsy #1 at baseline. 
Biopsy #2 on C2D1 (window 
ClD15 to C2D1, biopsy before 
pembrolizumab 
administration). 
Biopsy #3 dming Week 8 or 9. 
HNSCC (5-8) 
Melanoma (5-8) 
Urothelial carcinoma 
(5-8) 
MSS CRC (5-8) 
Expansion Coh01t C-13 
INCB059872, epacadostat and 
pembrolizumab  beginning C1. 
Biopsy #1 at baseline. 
Biopsy #2 dming Week 5 or 6 
HNSCC (5-8) 
Melanoma (5-8) 
Urothelial carcinoma 
(5-8) 
MSS CRC (5-8) 
 
The sponsor will manage emollment so that there are 5 to 8 evaluable subjects for a given tumor 
type.  Subjects may be replaced if they have not completed  all of the biopsy requirements. 


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Figure 1: 
Study Design:  Treatment Group  A 
 
Part 2 Expansion 
Simon 2-Stage Cohorts 
 
 
 
 
 
 
Part 1Dose Escalation 
 
Azacitidine 
75 mg to 100 mg SC or IV 
for 5 days in Cycles 1and 2 
+ 
Pembrolizumab  
  
) 
200 mg IVQ3W 
+ 
Epacadostat 
100 to 300 mg PO BID 
 
 
 
 
 
 
Dose Selected 
 
Azacitidine 
+ 
Pembrolizumab 
+ 
Epacadostat 
 
MTD or PAD 
Cohort A-1 
Up to 27 subjects with Stage IV or 
recurrent NSCLC with prior PD-1 
pathway-targeted treatment 
 
Cohort A-2 
Up to 27 subjects with Stage IV MSS CRC 
 
 
 
Part 2 Expansion Treatment 
Sequencing Tumor Biopsy 
Cohorts 
 
Cohort A-3 
Azacitidine monotherapy lead-in for 
1week prior to Pembrolizumab and 
Epacadostat 
 
CohortA-4 
Pembrolizumab and Epacadostat 
for 1cycle; 
Azacitidine added at Cycle 2 
 
Cohort A-S Pembrolizumab monotherapy 
for 1cycle; Epacadostat and Azacitidine 
added at Cycle 2 


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---
s---
....... ---
 
... -,.
 
Figu re 2: 
Study Design:  Treatment Group B 
 
Part 1:Dose-Escalation and Expansion Cohorts 
 
 
 
Part 2: Simon 2-Stage and Biopsy Cohorts 
 
 
 
81: INCB057643 4 mg + 
 
 
NSCLC 
Simon 2-Stage Cohorts 
 
87: INC8057643 RP2D + 
 
 
INC8057643 4 mg + 
Epacadostat 100 mg/ 
Pembrolizumab 200 mg 
 
 
 
 
 
 
 
 
INC8057643 8 mg + 
Epacadostat 100 mg/ 
Pembrolizumab 200 mg 
_ ... -
s-
N-
s-
c.:c.   - - _,. 
---5---..... 
IVIss CR... -- ......_ 
 
 
 
 
Nsc.\.c.  
... _,. 
---5--......... 
IVIss CR... -- ....._ 
Epacadostat 100 mg/ 
Pembrolizumab 200 mg 
 
 
82: INC8057643 4 mg + 
Epacadostat 100 mg/ 
Pembrolizumab 200 mg 
 
 
83: INC8057643 8 mg + 
Epacadostat 100 mg/ 
Pembrolizumab 200 mg 
 
 
84:INCB057643 8 mg + 
Epacadostat 100 mg/ 
Pembrolizumab 200 mg 
 
 
85:INCB057643 12 mg + 
---------+ 
 
 
 
MSS CRC 
---------+ 
 
 
 
 
 
 
 
---------+ 
 
 
 
 ---------+ 
 
Epacadostat 100 mg/ 
Pembrolizumab 200 mg 
 
 
88: INC8057643 RP2D + 
Epacadostat 100 mg/ 
Pembrolizumab 200 mg 
 
 
 
Biopsy Cohorts 
 
89: INCB057643 RP2D (C1) + 
Epacadostat 100 mg/ 
Pembrolizumab 200 mg (C2) 
 
 
810: INCB057643 RP2D + 
Epacadostat 100 mg (C1)/ 
Pembrolizumab 200 mg (C2) 
s-
e\-
'.I.\sc.\.C.  
...... 
Epacadostat 100 mg/ 
Pembrolizumab 200 mg 
INC8057643 12 mg + 
---
 ......... 
811:INC8057643 RP2D + 
 
Epacadostat 100 mg/ 
Pembrolizumab 200 mg 
... 
 
5--.......... 
IVIss CR 
 
 
 
- - - ......_ 
 
 
86: INC8057643 12 mg + 
Epacadostat 100 mg/ 
Pembrolizumab 200 mg 
---------+ 
Epacadostat 100 mg/ 
Pembrolizumab 200 mg (C1) 


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u
NSCLC 
MSS CRC
----
 
Figure 3:  
Study Design: Treatment Group  C 
 
Part 1: Dose-Escalation and Expansion Cohorts 
Part 2: Simon 2-Stage and Biopsy Cohorts 
 
 
Simon 2-Stage Cohorts 
 
 
 
INCBOS98721mg QoD 
+ Epacadostat 100 mg/ 
Pembrolizumab 200 mg 
  1   
INCBOS9872 2 mg QoD 
+ Epacadostat 100 mg/ 
Pembrollzumab 200 mg 
 
Cl:INCBOS9872 lmg QoD 
+ Epacadostat 100 mg/ 
Pembrollzumab 200 mg 
 
C2:INCB059872 1mg QoD 
+ Epacadostat 100 mg/ 
Pembrollzumab 200 mg 
  
 
/':_ 3:INCB059872 2 mg QoD 
+ Epacadostat 100 mg/ 
Pembrollzumab 200 mg 
 
C4:INCB059872 2 mg QoD 
+ Epacadostat 100 mg/ 
Pembrolizumab 200 mg 
 
 
 
 
 
 
 
c 
·;:;; 
"::'I 
Ill 0 
 
---------· 
 
 
 
---------· 
 
C9:INCB059872 RP2D + 
Epacadostat 100 mg/ 
Pembrolizumab 200 mg 
 
 
ClO:INCB059872 RP2D + 
Epacadostat 100 mg/ 
Pembrolizumab 200 mg 
 
 
 
Biopsy Cohorts 
 
Cl:l INCBOS9872 RP2D (C1) 
 
lr 
 
INCB059872 1mgQD+ 
Epacadostat lOOmg/ ----- 
< 
 
-s--s;. s-.. 
s sscRc-... 
 
CS:INCBOS9872 1mg QD 
+ Epacadostat 100 mg/ 
Pembrolizumab 200 mg 
 
 
+ Epacadostat 100 mg/ 
- - - - - - - - - + 
+ Epacadostat 100 mg/ 
Pembrolizumab 200 mg {C2) 
 
 
 
- - - - - - - - - + 
Pembrollzumab 200 mg 
 
 
 
 
INC8059872 3 mg QoD 
+ Epacadostat 100 mg/ 
Pembrolizumab 200 mg 
C6:INCB0598721mg QD 
 
Pembrolfzumab 200 mg 
 
C7: INCBOS9872 3 mg QoD 
+ Epacadostat 100 mg/ 
Pembrollzumab 200 mg 
 
CS:INCB059872 3 mg QoD 
+ Epacadostat 100 mg/ 
Pembrollzumab 200 mg 
C12: INCBOS9872 RP2D/ 
Epacadostat 100 mg (C1) + 
Pembrolizumab 200 mg (C2) 
 
 
C13:INCBOS9872 RP2D/ 
- - - - - - - - - + 
Epacadostat 100 mg/ 
Pembrolizumab 200 mg (C1) 


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4-2- 
Measures Taken to Avoid Bias 
 
Assessments of safety and efficacy are objective measurements. 
 
4_3_ 
Number of Subjects 
 
4.3.1. 
 Planned Number of Subjects 
 
Up to approximately 531 subjects will be emolled in the study.  In Treatment Group A, 
approximately 15 to 45 subjects will be emolled in Pa1t 1 (Dose Escalation), and approximately 
76 to 114 subjects will be emolled in Pa1t 2 (up to 16 subjects in Stage 1 and up to 38 additional 
subjects in Stage 2; 60 subjects planned in the sequencing tumor biopsy cohmts).  In Treatment 
Group B, up to approximately 186 subjects will be emolled; approximately 39 to 57 subjects will 
be emolled in Pa1t 1, and up to approximately 129 subjects will be emolled in Pa1t 2. In 
Treatment Group C, up to approximately 186 subjects will be emolled; approximately 39 to 
57 subjects will be emolled in Pa1t 1, and up to approximately 129 subjects will be emolled in 
Part 2. 
 
4.3.2. 
 Replacement of Subjects 
 
Subjects may be replaced for any of the following reasons: 
 
• Subject is not evaluable for DLTs (see Section 5.4.1.1). 
 
• In Pa1t 1, Stage 1 of Pa1t 2, and the treatment sequencing tumor biopsy cohmts, 
subject has not met the biopsy requirements for the study (ie, pre- and on-treatment 
samples). 
 
•  Subject does not meet the eligibility requirements of the study (eg, accidental 
emollment). 
 
4.4. 
Duration of Treatment and Subject Participation 
 
After signing the infmmed consent fmm (ICF),  screening assessments may be completed over a 
period of up to 28 days.  Each subject emolled in the study may continue to receive study 
treatment in continuous 21-day cycles if, in the judgment of the treating physician, the subject is 
deriving benefit from treatment and has not met any crite1ia for study withdrawal, or until the 
subject has received 35 administrations  ofpembrolizumab (approximately 2 years).  Subjects 
who achieve a CR may discontinue therapy after 2 cycles upon consultation with the medical 
monitor.  Subjects who achieve aPR or SD should remain on study treatment.  Re-treatment with 
azacitidine along with pembrolizumab  and epacadostat may be administered for subjects who 
had a CR, PR, or SD (for > 6 months) and later had evidence of progressive disease (PD)  while 
receiving pembrolizumab and epacadostat with medical monitor approval.  Three additional 
cycles of azacitidine are pe1mitted. 
 
Once it is dete1mined that a subject will not continue on study treatment, the subject will enter the 
follow-up period (see Section 6.4).  Study pa1ticipation is expected to average approximately 
18 months  per individual subject (screening/study treatment for 6 months and follow-up for an 
additional12 months).  Upon implementation  of Amendment 4, the follow-up period will end 
with the safety follow-up visit (42-49 days after EOT). 


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4.5. 
Overall Study Duration 
 
The study begins when the first subject signs the ICF.  The end of the study will occur when all 
subjects have discontinued the study and the last follow-up visit has been perfmmed. 
 
If there have been:::; 5 subjects on study for more than 6 months, a database lock of the study 
may occur to allow the analysis of the study data.  Any remaining subjects may continue to 
receive study treatment and be seen by the investigator per protocol.  The investigator will be 
expected to monitor for and repmt any SAEs, AEs of special interest, and pregnancies, as 
detailed in Section 8.  The remaining subjects are considered to be on study until a 
discontinuation  criterion is met and written notification is provided to the sponsor. 
 
4.6. 
Study Termination 
 
The investigator  retains the right to terminate study participation at any time, according to the 
terms specified in the study contract.  The investigator is to notify the institutional  review board 
(IRB)/independent ethics committee (IEC) in writing of the study's completion or early 
termination, send a copy of the notification to the sponsor or sponsor's designee, and retain 
1 copy for the site study regulatory file. 
 
The sponsor may terminate the study electively, if required by regulatory decision, or upon 
review of emerging data.  If the study is terminated prematurely, the sponsor will notify the 
investigators, the IRBs and IECs, and regulatory bodies of the decision and reason for 
termination of the study. 
 
 
5. 
TREATMENT 
 
5.1. 
Treatment Assignment 
 
5.1.1.  
Subject Numbering and Treatment Assignment 
 
Study sites will enter subject demographic and baseline data into the interactive voice/web 
response system (IRT) in order to receive a subject number and treatment allocation. 
 
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 initial number. 
 
Site staff will contact the IRT to obtain the initial study drug assignment.  The investigator  or 
designee will select the assigned bottles of study drug from their stock that conespond to the 
number provided by the IRT and dispense the study drug to the subject.  All subsequent 
dispensing of study drug should follow this process.  Refer to the IRT manual for detailed 
infmmation. 
 
If a subject is mistakenly given a bottle of study drug that is not the bottle assigned by the IRT, 
then the IRT help desk must be notified immediately.  The reason for the misallocation  of the 
study drug must be documented  by the study site. 


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For subjects who signed an ICF but are not allocated and for subjects who are allocated but were 
not treated, refer to the electronic case repmt fmm (eCRF) Completion Guidelines for instruction 
on which eCRFs to complete. 
 
5.1.2.  
Randomization and Blinding 
 
Not applicable. 
 
5.2. 
Study Drugs 
 
5.2.1.  
Epacadostat 
 
5.2.1.1. 
Description and Administration 
 
Epacadostat will be available as 25 or 100 mg tablets to be administered in a BID administr·ation 
schedule. All BID doses  of epacadostat will be taken PO in the moming and evening, 
approximately 12 hours apa1t without regard to food.  If the moming  or evening dose is missed 
by more than 4 hours, then that dose should  be skipped, and the next scheduled dose should be 
taken at the usual time.  Doses of epacadostat will be self-administered except on the days 
scheduled to be given at the study clinic (see Section 6). 
 
Subjects should  be counseled by the investigator to maintain str·ict adherence to the study 
regimen as prescribed and to keep a record  of any missed doses. The subject  will be instmcted 
to bring all unopened, empty, and opened/pa1tially used bottles of study dmg at Day 1 study 
visits, at which time compliance will be assessed. 
 
5.2.1.2.  
Supply, Packaging, and Labeling 
 
Study dmg tablets are packaged in high-density polyethylene bottles; no preparation is required. 
All Incyte study dmgs will be color coded to avoid erTor. 
 
All Incyte investigational product labels will be in the local language and will comply with the 
legal requirements of each country. 
 
5.2.1.3. 
Storage 
 
Bottles should  be stored at room temperature, 15°C to 30°C (59°F to 86°F)  and closed tightly to 
protect the tablets from humidity. 
 
5.2.1.4.  
Instruction to Subjects for Handling Epacadostat 
 
The subject must be instructed in the handling of study dmg as follows: 
 
• To store the study dmg at room temperature. 
 
• To only remove from the study dmg bottle/kit the number of tablets needed at the 
time of administr·ation. 
 
• Not to remove doses in advance of the next scheduled  administration. 
 
• To make every effmt to take doses on schedule. 
 
• To repmt any missed  doses. 


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• If the subject vomits after taking study dmg, the subject should not take another dose. 
 
• If the moming or evening dose of epacadostat is missed by more than 4 hours, then 
that dose should be skipped, and the next scheduled dose should be taken at the usual 
time. 
 
• To keep study dmg in a safe place and out of reach and sight of children. 
 
• To bring all used and unused study dmg kits to the site at each visit. 
 
5.2.2. 
Pembrolizumab 
 
5.2.2.1. 
Description  and Administration 
 
Pembrolizumab is available in single dose vials as a 100 mg/4 mL solution and 50 mg powder 
for injection.  All subjects will receive pembrolizumab 200 mg via a 30-minute IV infusion Q3W 
on Day 1 of each 21-day cycle.  Sites should make every effmt to target infusion timing to be as 
close to 30 minutes as possible.   At the end of the infusion, the line should be flushed with a 
sufficient quantity of normal saline.  On days when epacadostat and azacitidine is administered 
in the clinic, epacadostat and azacitidine should be administered just before beginning the 
infusion of pembrolizumab. 
 
Subjects may be administered pembrolizumab no less than 18 days between doses and no more 
than 3 days after the scheduled  administration date.  Doses given after the 3-day window are 
considered a dose delay.  A maximum delay of 42 days between doses is allowed.  If the delay is 
greater than 14 days, this must be discussed with medical monitor. 
 
5.2.2.2. 
Supply, Packaging, and Labeling 
 
Pembrolizumab vials will be affixed with a clinical label in accordance with regulatory 
requirements. 
 
5.2.2.3. 
Storage 
 
Pembrolizumab should be stored under refrigeration at 2°C to 8°C  (36°F-46°F) and protected 
from light by stming it in the original package until time of use.  Pembrolizumab should not be 
frozen or shaken. 
 
5.2.3. 
Azacitidine 
 
5.2.3.1. 
Description  and Administration 
 
Azacitidine is provided as a lyophilized powder in 100 mg single-use vials to be administered by 
SC injection or IV infusion.  In the European Union, azacitidine will be administered SC only. 
 
Five doses of azacitidine will be administered in the clinic during Cycles 1 through 3.  Details for 
study dmg administration in the treatment sequencing tumor biopsy cohmts (Cohmts A-3 
through A-5) are presented in Table 5 and the study assessments tables (see Section 6).  Subjects 
who remain on treatment beyond the Week 9 scan should continue to receive azacitidine until the 
second on-study scan (up to the Week 18 scan, for a maximum of 3 additional cycles) and then 
continue pembrolizumab and epacadostat as long as there is benefit.  The 5 doses should be 
administered over the Day 1 to 7 period.  Re-treatment  with azacitidine (based on original 


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treatment assignment) along with pembrolizumab  and epacadostat  may be administered for 
subjects who had a CR, PR, or SD (for > 6 months) and later had evidence of PD while receiving 
pembrolizumab  and epacadostat  with medical monitor  approval.  Three additional cycles of 
azacitidine  are pennitted. 
 
5.2.3.2. 
Supply, Packaging, and Labeling 
 
Azacitidine vials will be affixed with a clinical label in accordance with regulatmy requirements. 
 
5.2.3.3. Storage 
 
Umeconstituted vials of azacitidine should be stored at 25°C (77°F); excursions are pe1mitted to 
15°C to 30°C (59°F-86°F). 
 
5.2.4. 
INCB057643 
 
5.2.4.1. 
Description and Administration 
 
Physical and chemical properties of iNCB057643 are summarized  in the INCB057643 IB. 
INCB057643 is fmmulated as 4 mg immediate-release tablets.  The tablet is round and white to 
off-white and contains the active dmg substance along with compendia!grade excipients lactose 
monohydrate, sodium starch glycolate,  and magnesium stearate. 
 
Subjects  will self-administer INCB057643 orally QD, as instmcted  by the investigator. It will be 
administered in the clinic on the schedule outlined  in Section 6.  The starting dose in Part 1 is 
4 mg.  INCB057643 doses  should be taken in the moming on an empty stomach when possible. 
Subjects should fast for approximately 2 hours before and 1 hour after INCB057643 
administration, except on days when serial  
sampling is conducted, 
then subjects will fast at least 8 hours before  
 or as indicated in 
Section 7.8.  If a dose is missed by more than 8 hours, then the subject should skip that dose and 
take the next scheduled dose at the usual time.  The sponsor may implement altemate 
· 
such as inte1mediate doses,  altemate  dosing schedules, or altemate  fmmulations, 
safety results. 
 
5.2.4.2. 
Supply, Packaging, a nd Labeling 
 
INCB057643 will be provided as 4 mg tablets packaged in high-density polyethylene bottles. 
No preparation is required. The investigational product labels will be in the local language and 
will comply with the legal requirements of each count1y. 
 
5.2.4.3. 
Storage 
 
INCB057643 dmg product should be stored at ambient conditions (15°C-30°C or 59°F-86°F). 


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5.2.4.4. 
Instruction to Subjects for Handling INCB057643 
 
The subject must be instructed  in the handling ofiNCB057643 as follows: 
 
• To store INCB057643 at room temperature. 
 
• To only remove from the study dmg bottle the number of tablets needed at the time of 
administr·ation. 
 
• Not to remove doses in advance of the next scheduled  administration. 
 
• To make every effort to take doses on schedule. 
 
• To fast for approximately 2 hours before and 1 hour after INCB057643 
administr·ation. 
 
• If a dose is missed by more than 8 hours, then the subject should skip that dose and 
take next scheduled dose at the usual time. 
 
• To report any missed doses. 
 
• If the subject vomits after taking study dmg, the subject should not take another dose; 
dosing should be resumed at the next scheduled dose. 
 
• To keep study dmg in a safe place and out of reach of children. 
 
• To bring all used and unused study dmg bottles to the site at each visit. 
 
5.2.5. 
INCB059872 
 
5.2.5.1. 
Description  and Administration 
 
Physical and chemical properties of INCB059872 are summarized  in the INCB059872 lB. 
INCB059872 is formulated as 1 mg tablets. 
 
INCB059872 is only for use in the United States.  Subjects will self-administer INCB059872 
orally QD or QoD as instructed by the investigator.  It will be administered in the clinic on the 
schedule outlined in Section 6.  The statting dose in Patt 1 is 1 mg QoD.  INCB059872 doses 
should be taken in the moming on an empty stomach when possible.  Subjects should fast for 
a01::•rmm·mat:eJ  2 hours before and 1 hour after INCB059872 administration, except on days when 
 sampling is conducted, then subjects will fast at least 8 hours 
before 
 
or as indicated in Section 7.8.  If a dose is missed by more 
than 8 hours, then the subject  should skip that dose and take next scheduled dose at the usual 
time.  The sponsor may implement altemate  
· 
such as intetmediate 
altemate 
dosing schedules,  or altemate formulations, depending on 
results. 
safety 
 
5.2.5.2. 
Supply, Packaging, and Labeling 
 
INCB059872 will be provided as 1 mg tablets packaged in high-density polyethylene bottles. 
No preparation is required.  The investigational product labels will state "Caution: New Dmg- 
Limited by Federal (or United States) law to investigational  use." 


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5.2.5.3.  
Storage 
 
Bottles of tablets should be stored in a refrigerator and maintained at a temperature between 2°C 
and 8°C (36°F-46°F). 
 
5.2.5.4.  
Instruction to Subjects for Handling INCB059872 
 
The subject must be instructed in the handling ofiNCB059872 as follows: 
 
• To store INCB059872 in a refrigerator. 
 
• To only remove from the study dmg bottle the number of tablets needed at the time of 
administr·ation. 
 
• Not to remove doses in advance of the next scheduled  administration. 
 
• To make every effort to take doses on schedule. 
 
• To fast for approximately 2 hours before and 1 hour after INCB059872 
administr·ation. 
 
• If a dose is missed by more than 8 hours, then the subject should skip that dose and 
take next scheduled dose at the usual time. 
 
• To report any missed doses. 
 
• If the subject vomits after taking study dmg, the subject should not take another dose; 
dosing should be resumed at the next scheduled dose. 
 
• To keep study dmg in a safe place and out of reach of children. 
 
• To bring all used and unused  study dmg bottles to the site at each visit. 
 
5.3.  
Treatment  Compliance 
 
Compliance  with all study-related tr·eatlnents should  be emphasized to the subject by the site 
personnel, and appropriate steps should be taken to optimize compliance during the study. 
Compliance  with epacadostat, INCB057643, and INCB059872 will be calculated by the sponsor 
based on the dmg accountability documented  by the site staff and monitored by the 
sponsor/designee (tablet counts).  Subjects will be instructed to bring all study dmgs  with them 
to the study visits in order for site personnel to conduct  tablet counts to assess study dmg 
accountability. The dmg accountability documentation will be used by the sponsor to calculate 
tr·eatlnent compliance. 
 
Pembrolizumab and azacitidine  are administered as either IV or SC inf usions by the site 
personnel.  Receipt of infusions will be documented  by the site staff and monitored by the 
sponsor or the sponsor's designee. 


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5-4_ 
Treatment Interruptions and Adjustments 
 
5.4.1.  
Dose Modifications 
 
Selections and modifications  to the study dmg regimen are plaillled for dose-escalation cohmts. 
Dose intenuptions and modifications also may occur for individual study subjects.  The 
identification ofDLTs will define the doses used in Phase 2.  Fmther, the occunence ofDLTs 
and other toxicities (related or unrelated to study dmg) will guide decisions for treatment 
inten11ptions and discontinuation for individual subjects. 
 
Intrasubject dose escalation will not be pe1mitted. 
 
5.4.1.1. 
Dose-Limiting Toxicity and Determination of Maximum Tolerated Dose 
 
A DLT will be defined as the occmTence of any of the toxicities  in Table 10 occmTing up to and 
including Day 21 for Treatment Group A or Day 42 for Treatment Groups Band C.  Only 
toxicities with a clear altemative explanation (eg, due to disease progression), transient 
(72 hours) abnmmallaboratmy values without associated clinically significant signs or 
symptoms based on investigator dete1mination, ii·AEs of Grade 3 or higher that improve to Grade 
1 or lower in < 5 days by appropriate care or with cmticosteroid  therapy can be deemed a non-
DLT.  All DLTs will be assessed by the investigator using the cmTent CTCAE v4.03 crite1ia.  
Subjects who receive 2: 75% doses of study dmg (Treatment Group A:  azacitidine 
[4 doses], epacadostat [32 doses], and pembrolizumab [1 dose]; Treatment Group B: 
INCB057643 [32 doses], epacadostat [32 doses], and pembrolizumab  [1 dose]; Treatment 
Group C:  INCB059872 [QD dosing, 32 doses; QoD dosing, 16 doses], epacadostat [32 doses], 
and pembrolizumab [1 dose]) at the level assigned or have a DLT will be considered evaluable 
for dete1mining tolerability of the dose. 
 
Individual subject dose reductions may be made based on events observed at any time dming 
treatment with study dmg; however,  for the purposes of dose cohmt escalation/de-escalation, 
expanding a dose cohmt,  and dete1mining the MTD of the study drugs, decisions will be made 
based on events that are observed from the first day of study dmg administration through and 
including the final day of Cycle 1 (Day 21) for Treatment Group A or Cycle 2 (Day 42) for 
Treatment Groups B and C.  A lower MTD may subsequently be dete1mined based on relevant 
toxicities that become evident after Day 21 (Treatment  Group A) or Day 42 (Treatment 
Groups Band C). 


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CO IDEmiAL 
 
 
 
Table 10: 
Definition of Dose-Limiting Toxicity 
 
Toxicity 
o!Unennatologic 
• Grade 4 (life-threatening) vomiting or diarrhea 
• Grade 4 electrolyte abnormality 
• Grade 4 systemic reaction 
• Any 2:: Grade 3 no!Unematologic toxicity EXCEPT the following: 
- Transient(72 hours) abno1mal laboratory values without associated clinically significant  signs or symptoms. 
- ausea, vomiting, and diarrhea adequately controlled with medical therapy within 48 hours. 
- Grade 3 rash in the absence of desquamation, with no mucosal involvement, that does not require systemic 
steroids, and that resolves to Grade 1 within 14 days. 
- An event clearly associated with the underlying disease, disease progression, a concomitant medication, or 
comorbidity. 
- Asymptonnatic changes in lipid profiles. 
- Singular or nonfasting elevations in blood glucose (ie, blood glucose excursions will be considered toxicities  if 
fasting blood glucose is elevated on 2 separate occasions). 
- lmmtme-related adverse events of Grade 3 or higher that improve toGrade 1 in < 5 days by appropriate  care 
or with corticosteroid therapy. 
Hennatologic 
• 2:: Grade 3 thrombocytopenia with clinically significant  bleeding (requires hospitalization, transfusion of blood 
products, or other urgent medical intervention). 
• Grade 4 thrombocytopenia of any duration 
• Grade 4 neutropenia lasting > 3 days 
• 2:: Grade 3 febrile neutropenia (absolute neutrophil cotmt < 1.0 x 109/L and fever > 101°F/38.5°C). 
• Grade 4 neutropenia that does not recover toGrade 2 in3 days after intem1pting study dmg. 
• Grade 4 anemia not explained by underlying disease or some other concomitant disorder. 
General 
• Subjects being unable to receive 2:: 75% of study dmg doses during the DLT observation period because of 
toxicity, even if the toxicity does not meet DLT criteria defined above. 
ote:Exceptions include the DLT exclusions mentioned  above. 
MTD 
• 1 dose level below that at which 2:: one-third of subjects in a pa1ticular cohort has DLTs.  Dose-limiting toxicity 
will be defined as the occull'ence of any of the toxicities in this table occUlTing up to and including study Day 21. 


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5.4.1.1.1.  Management of Dose-Limiting Toxicities or Other  Urgent Situations 
CONFIDENTIAL 
 
 
 
In all cases, investigators  may employ any measures or concomitant medications, after 
discussion with the sponsor (whenever possible), necessa1y to optimally treat the subject. 
 
5.4.1.1.2.   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.  During follow-up, subjects should be seen as often as medically indicated 
to assure safety. 
 
5.4.1.1.3.  Procedures for Cohort Review and Dose Escalation 
 
Telephone conferences will be scheduled by the sponsor with study investigators in order to 
review cohort-specific  data and overall safety data, agree on dose escalation, adjudicate 
individual high-grade AEs as potentially dose-limiting, and guide other major study decisions. 
 
5.4.1.2. 
Criteria and Procedures for Dose Interruptions and Adjustments of Study Drug 
 
Treatment with study dmg may be delayed up to 2 weeks (14 days) to allow for resolution of 
toxicity.  If only 1 of the 2 agents is suspected  to be responsible for the toxicity, only the 
suspected agent should be held (while the other treatment continues).  In some circumstances, it 
may be necessa1y to temporarily inten11pt the combination as a result of AEs that may not have a 
cause attributable to a single dmg or that may be the result of combined toxicity. 
 
Subjects may resume treatment if no medical condition or other circumstance  exists that, in the 
opinion of the investigator, would make fmther pmticipation in the study unsuitable. The 
treating investigator should contact the sponsor to discuss the case of any subject whose 
treatment has been delayed for more than 14 days before resta1ting treatment with the study 
dmgs. 
 
Because subjects may enter the study with extensive pretreatment and/or severe bone manow 
infiltration  by the prima1y disease, these dose reduction mles are provided as guidelines (see 
Table 15 through Table 17).  Individual decisions regarding dose reduction should be made using 
clinical judgment and in consultation with the sponsor's  medical monitor, taking into account 
relatedness of the AE to the study dmg and the subject's  underlying condition.  Adverse events 
that have a clear altemative explanation or transient (:S 72 hours) abnmmallaboratmy values 
without associated clinically significant  signs or symptmns may be exempt from dose-reduction 
mles. 
 
5.4.1.2.1.  Pembrolizumab Dose Modifications 
 
There will be no dose reductions of pembrolizumab allowed for the management of toxicities of 
individual subjects.  Doses of pembrolizumab may be delayed for toxicity management. 
 
5.4.1.2.2.   Epacadostat Dose Modifications 
 
Table 11 describes epacadostat dose reductions that may occur due to any related AEs.  Dose 
reductions should occur in a step-wise fashion from the initial sta1ting dose of the cohmt, and a 
maximum of 2 dose reductions of epacadostat are allowed for the management of an AE, 
regardless of the initial sta1ting dose.  If an AE recurs/does not retum to baseline after the second 


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dose reduction of epacadostat, then the subject must pe1manently discontinue epacadostat.  The 
lowest pe1missible dose of epacadostat is 25 mg BID.  If a subject  does not tolerate 25 mg BID, 
then the subject must pe1manently discontinue epacadostat. 
 
Table 11:        Epacadostat Dose Reductions 
 
Dose Level 
300mgBID 
lOOmgBID 
50mgBID 
25 mgBID 
 
5.4.1.2.3.   Azacitidine Dose Modifications 
 
Table 12 describes  azacitidine dose reductions that may occur due to any related AEs.  Dose 
reductions should occur in a step-wise fashion from the initial starting dose of the cohmt, and a 
maximum of 2 dose reductions of azacitidine are allowed for the management of an AE, 
regardless of the initial starting dose.  If an AE recurs/does not retum to baseline after the second 
dose reduction of azacitidine, then the subject must pe1manently discontinue azacitidine.  The 
lowest pe1missible dose of azacitidine is 50 mg.  If a subject does not tolerate 50 mg, then the 
subject must pe1manently discontinue azacitidine. 
 
Table 12:  
Azacitidine Dose Reductions 
 
Dose Level 
lOOmg 
75mg 
50mg 
 
5.4.1.2.4.  INCB057643 Dose Modifications 
 
Table 13 describes INCB057643 dose reductions that may occur due to any related AEs.  Dose 
reductions should occur in a step-wise fashion from the initial starting dose of the cohmt, and a 
maximum of 2 dose reductions of INCB057643 are allowed for the management of an AE, 
regardless of the initial starting dose.  If an AE recurs/does not retum to baseline after the second 
dose reduction ofiNCB057643, then the subject must pe1manently discontinue INCB057643. 
The lowest pe1missible dose of INCB057643 is 4 mg. If a subject does not tolerate 4 mg, 
altemative dose schedules may be evaluated. 
 
Table 13:  
INCB057643 Dose Reductions 
 
Dose Level 
12mgQD 
8mgQD 
4mgQD 


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5.4.1.2.5.   INCB059872 Dose Modifications 
 
Table 14 describes INCB059872 dose reductions that may occur due to any related AEs.  Dose 
reductions should occur in a step-wise fashion from the initial starting dose of the cohmt, and a 
maximum of 2 dose reductions of INCB059872 are allowed for the management of an AE, 
regardless of the initial sta1ting dose.  If an AE recurs/does not retum to baseline after the second 
dose reduction ofiNCB059872, then the subject must pe1manently discontinue INCB057643. 
The lowest pe1missible dose ofiNCB059872 is 1 mg QoD.  If a subject does not tolerate 1 mg 
QoD, altemative dose schedules may be evaluated. 
 
Table 14: 
INCB059872 Dose Reductions 
 
Dose Level 
 
3 mgQoD 
a 
2 mg QoD/1 mg QD 
 
1 mgQoD 
.. 


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Table 15: 
Dose Modification  Guidelines for Drug-Related Adverse Events (Treatment Group  A) 
CONFIDENTIAL 
 
 
 
Toxicity 
Grade 
Hold 
Treatment 
(YIN) 
Timing for 
Treatment 
Restat1 
Dose/Schedule for Treatment Restat1 
Discontinue Subject 
(After Medical Monitor 
Consultation) 
Azacitidine 
Epacadostat 
Pembrolizumab 
Hematologic toxicity 
1, 2 
No 
N/A 
NIA 
N/A 
N/A 
N/A 
3 
Hold 
azacitidine 
Toxicity 
resolves to 
Grade 1 or 
baseline. 
Restart at same 
dose if the 
toxicity resolves 
within 7 days. 
N/A 
N/A 
N/A 
4 
Yes 
Toxicity 
resolves to 
Grade 1 or 
baseline. 
Restart at 1 dose 
level lower if the 
toxicity resolves 
within 7 days. 
Reduce dose 
by 1 dose 
level. 
Restrut at srune dose for the 
following events:  Grade 4 
neutropenia lasting7  days, 
Grade 4 lymphopenia or 
leukopenia.  For all other  Grade 4 
hematologic toxicities, treatment 
with pembroliztunab tnay not be 
restarted. 
Toxicity does not resolve 
within 6 weeks of last 
infusion.  Pennanent 
discontinuation should be 
considered for any severe 
or life-tlu·eatening event. 
Nonhetnatologic toxicity 
Note:  Exception  to be 
treated to similar  Grade 1 
toxicity: 
- Grade 2 alopecia 
- Grade 2 fatigue 
- Grade 3 rash in the absence 
of desqurunation, without 
mucosal involvement, not 
requiring systemic steroids, 
and that resolves to Grade 1 
within 14 days. 
For additional infonnation 
regarding AE with potential 
imnume etiology, see 
Section  5.4.1.3. 
1 
No 
N/A 
NIA 
N/A 
N/A 
N/A 
2 
Consider 
holding for 
persistent 
symptoms 
Toxicity 
resolves to 
Grade 1 or 
baseline. 
Restart at same 
dose. 
Restart at 
same dose. 
Restrut at srune dose. 
Toxicity does not resolve 
within 6 weeks of last 
infusion. 
3. 
Yes• 
Toxicity 
resolves to 
Grade 1 or 
baseline. 
Restart at same 
dose. 
Restart at 
1 dose level 
lower. 
Restrut at srune dose.• 
Toxicity does not resolve 
within 6 weeks of last 
infusion.  Pennanent 
discontinuation should be 
considered for any severe 
or life-tlu·eatening event. 
4 
Yes 
Toxicity 
resolves to 
Grade 1 or 
baseline. 
Restart at 1 dose 
level lower. 
Restart at 
1 dose level 
lower. 
Restrut only pennitted only as 
noted.b For all other Grade 4 
nonhematologic toxicities, 
treatment with pembroliztuna.b 
may not be restruted. 
Toxicity does not resolve 
within 6 weeks of last 
infusion.  Pennanent 
discontinuation should be 
considered for any severe 
or life-tlu·eatening event. 
Note:  SubJects who expenence a rectuTence of the srune severe or hfe-threatenmg AE at the srune grade or greater treatment should be dtscontmued from study treatment. 
• The following exceptions for asympt01natic amylase or lipase do not require a dose delay:  Grade 3 amylase or lipase abnonnalities that are not associated with symptotns or 
clinical manifestations of pancreatitis.  It is recommended  to consult with the medical monitor for Grade 3 runylase or lipase abnonna.lities. 
b Isolated  Grade 4 lipase or runylase abnonnalities not associated witl1 symptoms or clinical manifestations of pancreatitis.  Medical monitor should be consulted for any Grade 4 
amylase or lipase abnonna.lity. 


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Table 16: 
Dose Modification  Guidelines for Drug-Related Adverse Events (Treatment Group  B) 
 
 
Toxicity 
Grade 
Hold 
Treatment 
(YIN) 
Timing for 
Treatment 
Restat1 
Dose/Schedule for Treatment Restat1 
Discontinue Subject 
(After Medical Monitor 
Consultation) 
INCB057643 
Epacadostat 
Pembrolizumab 
Hematologic toxicity 
1, 2 
No 
NIA 
NIA 
N/A 
NIA 
NIA 
3 
Hold 
INCB057643 
Toxicity 
resolves to 
Grade 1 or 
baseline. 
Restart at 1 dose 
level lower if the 
toxicity resolves 
within 7 days. 
N/A 
NIA 
NIA 
4 
Yes 
Toxicity 
resolves to 
Grade 1 or 
baseline. 
Restart at 1 dose 
level lower if the 
toxicity resolves 
within 7 days.  If 
already at lowest 
dose, discontinue. 
If evidence of 
bleeding, patient 
should 
pennanently 
discontinue. 
Reduce dose 
by 1 dose 
level.  If 
already at 
lowest dose, 
discontinue 
Restart at same dose. 
Toxicity does not resolve 
within 6 weeks oflast 
infhsion.  Permanent 
discontinuation should be 
considered for any severe 
or life-threatening event. 


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Table 16:  
Dose Modification  Guidelines for Drug-Related Adverse Events (Treatment Group  B) (Continued) 
 
Toxicity 
Grade 
Hold 
Treatment 
(YIN) 
Timing for 
Treatment 
Restat1 
Dose/Schedule for Treatment Restat1 
Discontinue Subject 
(After Medical Monitor 
Consultation) 
INCB057643 
Epacadostat 
Pembrolizumab 
Nonhematologic toxicity 
Note:  Exception to be 
treated to similar Grade 1 
toxicity: 
- Grade 2 alopecia 
- Grade 2 fatigue 
- Grade 3 rash in the absence 
of desquruuation, without 
mucosal involvement, not 
requiring systemic steroids, 
and that resolves to Grade 1 
within 14 days. 
For additional information 
regarding AE with potential 
inumme etiology, see 
Section 5.4.1.3. 
1 
No 
NIA 
NIA 
NIA 
NIA 
NIA 
2 
Consider 
holding for 
persistent 
symptoms 
Toxicity 
resolves to 
Grade 1 or 
baseline. 
Restart at same 
dose. 
Restart at 
same dose. 
Restart at same dose. 
Toxicity does not resolve 
within 6 weeks oflast 
infhsion. 
3. 
Yes• 
Toxicity 
resolves to 
Grade 1 or 
baseline. 
Restart at same 
dose. 
Restrut at 
1 dose level 
lower. 
Restart at same dose.• 
Toxicity does not resolve 
within 6 weeks oflast 
infhsion.   Permanent 
discontinuation should be 
considered for any severe 
or life-tlu·eatening event. 
4 
Yes 
Toxicity 
resolves to 
Grade 1 or 
baseline. 
Restart at 1 dose 
level lower.  If 
already at lowest 
dose, discontinue. 
Restart at 
1 dose level 
lower.  If 
already at 
lowest dose, 
discontinue. 
Restart only permitted  only as 
noted.b For all other Grade 4 
nonhetuatologic toxicities, 
treatment with pembroliztuuab 
may not be restarted. 
Toxicity does not resolve 
within 6 weeks of last 
infhsion.   Permanent 
discontinuation should be 
considered for any severe 
or life-tlu·eatening event. 
Note:  SubJects who expenence a rectuTence of the srune severe or hfe-threatenmg AE at the srune grade or greater treatment should be dtscontmued from study treatment. 
• The following exceptions for asympt01uatic amylase or lipase do not require a dose delay:  Grade 3 amylase or lipase abnormalities that are not associated with symptoms or 
clinical manifestations of pancreatitis. It is reconllllended  to consult with the medical monitor for Grade 3 runylase or lipase abnonnalities. 
b Isolated Grade 4 lipase or runylase abnonualities not associated with symptoms or clinical manifestations of pancreatitis. Medical monitor  should be consulted for any Grade 4 
amylase or lipase abnonnality. 


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Table 17: 
Dose Modification  Guidelines for Drug-Related Adverse Events (Treatment Group  C) 
 
Toxicity 
Grade 
Hold 
Treatment 
(YIN) 
Timing for 
Treatment 
Restat1 
Dose/Schedule for Treatment Restat1 
Discontinue Subject 
(After Medical Monitor 
Consultation) 
INCB059872 
Epacadostat 
Pembrolizumab 
Hematologic toxicity 
1, 2 
No 
NIA 
NIA 
NIA 
NIA 
NIA 
3 
Hold 
INCB059872 
Toxicity 
resolves to 
Grade 1 or 
baseline. 
Restart at 1 dose 
level lower if the 
toxicity resolves 
within 7 days. 
NIA 
NIA 
NIA 
4 
Yes 
Toxicity 
resolves to 
Grade 1 or 
baseline. 
Restart at 1 dose 
level lower if the 
toxicity resolves 
within 7 days.  If 
already at lowest 
dose, discontinue. 
If evidence of 
bleeding, patient 
should 
pennanently 
discontinue. 
Reduce dose 
by 1 dose 
level.  If 
already at 
lowest dose, 
discontinue 
Restart at same dose. 
Toxicity does not resolve 
within 6 weeks oflast 
infhsion.  Permanent 
discontinuation should be 
considered for any severe 
or life-tlu·eatening event. 


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Table 17: 
Dose Modification  Guidelines for Drug-Related Adverse Events (Treatment Group  C) (Continued) 
 
Toxicity 
Grade 
Hold 
Treatment 
(YIN) 
Timing for 
Treatment 
Restat1 
Dose/Schedule for Treatment Restat1 
Discontinue Subject 
(After Medical Monitor 
Consultation) 
INCB059872 
Epacadostat 
Pembrolizumab 
Nonhematologic toxicity 
Note:  Exception to be 
treated to similar Grade 1 
toxicity: 
- Grade 2 alopecia 
- Grade 2 fatigue 
- Grade 3 rash in the absence 
of desquruuation, without 
mucosal involvement, not 
requiring systemic steroids, 
and that resolves to Grade 1 
within 14 days. 
For additional information 
regarding AE with potential 
inumme etiology, see 
Section 5.4.1.3. 
1 
No 
NIA 
NIA 
NIA 
NIA 
NIA 
2 
Consider 
holding for 
persistent 
symptoms 
Toxicity 
resolves to 
Grade 1 or 
baseline. 
Restart at same 
dose. 
Restart at 
same dose. 
Restart at same dose. 
Toxicity does not resolve 
within 6 weeks oflast 
infhsion. 
3. 
Yes• 
Toxicity 
resolves to 
Grade 1 or 
baseline. 
Restart at same 
dose. 
Restrut at 
1 dose level 
lower. 
Restart at same dose.• 
Toxicity does not resolve 
within 6 weeks oflast 
infhsion.  Permanent 
discontinuation should be 
considered for any severe 
or life-tlu·eatening event. 
4 
Yes 
Toxicity 
resolves to 
Grade 1 or 
baseline. 
Restart at 1 dose 
level lower. If 
already at lowest 
dose, discontinue. 
Restart at 
1 dose level 
lower. If 
already at 
lowest dose, 
discontinue. 
Restart only permitted only as 
noted.b For all other Grade 4 
nonhetuatologic toxicities, 
treatment with pembroliztuuab 
may not be restarted. 
Toxicity does not resolve 
within 6 weeks of last 
infhsion.  Permanent 
discontinuation should be 
considered for any severe 
or life-tlu·eatening event. 
Note:  SubJects who expenence a rectuTence of the srune severe or hfe-threatenmg AE at the srune grade or greater treatment should be dtscontmued from study treatment. 
• The following exceptions for asymptomatic amylase or lipase do not require a dose delay:  Grade 3 runylase or lipase abnormalities that are not associated with symptoms or 
clinical manifestations of pancreatitis.  It is recommended to consult with the medical monitor for Grade 3 runylase or lipase abnonnalities. 
b  Isolated Grade 4 lipase or runylase abnonualities not associated with symptoms or clinical manifestations of pancreatitis.  Medical monitor should be consulted for any Grade 4 
amylase or lipase abnonnality. 


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5.4.1.3. Procedu res for Subjects  Exhibiting Immune-Related Adverse Events 
 
This section is meant to apply to suspected  irAEs from epacadostat, pembrolizumab, or the 
combination. 
 
Immune-related AEs may be defmed as an AE of unknown etiology, associated with dmg 
exposure  and consistent with an immune phenomenon.  Immune-related  AEs may be predicted 
based on the nature of the pembrolizumab or epacadostat compounds, their mechanism of action, 
and repmted experience with immunotherapies that have a similar mechanism of action.  Special 
attention should be paid to AEs that may be suggestive of potential irAEs.  An irAE can occur 
shmtly after the first dose or several  months after the last dose of treatment. 
 
If an irAE is suspected, effmts should be made to mle out neoplastic, infectious, metabolic, toxin 
or other etiologic causes  before labeling an AE as an irAE.  Subjects who develop aGrade 2 
irAE should be discussed immediately with the sponsor. 
 
General recommendations to managing irAEs not detailed elsewhere in the Protocol are detailed 
in Table 18.  Recommendations for management of specific immune-mediated  AEs such as 
pneumonitis (Section 5.4.1.3.1),  enterocolitis (Section 5.4.1.3.2), hepatitis (Section 5.4.1.3.3), 
de1matitis (Section 5.4.1.3.4), neuropathies (Section 5.4.1.3.5), endocrinopathies 
(Section 5.4.1.3.6), myocarditis (Section 5.4.1.3.7), and other immune-mediated  AEs 
(Section 5.4.1.3.8) are detailed in the sections below. 
 
Table 18: 
General Approach to Handling Immune-Related Adverse Events 
 
irAE 
Withhold/Discontinue 
Pembrolizumab a nd 
Epacadostat 
Guida nce for Restarting Study 
Treatment 
Supportive Care 
Grade  1 
No action. 
Not applicable. 
Provide symptomatic 
treatment. 
Grade  2 
May withhold 
pembrolizumab and 
epacadostat per 
investigator's 
discretion. 
May retum to treatment if improves to 
Grade 1 or resolves within 6 weeks. If 
AE resolves within 4 weeks, subject may 
restrut at the same dose and schedule for 
both pembrolizumab and epacadostat. 
For an AE that does not resolve within 
4 weeks, epacadostat should be reduced 
1 dose level, but pembrolizumab  may be 
restruted at the same dose and schedule. 
If AE does not resolve within 6 weeks, 
sntdy treatment with both study dmgs 
should be discontinued or discussed with 
medical monitor. 
Consider systemic 
c01ticosteroids in 
addition to appropriate 
symptomatic treatment. 


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Table 18: 
General Approach to Handling Immune-Related Adverse Events 
(Continued) 
 
irAE 
Withhold/Discontinue 
Pembrolizu mab and 
Epacadostat 
Guidance for Restarting 
Study Treatment 
Supportive Care 
Grade 3 
Withhold or 
discontinue 
pembrolizumab and 
epacadostat. 
Discontinue if lmable 
to reduce 
corticosteroid dose to 
< 10 mglday of 
prednisone or 
equivalent within 
6 weeks of toxicity. 
Any restrut of study treatment must be 
discussed with medical monitor before 
restruting treatment. 
Systemic 
corticosteroids ru·e 
indicated in addition to 
appropriate 
symptomatic treatment. 
May use 1 to 2 mglkg 
of prednisone or 
equivalent per day. 
Steroid taper should be 
considered once 
symptoms improve to 
Grade 1 and tapered 
over at least 4 weeks in 
most cases. 
Grade4 
Discontinue 
pembrolizumab and 
epacadostat. 
Not applicable.  Any exceptions require 
medical monitor approval. 
Systemic 
corticosteroids ru·e 
indicated in addition to 
appropriate 
symptomatic treatment. 
May use 1 to 2 mglkg 
of prednisone or 
equivalent per day. 
 
5.4.1.3.1.   Procedu res and Guidelines  for Pneumonitis 
 
Subjects with symptomatic pneumonitis should immediately stop receiving pembrolizumab and 
epacadostat and have an evaluation. The evaluation may include  bronchoscopy to mle out other 
causes such as infection. If the subject is dete1mined to have study dmg-associated pneumonitis, 
the suggested treatment plan  is detailed in Table 19. 


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Table 19:  
Recommended Approach for Handling Noninfectious Pneumonitis 
 
Study Drug(s) 
Associated 
Pnemnonitis 
Withhold/Discontinue 
Pembrolizumab and 
Epacadosta t 
Guidance for Resta rting Study 
Treatment 
Supportive Ca re 
Grade 1 
(asymptomatic) 
No action. 
Not applicable. 
Intervention not 
indicated. 
Grade 2 
Withhold 
pembrolizumab and 
epacadostat. 
First episode of pneumonitis: If 
improves to near baseline: Decrease 
the dose of epacadostat by 
1 dose level, and for pembrolizumab, 
restrut at same dose and schedule 
subsequent cycles. 
If not improved after 2 weeks or 
worsening, pe1manently discontinue 
pembrolizumab.  Discuss with medical 
monitor if restrut with epacadostat is 
pennitted. 
Second episode of pneumonitis: 
Pe1manently discontinue 
pembrolizumab and epacadostat if upon 
rechallenge subject develops 
pneumonitisGrade 2. 
Systemic 
corticosteroids are 
indicated.  Taper 
if necessruy. 
Grades 3 and 4 
Discontinue 
pembrolizumab and 
epacadostat. 
Not applicable. Any exceptions require 
medical monitor approval. 
Syste1nic 
cmticosteroids ru·e 
indicated.  The 
use of infliximab 
may be indicated 
as appropriate. 
 
5.4.1.3.2.   Procedures and Guidance for Enterocolitis 
 
Subjects should be carefully monitored for signs and symptoms  of enterocolitis (such as dianhea, 
abdominal  pain, mucus or blood in stool,  with or without fever) and of bowel perforation (such 
as peritoneal  signs and ileus).  In symptomatic subjects, infectious etiologies should be mled out, 
and endoscopic evaluation should be considered for persistent or severe symptoms. 
Recommendations for management of enterocolitis are shown in Table 20. 


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Table 20: 
Recommended Approach for Handling Enterocolitis 
 
 
 
Study 
Drug(s) 
Associated 
Enterocolitis 
Withhold/Discontinue 
Pembrolizumab a nd 
Epacadostat 
Guidance for Restarting Study 
Treatment 
Supportive Care 
Grade 1 
No action. 
Not applicable. 
All subjects who experience 
dianhea should be advised  
to drink liberal quantities of 
clear fluids.  If sufficient 
oral fluid intake 
is not feasible, fluid and 
electrolytes should be 
substituted via IV infhsion. 
An antidianheal can be 
statted. 
Grade 2 
Withhold 
pembrolizumab and 
epacadostat. 
May renun to treatment if 
improves to Grade 1. If AE 
resolves within 4 weeks, subject 
may resta1t at the same dose and 
schedule for both pembrolizumab 
and epacadostat. 
For an AE that does not resolve 
within 4 weeks, epacadostat 
should be reduced 1 dose level, 
but pembrolizmnab may be 
restaited at the same dose and 
schedule.  If AE does not resolve 
within 6 weeks, study treatment 
with both study dmgs should be 
discontinued or discussed with 
medical monitor. 
An antidianheal should be 
statted. If symptoms are 
persistent for > 1 week, 
systemic c01ticosteroids 
should be initiated (eg, 
0.5-1 mglkg per day of 
prednisone or equivalent). 
When symptoms improve 
toGrade 1, corticosteroid 
taper should be staited and 
continued  over at least 
1 month. 
Grades 3 
and4 
Discontinue 
pembrolizumab and 
epacadostat. 
Not applicable. Any exceptions 
require medical monitor 
approval. 
Treatment with systemic 
cOiticosteroids should be 
initiated at a dose of 1 to 
2 mglkg per day of 
prednisone or equivalent. 
Systemic c01ticosteroids 
are indicated. The use of 
infliximab may be 
indicated as appropriate. 
When sympt01ns improve 
toGrade 1, cOiticosteroid 
taper should be staited and 
continued  over at least 
1 month. 


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5.4.1.3.3.   Procedu res and Guidance for Hepatitis
 
 
 
Liver chemistry tests (hepatic transaminase and bilimbin levels) should be monitored and signs 
and symptoms  of hepatotoxicity should be assessed before each dose of pembrolizumab  and 
epacadostat.  In subjects with hepatotoxicity, infectious or malignant causes should be mled out, 
and frequency of LFT monitming should be increased until resolution.  Recommendations for 
managing hepatitis are shown in Table  21. 
 
Table 21: 
Recommended Approach for Handling  Hepatitis 
 
Study 
Drug(s) 
Associated 
Hepatitis 
Withhold/Discontinue 
Pembrolizumab and 
Epacadostat 
Guida nce for Restarting 
Study Treatment 
Supportive Ca re 
Grade 1 
No action. 
Not applicable. 
Increase frequency of LFT 
monitoring to twice per 
week lmtil LFTs retum to 
baseline. 
Grade 2 
Withhold 
pembrolizmnab and 
epacadostat. 
If AE resolves toGrade 1 or 
baseline within 4 weeks, 
subject may resta1t at the same 
dose and schedule for both 
pembrolizumab and 
epacadostat.  For an AE that 
does not resolve within 
4 weeks, epacadostat should be 
reduced 1 dose level but 
pembrolizumab may be 
restalted at the same dose and 
schedule.  If AE does not 
resolve within 6 weeks, study 
treatment with both study drugs 
should be discontinued. 
Increase frequency of LFT 
monitoring to twice per 
week until LFTs retllln to 
baseline. If elevation 
persists for > 1 week, 
systemic c01ticosteroids 
should be initiated (eg, 
0.5 mglkg per day of 
prednisone or equivalent). 
When symptoms improve to 
Grade 1, c01ticosteroid 
taper should be stalted and 
continued  over at least 
1 month. 
Grades 3 
and4 
Discontinue 
pembrolizumab and 
epacadostat. 
Not applicable.  Any exceptions 
require medical monitor 
approval. 
Increase frequency of LFT 
monitoring to eve1y 
1-2 days.  Treatment with 
systemic c01ticosteroids 
should be initiated at a dose 
of 1 to 2 mg/kg per day of 
prednisone or equivalent. 
When sympt01ns improve to 
Grade 1, c01ticosteroid 
taper should be stalted and 
continued over at least 
1 month. 


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5.4.1.3.4.  Procedu res for Immune-Mediated Dermatitis 
 
Monitor subjects for signs and symptoms  of detmatitis such as rash and pm1itus.  Unless an 
altemate etiology has been identified, signs or symptoms of detmatitis should be considered 
immune-mediated. Recommendations for management of detmatitis are shown in Table 22. 
 
Table 22:       Recommended Approach for Handling Dermatitis 
 
irAE 
Withhold/Discontinue 
Pembrolizumab a nd 
Epacadostat 
Guida nce for Restarting 
Study  Treatment 
Supportive Care 
Grade 1 
No action. 
Not applicable. 
For mild to moderate 
de1matitis, such as localized 
rash and pmritus, treat 
symptomatically. 
Administer  topical or 
systemic cmticosteroids if 
there is no improvement of 
symptoms within 1 week. 
Grade 2 
No action. 
Not applicable. 
For mild to moderate 
de1matitis, such as localized 
rash and pmritus, treat 
symptomatically. 
Administer  topical or 
systemic cmticosteroids if 
there is no improvement of 
symptoms within 1 week. 
Grades 3 
and4 
Withhold  epacadostat 
and pembrolizumab  in 
subjects with moderate 
to severe signs and 
symptoms of rash. 
Pe1manently discontinue 
epacadostat and 
pembrolizumab  in 
subjects with Stevens- 
Johnson syndrome, toxic 
epide1mal necrolysis,  or 
rash complicated  by full 
thickness de1mal 
ulceration or by 
necrotic, bullous, or 
hemonhagic 
manifestations. 
If AE resolves to baseline 
within 4 weeks, subject may 
restart at the same dose and 
schedule for both 
pembrolizumab  and 
epacadostat.   For an AE that 
does not resolve within 
4 weeks, epacadostat should be 
reduced 1 dose level, but 
pembrolizumab  may be 
restarted at the same dose and 
schedule. If AE does not 
resolve within 6 weeks, study 
treatment with both study drugs 
should be discontinued or 
discussed with medical 
monitor. 
Administer systemic 
cmticosteroids at a dose of 
1 to 2 mg/kg per day of 
prednisone or equivalent. 
When de1matitis is 
controlled, cmticosteroid 
tapering should occur over a 
period of at least 1 month. 
 
5.4.1.3.5.  Procedu res for Immune-Mediated Neuropathies 
 
Subjects should be monitored for symptoms of motor or sensmy neuropathy such as unilateral or 
bilateral weakness, sensmy alterations, or paresthesia.  Recommendations for management of 
neuropathies are shown in Table 23. 


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Table 23: 
Recommended Approach for Handling Neuropathies 
 
 
 
irAE 
Withhold/Discontinue 
Pembrolizumab and 
Epacadostat 
Guidance for Restarting 
Study Treatment 
Supportive Care 
Grade 1 
No action. 
Not applicable. 
Provide symptomatic 
treatment. 
Grade 2 
May withhold 
pembrolizmnab and 
epacadostat. 
If AE resolves to ::::;  Grade 1 or 
baseline within 4 weeks, 
subject may resta1t at the same 
dose and schedule for both 
pembrolizumab and 
epacadostat.  For an AE that 
does not resolve within 
4 weeks, epacadostat should be 
reduced 1 dose level but 
pembrolizumab may be 
restruted at the same dose and 
schedule.  If AE does not 
resolve within 6 weeks, sntdy 
treatment with both sntdy dmgs 
should be discontinued or 
discussed with medical 
monitor. 
Consider systemic 
c01ticosteroids in addition to 
appropriate symptomatic 
treatment. 
Grades 3 
and4 
Discontinue 
pembrolizumab and 
epacadostat. 
Not applicable. Any exceptions 
require medical monitor 
approval. 
Consider initiation of 
systemic c01ticosteroids at a 
dose of 1 to 2 mg/kg per day 
prednisone or equivalent for 
severe nemopathies. 
Institute medical 
intervention as appropriate 
for management of severe 
nemopathy. 
 
5.4.1.3.6.  Procedures for Immune-Mediated Endocrinopathies 
 
Subjects should be monitored for clinical signs and symptoms ofhypophysitis, adrenal 
insufficiency (including  adrenal crisis), and hyper- or hypothyroidism.   Subjects may have 
fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension 
or have nonspecific symptoms that may resemble other causes such as brain metastasis or 
underlying disease.  Unless an altemate etiology has been identified, signs or symptoms of 
endocrinopathies should be considered  immune-mediated. 
 
Thyroid function tests and clinical chemistries should be monitored at the statt of treatment, 
before each dose and as clinically indicated  based on symptoms.   fu a limited number of subjects, 
hypophysitis was diagnosed by imaging studies through enlargement of the pituitaty gland. 
Recommendations for management of endocrinopathies are shown in Table 24. 


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Table 24: 
Recommended Approach for Handling Endocrinopathies 
 
 
 
irAE 
Withhold/Discontinue 
Pembrolizumab and 
Epacadostat 
Guidance for Restarting Study 
Treatment 
Supportive Care 
Grade 1 
No action. 
Not applicable. 
Provide symptomatic 
treatment. 
Grade 2 
May withhold 
pembrolizumab and 
epacadostat. 
If AE resolves within 4 weeks, 
subject may restalt at the same dose 
and schedule for both 
pembrolizumab and epacadostat. 
For an AE that does not resolve 
within 4 weeks, epacadostat should 
be reduced 1 dose level, but 
pembrolizumab may be resta1ted at 
the same dose and schedule.  If AE 
does not resolve within 6 weeks, 
study treatment with both sn1dy 
d!ugs should be discontinued. 
Initiate systemic 
c01ticosteroids treatment at 
a dose of 1 to 2 mg/kg per 
day of prednisone or 
equivalent, and initiate 
appropriate ho1mone 
replacement therapy. 
Grade 3 
Withhold or discontinue 
both pembrolizumab 
and epacadostat. 
If AE resolves or is controlled 
within 4 weeks, subject may resta1t 
at the same dose and schedule for 
both pembrolizumab and 
epacadostat.  For an AE that does 
not resolve within 4 weeks, 
epacadostat should be reduced 
1 dose level, but pembrolizumab 
may be restalted at the same dose 
and schedule.  If AE does not 
resolve within 6 weeks, sn1dy 
treatment with both sn1dy dmgs 
should be discontinued or discussed 
with medical monitor 
Consider initiating systemic 
c01ticosteroids treatment at 
a dose of 1 to 2 mg/kg per 
day of prednisone or 
equivalent, and initiate 
appropriate ho1mone 
replacement therapy. 
Grade4 
Discontinue both 
pembrolizumab and 
epacadostat. 
Not applicable.  Any exceptions 
require medical monitor approval. 
Consider initiation of 
syste1nic c01ticosteroids at a 
dose of 1 to 2 mg/kg per 
day of prednisone or 
equivalent, and initiate 
appropriate ho1mone 
replacement therapy. 
 
5.4.1.3.7.  Procedures for Immune-Mediated Myocarditis 
 
Subjects should be monitored for clinical signs and symptoms of myocarditis.  Subjects may 
have fatigue, chest pain, decreased exercise capacity, increased jugular venous pressure, 
hepatomegaly, dyspnea, orthopnea, pulmonary rales, pulmonary edema, heart failure, or 
cardiogenic shock.  Unless an altemate etiology has been identified, signs or symptoms of 


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myocarditis should be considered immune-mediated.  Recommendations for management of 
myocarditis are shown in Table 25. 
 
Table 25: 
Recommended Approach for Handling Myocarditis 
 
irAE 
Withhold/Discontinue 
Pembrolizumab and 
Epacadostat 
Guidance for Restarting Study 
Treatment 
Supportive Care 
Grade 1 
and 2 
Withhold 
pembrolizumab and 
epacadostat. 
Withhold both epacadostat and 
pembrolizumab until Grade 0.  May 
resta1t at same dose level. 
Based on severity of AE 
administer c01ticosteroids. 
Grade 3 
and4 
Withhold 
pembrolizumab and 
epacadostat. 
Pe1manently discontinue. 
 
5.4.1.3.8.   Procedures for Other Immune-Mediated Adverse Reactions, Including Ocular 
Manifestations 
 
Epacadostat and pembrolizumab should be petmanently discontinued for severe 
immune-mediated  adverse reactions.  Systemic cmticosteroids  treatment should be initiated at a 
dose of 1 to 2 mg/kg per day of prednisone or equivalent for severe immune-mediated adverse 
reactions. 
 
Cmticosteroid eye drops should be administered to subjects who develop uveitis, iritis, or 
episcletitis. Epacadostat and pembrolizumab should be petmanently discontinued for 
immune-mediated  ocular disease that is umesponsive to local immunosuppressive therapy. 
 
5.4.2. 
Treatment After Initial Evidence of Radiographic Disease Progression 
 
Immunotherapeutic agents such as pembrolizumab and epacadostat may produce antitumor 
effects by potentiating endogenous cancer-specific immune responses.  The response pattems 
seen with such as approach may extend beyond the typical time course of responses seen with 
cytotoxic agents and can manifest as a clinical response after an initial increase in tumor burden 
or even the appearance of new lesions. 
 
If radiographic imaging shows PD, tumor assessment should be repeated 2:: 4 weeks and no later 
than 8 weeks after the initial assessment to confi1m PD, with the option of continuing treatment 
as outlined below, while awaiting radiographic confnmation of progression. If repeat imaging 
shows a reduction in the tumor burden compared to the initial scan demonstrating PD, treatment 
may be continued as per treatment calendar.  If repeat imaging confnms PD, subjects will be 
discontinued from study therapy.  In dete1mining whether the tumor burden has increased or 
decreased, investigators should consider all target lesions as well as nontarget lesions. 
 
When feasible, subjects should not be discontinued  until progression is confiimed; however, the 
decision to continue study treatment after the first evidence of disease progression is at the 
investigator's discretion  based on the clinical status of the subject as described in Table 26. 


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Subjects may receive study treatment while waiting for confiimation of PD if they are clinically 
stable as defined by the following c1iteria: 
 
• Absence of signs and symptoms  (including worsening of laboratmy values) indicating 
disease progression. 
 
• No decline in ECOG pe1fmmance status. 
 
• Absence of rapid progression of disease. 
 
• Absence of progressive tumor at critical anatomical  sites (eg, cord compression) 
requiring urgent altemative medical intervention. 
 
Table 26: 
Imaging and Treatment After First Radiographic Evidence of Progressive 
Disease 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
First radiographic 
evidence of PD 
Repeat imaging at 
4  and8 weeks 
to confum PD 
May continue 
study treatment at 
the investigator's 
discretion while 
awaiting 
confmnat01y scan 
Repeat imaging at 
4 and8 weeks 
to confmn PD if 
possible 
Discontinue 
treatment 
Repeat scan at 
4 and8 weeks 
confums PD 
No additional 
imaging required 
Discontinue 
treatment 
No additional 
imaging required 
NIA 
Repeat scan at 
4 and8 weeks 
shows SD, PR, or 
CR 
Continue regularly 
scheduled imaging 
assessments eve1y 
9 weeks 
Continue study 
treatment at the 
investigator's 
discretion 
Continue regularly 
scheduled imaging 
assessments eve1y 
9 weeks 
May restait study 
treatment if 
condition has 
improved and/or 
clinically stable 
per investigator's 
discretion 
 
5.4.3.  
Procedu res for Subjects Exhibiting Serotonin  Syndrome 
 
As noted in Section 1.8.1, there is a rare possibility that epacadostat could cause an increase in 
serotonin levels in the brain that might t1igger SS (Boyer and Shannon 2005) when administered 
in combination with other serotonergic agents.  This syndrome has been most closely associated 
with the use of MAOis, meperidine, tramadol, linezolid, or methylene blue; all of these agents 
are prohibited during the study.  Selective SSRis and serotonin-norepinephrine reuptake 
inhibitors (SNRis) are pe1mitted during the study.  The following procedures will be 
implemented if subjects exhibit the signs/symptoms of SS (Table 27), including tremor, 
hypeneflexia, spontaneous, ocular, or inducible  clonus together with agitation, fever, diaphoresis, 
or muscle 1igidity: 
 
• Immediately inten11pt epacadostat administration. 
 
• Immediately inten11pt  any SSRI or SNRI administration. 


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• Provide appropriate medical management of the subject until all signs/symptoms are 
resolved (eg, IV fluids and/or sympathomimetic amines for hypotension, 
benzodiazepines for agitation, administration of 5-hydroxytryptamine antagonists 
such as cyproheptadine). 
 
• If the subject chooses to remain in the study, resta1t treatment with epacadostat after 
the SSRI or SNRI has been discontinued no sooner than 5 half-lives have elapsed for 
the specific SSRI or SNRI in question and after resolution of signs/symptoms of SS. 
The SSRI or SNRI dosing MAY NOT be restarted. 
 
• If the subject chooses to discontinue the study or must resta1t treatment with SSRI or 
SNRI,  the subject should be scheduled for a follow-up visit.  Selective serotonin 
reuptake inhibitor or SNRI treatment may be initiated 2 weeks after resolution of 
signs and symptoms of SS. 
 
Table 27: 
 
Signs and Symptoms of Serotonin Syndrome 
 
Tremor and hypeneflexia 
Spontaneous clonus 
Muscle rigidity, temperature > 38°C (100.4°F), and either  ocular clonus or inducible clonus 
Ocular  clonus and either agitation or diaphoresis 
Inducible clonus and either agitation or diaphoresis 
 
5.4.4.  
Criteria for Permanent Discontinuation of Study Drug 
 
The occmTence of unacceptable toxicity not caused by the underlying malignancy will be 
presumed  to be related to study dmg treatment and will require that the study drugs be 
pe1manently discontinued.   Unacceptable  toxicity is defined as follows: 
 
•  Occunence of an AE that is related to treatment with the study dmg 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. 
 
• Persistent AE requiring a delay of therapy for more than 2 weeks (14 days) unless a 
greater delay has been approved by the sponsor. 
 
•  Concunent elevation of ALT > 3 x ULN and total bilimbin > 2 x ULN in subjects 
who do not have evidence of bilia1y obstruction or other causes that can reasonably 
explain the concunent elevations. 
 
If study dmg is pe1manently discontinued, see Sections 6.3 and 6.4 for follow-up assessments. 


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5_5_ 
Withdrawal of Subjects From Study Treatment 
 
5.5.1. 
Withdrawal Criteria 
 
Subjects must be withdrawn from study treatment for the following reasons: 
 
• The subject becomes pregnant. 
 
• Consent is withdrawn. 
 
• Further participation would be injurious to the subject's health or well-being, in the 
investigator's medical judgment. 
 
• The study is tenninated by the sponsor. 
 
• The study is tenninated by the local health authority, IRB, or IEC. 
 
• Unacceptable toxicity has occmTed. 
 
• Confi1med radiographic progression of disease per RECIST v1.1 
(Eisenhauer et al2009). See Section 5.4.2. 
 
- Note:  For unconfi1med radiographic disease progression, see Section 5.4.2. 
 
- Note:  A subject may be granted an exception  to continue on treatment with 
confi1med radiographic progression if clinically stable or clinically improved. 
See Section 7.6.1. 
 
A subject may be discontinued from study treatment as follows: 
 
• If, during the course of the study, a subject  is found not to have met eligibility 
criteria, the medical monitor, in collaboration  with the investigator, will dete1mine 
whether the subject should be withdrawn from the study. 
 
• If a subject is noncompliant with study procedures or study dmg administration  in the 
investigator's opinion, the sponsor should be consulted for instruction on handling the 
subject. 
 
5.5.2. 
Withdrawal Procedures 
 
In the event that the decision is made to pe1manently discontinue the study dmg, the 
end-of-n·eatment (EOT) visit should be conducted. Reasonable effmts should be made to have 
the subject retum for a follow-up visit. These visits are desc1ibed in Section 6.  The last date of 
the last dose of study dmg and the reason for subject withdrawal will be recorded in the eCRF. 
 
If a subject  is withdrawn from study  treatment: 
 
• 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 perfmmed. 


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• The date of the EOT visit should be recorded in the eCRF and IRT. 
 
•  Subjects must be followed for safety until the time of the follow-up visit or until 
study dmg-related toxicities resolve,  retum to baseline, or are deemed ineversible, 
whichever is longest. 
 
If the subject discontinues study treatment 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 treatment 
but continuing in the follow-up period of the study for safety/efficacy assessments.  Upon 
implementation  of Amendment 4, disease assessment follow-up is no longer required. 
 
5.6.  
Concomitant Medications 
 
All concomitant medications and treatments must be recorded in the eCRF.  Any prior 
medication received up to 30 days before the first dose of study dmg and 60 days after the last 
dose of study dmg 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 dmg 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 necessa1y 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  medication 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 dmg dosage, frequency, route, and date may 
also be included on the eCRF. 
 
Use of prophylactic growth factors should be based on American Society of Clinical Oncology 
guidelines for the use of white blood cell (WBC) growth factors (Smith et al 2006) and the 
investigator's clinical judgment.  Bisphosphonates are allowed while subjects are receiving study 
treatment. 
 
5.6.2. 
Restricted Medications 
 
•  Systemic steroids may be used at doses:::; 10 mg/day prednisone or equivalents with 
medical monitor approval. 
 
• Treatment Groups A and Conly: Use of coumarin-based anticoagulants (eg, 
Coumadin®) is discouraged.  Low-dose Coumadin (1 mg) is acceptable; however, 
other higher doses are discouraged.  If an altemative to coumarin-based 
anticoagulants cannot be used, dose adjustment of the Coumadin dose may be needed. 
(Note:  Coumarin-based  anticoagulants are prohibited in Treatment Group B.)  Based 
on the observed magnitude of epacadostat/warfa1in PK interaction and 
PK/phaimacodynamic modeling results, for an epacadostat dose of 300 mg BID, the 
dose of warfarin should be reduced by approximately  one-third after initiation of 
epacadostat administration based on approximately 30% to 40% reduction inS- and 


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R-warfa1in oral clearance values.   Close INR monitming is recommended  for subjects 
on a stable dose of warfarin who are sta1ting treatment with epacadostat.   Based on 
PK/pha1macodynamic modeling,  recommendations for warfa1in dose modifications 
for subjects receiving other epacadostat  doses  are summa1ized in Table 28 based on 
the INR before sta1ting epacadostat. 
 
• Use of the anticonvulsant carbamazepine (a UGTIA9 inducer) is discouraged. 
Because there is a potential interaction that could result in lower epacadostat 
exposures, an altemative to carbamazepine should  be used, if possible. 
 
Table 28: 
Warfarin Dose Modifications 
 
Stable Baseline INR 
Epacadostat Dose 
100  mg BID 
200 mg BID 
300 mgBID 
INR2.5 
Close INR monitodng 
Close INR monitodng 
Reduce  warfruin by 
33% and monitor INR 
INR > 2.5 
Close INR monitodng 
Reduce wru·fruin by 
20%-25% and monitor INR 
Reduce wru·fruin by 
33% and monitor INR 
 
5.6.3. 
Prohibited Medications 
 
Subjects are prohibited from receiving the following therapies  during the screening and treatment 
phase of this study unless othe1wise noted below: 
 
• Any investigational medication other than the study dmgs. 
 
• Any anticancer medications, including chemotherapy or biologic therapy other than 
the study medications. 
 
• Any immunological-based treatment for any reason.  (NOTE:  Completed adjuvant 
therapy [eg, vaccines] is pe1mitted with medical monitor approval).  Inhaled or 
topical steroids are allowed, and systemic steroids at doses10 mg/day prednisone or 
equivalents are allowed with medical monitor approval, as described in Section 5.6.2, 
and immune suppressants are allowed for treatment for immune toxicities.) 
 
• Radiation therapy. 
 
NOTE:  Radiation therapy to a symptomatic solita1y lesion or to the brain may be 
allowed after consultation with the sponsor's medical monitor. 
 
• Live vaccines within 30 days before the first dose of study treatment and while 
patticipating in the study.  Examples  of live vaccines include, but are not limited to, 
the following: measles, mumps, mbella, chicken pox, yellow  fever, rabies, Bacillus 
Calmette-Guerin, and typhoid vaccine.  Seasonal influenza vaccines for injection are 
generally killed vims vaccines and are allowed; however, intranasal influenza 
vaccines (eg, FluMist) are live attenuated vaccines and are not allowed. 


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• Any MAOI or dmg associated with significant MAO inhibitmy activity agents is 
prohibited from 21 days before Day 1 through 2 weeks after the fmal dose of 
epacadostat has been taken (see Appendix C). 
 
• Any UGT1A9 inhibitor, including acitretin, amitriptyline, androsterone, cyclospmine, 
dasatinib, diclofenac, diflunisal,  efavirenz, erlotinib, estradiol (17-beta), flutamide, 
gefitinib, gemfibrozil, glycynhetinic acid glycynhizin, imatinib, imipramine, 
ketoconazole, linoleic acid, mefenamic acid, mycophenolic acid, niflumic acid, 
nilotinib, phenobarbital, phenylbutazone, phenytoin, probenecid, quinidine, ritonavir, 
Sorafenib, sulfinpyrazone, valproic acid, and verapamil. 
 
• Treatment Group B only:  Use of couma1in-based anticoagulants (eg, Coumadin) is 
prohibited.  Investigators are encouraged to switch subjects to altemate 
anticoagulation therapies such as Eliquis®, Pradaxa®, Savaysa®, or Xarelto®. 
Coagulation panel should be monitored more closely while a subject is on any 
anticoagulant. 
 
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 necessaiy. 
 
 
6_ 
STUDY ASSESSMENTS 
 
All study assessments will be perfmmed as indicated in the schedule of assessments  (Table 29, 
Table 31, Table 33, Table 35, Table 37, Table 39, Table 41, Table 43, Table 45, and Table 47), 
and alllaboratmy assessments will be pe1fmmed as indicated in Table 30, Table 32, Table 34, 
Table 36, Table 38, Table 40, Table 42, Table 44, Table 46, and Table 48. 
 
Table 49 presents a summay of clinicallaboratmy analytes to be assessed. The order of 
assessments is suggested by the order of mention within the schedule.  See Section 7 for 
instructions on each assessment.  Fmther details of study procedures and assessments can be 
found in the study reference manual. 


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Table 29: 
Schedule of Assessments (Treatment Group A: Part 1and Part 2 Expansion  Cohorts  A-1 and A-2) 
CONFIDENTIAL 
 
 
 
Visit  Day 
Screening 
Treatment 
EOT 
Safety 
Follow-Up 
Notes 
CI 
DI 
CI 
DS-7 
CI 
DIS 
C2 
DI 
C2 
DS-7 
C2 
DIS 
C3+ 
DI 
Evaluation Window 
Day -28 to 
Day-I 
DI 
DS-7 
± 3d 
± 3d 
DS-7 
±3 d 
±3 d 
+S d 
EOT + 
42-49 d 
ADMINISTRATIVE PROCEDURES 
Infonned consent 
X 
ContactiRT 
X 
X 
X 
X 
X 
Inclusion/exclusion criteria 
X 
X 
Medical and cancer hist01y 
X 
Prior/concomitant 
medications 
X 
X 
X* 
X 
X 
X* 
X** 
X 
X 
X 
* Visit to occm on the fifth day of azacitidine 
dose administration. 
** Cycle 2 Day 15 visits are not required for 
subjects in Patt 2. 
Disttibute reminder cards 
X 
X 
X* 
X 
X 
X* 
X** 
X 
X 
* Visit to occm·on the fifth day of azacitidine 
dose administration. 
** Cycle 2 Day 15 visits ru·e not required for 
subjects in Patt 2. 
Study drug dispensing 
X 
X 
X 
Assess study dmg 
compliance 
X 
X 
X 
CLII\'ICAL PROCEDURES AND ASSESSMENTS 
Physical examination/body 
weight and height* 
X 
X 
X** 
X 
X 
X** 
X*** 
X 
X 
X 
* Comprehensive exatnination at screening, 
targeted physical exatnination thereafter. 
Height at screening only. 
** Visit to occm on the fifth day of azacitidine 
dose adtninistration. 
*** Cycle 2 Day 15 visits ru·e not required for 
subjects in Patt 2. 
Vital signs 
X 
X 
X* 
X 
X 
X* 
X** 
X 
X 
X 
* Visit to occm on the fifth day of azacitidine 
dose adtninistration. 
** Cycle 2 Day 15 visits ru·e not required for 
subjects in Patt 2. 
ECOG petfonnance status 
X 
X 
X* 
X 
X 
X* 
X** 
X 
X 
X 
* Visit to occm on the fifth day of azacitidine 
dose adtninistration. 
** Cycle 2 Day 15 visits ru·e not required for 
subjects in Patt 2. 


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Table 29: 
Schedule of Assessments (Treatment Group A: Part 1and Part 2 Expansion  Cohorts  A-1 and A-2) (Continued) 
 
 
 
Visit  Day 
Screening 
Treatment 
EOT 
Safety 
Follow-Up 
Notes 
CI 
DI 
CI 
DS-7 
CI 
DIS 
C2 
DI 
C2 
DS-7 
C2 
DIS 
C3+ 
DI 
Evaluation Window 
Day -28 to 
Day-I 
DI 
DS-7 
± 3d 
± 3d 
DS-7 
±3 d 
±3 d 
+S d 
EOT + 
42-49 d 
12-lead ECG 
X* 
X** 
X** 
X***·" 
X" 
X" 
* Ttiplicate ECG at baseline. 
** Timed t:Iiplicate ECGs (separated by 5 min 
± 2 min) at predose and at 2 and 4 hours 
(± 15 min) postdose. 
*** ECG will be petfonned on DI of every 
other cycle after C2 (eg, C4, C6, and C8). 
" ECGs only need to be performed in t:Iiplicate 
if there has been a QT prolongation on study or 
the ECG shows a clinically significant 
abnonnality not present at baseline. 
AE assessment 
X 
X 
X* 
X 
X 
X* 
X** 
X 
X 
X 
* Visit to occm on the fifth day of azacitidine 
dose administration. 
**Cycle 2 Day 15 visits are not required for 
subjects in Prut 2. 
Laboratory assessments 
X 
X 
X* 
X 
X 
X* 
X** 
X 
X 
X 
* Visit to occm on the fifth day of azacitidine 
dose administration. 
**Cycle 2 Day 15 visits ru·e not required for 
subjects in Prut 2. 
TUMOR BIOPSY COLLECTION 
Tumor biopsy/ tissue 
collection* 
X 
X* 
* An additional mandat01y on-treat:Inent biopsy 
will be collected during Week 5 or Week 6.  The 
on-treat:Inent biopsy is optional for Stage 2 of 
Patt2. 
An additional optional biopsy may be collected 
once the subject meets the requirements for SD, 
response, or progression by radiographic disease 
assessment. 
Detailed instmctions for tissue collection, 
processing, and storage can be found in the 
study procedmes manual. Fine needle aspirates 
ru·e not acceptable. 


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Table 29: 
Schedule of Assessments (Treatment Group A: Part 1and Part 2 Expansion  Cohorts  A-1 and A-2) (Continued) 
 
 
 
Treamnt 
Cl 
Cl 
Cl 
C2 
C2 
C2 
C3+ 
Safety 
Visit  Day  
U <:O:liWl;; 
Dl 
DS-7 
DIS  
Dl 
DS-7 
 DIS 
Dl 
EOT  
Follow-Up 
Day -28 to  
EOT + 
Evaluation Window  
Day -1 
Dl  
DS-7 
± 3d 
±3 d 
DS-7  
±3 d 
±3 d 
+ S d 
42-49 d 
Notes 
STUDY DRUG A 
, fRATION 
 "  
 
azacitidine in 
X 
X 
X 
X 
X 
• Five doses of azacitidine will be administered 
clinic•  
 
 
 
 
 
 
in the clinic on D1-D7 of Cycles 1 through 3. 
 
 
 
r «>ll«tion on CIDI  •nd C2DI.
 
" 
epacadostat in 
X 
X 
clinic• 
 
 
" 
pembrolizumab 
X 
X 
X 
in clinic 
EFFICACY  '.;::· 
' 1:s 
Radiologic twnor  
X 
X 
X 
• Evety 9 weeks (63 ± 7 days) until disease 
assessments•  
 
 
 
progression. After 12 months of study 
treatment, imaging frequency may be reduced to 
eve1y 12 weeks.  Imaging should not be delayed 
for delays in cycle starts or extension of 
combination treatment cycle intervals. 


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Table 30: 
Laboratory Assessments (Treatment Group  A: Part 1 and Part  2 Expansion Cohorts A-1and A-2) 
 
Treatment 
 
Cl 
  Cl 
 Cl 
  C2 
 C2 
  C2 
 C3+ 
 
  Safety 
Laboratory 
 Screening 
Dl  
D5-7 
 D15  
 Dl  
D5-7  
 D15  
  Dl  
EOT  
Follow-Up 
Assessment  
 Day -28 to  
 
 
  
  
  
 
 
 
  EOT+ 
Window  
    Day-1 
Dl  
D5-7 ±3 d 
±3 d 
D5-7  
±3 d 
±3 d 
+5 d 
 42-49 d 
 
LOCAL LABORATORY TESTS 
Comprehensive  
X 
X 
X* 
X 
X 
X* 
X** 
X 
X 
X 
senun chemistry 
 
 
 
Hematology  
X 
X 
X* 
X 
X 
X* 
X** 
X 
X 
X 
with differential 
 
 
 
HgbA1c  
X 
 
Coagulation  
X 
X 
X* 
X 
panel 
 
Endocrine panel 
X 
X 
X* 
X 
U!inalysis 
X 
X 
X* 
Senun  
X* 
X 
pregnancy test 
 
 
 
 
 
Notes 
 
 
* Visit to occur on the fifth day of azacitidine dose 
administration. 
** Cycle 2 Day 15 visits are not required for subjects in 
Part2. 
* Visit to occur on the fifth day of azacitidine dose 
administration. 
** Cycle 2 Day 15 visits are not required for subjects in 
Part2. 
 
 
*Only at Cycles 4, 7, 10, etc. 
 
* Only at Cycles 4, 7, 10, etc. 
 
* Only at Cycles 4, 7, 10, etc. 
* A senun pregnancy test will be required for all women 
of childbearing potential during screening and must be 
perfonned within 72 hours before the first dose of study 
dmg. 
 
 
CEAICA19-9* 
X 
X 
X** 
X 
* CEA to be petfonned in subjects with CRC only. 
CA 19-9 to be performed in subjects with pancreatic 
cancer only. 
** CEA and CA 19-9 will be collected every other cycle 
aftet·C2. 


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Table 30:  
Laboratory Assessments (Treatment Group  A: Part 1 and Part  2 Expansion Cohorts A-1and  A-2) (Continued) 
 
 
 
 
Laboratory 
Assessment 
 
 
Cl 
Screening  
Dl 
Day -28 to 
-1 
 
 
Cl 
Cl 
D5-7 
D15 
Treatment 
C2  
C2  
C2  
C3+ 
Dl  
D5-7  
D15 
Dl  
EOT 


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Table 31: 
Schedule of Assessments (Treatment  Group A:  Part 2 Expansion Cohort A-3, Azacitidine Monotherapy 
Lead-In) 
 
Visit  Day 
Screening 
Treatment 
EOT 
Safety 
Follow-Up 
Notes 
Week-1 
C1 
D1 
C2 
D1 
C2 
DS-7 
C3+ 
D1 
Evaluation Window 
Day -28 to 
Day -1 
ClD1-7 
days 
D1 
± 3 d 
DS-7 
±3 d 
+Sd 
EOT 
+ 42-49 d 
ADMINISTRATIVE PROCEDURES 
Infonned consent 
X 
ContactiRT 
X 
X 
X 
X 
X 
X 
Inclusion/exclusion 
ctitetia 
X 
X 
Medical and cancer 
history 
X 
Prior/concomitant 
medications 
X 
X* 
X 
X 
X* 
X 
X 
X 
* To be assessed at baseline before first azacitidine 
dose and on the fifth day of azacitidine dose 
administration. 
Disttibute reminder 
cards 
X 
X 
X 
X 
X 
X 
X 
Study drug dispensing 
X 
X 
X 
Assess study dmg 
compliance 
X 
X 
X 
CLINICAL PROCEDURES AND ASSESSMENTS 
Physical 
examination/body 
weight and height* 
X 
X** 
X 
X 
X** 
X 
X 
X 
* Comprehensive examination at screening, targeted 
physical exatnination thereafter. Height at screening 
only. 
** To be assessed at baseline before first azacitidine 
dose and on the fifth day of azacitidine dose 
administration. 
Vital signs 
X 
X* 
X 
X 
X** 
X 
X 
X 
* To be assessed at baseline before first azacitidine 
dose and on the fifth day of azacitidine dose 
administration. 
**Visit to occur on the fifth day of azacitidine dose 
administration. 


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Schedule of Assessments (Treatment Group A:  Part 2 Expansion Cohort A-3, Azacitidine Monotherapy 
Lead-In) (Continued) 
Table 31: 
 
 
Visit  Day 
Screening 
Treatment 
EOT 
Safety 
Follow-Up 
Notes 
Week-1 
C1 
D1 
C2 
D1 
C2 
DS-7 
C3+ 
D1 
Evaluation Window 
Day -28 to 
Day -1 
ClD1-7 
days 
D1 
± 3d 
DS-7 
±3 d 
+S d 
EOT 
+ 42-49 d 
ECOG petfonnance 
status 
X 
X* 
X 
X 
X** 
X 
X 
X 
* To be assessed at baseline before first azacitidine 
dose and on the fifth day of azacitidine dose 
administration. 
**Visit to occur on the fifth day of azacitidine dose 
administration. 
12-lead ECG 
X* 
X** 
X** 
X***·" 
X" 
X" 
* Ttiplicate ECG at baseline. 
** Timed triplicate ECGs (separated by 5 min 
± 2 min) at predose and at 2 and 4 hours(± 15 min) 
postdose. 
*** ECG will be petfonned on DI of evety other 
cycle after C2 (eg, C4, C6, and C8). 
" ECGs only need to be perf01med in ttiplicate if 
there has been a QT prolongation on study or the 
ECG shows a clinically significant abnonnality not 
present at baseline. 
AE assessment 
X 
X* 
X 
X 
X* 
X 
X 
X 
* To be assessed at baseline before first azacitidine 
dose and on the fifth day of azacitidine dose 
administration. 
Laboratory 
assessments 
X 
X* 
X 
X 
X* 
X 
X 
X 
* Visit to occm on the fifth day of azacitidine dose 
administration. 
TUMOR BIOPSY COLLECTION 
Tumor biopsy/ tissue 
collection 
X 
X* 
X** 
* A second mandatory on-tt·eattnent biopsy will be 
collected ptior to CIDI  (window Day -5 to predose 
on ClDl). 
**A third tnandatory on-treattnent biopsy will be 
collected dming Week 5 or 6. 
Additional biopsies may be collected once the 
subject meets the requirements for SD, response, or 
progression by radiographic disease assessment. 
Detailed instmctions for tissue collection, 
processing, and storage can be found in the study 
procedures manual. Fine needle aspirates are not 
acceptable. 


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Schedule of Assessments (Treatment Group A:  Part 2 Expansion Cohort A-3, Azacitidine Monotherapy 
Lead-In) (Continued) 
Table 31: 
 
 
 
Visit  Day 
Scl'eening 
Tl'eatment 
EOT 
Safety 
Follow-Up 
Notes 
Week 
-1 
C1 
D1 
C2 
D1 
C2 
D5-7 
C3+ 
D1 
Evaluation Window 
Day -28 to 
Day -1 
C1D1-7 
days 
D1 
± 3d 
D5-7 
±3 d 
+ 5 d 
EOT 
+ 42-49 d 
STUDY DRUG ADMINISTRATION 
Administer azacitidine 
in clinic 
X* 
X** 
X** 
X** 
* Five doses of azacitidine will be administered in 
the clinic over a 5- to 7-day period in Week -1 
(before ClD1 of pembroliztunab/epacadostat). 
** Azacitidine administration should continue with 
5 doses administered in the clinic on Dl-D7 of 
Cycles 2 and 3. Subjects who remain on treatment 
beyond the Week 9 scan should continue to receive 
azacitidine until the second on-study scan (up to the 
Week 18 scan, for a maximum of3 additional 
cycles). 
Administer 
epacadostat in clinic* 
X** 
X 
* Subjects should withhold their AM dose of 
epacadostat  ondays. It should be adtninistered 
in the clinic fo  owing the trough 
collection on 
ClDl and C2Dl. 
** ClDl treatment should be initiated within a 
+ 5 day window from the date of the fifth azacitidine 
dose. 
Administer 
pembroliztunab in 
clinic 
X* 
X 
X 
* ClDl treatment should be initiated within a 
+ 5 day window from the date of the fifth azacitidine 
dose. 
EFFICACY ASSESSMENTS 
Radiologic twnor 
assessments* 
X 
X 
X 
* Eve1y 9 weeks (63 ± 7 days) until disease 
progression.  After 12 months of study treatment, 
imaging frequency may be reduced to evey 
12 weeks.  Imaging should not be delayed for delays 
in cycle struts or extension of combination treatment 
cycle inte vals. 


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Table 32: 
Laboratory Assessments (Treatment Group A: Part 2 Expansion  Cohort A-3, Azacitidine Monotherapy 
Lead-In) 
 
 
Cl 
C2  
C2  
C3+  
Safety 
Dl  
Dl 
DS-7 
Dl 
EOT 
EOT+ 
Dl  
±3d 
DS-7 
±3d 
+Sd 
42-49d 
Notes 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
 * A senun pregnancy test will be required for all 
women of childbearing potential during  screening and 
must be pe1fonned within 72 hours before the first 
dose of 


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Table 33: 
Schedule of Assessments (Treatment Group A: Part 2 Expansion Cohort A-4, Pembrolizumab/Epacadostat 
Lead-In) 
 
Visit  Day 
Screening 
Treatment 
EOT 
Safety 
Follow-Up 
Notes 
Cl 
Dl 
C2 
Dl 
C2 
DS-7 
C3+ 
Dl 
Evaluation Window 
Day -28 to 
Day-1 
Dl 
± 3 d 
DS-7 
±3 d 
+Sd 
EOT 
+ 42-49 d 
ADMINISTRATIVE PROCEDURES 
Infonned consent 
X 
Contact iRT 
X 
X 
X 
X 
X 
Inclusion/exclusion 
ctitetia 
X 
X 
Medical and cancer 
history 
X 
Prior/concomitant 
medications 
X 
X 
X 
x• 
X 
X 
X 
• Visit to occur on the fifth day of azacitidine dose 
administration. 
Disttibute reminder 
cards 
X 
X 
X 
x• 
X 
X 
• Visit to occur on the fifth day of azacitidine dose 
administration. 
Study drug dispensing 
X 
X 
X 
Assess study dmg 
compliance 
X 
X 
X 
CLII\'ICAL PROCEDURES AND ASSESSMENTS 
Physical 
examination/body 
weight and height* 
X 
X 
X 
x•• 
X 
X 
X 
• Comprehensive examination at screening, targeted 
physical examination thereafter. Height at screening 
only. 
•• Visit to occm on the fifth day of azacitidine dose 
administration. 
Vital signs 
X 
X 
X 
x• 
X 
X 
X 
• Visit to occur on the fifth day of azacitidine dose 
administration. 
ECOG petfonnance 
status 
X 
X 
X 
x• 
X 
X 
X 
• Visit to occur on the fifth day of azacitidine dose 
administration. 


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Version 4 
Table 33: 
Schedule of Assessments (Treatment Group A: Part  2 Expansion Cohort A-4, Pembrolizumab/Epacadostat 
Lead-In) (Continued) 
 
 
 
Visit  Day 
Screening 
Treatment 
EOT 
Safety 
Follow-Up 
Notes 
Cl 
Dl 
C2 
Dl 
C2 
DS-7 
C3+ 
Dl 
Evaluation Window 
Day -28 to 
Day -1 
Dl 
± 3 d 
DS-7 
±3 d 
+ S d 
EOT 
+ 42-49 d 
12-lead ECG 
X* 
X** 
X** 
X***" 
X" 
X" 
* Triplicate ECG at baseline. 
** Timed triplicate ECGs (separated by 5 min± 2 min) 
at predose and at 2 and 4 hom-s (± 15 min) postdose. 
*** ECG will be performed on Dl of every other cycle 
after C2 (eg, C4, C6, and C8). 
" ECGs only need to be petfonned in triplicate if there 
has been a QT prolongation on study or the ECG shows 
a clinically significant abnormality not present at 
baseline. 
AE assessment 
X 
X 
X 
X* 
X 
X 
X 
* Visit to occur on the fifth day of azacitidine dose 
administration. 
Laboratory assessments 
X 
X 
X 
X* 
X 
X 
X 
* Visit to occur on the fifth day of azacitidine dose 
administration. 
TUMOR BIOPSY COLLECTION 
Tmnor biopsy/ tissue 
collection 
X 
X* 
X** 
* A second mandatory on-treatment biopsy will be 
collected on C2Dl (window C1D15 to C2Dl, biopsy 
before azacitidine administration). 
**A third mandatory on treatment biopsy will be 
collected during Week 8 or 9. 
Additional biopsies may be collected once the subject 
meets the requirements for SD, response, or progression 
by radiographic disease assessment. 
Detailed instmctions for tissue collection, processing, 
and storage can be found in the study procedures 
manual.  Fine needle aspirates are not acceptable. 


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Protocol INCB 24360-206 Am 4 
Page 126 of219 
30AUG 2018 
Version 4 
Table 33: 
Schedule of Assessments (Treatment Group A: Part  2 Expansion Cohort A-4, Pembrolizumab/Epacadostat 
Lead-In) (Continued) 
 
 
 
Visit  Day 
Screening 
Treatment 
EOT 
Safety 
Follow-Up 
Notes 
Cl 
Dl 
C2 
Dl 
C2 
DS-7 
C3+ 
Dl 
Evaluation Window 
Day -28 to 
Day -1 
Dl 
± 3 d 
DS-7 
±3 d 
+ S d 
EOT 
+ 42-49 d 
STUDY DRUG ADMINISTRATION 
Administer azacitidine 
in clinic* 
X 
X 
X 
* Five doses of azacitidine will be administered in the 
clinic on Dl-D7 of Cycles 2 and 3. Subjects who 
remain on treatment beyond the Week 9 scan should 
continue to receive azacitidine tmtil the second on-study 
scan (up to the Week 18 scan, for a maximum of 
3 additional cycles). 
Administer epacadostat 
in clinic* 
X 
X 
* Subjects should withhold their AM dose of 
epacadostat on 
days. It should be administered in 
the clinic followmg the trough 
collection on CIDI 
and C2DI . 
Administer 
pembrolizumab in clinic 
X 
X 
X 
EFFICACY ASSESSMENTS 
Radiologic twnor 
assessments* 
X 
X 
X 
*Every 9 weeks (63 ± 7 days) tmtil disease progression. 
After 12 months of study treatment, imaging frequency 
may be reduced to evety 12 weeks.  Imaging should not 
be delayed for delays in cycle starts or extension of 
combination treatment cycle intervals. 


CONFIDENTIAL 
Incyte Corporation 
Protocol INCB 24360-206 Am 4 
Page 127 of219 
30AUG 2018 
Version 4 
Table 34: 
Laboratory Assessments (Treatment  Group A: Part 2 Expansion Cohort A-4, Pembrolizumab/Epacadostat 
Lead-In) 
 
 
 
 
Cl 
C2 
C2  
C3+ 
Dl 
Dl  
DS-7 
Dl 
EOT 
 
Dl 
±3d  
DS-7 ±3d  
+Sd 
 
X 
X 
X*  
X 
X 
X 
X 
X*  
X 
X 
Safety 
 
EOT+ 
42-49  d 
 
 
X 
X 
 
 
 
 
Notes 
 
* Visit to occur on the fifth day of azacitidine dose administration. 
 
* Visit to occur on the fifth day of azacitidine dose administration. 


CONFIDENTIAL 
Incyte Corporation 
Protocol INCB 24360-206 Am 4 
Page 128 of219 
30AUG 2018 
Version 4 
Table 35: 
Schedule of Assessments (Treatment  Group A:  Part 2 Expansion Cohort A-5, Pembrolizumab Monotherapy 
Lead-In) 
 
 
Visit  Day 
Screening 
Treatment 
EOT 
Safety 
Follow-Up 
Notes 
Cl 
Dl 
C2 
Dl 
C2 
DS-7 
C3+ 
Dl 
Evaluation Window 
Day -28 to 
Day -1 
Dl 
±3 d 
D5-7 
± 3 d 
+S d 
EOT 
+ 42-49 d 
ADMINISTRATIVE PROCEDURES 
Infonned consent 
X 
Contact iRT 
X 
X 
X 
X 
X 
Inclusion/exclusion 
ctitetia 
X 
X 
Medical and cancer 
history 
X 
Prior/concomitant 
medications 
X 
X 
X 
X* 
X 
X 
X 
* Visit to occur on the fifth day of azacitidine dose 
administration. 
Disttibute reminder 
cards 
X 
X 
X 
X* 
X 
X 
* Visit to occur on the fifth day of azacitidine dose 
administration. 
Study drug dispensing 
X 
X 
Assess study dmg 
compliance 
X 
X 
CLINICAL PROCEDURES AND ASSESSMENTS 
Physical 
examination/body 
weight and height* 
X 
X 
X 
X** 
X 
X 
X 
* Comprehensive examination at screening, targeted 
physical examination thereafter.  Height at screening 
only. 
** Visit to occur on the fifth day of azacitidine dose 
administration. 
Vital signs 
X 
X 
X 
X* 
X 
X 
X 
* Visit to occm on the fifth day of azacitidine dose 
administration. 
ECOG petfonnance 
status 
X 
X 
X 
X* 
X 
X 
X 
* Visit to occm on the fifth day of azacitidine dose 
administration. 


CONFIDENTIAL 
Incyte Corporation 
Protocol INCB 24360-206 Am 4 
Page 129 of219 
30AUG 2018 
Version 4 
Table 35: 
Schedule of Assessments (Treatment Group A:  Part 2 Expansion Cohort A-5, Pembrolizumab  Monotherapy 
Lead-In) (Continued) 
 
 
 
Visit  Day 
Screening 
Treatment 
EOT 
Safety 
Follow-Up 
Notes 
Cl 
Dl 
C2 
Dl 
C2 
DS-7 
C3+ 
Dl 
Evaluation Window 
Day -28 to 
Day -1 
Dl 
±3 d 
D5-7 
± 3 d 
+S d 
EOT 
+ 42-49 d 
12-lead ECG 
x• 
x•• 
x•• 
x•••·" 
X" 
X" 
• Triplicate ECG at baseline. 
•• Timed triplicate ECGs (separated by 5 min± 2 min) 
at predose and at 2 and 4 hom-s (± 15 min) postdose. 
••• ECG will be performed on Dl of every other cycle 
after C2 (eg, C4, C6, and C8). 
" ECGs only need to be petfonned in triplicate if there 
has been a QT prolongation on study or the ECG shows 
a clinically significant abnormality not present at 
baseline. 
AE assessment 
X 
X 
X 
x• 
X 
X 
X 
• Visit to occur on the fifth day of azacitidine dose 
administration. 
Laboratory assessments 
X 
X 
X 
x• 
X 
X 
X 
• Visit to occur on the fifth day of azacitidine dose 
administration. 
TUMOR BIOPSY COLLECTION 
Tmnor biopsy/ tissue 
collection 
X 
x• 
x•• 
• A second mandatory on-treatment biopsy will be 
collected on C2Dl (window CIDI5 to C2Dl, biopsy 
before azacitidine administration). 
"""A third mandatory on treatment biopsy will be 
collected dming Week 8 or 9. 
Additional biopsies may be collected once the subject 
meets the requirements for SD, response, or progression 
by radiographic disease assessment. 
Detailed instmctions for tissue collection, processing, 
and storage can be found in the study procedures 
manual. Fine-needle aspirates are not acceptable. 


CONFIDENTIAL 
Incyte Corporation 
Protocol INCB 24360-206 Am 4 
Page 130 of219 
30AUG 2018 
Version 4 
Table 35: 
Schedule of Assessments (Treatment Group A:  Part 2 Expansion Cohort A-5, Pembrolizumab  Monotherapy 
Lead-In) (Continued) 
 
 
 
Visit  Day 
Screening 
Treatment 
EOT 
Safety 
Follow-Up 
Notes 
Cl 
Dl 
C2 
Dl 
C2 
DS-7 
C3+ 
Dl 
Evaluation Window 
Day -28 to 
Day -1 
Dl 
±3 d 
D5-7 
± 3 d 
+S d 
EOT 
+ 42-49 d 
STUDY DRUG ADMINISTRATION 
Administer azacitidine 
in clinic* 
X 
X 
X 
* Five doses of azacitidine will be administered in the 
clinic on Dl-D7 of Cycles 2 and 3.  Subjects who 
remain on treatment beyond the Week 9 scan should 
continue to receive azacitidine until the second on-study 
scan (up to the Week 18 scan, for a maximum of 
3 additional cycles). 
Administer epacadostat 
in clinic* 
X 
X 
* Subjects should withhold their AM dose of 
epacadostat on 
days. It should be administered in 
the clinic followmg the trough 
collection on C2D1 
and C3Dl. 
Administer 
pembrolizumab in clinic 
X 
X 
X 
EFFICACY ASSESSMENTS 
Radiologic twnor 
assessments* 
X 
X 
X 
* Every 9 weeks (63 ± 7 days) until disease progression. 
After 12 months of study treatment, imaging frequency 
may be reduced to every 12 weeks.  Imaging should not 
be delayed for delays in cycle starts or extension of 
combination treatment cycle intetvals. 


CONFIDENTIAL 
Incyte Corporation 
Protocol INCB 24360-206 Am 4 
Page 131 of219 
30AUG 2018 
Version 4 
Table 37: 
Schedule of Assessments (Treatment Group B: Part 1 Dose-Escalation a nd Expansion Cohorts B-1to B-6 and 
Part 2 Expansion Cohorts B-7, B-8, and B-9) (Continued) 
 
 
 
 
Table 36: 
Laboratory Assessments (Treatment  Group A: Part 2 Expansion Cohort A-5, Pembrolizumab Monotherapy 
Lead-In) 
 
 
Cl 
C2 
C2  
C3+ 
Dl 
Dl  
DS-7 
Dl 
EOT 
 
Dl 
±3d  
DS-7 ±3d  
+Sd 
 
X 
X 
X*  
X 
X 
X 
X 
X*  
X 
X 
Safety 
 
EOT+ 
42-49  d 
 
 
X 
X 
 
 
 
 
Notes 
 
* Visit to occur on the fifth day of azacitidine dose administration. 
 
* Visit to occur on the fifth day of azacitidine dose administration. 


CONFIDENTIAL 
Incyte Corporation 
Protocol INCB 24360-206 Am 4 
Page 132 of219 
30AUG 2018 
Version 4 
Table 37: 
Schedule of Assessments (Treatment Group B: Part 1 Dose-Escalation a nd Expansion Cohorts B-1to B-6 and 
Part 2 Expansion Cohorts B-7, B-8, and B-9) (Continued) 
 
 
 
 
Table 37: 
Schedule of Assessments (Treatment Group B: Part 1 Dose-Escalation  and Expansion Cohorts B-1to B-6 and 
Part  2 Expansion Cohorts B-7, B-8, and B-9) 
 
NOTE:  Upon implementation of Amendment  4, this table is no longer applicable. 
 
Visit  Day 
Screening 
Treatment 
EOT 
Follow-Up 
Notes 
Cl 
Dl 
Cl 
DS 
Cl 
DIS 
C2 
Dl 
C2 
DS 
C2 
DIS 
C3 
Dl 
C4+ 
Dl 
Safety 
Disease 
Status 
Survival 
Evaluation 
Window 
Day -28 to 
Day-1 
Dl 
±3 d 
± 3 d 
±3 d ±3 d 
± 3d ±3 d 
± 3 d 
+ S d 
EOT + 
42-49 d 
Q9W(± 7 d) 
AfterEOT 
Q12W 
(+ 7 d) 
ADMINISTRATIVE PROCEDURES 
Infonned  consent 
X 
Contact iRT 
X 
X 
X 
X 
X 
X 
Inclusion! 
exclusion criteria 
X 
X 
Medical and cancer 
history 
X 
Prior/concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Disttibute reminder 
cards 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug 
dispensing 
X 
X 
X 
X 
Assess study dmg 
compliance 
X 
X 
X 
X 
Post-treatment 
anticancer therapy 
status 
X 
X 
Data collection for 
survival 
X 


CONFIDENTIAL 
Incyte Corporation 
Protocol INCB 24360-206 Am 4 
Page 133 of219 
30AUG 2018 
Version 4 
Table 37: 
Schedule of Assessments (Treatment Group B: Part 1 Dose-Escalation a nd Expansion Cohorts B-1to B-6 and 
Part 2 Expansion Cohorts B-7, B-8, and B-9) (Continued) 
 
 
 
Visit Day 
Screening 
Treatment 
EOT 
Follow-Up 
Notes 
Cl 
Dl 
Cl 
DS 
Cl 
DIS 
C2 
Dl 
C2 
DS 
C2 
DIS 
C3 
Dl 
C4+ 
Dl 
Safety 
Disease 
Status 
Survival 
Evaluation 
Window 
Day -28 to 
Day-1 
Dl 
±3 d 
± 3 d 
±3 d 
±3 d 
± 3 d 
±3 d 
± 3 d 
+S d 
EOT + 
42-49  d 
Q9W(± 7 d) 
AfterEOT 
Q12W 
(+7 d) 
CLINICAL PROCEDURES AND ASSESSMENTS 
Physical 
examination/body 
weight and height* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
* Comprehensive examination at 
screening, targeted physical 
examination thereafter.  Height 
at screening only. 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG 
performance status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X* 
X** 
X** 
X*** 
1\ 
X*** 
1\ 
XA 
XA 
* Triplicate ECG at baseline. 
** Timed  triplicate ECGs 
(separated by 5 min± 2 min) at 
predose and at 2 and 4 hours 
(± 15 min) postdose. 
*** ECG will be performed on 
D1 of evety other cycle after C3 
(eg, C5, C7, and C9). 
1\ ECGs only need to be 
perfonned in ttiplicate if there 
has been a QT prolongation  on 
study or the ECG shows a 
clinically significant  abnonnality 
not present at baseline. 
AE assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory 
assessments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


CONFIDENTIAL 
Incyte Corporation 
Protocol INCB 24360-206 Am 4 
Page 134 of219 
30AUG 2018 
Version 4 
Table 37: 
Schedule of Assessments (Treatment Group B: Part 1 Dose-Escalation a nd Expansion Cohorts B-1to B-6 and 
Part 2 Expansion Cohorts B-7, B-8, and B-9) (Continued) 
 
 
Visit  Day 
Screening 
Treatment 
EOT 
Follow-Up 
Notes 
Cl 
Dl 
Cl 
DS 
Cl 
DIS 
C2 
Dl 
C2 
DS 
C2 
DIS 
C3 
Dl 
C4+ 
Dl 
Safety 
Disease 
Status 
Survival 
Evaluation 
Window 
Day -28 to 
Day-1 
Dl 
±3 d 
± 3 d 
±3 d ±3 d 
± 3d ±3 d 
± 3 d 
+S d 
EOT + 
42-49 d 
Q9W(± 7 d) 
AfterEOT 
Q12W 
(+7 d) 
TUMOR BIOPSY COLLECTION 
Tumor biopsy/ 
tissue collection 
X 
x• 
x•• 
• Only Expansion  Cohort B-9 
will have an additional 
mandatory on-treatment biopsy 
will be collected at C2D1 
(window ClD15 to C2Dl). 
•• An additionalmandat01y on-
treatment biopsy will be 
collected during Week 8 or 
Week 9. The on-treatment 
biopsy is optional for Stage 2 of 
Part2. 
An additional optional biopsy 
may be collected once the 
subject meets the requirements 
for SD, response, or progression 
by radiographic disease 
assessment. 
Detailed instmctions for tissue 
collection, processing, and 
storage can be found in the study 
procedm·es manual. Fine needle 
aspirates are not acceptable. 


CONFIDENTIAL 
Incyte Corporation 
Protocol INCB 24360-206 Am 4 
Page 135 of219 
30AUG 2018 
Version 4 
Table 37: 
Schedule of Assessments (Treatment Group B: Part 1 Dose-Escalation a nd Expansion Cohorts B-1to B-6 and 
Part 2 Expansion Cohorts B-7, B-8, and B-9) (Continued) 
 
 
Visit  Day 
Screening 
Treatment 
EOT 
Follow-Up 
Notes 
Cl 
Dl 
Cl 
DS 
Cl 
DIS 
C2 
Dl 
C2 
DS 
C2 
DIS 
C3 
Dl 
C4+ 
Dl 
Safety 
Disease 
Status 
Survival 
Evaluation 
Window 
Day -28 to 
Day-1 
Dl 
±3 d 
± 3 d 
±3 d ±3 d 
± 3 d ±3 d 
± 3 d 
+S d 
EOT + 
42-49 d 
Q9W(± 7 d) 
AfterEOT 
Q12W 
(+7 d) 
STUDY DRUG ADMINISTRATION 
Administer 
INCB057643  in 
clinic* 
X 
X 
X 
X 
.
 
*INCB057643 and epacadostat 
should be administered at the 
same time p1ior to the 
pembrolizmnab infusion. 
Subjects should withhold their 
AM dose of iNCB057643 on 
days. It should be administer 
in the clinic following the trough 
collection on CIDI , CID8, 
C2DI, and C2D8. 
Administer 
epacadostat in 
clinic* 
X 
X 
.
 
*INCB057643 and epacadostat 
should be administered at the 
same time p1ior to the 
pembrolizmnab infusion. 
Subjects should withhold their 
AM dose of epacadostat on 
days. It should be administered 
in the clinic following the trough 
collection on C2DI and 
C2D8. 
Administer 
pembrolizumab in 
clinic 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 


CONFIDENTIAL 
Incyte Corporation 
Protocol INCB 24360-206 Am 4 
Page 136 of219 
30AUG 2018 
Version 4 
 
 
 
 
Table 37: 
Schedule of Assessments (Treatment Group B: Part 1 Dose-Escalation a nd Expansion Cohorts B-1to B-6 and 
Part 2 Expansion Cohorts B-7, B-8, and B-9) (Continued) 
 
Visit  Day 
Screening 
Treatment 
EOT 
Follow-Up 
Notes 
Cl 
Dl 
Cl 
DS 
Cl 
DIS 
C2 
Dl 
C2 
DS 
C2 
DIS 
C3 
Dl 
C4+ 
Dl 
Safety 
Disease 
Status 
Survival 
Evaluation 
Window 
Day -28 to 
Day -1 
Dl 
± 3d ±3d 
± 3d 
± 3 d 
±3d 
± 3d ±3d 
+ Sd 
EOT + 
42-49 d 
Q9W(± 7 d) 
AfterEOT 
Q12W 
(+7 d) 
EFFICACY ASSESSMENTS 
Radiologic twnor 
assessments* 
X 
X 
X 
X 
X 
* Every 9 weeks (63 ± 7 days) 
tmtil disease progression.  After 
12 months of study treatment, 
imaging frequency may be 
reduced to every 12 weeks. 
Imaging should not be delayed 
for delays in cycle starts or 
extension of combination 
treatment cycle intetvals. 


CONFIDENTIAL 
Incyte Corporation 
Protocol INCB 24360-206 Am 4 
Page 137 of219 
30AUG 2018 
Version 4 
 
 
 
 
Table 38: 
Laboratory Assessments (Treatment Group B: Part 1Dose-Escalation and Expansion Cohorts B-1to B-6 and 
Part 2 Expansion Cohorts B-7, B-8, and B-9) 
 
NOTE:  Upon implementation of Amendment  4, this table is no longer applicable. 
 
 
Cl 
Cl 
Cl 
C2  
C2 
C2 
C3 
C4+  
Safety 
Laboratory 
Dl 
D8  
DIS  
Dl 
D8  
DIS 
Dl 
Dl 
EOT 
Assessment 
EOT+ 
±3d  ±3d  ±3d  ±3d  ±3d  ±3d  ±3d  +Sd  
42-49d 
Notes 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
x•• 
X 
X 
• A senun pregnancy test will be required for all 
women  of childbearing potential dming screening 
and must be perfonned within 72 hours before the 
first dose of 
 
 
•CEA to be performed insubjects with CRConly. 
CA 19-9 to be petfonned in subjects with pancreatic 
cancer  only. 
••CEA and CA 19-9  will be collected every othet· 


CONFIDENTIAL 
Incyte Corporation 
Protocol INCB 24360-206 Am 4 
Page 138 of219 
30AUG 2018 
Version 4 
Table 38: 
Laboratory Assessments (Treatment  Group B: Part 1Dose-Escalation and Expansion Cohorts B-1to B-6 and 
 
 
Cl 
Dl 
Cl 
D8 
Cl 
DIS 
C2 
Dl 
C2 
D8 
C2 
DIS 
C3 
Dl 
C4+ 
Dl 
Part 2 Expansion Cohorts B-7, B-8, and B-9) (Continued) 
 
 
 
 
Laboratory 
Assessment 
Safety 


CONFIDENTIAL 
Incyte Corporation 
Protocol INCB 24360-206 Am 4 
Page 139 of219 
30AUG 2018 
Version 4 
Table 39: 
Schedule of Assessments (Treatment Group B: Part 2 Expansion  Cohort B-10) 
 
 
NOTE:  Upon implementation of Amendment 4, this table is no longer applicable. 
 
Visit  Day 
Screening 
Treatment 
EOT 
Follow-Up 
Notes 
CI 
DI 
CI 
D8 
CI 
DIS 
C2 
DI 
C2 
D8 
C2 
DIS 
C3 
DI 
C4+ 
DI 
Safety 
Disease 
Status 
Sm'Vival 
Evaluation 
Window 
Day -28 
to Day -I 
DI 
± 3 d ±3 d ± 3d ±3 d ± 3 d ±3 d ± 3d 
+ S d 
EOT+ 
42-49 d 
Q9W (± 7 d) 
After EOT 
QI2W 
(+ 7 d) 
ADMINISTRATIVE PROCEDURES 
Infonned consent 
X 
Contact iRT 
X 
X 
X 
X 
X 
X 
Inclusion! 
exclusion criteria 
X 
X 
Medical and cancer 
history 
X 
Prior/concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Disttibute reminder 
cards 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug 
dispensing 
X 
X 
X 
X 
Assess study dmg 
compliance 
X 
X 
X 
X 
Post-treatment 
anticancer therapy 
status 
X 
X 
Data collection for 
survival 
X 


CONFIDENTIAL 
Incyte Corporation 
Protocol INCB 24360-206 Am 4 
Page 140 of219 
30AUG2018 
Version 4 
 
 
 
 
Table 39:  
Schedule of Assessments (Treatment  Group B: Part 2 Expansion Cohort  B-10) (Continued) 
 
Visit  Day 
Screening 
Treatment 
EOT 
Follow-Up 
Notes 
CI 
DI 
CI 
D8 
CI 
DIS 
C2 
DI 
C2 
D8 
C2 
DIS 
C3 
DI 
C4+ 
DI 
Safety 
Disease 
Status 
Sm'Vival 
Evaluation 
Window 
Day -28 
to Day -I 
DI 
±3 d ± 3d ±3 d ± 3 d ±3 d ± 3d ±3 d 
+S d 
EOT+ 
42-49 d 
Q9W(± 7 d) 
After EOT 
QI2W 
(+ 7 d) 
CLII\'ICAL PROCEDURES AND ASSESSMENTS 
Physical 
examination/body 
weight and height* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
• Comprehensive examination at 
screening, targeted physical 
examination thereafter.  Height at 
screening only. 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG 
performance status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
x• 
x•• 
x•• 
x••• 
1\ 
x••• 
1\ 
X" 
X" 
• Ttiplicate ECG at baseline. 
•• Timed tiiplicate ECGs 
(separated by 5 min± 2 min) at 
predose and at 2 and 4 hours 
(± 15 min) postdose. 
"'""" ECG will be petfonned on D1 
of evety other cycle after C3 (eg, 
C5, C7, and C9). 
" ECGs only need to be performed 
in tiiplicate if there has been a QT 
prolongation on study or the ECG 
shows a clinically significant 
abnonnality not present at 
baseline. 
AE assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory 
assessments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


CONFIDENTIAL 
Incyte Corporation 
Protocol INCB 24360-206 Am 4 
Page 141 of219 
30AUG2018 
Version 4 
 
 
 
 
Table 39:  
Schedule of Assessments (Treatment Group B: Part 2 Expansion Cohort B-10) (Continued) 
 
Visit  Day 
Screening 
Treatment 
EOT 
Follow-Up 
Notes 
CI 
DI 
CI 
D8 
CI 
DIS 
C2 
DI 
C2 
D8 
C2 
DIS 
C3 
DI 
C4+ 
DI 
Safety 
Disease 
Status 
Sm'Vival 
Evaluation 
Window 
Day -28 
to Day -I 
DI 
±3 d ± 3d ±3 d ± 3 d ±3 d ± 3d ±3 d 
+ S d 
EOT+ 
42-49 d 
Q9W(± 7 d) 
After EOT 
QI2W 
(+ 7 d) 
TUMOR BIOPSY COLLECTION 
Tumor biopsy/ 
tissue collection* 
X 
X* 
X* 
* Two additional mandatory on- 
treatment biopsies will be 
collected at C2Dl (window 
ClD15 to C2DI) and dtuing 
Week 8 or Week 9. 
An additional optional biopsy may 
be collected once the subject 
meets the requirements for SD, 
response, or progression by 
radiographic disease assessment. 
Detailed instructions for tissue 
collection, processing, and storage 
can be found in the study 
procedures manual. Fine needle 
aspirates are not acceptable. 


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Table 39:  
Schedule of Assessments (Treatment Group B: Part 2 Expansion Cohort B-10) (Continued) 
 
Visit  Day 
Screening 
Treatment 
EOT 
Follow-Up 
Notes 
CI 
DI 
CI 
D8 
CI 
DIS 
C2 
DI 
C2 
D8 
C2 
DIS 
C3 
DI 
C4+ 
DI 
Safety 
Disease 
Status 
Sm'Vival 
Evaluation 
Window 
Day -28 
to Day -I 
DI 
±3 d ± 3d ±3 d ± 3 d ±3 d ± 3d ±3 d 
+S d 
EOT+ 
42-49 d 
Q9W(± 7 d) 
After EOT 
QI2W 
(+ 7 d) 
STUDY DRUG ADMINISTRATION 
Administer 
INCB057643 in 
clinic• 
X 
X 
X 
X 
• INCB057643 and epacadostat 
should be administered at the 
same time prior to the 
pembrolizumab infusion.  Subjects 
should withhold their AM dose of 
INCB057643 on 
days. It 
should be administered in the 
clirlic following the trough. 
collection on CIDI , CID8, C2D1, 
andC2D8. 
Administer 
epacadostat in 
clinic• 
X 
X 
X 
X 
• INCB057643 and epacadostat 
should be administered at the 
same time prior to the 
pembrolizum.ab infusion.  Subjects 
should withhold their AM dose of 
epacadostat onJ!Idays. It should 
be admirlistere  m the clirlic 
following the trough 
collection 
on C1D1, C1D8, C2D1, and 
C2D8. 
Administer 
pembroliztunab in 
clinic 
X 
X 
X 
EFFICACY ASSESSMENTS 
Radiologic tumor 
assessments• 
X 
X 
X 
X 
X 
• Evety 9 weeks (63 ± 7 days) 
until disease progression. After 
12 months of study treatment, 
imaging frequency may be 
reduced to evety 12 weeks. 
Imaging should not be delayed for 
delays in cycle starts or extension 
of combination treatment cycle 
intetvals. 


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Version 4 
 
 
 
 
Table 40:  
Laboratory Assessments (Treatment Group  B: Part  2 Expansion  Cohort B-10) 
NOTE:  Upon implementation of Amendment  4, this table is no longer applicable. 
 
 
Cl 
Cl 
Cl 
C2  
C2  
C2  
C3 
C4+  
Safety 
Laboratory 
Dl  
D8 
 
D15 
Dl 
D8  
D15 
Dl  
Dl  
EOT 
Assessment  
EOT+ 
Dl  
±3d  ±3d  ±3d  ±3d  ±3d  ±3d  ±3d  +5d 
42-49d  
Notes 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Version 4 
 
 
 
 
Table 40: 
Laboratory Assessments (Treatment  Group B: Part 2 Expansion Cohort B-10) (Continued) 
 
 
 
Laboratory 
Assessment 
Cl 
Cl 
Dl  
D8 
Cl 
C2 
D15  
Dl 
C2  
C2 
D8 
D15 
C3 
C4+ 
Dl  
Dl 
Safety 


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Table 41:  
Schedule of Assessments (Treatment Group B: Part  2 Expansion Cohort B-11) 
NOTE:  Upon implementation of Amendment  4, this table is no longer applicable. 
Visit  Day 
Screening 
Treatment 
EOT 
Follow-Up 
Notes 
Cl 
Dl 
Cl 
DS 
Cl 
DIS 
C2 
Dl 
C2 
DS 
C2 
DIS 
C3 
Dl 
C4+ 
Dl 
Safety 
Disease 
Status 
Sm'Vival 
Evaluation 
Window 
Day -28 to 
Day -I 
Dl 
± 3 d ±3 d ± 3 d ± 3d ± 3 d ± 3 d ±3 d 
+ Sd 
EOT + 
42-49 d 
Q9W(± 7 d) 
After EOT 
Q12W 
(+ 7 d) 
ADMINISTRATIVE PROCEDURES 
Infonned consent 
X 
Contact iRT 
X 
X 
X 
X 
X 
X 
Inclusion/exclusion 
ctitetia 
X 
X 
Medical and cancer 
history 
X 
Prior/concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Disttibute reminder 
cards 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug 
dispensing 
X 
X 
X 
X 
Assess study dmg 
compliance 
X 
X 
X 
X 
Post-treatment 
anticancer therapy 
status 
X 
X 
Data collection for 
survival 
X 


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Version 4 
 
 
 
 
Table 41: 
Schedule of Assessments (Treatment  Group B: Part 2 Expansion Cohort B-11) (Continued) 
 
Visit  Day 
Screening 
Treatment 
EOT 
Follow-Up 
Notes 
Cl 
Dl 
Cl 
DS 
Cl 
DIS 
C2 
Dl 
C2 
DS 
C2 
DIS 
C3 
Dl 
C4+ 
Dl 
Safety 
Disease 
Status 
Sm'Vival 
Evaluation 
Window 
Day -28 to 
Day -I 
Dl 
± 3 d ±3 d ±3 d ± 3d ±3 d ± 3 d ±3 d 
+ S d 
EOT + 
42-49 d 
Q9W(± 7 d) 
After EOT 
Q12W 
(+ 7 d) 
CLII\'ICAL PROCEDURES AND ASSESSMENTS 
Physical 
examination/body 
weight and height* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
• Comprehensive examination at 
screening, targeted physical 
examination thereafter.  Height at 
screening only. 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG petfonnance 
status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
x• 
x•• 
x•• 
x••• 
1\ 
x••• 
1\ 
XA 
XA 
• Ttiplicate ECG at baseline. 
•• Timed ttiplicate ECGs 
(separated by 5 min± 2min) at 
predose and at 2 and 4 hours 
(± 15 min) postdose. 
"'""" ECG will be petfonned on D1 
of evety other cycle after C3 (eg, 
C5, C7, and C9). 
1\ ECGs only need to be performed 
in ttiplicate if there has been a QT 
prolongation on study or the ECG 
shows a clinically significant 
abnonnality not present at 
baseline. 
AE assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory 
assessments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Version 4 
 
 
 
 
Table 41: 
Schedule of Assessments (Treatment  Group B: Part 2 Expansion Cohort B-11) (Continued) 
 
Visit  Day 
Screening 
Treatment 
EOT 
Follow-Up 
Notes 
Cl 
Dl 
Cl 
DS 
Cl 
DIS 
C2 
Dl 
C2 
DS 
C2 
DIS 
C3 
Dl 
C4+ 
Dl 
Safety 
Disease 
Status 
Sm'Vival 
Evaluation 
Window 
Day -28 to 
Day -I 
Dl 
± 3 d ±3 d ±3 d ± 3d ±3 d ± 3 d ±3 d 
+ S d 
EOT + 
42-49 d 
Q9W(± 7 d) 
After EOT 
Q12W 
(+ 7 d) 
TUMOR BIOPSY COLLECTION 
Tumor biopsy/ 
tissue collection* 
X 
X* 
• An additional nllllldatOiy 
on-treatment biopsy will be 
collected dming Week 5 or 
Week 6. 
An additional optional biopsy may 
be collected once the subject 
meets the requirements for SD, 
response, or progression by 
radiographic disease assessment. 
Detailed instmctions for tissue 
collection, processing, and storage 
can be found in the study 
procedures manual. Fine needle 
aspirates are not acceptable. 


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Protocol INCB 24360-206 Am 4 
Page 148 of219 
30AUG2018 
Version 4 
 
 
 
 
Table 41: 
Schedule of Assessments (Treatment Group B: Part 2 Expansion Cohort B-11) (Continued) 
 
Visit  Day 
Screening 
Treatment 
EOT 
Follow-Up 
Notes 
Cl 
Dl 
Cl 
DS 
Cl 
DIS 
C2 
Dl 
C2 
DS 
C2 
DIS 
C3 
Dl 
C4+ 
Dl 
Safety 
Disease 
Status 
Sm'Vival 
Evaluation 
Window 
Day -28 to 
Day -I 
Dl 
± 3 d ±3 d ±3 d ± 3d ±3 d ± 3 d ±3 d 
+ S d 
EOT + 
42-49 d 
Q9W(± 7 d) 
After EOT 
Q12W 
(+ 7 d) 
STUDY DRUG ADMINISTRATION 
Administer 
INCB057643 in 
clinic• 
X 
X 
X 
X 
• INCB057643 and epacadostat 
should be administered at the 
same time prior to the 
pembrolizumab infusion.  Subjects 
should withhold their AM dose of 
INCB057643 on 
days. It 
should be administered in the 
clirlic following the trough. 
collection on CIDI , CID8, C2D1, 
andC2D8. 
Adrnirlister 
epacadostat in 
clinic• 
X 
X 
X 
X 
• INCB057643 and epacadostat 
should be administered at the 
same time prior to the 
pembrolizum.ab infusion.  Subjects 
should withhold their AM dose of 
epacadostat ondays. It should 
be admirlistere  m the clirlic 
following the trough 
collection 
on C1D1, C1D8, C2D1, and 
C2D8. 
Administer 
pembroliztunab in 
clinic 
X 
X 
X 
X 
EFFICACY ASSESSMENTS 
Radiologic tumor 
assessments• 
X 
X 
X 
X 
X 
• Evety 9 weeks (63 ± 7 days) 
until disease progression. After 
12 months of study treatment, 
imaging frequency may be 
reduced to evety 12 weeks. 
Imaging should not be delayed for 
delays in cycle starts or extension 
of combination treatment cycle 
intetvals. 


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Version 4 
 
 
EOT 
Safety 
Follow 
Cl 
Dl 
Cl 
D8 
Cl 
DIS 
C2 
Dl 
C2 
D8 
C2 
DIS 
C3 
Dl 
C4+ 
Dl 
±3d ±3d ±3d ±3d ±3d ±3d ±3d 
+Sd 
EOT+ 
42-49 d 
 
 
Table 42:  
Laboratory Assessments (Treatment Group B:  Part 2 Expansion Cohort B-11) 
 
NOTE:  Upon implementation of Amendment 4, this table is no longer applicable. 
 
 
 
Laboratory 
Assessment 
 
 
Notes 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Version 4 
 
 
Cl 
Dl 
Cl 
D8 
Cl 
DIS 
 
 
Table 42: 
Laboratory Assessments (Treatment  Group B: Part 2 Expansion Cohort B-11) (Continued) 
 
 
 
Laboratory 
Assessment 
C2  
C3 
DIS  
Dl 
C4+ 
Dl 
EOT 


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Table 43: 
Schedule of Assessments (Treatment Group C: Part 1Dose-Escalation and Expansion Cohorts C-1to C-8 and 
Part  2 Expansion Cohorts C-9, C-10, and C-11) 
 
NOTE:  Upon implementation of Amendment  4, this table is no longer applicable. 
 
Visit  Day 
Screening 
Treatment 
EOT 
Follow-Up 
Notes 
Cl 
Dl 
Cl 
D8 
Cl 
DIS 
C2 
Dl 
C2 
D2/4* 
C2 
D8 
C2 
DIS 
C3 
Dl 
C4+ 
Dl 
Safety 
Disease 
Status Survival * For subjects receiving 
INCB059872 QoD, an additional 
visit is required during C2 on D2 or 
D4 so that the 
samples and 
ECGs are collected on the day when 
INCB059872 is administered. 
Evaluation 
Window 
Day -28 to 
Day-1 
Dl 
± 3 d ± 3 d ± 3 d 
D2or 
D4 
± 3 d 
± 3 d ± 3 d ± 3 d +S d 
EOT 
+ 42- 
49 d 
Q9W 
(± 7 d) 
After 
EOT 
Q12W 
(+ 7 d) 
ADMINISTRATIVE PROCEDURES 
Infonned consent 
X 
Contact iRT 
X 
X 
X 
X 
X 
X 
Inclusion! 
exclusion criteria 
X 
X 
Medical and 
cancer hist01y 
X 
Prior/concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Disttibute 
reminder cards 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug 
dispensing 
X 
X 
X 
X 
Assess study dmg 
compliance 
X 
X 
X 
X 
Post-treatment 
anticancer therapy 
status 
X 
X 
Data collection 
for smvival 
X 


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Version 4 
Table 43: 
Schedule of Assessments (Treatment Group C: Part 1Dose-Escalation and Expansion Cohorts C-1to C-8 and 
Part  2 Expansion Cohorts  C-9, C-10, and C-11) (Continued) 
 
 
 
Visit  Day 
· 
Ti<:a iUJ<:UI 
EOT 
Follow-Up 
Notes 
Cl 
Dl 
Cl 
D8 
Cl 
DIS 
C2 
Dl 
C2 
D2/4* 
C2 
D8 
C2 
DIS 
C3 
Dl 
C4+ 
Dl 
Safety 
Disease 
Status Survival 
* For subjects receiving 
INCB059872 QoD, an additional 
visit is required during C2 on D2 or 
D4 so that the 
samples and 
ECGs are collected on the day when 
INCB059872 is administered. 
.....!> 
Evaluation 
Window 
Day -28 to 
Day-1 
Dl 
± 3 d ± 3 d ± 3 d 
D2or 
D4 
± 3 d 
± 3 d ± 3 d ± 3 d +S d 
EOT 
+ 42- 
49 d 
Q9W 
(± 7 d) 
After 
EOT 
Q12W 
(+ 7 d) 
CCI.TNTCC AT  PROrF.nTJRF.S AND ASSF.SSMF.NTS 
Physical 
examination/body 
weight and 
height* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
* Comprehensive examination at 
screening, targeted physical 
examination thereafter.  Height at 
only. 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG 
performance 
status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X* 
X** 
.
 
x•d x•d 
X*** 
1\ 
X*** 
1\ 
X" 
X" 
* Triplicate ECG at baseline. 
**Timed triplicate ECGs (separated 
by 5 min ± 2 min) at predose and at 
2 and 4 hours(± 15 min) postdose. 
*** ECG will be perfonned on D1 
of every other cycle after C3 (eg, 
C5, C7, and C9). 
" ECGs only need to be perfonned 
in ttiplicate if there has been a QT 
prolongation on study or the ECG 
shows a clinically significant 
abnonnality not present at baseline. 
# For subjects receiving 
INCB059872 QoD, an additional 
visit is required  during C2 on D2 or 
D4 so that the ECGs are collected 
on the day when INCB059872 is 
administered. The ECGs only need 
e performed on the day of the 
collection (C2D2 or C2D4). 


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Incyte Corporation 
Protocol INCB 24360-206 Am 4 
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30AUG 2018 
Version 4 
Table 43: 
Schedule of Assessments (Treatment Group C: Part 1Dose-Escalation and Expansion Cohorts C-1to C-8 and 
Part  2 Expansion Cohorts  C-9, C-10, and C-11) (Continued) 
 
 
 
Visit  Day 
Screening 
Treatment 
EOT 
Follow-Up 
Notes 
Cl 
Dl 
Cl 
D8 
Cl 
DIS 
C2 
Dl 
C2 
D2/4* 
C2 
D8 
C2 
DIS 
C3 
Dl 
C4+ 
Dl 
Safety 
Disease 
Status Survival 
* For subjects receiving 
INCB059872 QoD, an additional 
visit is required during C2 on D2 or 
D4 so that the 
samples and 
ECGs are collected on the day when 
INCB059872 is administered. 
Evaluation 
Window 
Day -28 to 
Day-1 
Dl 
± 3 d ± 3 d ± 3 d 
D2or 
D4 
± 3 d 
± 3 d ± 3 d ± 3 d +S d 
EOT 
+ 42- 
49 d 
Q9W 
(± 7 d) 
After 
EOT 
Q12W 
(+ 7 d) 
AE assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory 
assessments 
X 
X 
X 
X 
X 
X* 
X 
X 
X 
X 
X 
X 
* For subjects receiving 
INCB059872 QoD, an additional 
visit is required during C2 on D2 or 
D4 so that the 
samples are 
collected on the day when 
INCB059872 is administered. 
TUMOR BIOPSY COLLECTION 
Tumor biopsy/ 
tissue collection* 
X 
X* 
X** 
* Only Expansion Cohort C-11 will 
have an additional mandatory on-
treatment biopsy will be collected 
at C2D1 (window C1D15 to 
C2D1). 
** An additional mandatory 
on-treatment biopsy will be 
collected during Week 8 or Week 9. 
T11e on-treatment biopsy is optional 
for Stage 2 of Part 2. 
An additional optional biopsy may 
be collected once the subject meets 
the requirements for SD, response, 
or progression by radiographic 
disease assessment. 
Detailed instructions for tissue 
collection, processing, and storage 
can be found in the study procedures 
manual. Fine needle aspirates are 
not acceptable. 


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Version 4 
Table 43: 
Schedule of Assessments (Treatment Group C: Part 1Dose-Escalation and Expansion Cohorts C-1to C-8 and 
Part  2 Expansion Cohorts  C-9, C-10, and C-11) (Continued) 
 
 
Visit  Day 
Screening 
Treatment 
EOT 
Follow-Up 
Notes 
Cl 
Dl 
Cl 
D8 
Cl 
DIS 
C2 
Dl 
C2 
D2/4* 
C2 
D8 
C2 
DIS 
C3 
Dl 
C4+ 
Dl 
Safety 
Disease 
Status Survival 
* For subjects receiving 
INCB059872 QoD, an additional 
visit is required during C2 on D2 or 
D4 so that the 
samples and 
ECGs are collected on the day when 
INCB059872 is administered. 
Evaluation 
Window 
Day -28 to 
Day-1 
Dl 
± 3 d ± 3 d ± 3 d 
D2or 
D4 
± 3 d ± 3 d ± 3 d ± 3 d +S d 
EOT 
+ 42- 
49 d 
Q9W 
(± 7 d) 
After 
EOT 
Q12W 
(+ 7 d) 
STUDY DRUG ADMINISTRATION 
Administer 
INCB059872 in 
clinic* 
X 
X 
X 
X 
X 
* INCB059872 and epacadostat 
should be administered at the same 
time prior to the pembrolizmnab 
infusion.  Subjects should withhold 
their AM dose ofiNCB057643 on 
• days. It should be 
administered 
m the clinic following the trough 
collection on C1D1, C1D8, C2D1 or 
Administer 
epacadostat in 
clinic* 
X 
X 
X 
* INCB059872 and epacadostat 
should be administered at the same 
time prior to the pembrolizmuab 
infusion.  Subjects should withhold 
their AM dose of epacadostat on 
days. It should be administered m 
the clinic following the trough 
collection on C2D1 or C2D2/C2D4 
andC2D8. 
Administer 
pembrolizumab in 
clinic 
X 
X 
X 
EFFICACY ASSESSMENTS 
Radiologic ttunor 
assessments* 
X 
X 
X 
X 
X 
* Evety 9 weeks (63 ± 7 days) until 
disease progression.  After 
12 months of study treatment, 
imaging frequency tuay be reduced 
to every 12 weeks. Imaging should 
not be delayed for delays in cycle 
struts or extension of combination 
treatment cycle intetvals. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
. 
 
. 


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Version 4 
Table 44: 
Laboratory Assessments (Treatment Group  C: Part 1 Dose-Escalation  and Expansion Cohorts C-1 to C-8 and 
 
 
Part  2 Expansion Cohorts  C-9, C-10, and C-11) 
 
NOTE:  Upon implementation of Amendment  4, this table is no longer applicable. 
 
 
Cl 
Cl 
Cl 
C2 
C2 
C2 
C2 
C3 
C4+  
Safety 
* For subjects receiving INCB059872 
Dl  
D8  
D15  
Dl  
D2/4*  
D8 
D15  
Dl  
Dl  
EOT  
 
QoD, an additional visit is required during 
Laboratory  
 
 
 
 
 
 
 
 
 
 
C2 on D2 or D4 so that the 
samples 
Assessment 
 
 
 
 D2 or 
 
 
 
 
 
EOT + 
are collected on the day when 
Dl  
± 3 d 
±3 d 
±3 d 
D4 
± 3 d ±3 d 
±3 d 
±3 d 
+S d 
42-49 d 
INCB059872 is administered. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X** 
X 
* CEA to be petfonned in subjects with 
CRC only.  CA 19-9 to be petfonned in 
subjects with pancreatic cancer only. 
** CEA and CA 19-9 will be collected 


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Version 4 
Table 44: 
Laboratory Assessments (Treatment Group  C: Part 1 Dose-Escalation  and Expansion Cohorts C-1 to C-8 and 
 
 
Part  2 Expansion Cohorts C-9, C-10, and C-11) (Continued) 
 
 
Cl 
Cl 
Dl 
D8 
Cl 
D15 
C2  
C2 
D8  
D15 
C3 
C4+ 
Dl  
Dl 
* For subjects receiving INCB059872 
QoD, an additional visit is required during 
Laboratory 
Assessment 
t---.....:::...+----l---+--t---+---+----lr----+--t---+---+ ----C2 on D2 or D4 so that the 
samples 
are collected on the day when 
INCB059872 is administered. 


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Version 4 
Schedule of Assessments (Treatment Group C:  Part 2 Expansion Cohort C-12) 
Table 45: 
 
 
 
NOTE:  Upon implementation of Amendment 4, this table is no longer applicable. 
 
Visit  Day 
Screening 
Treatment 
EOT 
Follow-Up 
Notes 
Cl 
Dl 
Cl 
D8 
Cl 
DIS 
C2 
Dl 
C2 
D2/4* 
C2 
D8 
C2 
DIS 
C3 
Dl 
C4+ 
Dl 
Safety 
Disease 
Status 
Survival • For subjects receiving 
INCB059872 QoD, an additional 
visit is required during C2 on D2 or 
D4 so that the 
samples and 
ECGs are collected on the day when 
INCB059872 is administered. 
Evaluation 
Window 
Day -28 to 
Day -1 
Dl ±3 d ±3 d ± 3 d 
D2 or 
D4 
± 3 d ± 3 d ±3 d ±3 d + S d 
EOT + 
42-49 d 
Q9W 
(± 7 d) 
After 
EOT 
Q12W 
(+ 7 d) 
ADMINISTRATIVE PROCEDURES 
Infonned consent 
X 
Contact iRT 
X 
X 
X 
X 
X 
X 
Inclusion! 
exclusion criteria 
X 
X 
Medical and cancer 
history 
X 
Prior/concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Disttibute reminder 
cards 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug 
dispensing 
X 
X 
X 
X 
Assess study dmg 
compliance 
X 
X 
X 
X 
Post-treatment 
anticancer therapy 
status 
X 
X 
Data collection for 
survival 
X 


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Table 45: 
Schedule of Assessments (Treatment Group C: Part 2 Expansion Cohort C-12) (Continued) 
 
 
Visit  Day 
Treatment 
EOT 
Follow-VI 
Notes 
Cl 
Dl 
Cl 
D8 
Cl 
DIS 
C2 
Dl 
C2 
D2/4* 
C2 
D8 
C2 
DIS 
C3 
Dl 
C4+ 
Dl 
Safety 
Disease 
Status 
Survival 
• For subjects receiving 
INCB059872 QoD, an additional 
visit is required during C2 on D2 or 
D4 so that the 
samples and 
ECGs are collected on the day when 
INCB059872 is administered. 
Ut:t:WU 
Evaluation 
Window 
Day -28 to 
Day -1 
Dl 
±3 d ±3 d ±3 d 
D2 or 
D4 
± 3 d ±3 d ±3 d ±3 d +S d 
EOT + 
42-49 
d 
Q9W (± 7 
d) 
AfterEOT 
Q12W 
(+ 7 d) 
CLINICAL PROCEDURES AND ASSESSMENTS 
Physical 
examination/body 
weight and height* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
• Comprehensive examination at 
screening, targeted physical 
examination thereafter.  Height at 
screening; only. 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ycifut.uum,... status 
12-lead ECG 
x• 
x•• 
x••# x••# 
x••• 
1\ 
X**"' 
1\ 
X" 
X" 
• Triplicate ECG at baseline. 
"'*Timed triplicate ECGs (separated 
by 5 min ± 2 min) at predose and at 
2 and 4 hours(± 15 min) postdose. 
**"' ECG will be petfonned on D1 
of every other cycle after C3 (eg, 
C5, C7, and C9). 
" ECGs only need to be petfonned 
in ttiplicate if there has been a QT 
prolongation on study or the ECG 
shows a clinically significant 
abnonnality not present at baseline. 
# For subjects receiving 
INCB059872 QoD, an additional 
visit is required  during C2 on D2 or 
D4 so that the ECGs are collected 
on the day when INCB059872 is 
administered. TI1e ECGs only need 
to be petformed on the day of the 
collection (C2D2 or C2D4). 


CONFIDENTIAL 
Incyte Corporation 
Protocol INCB 24360-206 Am 4 
Page 159 of219 
30AUG 2018 
Version 4 
Table 45: 
Schedule of Assessments (Treatment Group C: Part 2 Expansion Cohort C-12) (Continued) 
 
 
 
Visit  Day 
Screening 
Treatment 
EOT 
Follow-Up 
Notes 
Cl 
Dl 
Cl 
D8 
Cl 
DIS 
C2 
Dl 
C2 
D2/4* 
C2 
D8 
C2 
DIS 
C3 
Dl 
C4+ 
Dl 
Safety 
Disease 
Status 
Survival 
• For subjects receiving 
INCB059872 QoD, an additional 
visit is required during C2 on D2 or 
D4 so that the 
samples and 
ECGs are collected on the day when 
INCB059872 is administered. 
Evaluation 
Window 
Day -28 to 
Day -1 
Dl 
±3 d ±3 d ± 3d 
D2 or 
D4 
± 3 d ± 3 d ± 3d ±3 d +S d 
EOT + 
42-49 
d 
Q9W  (± 7 
d) 
AfterEOT 
Q12W 
(+ 7 d) 
AE assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory 
assessments 
X 
X 
X 
X 
X 
x• 
X 
X 
X 
X 
X 
X 
• For subjects receiving 
INCB059872 on a QoD schedule, 
an additional visit is required dtuing 
Cycle 2 on Day 2 or Day 4 so that 
thesamples are collected on the 
day w 1en INCB059872 is 
administered. 
TUMOR BIOPSY COLLECTION 
Tumor biopsy/ 
tissue collection* 
X 
x• 
x• 
• Two additional mandatory on- 
treatment biopsies will be collected 
at C2Dl (window ClD15 to C2Dl) 
and dming Week 8 or Week 9. 
An additional optional biopsy may 
be collected once the subject meets 
the requirements for SD, response, 
or progression by radiographic 
disease assessment. 
Detailed instructions for tissue 
collection, processing, and storage 
can be found in the study 
procedlU'es manual. Fine needle 
aspirates are not acceptable. 


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Protocol INCB 24360-206 Am 4 
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Version 4 
 
 
Visit  Day 
Screening 
Treatment 
EOT 
Follow-Up 
Notes 
Cl 
Dl 
Cl 
D8 
Cl 
DIS 
C2 
Dl 
C2 
D2/4* 
C2 
D8 
C2 
DIS 
C3 
Dl 
C4+ 
Dl 
Safety 
Disease 
Status 
Survival 
• For subjects receiving 
INCB059872 QoD, an additional 
visit is required during C2 on D2 or 
D4 so that the 
samples and 
ECGs are collected on the day when 
INCB059872 is administered. 
Evaluation 
Window 
Day -28 to 
Day -1 
Dl 
±3 d ±3 d ± 3d 
D2 or 
D4 
± 3 d ± 3 d ± 3d ±3 d +S d 
EOT + 
42-49 
d 
Q9W  (± 7 
d) 
AfterEOT 
Q12W 
(+ 7 d) 
STUDY DRUG ADMINISTRATION 
Administer 
INCB059872 in 
clinic• 
X 
X 
X 
X 
• INCB059872 and epacadostat 
should be administered at the same 
time prior to the pembrolizmuab 
infusion.  Subjects should withhold 
their AM dose ofiNCB057643 on 
• days. It should be 
administered in the clinic following 
the trough 
• collection on C2Dl or 
Administer 
epacadostat in 
clinic• 
X 
X 
X 
X 
• INCB059872 and epacadostat 
should be administered at the same 
time prior to the pembrolizmuab 
infusion.  Subjects should withhold 
their AM dose of epacadostat on 
days. It should be administered in 
the clinic following the trough 
collection on C2Dl or C2D2/C2D4, 
andC2D8. 
Administer 
pembroliztuuab in 
clinic 
X 
X 
X 
EFFICACY ASSESSMENTS 
Radiologic ttunor 
assessments• 
X 
X 
X 
X 
X 
• Evety 9 weeks (63 ± 7 days) until 
disease progression.  After 
12 months of study treatment, 
imaging frequency may be reduced 
to every 12 weeks. Imaging should 
not be delayed for delays in cycle 
struts or extension of combination 
treatment cycle inte1vals. 
 
 
Table 45:  
Schedule of Assessments (Treatment Group C: Part 2 Expansion Cohort C-12) (Continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
. 


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Version 4 
 
 
 
 
Table 46:  
Laboratory Assessments (Treatment Group C: Part 2 Expansion  Cohort C-12) 
NOTE:  Upon implementation of Amendment 4, this table is no longer applicable. 
 
Cl 
Cl 
Cl 
C2 
C2 
C2 
C2 
C3 
C4+  
Safety  
* For subjects receiving INCB059872 QoD, an 
Laboratory 
D8  
DIS  
Dl 
D2/4*  
D8  
DIS  
Dl 
Dl 
EOT 
additional visit is required dming C2 on D2 or 
Assessment  
D2 or  
D4 so that the 
samples are collected on the 
± 3 d 
± 3 d 
± 3 d 
D4 
±3 d 
± 3d 
± 3d 
± 3 d 
+ S d 
when INCB059872 is administered. 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 * A sermn pregnancy test will be required for 
all women of childbearing potential during 
screening and must be performed within 
72 hours before the first dose of study dmg. 


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Protocol INCB 24360-206 Am 4 
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30AUG 2018 
Version 4 
 
 
 
 
Table 46:  
Laboratory Assessments (Treatment Group  C: Part  2 Expansion Cohort C-12) (Continued) 
 
 
 
 
Laboratory 
Assessment 
Cl 
Cl 
C2 
C2 
C3 
C4+  
* For subjects receiving INCB059872 QoD, an 
+- D81-2D 15_2:D 1 4-2! -I- D l.:_S-+.  D l-1._2D l !-2=additional visit is required dming C2 on D2 or 
D4 so that the 
samples are collected on the 
when INCB059872 is administered. 


CONFIDENTIAL 
Incyte Corporation 
Protocol INCB 24360-206 Am 4 
Page 163 of219 
30AUG 2018 
Version 4 
 
 
 
 
Table 47: 
Schedule of Assessments (Treatment Group C: Part 2 Expansion Cohort C-13) 
NOTE:  Upon implementation of Amendment 4, this table is no longer applicable. 
Visit  Day 
Screening 
Treatment 
EOT 
Follow-Up 
Notes 
Cl 
Dl 
Cl 
DS 
Cl 
D15 
C2 
Dl 
C2 
D2/4* 
C2 
DS 
C2 
D15 
C3 
Dl 
C4+ 
Dl 
Safety 
Disease 
Status 
Survival * For subjects receiving 
INCB059872 QoD, an additional 
visit is required during C2 on D2 or 
D4 so that the 
samples and 
ECGs are collected on the day when 
INCB059872 is administered. 
Evaluation 
Window 
Day -28 to 
Day-1 
Dl 
± 3 d ± 3 d ± 3 d 
D2 or 
D4 
± 3 d ± 3 d ±3 d ± 3 d + 5 d 
EOT+ 
42-49 d 
Q9W 
(± 7 d) 
After 
EOT 
Q12W 
(+ 7 d) 
ADMINISTRATIVE PROCEDURES 
Infonned consent 
X 
Contact iRT 
X 
X 
X 
X 
X 
X 
Inclusion! 
exclusion criteria 
X 
X 
Medical and cancer 
history 
X 
Prior/concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Disttibute reminder 
cards 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug 
dispensing 
X 
X 
X 
X 
Assess study dmg 
compliance 
X 
X 
X 
X 
Post-treatment 
anticancer therapy 
status 
X 
X 
Data collection for 
survival 
X 


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Incyte Corporation 
Protocol INCB 24360-206 Am 4 
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Version 4 
Table 47: 
Schedule of Assessments (Treatment Group C: Part 2 Expansion Cohort C-13) (Continued) 
 
 
 
Visit Day 
Treatment 
EOT 
I<n.i l..  -Up 
Notes 
Cl 
Dl 
Cl 
DS 
Cl 
D15 
C2 
Dl 
C2 
D2/4* 
C2 
DS 
C2 
D15 
C3 
Dl 
C4+ 
Dl 
Safety 
Disease 
Status 
Survival * For subjects receiving 
INCB059872 QoD, an additional 
visit is required during C2 on D2 or 
D4 so that the 
samples and 
ECGs are collected on the day when 
INCB059872 is administered. 
Evaluation 
Window 
Day -28 to 
Day -1 
Dl 
± 3 d ± 3 d ± 3 d 
D2 or 
D4 
± 3 d ± 3 d ±3 d ± 3 d + 5 d 
EOT + 
42-49 d 
Q9W 
(± 7 d) 
After 
EOT 
Q12W 
(+ 7 d) 
CLII\'ICAL PROCEDURES AND ASSESSMENTS 
Physical 
exatninationlbody 
weight and height* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
* Comprehensive exatnination at 
screening, targeted physical 
examination thereafter.  Height at 
   ....,.,.,.nin o; only. 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
J:I¥1LV!Lll<lll'-¥ status 
12-lead ECG 
X* 
X** 
X*** 
X*** 
X*** 
1\ 
X*** 
1\ 
X" 
X" 
* Triplicate ECG at baseline. 
** Timed triplicate ECGs (separated 
by 5 tnin ± 2 tnin) at predose and at 
2 and 4 hours (± 15 Inin) postdose. 
*** ECG will be performed on Dl 
of every other cycle after C3 (eg, 
C5, C7, and C9). 
" ECGs only need to be petfonned 
in ttiplicate if there has been a QT 
prolongation on study or the ECG 
shows a clinically significant 
abnonnality not present at baseline. 
#For subjects receiving 
INCB059872 QoD, an additional 
visit is required during C2 on D2 or 
D4 so that the ECGs are collected 
on the day when INCB059872 is 
administered. The ECGs only need 
to be petfonned on the day of the 
collection (C2D2 or C2D4). 


CONFIDENTIAL 
Incyte Corporation 
Protocol INCB 24360-206 Am 4 
Page 165 of219 
30AUG 2018 
Version 4 
Table 47: 
Schedule of Assessments (Treatment Group C: Part 2 Expansion Cohort C-13) (Continued) 
 
 
Visit  Day 
Screening 
Treatment 
EOT 
Follow-Up 
Notes 
Cl 
Dl 
Cl 
DS 
Cl 
D15 
C2 
Dl 
C2 
D2/4* 
C2 
DS 
C2 
D15 
C3 
Dl 
C4+ 
Dl 
Safety 
Disease 
Status 
Survival 
* For subjects receiving 
INCB059872 QoD, an additional 
visit is required during C2 on D2 or 
D4 so that the 
samples and 
ECGs are collected on the day when 
INCB059872 is administered. 
Evaluation 
Window 
Day -28 to 
Day -1 
Dl 
± 3 d ± 3 d ± 3 d 
D2 or 
D4 
± 3 d ± 3 d ±3 d ± 3 d + 5 d 
EOT + 
42-49 d 
Q9W 
(± 7 d) 
After 
EOT 
Q12W 
(+ 7 d) 
AE assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory 
assessments 
X 
X 
X 
X 
X 
X* 
X 
X 
X 
X 
X 
X 
* For subjects receiving 
INCB059872 QoD, an additional 
visit is required during C2 on D2 or 
D4 so that the 
samples are 
collected on the day when 
INCB059872 is administered. 
TUMOR BIOPSY COLLECTION 
Tumor biopsy/ 
tissue collection* 
X 
X* 
* An additional mandatory on- 
treatment biopsy will be collected 
during Week 5 or Week 6. 
An additional optional biopsy may 
be collected once the subject meets 
the requirements for SD, response, 
or progression by radiographic 
disease assessment. 
Detailed instmctions for tissue 
collection, processing, and storage 
can be fotmd in the study 
procedmes manual.  Fine needle 
aspirates are not acceptable. 


CONFIDENTIAL 
Incyte Corporation 
Protocol INCB 24360-206 Am 4 
Page 166 of219 
30AUG 2018 
Version 4 
Table 47: 
Schedule of Assessments (Treatment Group C: Part 2 Expansion Cohort C-13) (Continued) 
 
 
Visit  Day 
Screening 
Treatment 
EOT 
Follow-Up 
Notes 
Cl 
Dl 
Cl 
DS 
Cl 
D15 
C2 
Dl 
C2 
D2/4* 
C2 
DS 
C2 
D15 
C3 
Dl 
C4+ 
Dl 
Safety 
Disease 
Status 
Survival 
* For subjects receiving 
INCB059872 QoD, an additional 
visit is required during C2 on D2 or 
D4 so that the 
samples and 
ECGs are collected on the day when 
INCB059872 is administered. 
Evaluation 
Window 
Day -28 to 
Day-1 
Dl 
± 3 d ± 3 d ± 3 d 
D2 or 
D4 
± 3 d ± 3 d ±3 d ± 3 d + 5 d 
EOT+ 
42-49 d 
Q9W 
(± 7 d) 
After 
EOT 
Q12W 
(+ 7 d) 
STUDY DRUG ADMINISTRATION 
Administer 
INCB059872  in 
clinic* 
X 
X 
X 
X 
X 
* INCB059872 and epacadostat 
should be administered at the same 
time prior to the pembroliztunab 
infusion.  Subjects should withhold 
their AM dose ofiNCB057643 on 
• days. It should be 
administered ill the clinic following 
the trough 
• collection on CIDS, C2Dl or 
C2 2/C2 4
d C2 8
Administer 
epacadostat in 
clinic* 
X 
X 
X 
X 
X 
* INCB059872 and epacadostat 
should be administered at the same 
time prior to the pembroliztunab 
infusion.  Subjects should withhold 
their AM dose of epacadostat on 
days. It should be adtninistered ill 
the clinic following the trough 
collection on ClDS, C2DI or 
C2D2/C2D4, and C2D8. 
Adtninister 
pembroliztunab in 
clinic 
X 
X 
X 
X 
EFFICACY ASSESSMENTS 
Radiologic twnor 
assessments* 
X 
X 
X 
X 
X 
*Every 9 weeks (63 ± 7 days) tilltil 
disease progression.  After 
12 months of study treatment, 
imaging frequency may be reduced 
to every 12 weeks. Imaging should 
not be delayed for delays in cycle 
starts or extension of combination 
treatment cycle intetvals. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
. 


CONFIDENTIAL 
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Protocol INCB 24360-206 Am 4 
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30AUG 2018 
Version 4 
 
 
 
 
Table 48:  
Laboratory Assessments (Treatment Group  C: Part  2 Expansion Cohort C-13) 
NOTE:  Upon implementation of Amendment  4, this table is no longer applicable. 
 
Cl 
Cl 
Cl 
C2 
C2 
C2 
C2 
C3 
C4+  
Safety  
* For subjects receiving INCB059872 QoD, an 
Laboratory 
D8  
DIS  
Dl  
D2/4*  
D8  
DIS  
Dl  
Dl  
EOT 
additional visit is required dming C2 on D2 or 
Assessment  
D2 or  
D4 so that the 
samples are collected on the 
± 3 d 
± 3 d 
± 3 d 
D4 
±3 d 
± 3d 
± 3d 
± 3 d 
+ S d 
when INCB059872 is administered. 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 * A sermn pregnancy test will be required for 
all women of childbearing potential during 
screening and must be performed within 
72 hours before the first dose of study dmg. 


CONFIDENTIAL 
Incyte Corporation 
Protocol INCB 24360-206 Am 4 
Page 168 of219 
30AUG 2018 
Version 4 
 
 
 
 
Table 48:  
Laboratory Assessments (Treatment Group  C: Part  2 Expansion Cohort C-13) (Continued) 
 
 
 
 
Laboratory 
Assessment 
Cl 
Cl 
C2 
C2 
C3 
C4+  
* For subjects receiving INCB059872 QoD, an 
+- D81-2D 15_2:D 1 4-2! -I- D l.:_S-+.  D l-1._2D l !-2=additional visit is required dming C2 on D2 or 
D4 so that the 
samples are collected on the 
when INCB059872 is administered. 


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Protocol INCB 24360-206 Am 4 
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Version 4 
 
 
 
 
Table 49: 
Local Laboratory Tests: Required Analytes 
 
Serum  Chemishies 
Hematology 
Urinalysis With 
Microscopic Exa mination 
Hepatitis Screening 
Coagulation 
Albumin 
Alkaline phosphatase 
ALT AST 
Bicarbonate 
Blood urea nitrogen 
Calcimn 
Chloride 
Creatinine 
Glucose 
Lactate dehydrogenase 
Phosphate 
Potassimn 
Sodimn 
Total bilimbin 
Direct bilimbin  (if total 
bilimbin is elevated above 
ULN) 
Total protein 
Uric acid 
Complete blood count, 
including: 
Hemoglobin 
Hematocrit 
Platelet count 
Red blood cell count 
White blood cell count 
Differential count, 
including: 
Basophils 
Eosinophils 
Lymphocytes 
Monocytes 
Neutrophils 
Absolute values must be 
provided for: 
WBC differential 
laborato1y results: 
Lymphocytes 
Neutrophils 
Color and appearance 
pH and specific gravity 
Bilirubin 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Occult blood 
Protein 
Urobilinogen 
HBV smface antige
HBV-DNA 
HCV antibody 
HCV-RNA 
n 
PT 
PTT 
INR 
Endocrine Monitoring 
Pregnancy Testing 
ACTH 
HgbAlc 
Semm c01tisol 
Prolactin 
TSH 
Free thyroxine (T4) 
Total triiodothyronine (T3) 
Semm testosterone 
Women of childbearing 
potential only require a 
semm test at screening 
(must be perfo1med 
within 72 hours before 
the first dose of stt1dy 
dmg) and at safety 
follow-up. 
Pregnancy tests (semm 
or urine) should be 
repeated if required by 
local regulations. 
ACTH = adrenocorticotropic hormone. 
Note:  Additional tests may be required, as agreed by investigator  and sponsor, based on emerging safety data. 


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CONFIDENTIAL 
 
 
 
 
6-L 
Screening 
 
Screening is the inte1val between signing the ICF and the day the subject is emolled in the study 
(Cycle 1 Day 1 or Day 1 of Week -1 for Expansion Cohmt A-3).  Screening may not exceed 
28 days.  Assessments that are required to demonstrate eligibility may be perfmmed over the 
course of 1 or more days during the screening process. 
 
Procedures conducted as part of the subject's routine clinical management (eg, blood count, 
imaging study) and obtained before signing of infmmed consent may be used for screening or 
baseline purposes provided the procedure meets the Protocol-defined crite1ia and has been 
perfmmed in the timeframe of the study (ie, within 28 days of Cycle 1 Day 1). All infmmation 
associated with eligibility requirements must be entered into the appropriate eCRF pages. 
 
Results  from the screening visit evaluations will be reviewed to confi1m subject eligibility before 
emollment or the administration of study dmg.  Tests with results that fail eligibility 
requirements may be repeated once during screening if the investigator believes the results to be 
in enor.   For screening assessments that are repeated, the most recent available result before 
treatment assignment will be used to dete1mine subject  eligibility.  Treatment should stmt as 
soon as possible, but within 7 days after the date of registration.  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). 
 
The screening period will be used to dete1mine the baseline assessments of clinical condition and 
disease status.  Tumor assessments appropriate to the type of malignancy will be perfmmed and 
recorded in the eCRF. 
 
6-2- 
Treatment 
 
The treatment pe1iod begins on the day that the subject  receives the first dose of study dmg 
(Cycle 1 Day I) through the point at which the investigator  dete1mines that the subject will be 
pe1manently discontinued from study dmg or until the subject has received 35 administrations of 
pembrolizumab  (approximately 2 years).  Subjects who stop pembrolizumab or the combination 
with SD, PR, or CR may be eligible for up to an additional 17 cycles (approximately 1 year) of 
additional combination therapy or pembrolizumab if they experience disease progression after 
stopping the combination treatment or pembrolizumab.   Re-treatment -w·th   embrolizumab or the 
combination must be discussed and approved by the medical monitor. 
mandatmy tumor biopsies will not be perfmmed.  Re-treatment with azacitidine, INCB057643, 
or INCB059872  (based on miginal treatment assignment) along with pembrolizumab and 
epacadostat  may be administered for subjects who had a CR, PR, or SD (for > 6 months) and 
later had evidence of PD while receiving pembrolizumab and epacadostat with medical monitor 
approval. Three additional cycles of azacitidine are pe1mitted (for subjects miginally emolled in 
Treatment Group A).  Cycle 1 Day 1 (or Day 1 of Week -1 for Expansion Cohmt A-3) 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 eve1y cycle± 3 days.  Additional 
visits will be required during Cycles 1 and 2 for study dmg administration and/or safety 
assessments.   During study visits, the subject  will have clinical and 
assessments as 
outlined in Section 6.  At certain study visits, subjects will have 


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CONFIDENTIAL 
 
 
 
Toxicities will be monitored continuously and will 
cnteria. 
 
6_3_ 
End of Treatment 
 
When the subject pe1manently discontinues study dmg, the EOT visit should be conducted (EOT 
+ 5 days).  If the EOT visit coincides with a regular study visit, the EOT evaluations will 
supersede those of that scheduled visit, and the data should be entered in the EOT visit in the 
eCRF.  The subject should be encouraged to retum for the follow-up visit. 
 
6-4- 
Follow-Up 
 
6.4.1. 
Safety Follow-Up 
 
The safety follow-up pe1iod is the inte1val between the EOT visit and the scheduled follow-up 
visits, which should occur 42 to 49 days after the EOT visit (or after the last dose of study dmg if 
the EOT visit was not perfmmed).  Adverse events and SAEs must be repmted up until at least 
42 days (90 days for SAEs) after the last dose of study dmg, the date of the follow-up visit, or 
until toxicities resolve, retum to baseline, or are deemed ineversible, whichever is longer, or if a 
subject initiates new anticancer therapy, whichever is earlier.  Reasonable effmts should be made 
to have the subject retum for the follow-up visit and report any AEs that may occur during this 
period.  If the subject cannot retum to the site for the safety follow-up visit (eg, lives far away), 
the subject should be contacted by telephone for assessment of AEs and SAEs.  This contact with 
the subject should be documented in the source. 
 
If a subject is scheduled to begin a new anticancer therapy before the end of the 42-day safety 
follow-up pe1iod, the safety follow-up visit should be perfmmed  before new anticancer therapy 
is sta1ted.  Once new anticancer therapy has been initiated, the subject will move into the 
smvival follow-up period.  Upon implementation  of Amendment 4, the smvival  follow-up visit 
will no longer be required. 
 
6.4.2. 
Disease Status  Follow-Up 
 
Subjects who discontinue study treatment for a reason other than disease progression will move 
into the disease status follow-up period and should be assessed every 9 weeks (63 ± 7 days) by 
radiologic imaging to monitor disease status.  Eve1y effort should be made to collect infmmation 
regarding disease status until: 
 
• The sta1t of new antineoplastic therapy. 
 
• Disease progression. 
 
• Death. 
 
• The end of the study. 
 
Upon implementation of Amendment 4, disease status follow-up will no longer be required. 
 
6.4.3. 
Survival Follow-Up 
 
Once a subject has confiimed disease progression or sta1ts a new anticancer therapy, the subject 
moves into the smvival follow-up period and should be contacted by telephone, email, or visit at 


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least every 12 weeks(+ 7 days) to assess for survival status until death, withdrawal of consent, or 
the end of the study, whichever occurs first.  Upon implementation of Amendment  4, survival 
follow-up will no longer be required. 
 
6.5.  
End of Study 
 
Subjects  will be considered as having completed  the study if they meet any of the following 
crite1ia: 
 
• Subject has completed the safety follow-up  period. 
 
• Subject dies and a date of death is available. 
 
• Subject is known to have died; however, the date of death cannot be obtained. 
(NOTE:   Eve1y effort must be made to obtain the date of death.) 
 
• Consent is withdrawn for any fu1ther contact related to this study. 
 
- 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 othe1wise 
entitled.  Eve1y reasonable  effmt should be made to determine the reason a 
subject withdraws prematurely, and this infmmation should be recorded in the 
eCRF. 
 
• The study is te1minated by the sponsor. 
 
• The study is te1minated by the local health authority or IRB or IEC. 
 
6.6.  
Unscheduled Visits 
 
Unscheduled visits may occur at any time as medically wananted.  Visits where study dmg is 
held are considered unscheduled visits. Any assessments perfmmed  at those visits should be 
recorded in the eCRF. 


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7_ 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES 
 
7-L 
Administration of Informed Consent Form 
 
Valid infmmed consent must be obtained from the study subject before conducting any 
study-specific procedures using an ICF approved by the local IRB/IEC  that contains all elements 
required by ICH E6 and describes the nature, scope, and possible consequences of the study in a 
fmm understandable to the study subject.  Local and institutional guidelines for ICF content and 
administration must be followed; the original signed ICF must be retained by the investigator, 
and a copy of the signed ICF must be provided to the study subject.  The infmmed consent 
process for each subject must be documented in writing within the subject source documentation. 
 
7-2- 
Interactive Response Technology Procedure 
 
The IRT will be contacted to obtain a subject ID number when a subject enters screening.  Upon 
dete1mining that the subject is eligible for study entiy, the IRT will be contacted to obtain the 
treatment assignment.  Additionally, the IRT will be contacted at each regular study visit to update 
the study dmg supply. Refer to the study procedures manual for specific details regarding IRT. 
 
7_3_ 
Demography and Medical History 
 
7.3.1. 
 Demographics and General Medical History 
 
Demographic data and general medical histmy will be collected at screening.   This will include 
complete documentation  of the histmy of medical or surgical  ti·eatment for the malignancy under 
study. 
 
7.3.2. 
 Disease Characteristics and Treatment History 
 
A disease-targeted medical and medication histmy will be collected at screening. 
 
7.4. 
Prior and Concomitant Medications and Procedures 
 
Prior and concomitant medications and procedures will be reviewed to dete1mine subject 
eligibility.  All concomitant medications and measures must be recorded in the eCRF, and any 
medication received or procedure perfmmed within 30 days before Cycle 1 Day 1 and up to the 
end of 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 ti·eatments and/or 
procedures that are required to manage a subject's medical condition dming the study will also be 
recorded in the eCRF. 


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7_5_ 
Safety Assessments 
 
7.5.1. 
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 occunence 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. 
 
7.5.2. 
Physical Examinations 
 
Physical examinations must be perfmmed by a medically qualified individual such as a licensed 
physician, physician's assistant, or an advanced registered nurse practitioner, as local law 
permits. 
 
Clinically notable abnmmalities  that are considered clinically significant in the judgement of the 
investigator  are to be repmted as AEs. 
 
7.5.2.1. 
Comprehensive Physical Examination 
 
The comprehensive physical examination will include height (at screening) and body weight, and 
assessment(s) of the following organ or body systems:  skin; head, eyes, ears, nose, and throat; 
thyroid; lungs; cardiovascular  system; abdomen (liver, spleen); ext:I·emities; and lymph nodes; as 
well as a brief neurological examination. 
 
7.5.2.2. 
Targeted Physical Examination 
 
The targeted physical examination will be a symptom-directed evaluation.  The targeted physical 
examination will include body weight and assessment(s) of the body systems or organs, as 
indicated by subject symptoms, AEs, or other fmdings. 
 
7.5.3. 
Vital Signs 
 
Vital sign measurements  include blood pressure, pulse, respiratmy rate, and body temperature. 
Blood pressure and pulse will be taken with the subject in the recumbent, semirecumbent, or 
sitting position after 5 minutes of rest.  Clinically notable abnmmalities that are considered 
clinically significant in the judgment of the investigator  are to be reported as AEs. 
 
7.5.4. 
Electrocardiograms 
 
All 12-lead ECGs will be perfmmed with the subject in a recumbent or semirecumbent position 
after 5 minutes of rest.  Baseline and Cycle 1 Day 1 and Cycle 2 Day 1 ECGs should be 
tr·iplicate. Subsequent ECGs only need to be perfmmed  in tr·iplicate if there has been a QT 
prolongation on study or the ECG shows a clinically significant abnmmality not present at 
baseline. 


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II 
II
 
The 12-lead ECGs will be interpreted by the investigator at the site to be used for immediate 
subject management.  The decision to include or exclude a subject or withdraw a subject from 
the study based on an ECG flagged as "Abnmmal, Clinically Significant" is the responsibility of 
the investigator, in consultation with the sponsor's medical monitor, as appropriate.  Clinically 
notable abnmmalities that are considered clinically significant in the judgment of the investigator 
are to be repmted as AEs.  The conection method (Fridericia) used for calculating QTc will need 
to be provided in the eCRF. 
 
7.5.4.1. 
Timed Electrocardiograms 
 
Timed triplicate (separated by 5 minutes ± 2 min) ECGs will be perfmmed at baseline, Cycle 1 
Day 1, and Cycle 2 Day 1. 
 
For subjects receiving INCB059872 QoD, an additional visit is required during Cycle 2 on Day 2 
or Day 4 so that the ECGs are collected on the day when INCB059872 is administered.  The 
ECGs only need to be pe1fmmed on the day of the 
collection (Cycle 2 Day 2 or Day 4). 
Electrocardiograms will be conducted  predose  and will be conducted in conjunction with the 
2-hour and 4-homll timepoints with a ± 30 minute window.  Electrocardiograms should be 
conducted before but within 30 minutes  ofthell blood draw at the COITesponding timepoint. 
The specified postdose  timepoint may be adjusted based on emerging  
data. 
 
7.5.5. 
Laboratory Assessments 
 
A laboratmy local to the study site and subject will pe1f01m all clinicallaboratmy assessments 
for safety.  The investigative site will enter the laboratory results and laboratmy nmmal ranges 
into the eCRF.  Hematology, sennn chemistry, and urinalysis should be perfmmed  using 
standard procedures on the days indicated in Section 6. 
 
7.5.5.1. 
Serum Chemistry Tests 
 
A panel of semm chemistr·ies will be perfmmed as indicated in Section 6; analytes required for 
this panel are listed in Table 49. 
 
7.5.5.2. 
Endocrine Function Testing 
 
Endocrine function testing will be perfmmed as indicated in Section 6; required analytes  are 
listed in Table 49. 
 
7.5.5.3. 
Pregnancy Testing 
 
A sennn 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 u·eatment. A semm pregnancy test 
should also be repeated at the safety follow-up visit.  Pregnancy testing is not required if a 
subject is going to hospice. Urine pregnancy tests will be conducted as medically indicated, or 
per countiy-specific requirement.   U1ine pregnancy tests will be perfmmed locally.  If a mine 
pregnancy test is positive,  the results  should be confi1med with a semm pregnancy test. 
 
If the semm pregnancy test is negative after a urine test was positive,  the investigator  will assess 
the potential benefit/risk to the subject  and dete1mine whether it is in the subject's  best interest to 
resume study dmg and continue pa1ticipation in the study. 


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7.5.5.4.  
Hepatitis Screening Tests 
 
Hepatitis  screening assessments will be perfmmed at the screening visit (see Section  6) to mle 
out hepatitis infection; required analytes are shown in Table 49.  Additional tests may be 
perfmmed if clinically indicated. 
 
7.5.5.5. 
CA 19-9 Testing 
 
CA 19-9 testing will be perfmmed in subjects with pancreatic cancer only as indicated  in 
Section 6. 
 
 
7.6.  
Efficacy  Assessments 
 
 


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7.6.1.1. 
Initial Tumor Imaging 
 
Initial tumor imaging must be perfmmed within 28 days before the first dose of study treatment. 
The site study team must review prestudy images to confirm the subject has measurable disease 
per RECIST v1.1.  Tumor lesions that are located in a previously inadiated area or in an area 
subjected  to other locoregional therapy should not be selected  as target lesions. If a subject to be 
emolled only has lesions that are found in an area previously  inadiated  or subjected to 
locoregional therapy, then the subject will be allowed to emoll.  Additionally, it is recommended 
that tumor lesions that will be biopsied should not be selected as target lesions. 
 
Scans performed as part of routine clinical management are acceptable for use as the screening 
scan if they are of diagnostic quality and perfmmed within 28 days before the first dose of study 
treatment.  The same imaging technique should be used in a subject throughout the study. 
Baseline scan must be a contrast computed tomography (CT) or magnetic resonance imaging 
(MRI), except in circumstances where there is a contrast allergy or with medical monitor 
approval.  A PET/CT scan that uses higher energy and thinner slices for the CT component may 
be acceptable (with medical monitor approval).  Images of the chest and abdomen are required 
for all subjects.  In addition, neck imaging is also required for subjects with SCCHN.  Imaging of 
the pelvis is only required for subjects with TCC of the GU tract but is strongly encouraged for 
all subjects. 
 
7.6.1.2.  
Tumor Imaging During the Study 
 
Tumor imaging may be perfmmed by CT or MRI, but the same imaging technique should be 
used in a subject throughout the study.  Scans must be a contrast CT or MRI, except in 
circumstances where there is a contrast allergy or with medical monitor approval.  A PET/CT 
scan that uses higher energy and thinner slices for the CT component may be acceptable (with 
medical monitor approval) if it was the same technique used for baseline.  Imaging should be 
perfmmed every 9 weeks (63 days ± 7 days) or more frequently if clinically indicated.  After 
12 months of study treatment, imaging frequency may be reduced to every 12 weeks.  Imaging 
should not be delayed for delays in cycle starts or extension of combination treatment cycle 
intervals. 
 
Imaging should continue to be perfmmed 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 confnmed at least 4 weeks and not later than 8 weeks after 
the fust scan indicating PD 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 7.6.1. 


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7.6.2. 
Tumor Biopsy 
 
Tumor biopsy samples are required  for subject participation in all patts of the study.  Mandatmy 
tumor biopsies will be collected at baseline (before Day 1 administration) and while the subject 
is receiving study treatment as specified in the following: 
 
• An additional mandatmy on-treatment  biopsy will be collected during Week 5 or 
Week 6 (Treatment Group A) or Week 8 or Week 9 (Treatment  Groups B and C); the 
on-treatment biopsy is optional for Stage 2 cohmts in Patt 2.  On-treatment  biopsies 
should be collected from the same tumor lesion that was biopsied at baseline. 
 
• Cohmts A-3, A-4, A-5, B-9, B-10, C-ll, and C-12: A baseline biopsy and 
2 on-treatment biopsies are required for subjects emolled in the treatment sequencing 
biopsy cohmts.  The timing for the biopsies is presented in Table 5, Table 7, and 
Table 9. 
 
• An additional optional biopsy may be collected once the subject meets the 
requirements for SD, response, or progression by radiographic disease assessment. 
 
Note:  If a subject  is scheduled to have a tumor biopsy for the purposes of this study and it is 
subsequently detetmined that tumor tissue cannot safely be obtained, then the subject may still 
emoll in the study, and such subjects may be replaced. 
 
Care should be taken to biopsy the same lesion for the baseline and on-treatment 
·ect has a 
this should not be   · 
 
 
 
Note:  As a quality control step, prior to submitting the tumor tissue to the centrallaboratmy 
vendor, all tumor tissue will be fmmalin-fixed and paraffin-embedded locally.  An H&E stain 
will be perfmmed  and reviewed  by a local pathologist  to verify the adequacy of the tumor 
biopsy.  Additionally, a quality control fotm will be signed and dated by the reviewing 
pathologist.   For the screening biopsy, this fmm will ideally be submitted to the sponsor at the 
same time the registration fmm is submitted for emollment. 
 
Details and methods for obtaining, processing, and 
the tumor · 
in the 
Manual for the study. 
 
 
 
7.7.  
Performance and Quality-of-Life Assessments 
 
ECOG perfmmance  status  (see Appendix D) must be assessed by a medically qualified 
individual and recorded in the eCRF at visits indicated in Section  6. 
 
 


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7_10.  
Other Study  Procedures 
 
7.10.1. 
Distribution of Subject Reminder Cards and Subject Diaries 
 
Subjects will be provided with subject reminder cards at each visit. The subject reminder cards 
will indicate the date and time of the next visit. Reminder cards will include instructions specific 
for Day 1visits, at which time the subject will refrain from taking the study dmg at home in the 
moming before the clinic visit.  All necessary  instmctions, such as administr·ation instructions for 
study dmg, concomitant medications, and reminders of visits to conduct laboratory tests, should 
be provided to the subject in writing on this reminder card, or on accompanying written 
materials.  Subject diaries will be provided for the purpose of documenting study dmg 
administr·ation and AEs.  The subject dia1y will have an area on which the date and time of the 
last dose taken before each visit will be recorded as well as the time (and content if applicable to 
the visit) of the last meal 
 
7.10.2. 
Data Collection for Survival Follow-Up 
 
For subjects having entered the survival follow-up  period of the study, the site will use continuing 
subject  records to supply data on subsequent  tr·eatment regimens, tumor assessments (if 
discontinued tr·eatlnent for a reason other than progression), and OS in the eCRF.  For subjects 
who do not intend to retum to the study investigator  for their ongoing care, follow-up should be 
maintained by phone contact, patient records, and public records/databases at intervals of no 
longer than 12 weeks (see Section 6.4.3).  Upon implementation  of Amendment 4, survival 
follow-up is no longer required. 


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8_ 
SAFETY MONITORING AND REPORTING 
 
8-L  
Adverse Events 
 
8.1.1. 
Definitions 
 
For the purposes of this Protocol, an AE is defined as any untoward medical occunence 
associated with the use of a dmg in humans, whether or not considered dmg related, that occurs 
after a subject provides infmmed consent.  Abnmmallaboratmy values or test results occmTing 
after infmmed consent  constitute AEs only if they induce clinical signs or symptoms, are 
considered clinically meaningful, require therapy (eg, hematologic abnmmality that requires 
transfusion), or require changes in the study dmg(s). 
 
8.1.2. 
Reporting 
 
Adverse events that begin or worsen after infmmed consent  should be recorded on the Adverse 
Events fmm of the eCRF.  Conditions that were already present  at the time of infmmed consent 
should be recorded on the Medical Histmy fmm in the eCRF.  Monitoring for the occunence of 
new AEs should be continued for at least 42 days after the last dose of study dmg.  Adverse 
events (including laboratmy abnmmalities  that constitute AEs) should be desc1ibed using a 
diagnosis whenever possible rather than by individual underlying signs and symptoms.  When a 
clear diagnosis cannot be identified, each sign or symptom should be reported as a separate AE. 
 
The teim "disease progression" should be recorded as an AE/SAE only ifthere are no other 
identifiable AEs/SAEs  associated with the disease  progression at the time of repmting.  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 repmted 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 
repmted 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 (repmted as a diagnosis or as signs 
and symptoms) is related to disease progression on the Adverse Events fmm of the eCRF. 
 
The seve1ity 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.  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 seve1ity. 
 
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. 


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The occmTence of AEs should be sought by nondirective questioning of the subject during the 
screening process after signing the ICF and at each visit dming 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, laboratmy test, or other assessments.  To the 
extent possible, each AE should be evaluated to dete1mine: 
 
• 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 sta1t and end dates, unless unresolved at final follow-up. 
• The action taken with regard to study dmg. 
• The event outcome (eg, not recovered/not resolved, recovered/resolved, 
recovering/resolving, recovered/resolved with sequelae, fatal, unknown). 
• The se1iousness, as per SAE definition provided in Section 8.3.1. 
 
Unlike routine safety assessments, SAEs are monitored continuously and have special repmting 
requirements  (see Section 8.3.2). 
 
All AEs should be treated appropriately. If an AE is treated with a concomitant medication or 
nondmg therapy, this action should be recorded on Adverse Event fmm and the treatment should 
be specified on the P1ior/Concomitant Medications or Procedures and Non-Dmg Therapy fmm 
in the eCRF. 
 
Once an AE is detected, it should be followed until it has resolved or until it is judged to be 
pe1manent; assessment should be made at each visit (or more frequently if necessa1y) of any 
changes in severity, the suspected  relationship to the study dmg, the interventions required to 
treat the event, and the outcome. 
 
When the severity of an AE changes over time for a repmting period (eg, between visits), each 
change in severity will be repmted as a separate AE until the event resolves.  For example, 
2 separate AEs will be repmted if a subject has Grade 1 dianhea, meeting the definition of an 
AE, that lasts for 3 days before worsening to a Grade 3 severity.  The Grade 1 event will be 
repmted as an AE with a sta1t 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 repmted as an AE, with the sta1t date equal to the day the event 
changed in intensity from Grade 1 to Grade 3 and a stop date equal to the day that the event 
either changed severity again or resolved. 
 
8-2- 
Laboratory Test Abnormalities 
 
Laboratmy  abnmmalities that constitute an AE in their own 1ight  (considered clinically 
meaningful, induce clinical signs or symptoms,  require concomitant therapy, or require changes in 
study dmg) should be recorded on the Adverse Event fmm in the eCRF.  Whenever possible, a 
diagnosis rather than a symptom should be provided (eg, "anemia" instead of "low hemoglobin"). 
Laboratory abnmmalities that meet the crite1ia for AEs should be followed until they have 
retumed to nmmal or an adequate explanation of the abnmmality  is found.  When an abnmmal 
laboratmy test result conesponds to a sign or symptom of a previously repmted AE, it is not 
necessa1y to separately record the laboratmy test result as an additional event. 


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Laboratmy  abnmmalities 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 laboratmy abnmmality may 
be required (see Section 5.4) and should not contribute to the designation of a laboratmy test 
abnmmality as an SAE. 
 
8_3_ 
Serious Adverse Events 
 
8.3.1. 
Definitions 
 
An SAE is defmed as an event that meets at least 1 of the following c1iteria: 
 
• 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 surge1y or preplanned  treatment for a pre-existing  condition that is 
umelated 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 adinission. 
- Any social reasons and respite care, in the absence of any dete1ioration in the 
subject's general condition. 
• Results in persistent or significant disability, incapacity,  or a substantial dismption of 
a person's ability to conduct nmmal life f unctions. 
• Constitutes a congenital anomaly or birth defect. 
• Is considered to be an impmtant  medical event or a medically significant event that 
may not result in death, be immediately life-threatening, or require hospitalization but 
may be considered serious when, based on appropriate medical judgment, the event 
may jeopardize the subject or may require medical or surgical intervention to prevent 
1 of the outcomes listed above. 
 
8.3.2. 
Reporting 
 
Eve1y SAE, regardless of suspected causality (eg, relationship to study dmg(s) or study 
procedure or disease progression),  occmTing after the subject has signed the ICF through the last 
study visit (or 90 days after the last dose of study dmg, whichever is later) must be repmted to 
the sponsor (or designee) within 24 hou rs of leaming of its occmTence, unless othe1wise 
specified by the Protocol.   Any SAEs occmTing more than 90 days after the last dose of study 
dmg should be reported to the sponsor or its designee only if the investigator suspects  a causal 
relationship to the study dmg. 
 
Infmmation about all SAEs is collected and recorded on the Adverse Event fmm of the eCRF. 
The investigator must assess and record the causal relationship of each SAE to the study 
treatment. 


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The investigator must also complete the Incyte Serious Adverse Event Repo1t Fmm, in English, 
and send the completed and signed fmm 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 Repmt Fmm. 
 
The contact infmmation of the sponsor's study-specific representatives is listed in the 
investigator manual provided to each site.  The original copy of the SAE Repmt Fmm and the 
confi1mation sheet must  be kept at the study site. 
 
Investigational site personnel must repmt any new infmmation regarding the SAE within 
24 hours of becoming aware of the infmmation in the same manner that the initial SAE Repmt 
Fmm was sent.  Follow-up infmmation is recorded on an amended or new SAE Repmt Fmm, 
with an indication that it is follow-up to the previously repo1ted SAE and the date of the miginal 
repmt.  The follow-up repmt should include infmmation that was not provided on the previous 
SAE Repmt Fmm, such as the outcome of the event (eg, resolved  or ongoing), treatment 
provided, action taken with study dmg because of the SAE (eg, dose reduced, intenupted, or 
discontinued), or subject disposition (eg, continued or withdrew from study pa1ticipation).  Each 
recurrence, complication, or progression of the miginal event should be repmted as follow-up to 
that event, regardless of when it occurs. 
 
If the SAE is not documented in the IB for the study dmg, or in the US package inse1t or 
Summa1y of Product Characte1istics for marketed drugs as approp1iate, (new occunence) and is 
thought to be related to the sponsor's study dmg, the sponsor  or its designee may urgently require 
fmther infmmation from the investigator  for repmting to health authmities.  The sponsor or its 
designee may need to issue an Investigator  Notification (IN) to infmm all investigators involved 
in any study with the same dmg that this SAE has been repmted.  Suspected Unexpected  Se1ious 
Adverse Reactions (SUSARs) will be collected and repmted to the competent authmities and 
relevant ethics committees in accordance with Directive 2001/20/EC, or as per national 
regulatmy requirements in pa1ticipating countries. 
 
8-4- 
Adverse  Events of Special Interest 
 
Adverse events of special interest include irAEs that are seen with immunotherapy and any other 
observed autoimmune phenomenon.  Guidance for the assessment, diagnosis, and management of 
irAEs is provided in Section 5.4.1.3.  Immune-related AEs will be monitored carefully at each 
cycle and dming the safety follow-up period. 
 
As noted in Section 1.8.1, there is an uncommon risk that epacadostat could cause an increase in 
serotonin levels in the brain that might t1igger SS (Boyer and Shannon 2005) when administered 
in combination with other serotonergic agents.  This syndi·ome has been most closely associated 
with use ofMAOis, mepe1idine, linezolid, or methylene blue; all of these agents are prohibited 
during the study.  Selective serotonin reuptake inhibitors and SNRis are pe1mitted in the study. 
Procedures listed in Section 5.4.3 will be implemented if subjects exhibit the signs/symptoms of 
SS, including tremor, hypeneflexia, spontaneous, ocular, or inducible clonus together with 
agitation, fever, diaphoresis, or muscle 1igidity. 


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8.5.  
Emergency Unblinding of Treatment Assignment 
 
Not applicable. 
 
8.6.  
Pregnancy 
 
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that study dmg may 
have interfered with the effectiveness of a contraceptive medication or method.  When a 
pregnancy has been confi1med in a subject dming matemal or patemal exposure to study dmg, 
the following procedures  should be followed in order to ensure subject safety: 
 
• The study dmg must be discontinued immediately (female subjects only; see 
Section 5.4.1.2 for the maximum pe1mitted duration of study dmg intenuption). 
 
• The investigator must complete and submit the Incyte Clinical Trial Pregnancy fmm 
to the sponsor or its designee within 24 hours of leaming of the pregnancy. 
 
Data on fetal outcome and breastfeeding are collected for regulatmy reporting and dmg safety 
evaluation.  Follow-up should be conducted for each pregnancy to dete1mine outcome, including 
spontaneous or volunta1y te1mination, details of the birth, and the presence or absence of any 
birth defects, congenital abnmmalities, or matemal and/or newbom complications, by following 
until the first well-baby visit.  Pregnancy should be recorded on a Clinical Trial Pregnancy fmm 
and repmted by the investigator  to the sponsor  or its designee.   Pregnancy follow-up infmmation 
should be recorded on the same fmm and should include an assessment of the possible causal 
relationship to the sponsor's study dmg 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 Fmm. 
 
Any SAE occurring during pregnancy  must be recorded  on the SAE report  form and 
submitted to the sponsor or designee. 
 
8.7.  
Warnings and Precautions 
 
Special wamings or precautions for the study dmg, derived from safety infmmation collected by 
the sponsor or its designee, are presented in the epacadostat  Investigator's Brochure (IB). 
Additional safety infmmation collected between IB updates will be communicated in the fmm of 
INs.  Any impmtant new safety infmmation should be discussed with the subject dming the 
study, as necessa1y. If new significant risks are identified, they will be added to the ICF. 
 
8.8.  
Data  Monitoring Committee 
 
Not applicable. 
 
8.9.  
Product Complaints 
 
The sponsor collects product complaints on study dmgs and dmg delive1y systems used in 
clinical studies  in order to ensure the safety of study pa1ticipants, monitor quality, and facilitate 
process and product improvements. 


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All product complaints associated with material packaged, labeled, and released by the sponsor 
or its designee will be repmted to the sponsor.   All product complaints associated with other 
study material will be reported directly to the respective manufacturer. 
 
The investigator or his/her designee  is responsible for reporting a complete description of the 
product complaint via email or other written communication to the sponsor  contact or respective 
manufacturer as noted in the packaging infmmation.  Any AE associated with a product 
complaint should be repmted as described in Section 8.1.2 of this Protocol. 
 
If the investigator  is asked to retum the product for investigation, he/she will retum a copy of the 
product complaint communication with the product. 
 
 
 
9.  
STATISTICS 
 
9.1.  
Study Populations 
 
The safety population includes all subjects emolled in the study who received at least 1 dose of 
study dmg (azacitidine, INCB057643, INCB059872, pembrolizumab, or epacadostat).  All safety 
analyses will be based on the safety population. 
 
The full analysis set includes all subjects emolled in the study who received at least 1 dose of 
study dmg (azacitidine, INCB057643, INCB059872, pembrolizumab, or epacadostat) and had at 
least 1 postbaseline assessment or discontinued treatment.  All efficacy analyses will be based on 
the full analysis set. 
 
 
9.2.  
Selection of Sample Size 
 
9.2.1. 
Sample Size in Part 1 
 
9.2.1.1. 
Dose Escalation 
 
The prima1y objective ofPa1t 1 of the study is to dete1mine the MTD, maximum tested dose, or 
PAD of the triplet combination  of azacitidine, INCB057643, or INCB059872 with 
pembrolizumab  and epacadostat.  The total number of subjects will depend on the number of 
dose levels tested before the MTD, maximum tested dose, or PAD is established. 
 
A 3 + 3 + 3 dose-escalation  design will be used in Pa1t 1.  Based on 3 + 3 + 3 design algorithm, 3 
to 9 subjects will be emolled at each dose level.  The algmithm of3+3+3 is detailed in 
Section 4.1.1.  The probability of dose de-escalation from a given dose level for the various DLT 
rates are provided in Table 55.  For example, if the tme DLT rate is 20% at a given dose level, 
there is a 78.4%  chance that the dose would be escalated. 


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Table 55:  
Probability of Dose De-Escalation  for Various Dose-Limiting Toxicity Rates 
 
True DLT Rate 
Probability of Dose De-Escalation 
20% 
21.6% 
30% 
43.9% 
40% 
65.0% 
50% 
81.1% 
60% 
91.2% 
 
9.2.1.2. 
Dose Expansion 
 
In addition to the dose-escalation cohmts, dose-expansion cohmts for Treatment Groups B and C 
in 5 NSCLC subjects who progressed on a PD-1 pathway-targeted agent and 5 MSS CRC 
·ects will be 
 at each dose level tested that clears the DLT window for signal detection 
analysis to guide an RP2D. 
 
The expansion will include: 
 
1.   Safety/efficacy cohorts in NSCLC 
 
a.   B-1:  INCB057643 4 mg QD followed by the pembrolizumab/epacadostat doublet 
b.   B-3:  INCB057643 8 mg QD followed by the pembrolizumab/epacadostat doublet 
c.   B-5:  INCB057643 12 mg QD followed by the pembrolizumab/epacadostat doublet 
d.   C-1:  INCB059872 1 mg QoD followed by the pembrolizumab/epacadostat doublet 
e.   C-3: INCB059872 2 mg QoD followed by the pembrolizumab/epacadostat doublet 
f. C-5:  INCB059872 1 mg QD followed by the pembrolizumab/epacadostat doublet 
g.  C-7:  INCB059872  3 mg QoD followed by the pembrolizumab/epacadostat doublet 
 
2.   Safety/efficacy cohmts in CRC 
 
a.   B-2:  INCB057643 4 mg QD followed by the pembrolizumab/epacadostat doublet 
b.   B-4:  INCB057643 8 mg QD followed by the pembrolizumab/epacadostat doublet 
c.   B-6:  INCB057643 12 mg QD followed by the pembrolizumab/epacadostat doublet 
d.   C-2:  INCB059872 1 mg QoD followed by the pembrolizumab/epacadostat doublet 
e.   C-4:  INCB059872 2 mg QoD followed by the pembrolizumab/epacadostat doublet 
f. C-6:  INCB059872  1 mg QD followed by the pembrolizumab/epacadostat doublet 
g.  C-8:  INCB059872 3 mg QoD followed by the pembrolizumab/epacadostat doublet 
 
9.2.2. 
Sample Size in Part  2 
 
9.2.2.1. 
Safety/Efficacy  Expansion Cohorts 
 
The safety/efficacy expansion in Part 2 will include 2 cohmts per treatment group, subjects with 
NSCLC who have had disease progression on a prior PD-1 pathway-targeted agent and subjects 
with MSS CRC.  A Simon 2-stage design will be used for each of the cohmts. The response 
rates for the histmical control  (po), desired response  rates for the combination (p1), number of 
subjects needed in Stage 1 (n1) and Stage 2 (n2), total number of subjects (n), first stage threshold 
declaring cohmt  undesirable (r1), and the upper limit of the number of responses  in n subjects 
such that f utility of the drug is concluded (r) are provided for each expansion cohmt in Table 56. 
The calculation is based on a 1-sided Type I error of 0.05 and power of 80%. 


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Table 56: 
Simon  2-Stage Design 
 
 
 
Cohort 
Tumor Type 
Po 
Pt 
nt 
nz 
n 
Tt 
r 
Expansion Cohmt A-1 
NSCLC subjects who 
have had disease 
progression on a prior 
PD-1 pathway-targeted 
agent 
3% 
20% 
8 
19 
27 
0 
2 
Expansion Cohmt A-2 
MSSCRC 
3% 
20% 
8 
19 
27 
0 
2 
Expansion Cohmt B-7 
NSCLC subjects who 
have had disease 
progression on a prior 
PD-1 pathway- targeted 
agent 
3% 
20% 
8 
19 
27 
0 
2 
Expansion Cohmt B-8 
MSSCRC 
3% 
20% 
8 
19 
27 
0 
2 
Expansion Cohmt C-9 
NSCLC subjects who 
have had disease 
progression on a prior 
PD-1 pathway- targeted 
agent 
3% 
20% 
8 
19 
27 
0 
2 
Expansion Cohmt C-10 
MSSCRC 
3% 
20% 
8 
19 
27 
0 
2 
 
9.2.2.2. 
Sample Size for Treatment Sequencing Tumor Biopsy Cohorts 
 
Three treatment sequencing tumor biopsy cohmts per treatment group will be emolled to 
evaluate epigenetic and tumor microenvironment changes.  Five to 8 evaluable subjects per each 
tumor type will be emolled in Expansion Cohmts A-3, A-4, B-9 through B-11, and C-11 through 
C-13.  The eligible tumor types are HNSCC, melanoma, urothelial carcinoma, and MSS CRC. 
Subjects with tumor types other than MSS CRC must have had disease progression on a p1ior 
PD-1 pathway-targeted agent.  Ten subjects with first-line melanoma will be emolled in 
Expansion Cohmt A-5.  See Table 5, Table 7, and Table 9 for more details regarding treatment 
sequences and biopsy sequences for Treatment Groups A, B, and C, respectively. 
 
Assuming the tme rate of subjects positive for the biomarker is 70%, the probability of observing 
16 or more subjects out of25 subjects with the biomarker is 81% for Expansion Cohorts A-3, 
A-4, B-9, through B-11, and C-11 through C-13, and the probability of obse1ving 6 or more 
subjects out of 10 subjects with the biomarker is 85% for Expansion Cohmt A-5. 
 
9.3. 
Level  of Significance 
 
For the prima1y efficacy endpoints, the 1-sided Type I enor  will be controlled at 0.05 for each 
individual cohmt expansion.  For other endpoints, Cis will be repmted at a 95% confidence 
level. Note that this level of significance does not account for the multiple expansion  cohmts. 


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9-4_ 
Statistical Analyses 
 
9.4.1. 
Primary Analyses 
 
Part 1:  The clinical safety data (vital signs, ECGs, routine laboratory tests, and AEs) for subjects 
with advanced or metastatic solid tumors will be summarized  using descriptive statistics (eg, 
mean, frequency) using the safety population, which is detailed in Section 9.4.4. 
 
Part 2:  The proportion of subjects with previously treated Stage IV or recunent NSCLC, 
Stage IV MSS CRC, and other selected solid tumors who meet the objective response crite1ia 
(CR + PR),  as per RECIST vl.1, will be estimated with 95% CI. 
 
9.4.2. 
Secondary Analyses 
 
Part 1:  The proportion of subjects with advanced or metastatic solid tumors who meet the 
objective response criteria (CR + PR), as per RECIST vl.1, will be estimated with 95% CI. 
 
Part 2:  The clinical safety data (vital signs, ECGs, routine laboratory tests, and AEs) for subjects 
with previously treated Stage IV or recunent NSCLC, Stage IV MSS CRC, and other select solid 
tumors will be summarized  using descriptive statistics  (eg, mean, frequency) using the safety 
population, which is detailed in Section 9.4.4. 
 
Parts 1 and 2:  The percentage of TIL responders for subjects with advanced or metastatic solid 
tumors and previously treated Stage IV or recunent NSCLC and Stage IV MSS CRC will be 
estimated with 95% CI.  A subject is considered a TIL responder if the subject has an increase in 
the number of TILs  or the ratio of CD8+ lymphocytes to Tregs infiltrating tumor post-treatment 
versus pretreatment with pembrolizumab and epacadostat  in combination with azacitidine, 
INCB057643, or INCB059872 evaluated  by IHC. 
 
Paits 1 and 2:  PFS and DOR of subjects with advanced or metastatic solid tumors and 
previously treated Stage IV or recunent NSCLC and Stage IV MSS CRC will be estimated using 
Kaplan-Meier method as per RECIST vl.1 ifthere are enough obse1vations. 
 
 


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9.4.4. 
Safety Analyses 
 
9.4.4.1. 
Adverse Events 
 
A TEAE is any AE either repmted for the first time or worsening of a pre-existing event after 
first dose of study dmg.  Analysis of AEs will be limited to TEAEs, but data listings  will include 
all AEs regardless of their timing to study dmg administration.  Adverse events will be tabulated 
by the MedDRA prefened te1m and system organ class.  Severity of AEs will be based on the 
NCI CTCAE v4.03 using Grades 1 through 4. 
 
The subset of AEs considered by the investigator  to have a relationship to study dmg will be 
considered to be treatment-related AEs.  If the investigator does not specify the relationship of 
the AE to study dmg, the AE will be considered treatment-related. The incidence of AEs and 
treatment-related AEs will be tabulated. 
 
9.4.4.2. 
Clinical Laboratory Tests 
 
Laboratmy test values outside the nmmal range will be assessed for severity based on the nmmal 
ranges for the clinical reference laboratmy. The incidence of abnmmallaboratory values and 
shift tables relative to baseline will be tabulated. 
 
Laboratmy data will be classified into Grades 1 through 4 using CTCAE v4.03.  The following 
summa1ies will be produced for the laboratory data: 
 
• Number and percentage of subjects with worst postbaseline CTCAE grade (regardless 
ofbaseline value).  Each subject will be counted only for the worst grade observed 
postbaseline. 
 
• Shift tables from baseline  to the worst postbaseline value using CTCAE grade. 
 
• For laboratmy parameters where CTCAE grades are not defmed, shift tables to the 
worst postbaseline value using the low/nmmal/high classifications based on 
laboratmy reference ranges. 
 
9.4.4.3. 
Vital Signs 
 
Descriptive statistics and mean change from baseline will be dete1mined for vital signs (blood 
pressure, pulse, respiratmy rate, and body temperature) at each assessment time.  Vital sign 
results will be reviewed for clinically notable abnmmalities  (see Table 57), and subjects 
exhibiting clinically notable vital sign abnmmalities will be listed.  A value will be considered an 
"ale1t" value if it is outside the established range and shows a > 25% change from baseline. 


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Parameter 
High Threshold 
Low Threshold 
QTcF 
> 460 msec 
< 295 msec 
PR 
> 220 msec 
< 75 msec 
QRS 
> 120 msec 
< 50 msec 
QT 
> 500 msec 
< 300 msec 
RR 
> 1330 msec 
< 600 msec 
Fndencta 
 
Table 57:  
Criteria for Clinically Notable Vital Sign Abnormalities 
 
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure 
> 155 rrunHg 
< 85 mmHg 
Diastolic blood pressure 
> 100 rrunHg 
< 40nunHg 
Pulse 
> 100 bpm 
< 45 bpm 
Temperature 
> 38°C 
< 3s.soc 
Respirato1y rate 
> 24/min 
< 8/min 
 
9.4.4.4. 
Electrocardiograms 
 
Descriptive statistics and mean change from baseline will be dete1mined for each ECG parameter 
at each assessment time.  Electrocardiogram results will be reviewed for clinically notable 
abnmmalities according to predefined crite1ia (see Table 58).  Subjects exhibiting clinically 
notable ECG abnmmalities  will be listed. 
 
Table 58:  
Criteria for Clinically Notable Electrocardiogram Abnormalities 
 
 
 
 
 
 
 
 
 
 
 
QTcF = 
.. correction. 
 
9.4.4.5. 
Adverse Events of Special Interest 
 
Adverse events of special interest include irAEs that are seen with immunotherapy and any other 
observed autoimmune phenomenon. 
 
An overall summary of irAEs will include number (%) of subjects reporting any irAEs, any 
Grade 3 or 4 irAEs, any treatment-related irAEs, any fatal irAEs, and any irAEs leading to 
treatment intenuption/dose reduction/discontinuation. 
 
 


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9_5_ 
Analyses for the Data Monitoring Committee 
 
Not applicable. 
 
9_6_ 
Interim Analysis 
 
In Pa1t 2, there will be a planned interim analysis for futility in Expansion Cohmts A-1, A-2, B-
7, B-8, C-9, and C-10.  The Simon 2-stage design will be applied to each safety/efficacy 
expansion cohmt independently.  During Stage 1, 8 NSCLC subjects who progressed on a PD-1 
pathway-targeted agent and 8 MSS CRC subjects will be emolled.  If no responses are observed 
in the NSCLC PD-1 failure and MSS CRC cohmts, the cohmt will be tenninated for futility.  If 
at least 1 response  is obsetved in the NSCLC PD-1 failure or MSS CRC cohmt, 19 additional 
NSCLC PD-1 failure or MSS CRC subjects will be emolled for Stage 2 evaluation. 
 
Based on this early termination mle, the probability of early temlination is 0.7837 for subjects 
with NSCLC who are PD-1 failures and subjects with MSS CRC under the assumption  of 
historical control response rate; the probability of early tetmination is 0.1678 for subjects with 
NSCLC who are PD-1 failures and subjects with MSS CRC under the assumption of desired 
response  rate. 
 
The interim analysis for each expansion cohort will be conducted once the first postbaseline 
radiologic tumor assessments for Stage 1 subjects within the cohmt are available. Emollment 
will be held at that time unless a sufficient number of responders have been obsetved before that 
time. 


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10. 
ETHICAL CONSIDERATIONS  AND ADMINISTRATIVE 
PROCEDURES 
 
10.1. 
Investigator Responsibilities 
 
This study will be performed in accordance with ethical principles that originate in the 
Declaration of Helsinki and conducted in adherence to the study Protocol; GCPs as defined in 
Title 21 of the US CFR Pa1ts 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: 
 
• Pe1mitting study-related monitoring, sponsor  audits, IRB/IEC review, and regulatmy 
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 predete1mined plan.  The 
investigator must allow the study monitors to review any study materials and 
subject records at each monitming 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. 
 
- Regulatmy inspection:  Regulatmy authmities 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 suppmting the eCRFs and other 
study-related documents.  The investigator  must immediately notify the sponsor 
when contacted by any regulatmy authority for the purposes of conducting an 
inspection. 
 
• Obtaining infmmed consent and ensming that the study subjects' questions have been 
answered and the subjects fully understand study procedures: 
 
- Infmmed consent must be obtained before any study-related procedures are 
conducted,  unless othe1wise specified by the Protocol. 
 
- Infmmed 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 regulatmy authmities 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 emolling 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 tetmination of the test atticle for 
investigation to ensure  the availability of study documentation should it become 
necessaty 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 anange altemative 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 dmg accountability at the study site; however, some of the 
dmg accountability duties may be assigned to an approptiate phatmacist 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 dmgs to the study site. 
 
• Inventory of study dmgs at the site. 
 
• Subject use of the study dmgs including pill or unit counts from each supply 
dispensed. 
 
• Retum of study dmgs to the investigator or designee by subjects. 


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The investigational products must be used only in accordance with the Protocol.  The 
investigator will also maintain records adequately documenting that the subjects were provided 
the specified study dmg.  These  records should include dates, quantities, and any available batch 
or serial numbers  or unique code numbers assigned to the investigational products  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 pa1tially used containers  of study dmgs 
until verified by the study monitor  (unless othe1wise agreed to by the sponsor). At the 
conclusion of the study, the investigator or designee will oversee shipment  of any remaining 
study dmgs back to the sponsor or its designee for destmction according to institutional standard 
operating procedures. If local procedures mandate on-site  destmction 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 dmgs are destroyed before 
monitor inspection,  the monitors rely on documentation of destmction per the site standard 
operating procedure. 
 
10.3. 
Data Management 
 
Data management  will be perfmmed  in a validated database via an Electronic Data Capture (EDC) 
system.  All data entry, verification, and validation  will be perfmmed in accordance with the 
cmTent standard operating procedures of the Data Management Depaitment  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.  Enn·ies 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 enn·ies, 
and will sign and date the designated fmms in each subject's eCRF, ve1ifying that the 
infmmation is hue and COITect.  The investigator is responsible for the review and approval of all 
que1y responses. 
 
Protocol deviations will be identified and recorded  in the Protocol  Deviation fmm of the eCRF. 
The study monitor will reference  the Monitoring Plan in order to ensure  that each issue identified 
is approp1iately documented,  repmted, and resolved in a timely manner in accordance with the 
plan's requirements. 
 
10.4. 
Data Privacy and Confidentiality of Study Records 
 
The investigator and the sponsor  or its designee  must adhere to applicable data privacy laws and 
regulations.  The investigator and the sponsor or its designee  are responsible for ensming that 
sensitive infmmation is handled in accordance with local requirements (eg, HIPAA). 
Approp1iate consent and authorizations for use and disclosure and/or n·ansfer  (if applicable) of 
protected infmmation 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 pe1mitted; if the subject's name appears on any 


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other document (eg, laboratmy repo1t), 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 infmmed that representatives of 
the sponsor or its designee, IRB or IEC, or regulatmy authorities may inspect  their medical 
records to verify the infmmation collected, and that all personal infmmation 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 pa1ticipating in clinical studies subject to FDA 
Regulation Title 21 CFR Pa1t 54 -Financial Disclosure  by Clinical Investigators (ie, "covered 
studies") are required to submit a completed Clinical Investigator Financial Disclosure fmm that 
sufficiently details any financial interests and anangements that apply.  For the purpose of this 
regulation, "clinical investigator" is defmed 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 Fmm.  During a covered clinical study, 
any changes to the financial infmmation previously  repmted by a clinical investigator must be 
repmted 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 neve1theless will remain obligated to repmt to the sponsor or 
its designee any changes to the financial infmmation previously repmted, as well as any changes 
in their fmancial infmmation for a period of 1 year after completion of the covered clinical study. 
 
10.6.  
Publication Policy 
 
By signing the study Protocol,  the investigator and his or her institution agree that the results of 
the study may be used by the sponsor,  Incyte Corporation (Incyte), for the purposes of national 
and intemational registration, publication, and infmmation for medical and pha1maceutical 
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 te1ms 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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Hamid 0, Bauer TM, Spira AI, et al. Epacadostat  plus pembrolizumab in patients with SCCHN: 
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Hamid 0, Gajewski TF, Frankel AE, et al. Epacadostat  plus pembrolizumab in patients with 
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Presented  at the ESMO Annual Meeting 2017; September 9, 2017b; Madrid, Spain. 
 
Hamid 0, Gajewski TF, Smith DC, et al. Prelimina1y data from a phase 112 study of epacadostat 
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at: Society for Melanoma Research 2015 Congress; November 18-21, 2015; San Francisco,  CA. 
 
Hamid 0, Rober C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) 
in melanoma. N Engl J Med 2013;369:134-144. 
 
Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, 
PD-L1 positive,  advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled 
trial. Lancet 2016;387:1540-1550. 
 
Hollenbach PW, Nguyen AN, Brady H, et al. A compa1ison of azacitidine and decitabine 
activities in acute myeloid leukemia cell lines. PLoS One 2010;5:e9001. 
 
INCB057643 Investigator's  Brochure (IB). Wilmington, DE: Incyte Corporation. 
INCB059872 Investigator's  Brochure (IB). Wilmington, DE: Incyte Corporation. 
Jacobs J, Smits E, Lardon F, Pauwels P, Deschoolmeester V. Immune checkpoint modulation in 
colorectal cancer: what's new and what to expect. J Immunol Res 2015;158038. 
 
Jin Y, Huo B, Fu X, et al. LSD1 collaborates with EZH2 to regulate expression of interferon- 
stimulated genes. Biomed Pha1macother 2017;88:728-737. 
 
Juergens RA, Wrangle J, Vendetti FP, et al. Combination epigenetic therapy has efficacy in 
patients with refractmy advanced non-small cell lung cancer. Cancer Discov 2011;1:598-607. 
 
Kagoya Y, Nakatsugawa M, Yamashita  Y, et al. BET bromodomain inhibition enhances T cell 
persistence and function in adoptive immunotherapy models. J Clin Invest 2016;126:3479-3494. 


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Keytmda (pembrolizumab) [prescribing infmmation]. Whitehouse Station, NJ: Merck Sharp & 
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Kim JH, Park HE, Cho NY, Lee HS, Kang GH. Characterization  ofPD-L1-positive subsets of 
microsatellite-unstable colorectal cancers. Br J Cancer 2016;115:490-496. 
 
Kim ST, Jeong H, Woo OH, et al. Tumor-infiltrating lymphocytes, tumor characteristics, and 
recurrence in patients with early breast cancer. Am J Clin Oncol2013;36:224-231. 
 
Koblish HK, Hansbmy M, Hall L, et al. The BET inhibitor INCB054329 enhances the activity of 
checkpoint modulation in syngeneic tumor models. Cancer Res 2016;76:Abstract 4904. 
 
Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in 
non-small-cell lung cancer. N Engl J Med 2010;363:1693-1703. 
 
Lara P, Bauer TM, Hamid 0, et al. Epacadostat plus pembrolizumab in patients with advanced 
RCC: prelimina1y phase 1/II results from ECH0-202/KEYNOTE-037. J Clin Oncol 
2017;35(suppl):Abstract 4515. 
 
Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair  deficiency. 
N Engl J Med 2015;372:2509-2520. 
 
Lee V, Murphy A, Le DT, Dias LA. Mismatch repair deficiency and response to immune 
checkpoint blockade. Oncologist 2016;21:1-12. 
 
Li H, Chiappinelli KB, GuzzettaAA, et al. Immune regulation by low doses ofthe DNA 
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2014;5:587-598. 
 
Lyons RM, CosgriffTM, Modi SS, et al. Hematologic response to three altemative dosing 
schedules of azacitidine in patients with myelodysplastic syndromes. J Clin Oncol 
2009;27:1850-1856. 
 
Mei Z, Liu Y, Liu C, et al. Tumour-infiltrating inflammation and prognosis  in colorectal cancer: 
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Mellor AL, Baban B, Chandler P, et al. Cutting edge: induced indoleamine 2,3 dioxygenase 
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Muro K, Chung HC, Shankm·an V, et al. Pembrolizumab  for patients with PD-L1-postive 
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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 conectly are considered as highly effective birth control methods. 
 
Such methods include: 
 
•  Combined (estrogen and progestogen containing) hmmonal contraception associated 
with inhibition of ovulation 1 
 
oral 
intravaginal 
transdetmal 
• Progestogen-only hmmonal contraception associated with inhibition of ovulation 1 
 
oral 
injectable 
implantable2 
• Intrauterine device (nJD)Z 
 
• Intrauterine hmmone-releasing system (nJSf 
 
• Bilateral tubal occlusion2 
 
• Vasectomised partne1.2,J 
 
• 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 defmed 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 c_ PROHIBITED MONOAMINE OXIDASE INIDBITORS 
AND DRUGS  ASSOCIATED WITH SIGNIFICANT 
MONOAMINE OXIDASE INHIBITORY ACTIVITY 
 
Monoamine  Oxidase Inhibitors 
Drugs Associated With Significa nt Monoamine 
Oxidase Inhibitory Activity 
Hydrazines (example phenelzine) 
Meperidine 
Caroxazone 
Linezolid 
Echinopsidine 
Methylene blue 
Furazolidone 
Tranylcypromine 
Brofaromine 
Metralindole 
Minapdne 
Moclobemide 
Pirlindole 
Toloxatone 
Lazbemide 
Pargyline 
Rasagiline 
Selegiline 


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APPENDIX D- EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFO ANCESTATUS 
 
Grade 
Performance Status 
0 
Fully active, able to cany  on all predisease perf01mance without restliction. 
1 
Restt·icted in physically stt·enuous activity but ambulat01y and able to cany out work of a light 
or sedentmy nature, eg, light house work, office work. 
2 
Ambulat01y and capable of all selfcare but unable to cm1y out any work activities. Up and 
about more than 50% of waking hours. 
3 
Capable of only limited self-care, confmed to bed or chair more than 50% of waking hours. 
4 
Completely disabled.  Cannot cm1y on any self-care.  Totally confined to bed or chair. 
5 
Dead. 
Source: Oken et al 1982. 


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APPENDIX E.  PROTOCOL AMENDMENT SUMMARY OF CHANGES 
 
Document 
Date 
Amendment (Version) 1: 
18 JAN2016 
Amendment (Version) 2: 
08 JUL2016 
Amendment (Version) 3: 
20 OCT 2017 
Amendment (Version) 4: 
30AUG2018 
 
Amendment  4 (30 AUG 2018) 
 
Overall Rationale for the Amendment: 
 
The prima1y purpose of this amendment is to 1) specify that scans to confi1m disease progression 
should be conducted  at least 4 weeks and no later than 8 weeks from the initial scans showing 
PD and 2) remove the disease assessment and survival follow up visits. 
 
1.  Synopsis; Section 4.4, Duration of Treatment and Subject Participation; 
Section 5.5.2, Withdrawal Procedures; Section 6, Study Assessments (schedule of 
assessment Tables 29, 31, 33, 35); Section 6.4.1, Safety Follow-Up; Section 6.4.2, 
Disease Status Follow-Up; Section 6.4.3, Survival  Follow-Up; Section 6.5, End of 
Study; Section 7.6.1, Assessment of Disease According to Modified RECIST v1.1; 
Section 7.10.2, Data Collection for Survival Follow-Up 
 
Description of change:  Follow-up  visits and contacts for disease assessment  and 
smvival will no longer be required.  For Treatment Group A, reference to subject contact 
after the safety follow-up visit (42-49 days after EOT) have been revised.   As of 
Amendment 4, Treatment Groups Band Care no longer applicable.  No subjects have 
been or will be emolled in these cohmts. 
 
Rationale for change:  Based on an Extemal Data Monitoring Committee's (eDMC) 
analysis of the ECH0-301/KEYNOTE-252 Phase 3 melanoma clinical study, fucyte 
made a strategic decision to stop further emollment in the INCB 24360-206 study.  The 
eDMC analysis dete1mined that the ECH0-301/KEYNOTE-252 clinical study did not 
meet the prespecified  endpoint of improvement in PFS for the combination of 
pembrolizumab  and epacadostat compared to pembrolizumab  and placebo.   Of note, 
based on review of the safety analysis, the eDMC concluded that there were no safety 
concems with the ECH0-301/KEYNOTE-252 investigational group compared to 
pembrolizumab  alone.  Data collection for disease assessment and smvival follow-up is 
no longer required. 
 
2.   Section 5.4.2, Treatment After Initial Evidence of Kat<114[)£l·ap 
Table 


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Rationale for change: This modification has been made per FDA request. 
 
3.   Synopsis; Section  4.1, Overall Study Design; Section  4.4, Duration of Treatment and 
Subject Participation; Section  5.2.3.1, Description and Administration 
 
Description of change: Text has been added to clarify that medical monitor approval is 
needed for those subjects with SD or better for at least 6 months who expe1ience disease 
progression and wish to be re-treated. 
 
Rationale for change: This is an administrative change made in order to hamonize the 
Synopsis and Sections 4.1 and 4.4 with Section 6.2. 
 
4.   Incorporation of administrative changes. Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment 


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Amendment 3 (20 OCT 2017) 
 
Overall Rationale for the Amendment: 
 
The prima1y purpose of this amendment is to add 2 additional treatment groups, which include 
epigenetic p1iming regimens with a bromodomain and extra-te1minal protein (BET) inhibitor 
(INCB057643) and with a lysine-specific demethylase IA (LSDI)  inhibitor (INCB059872). 
 
This amendment includes the changes to Protocol INCB 24360-206 Amendment 2 
(02 JUN 2017) summarized below.  A redline version of the amendment depicting the updated 
and previous text is also provided. 
 
1.   Synopsis; Section 1, Introduction; Section 2, Study Objectives and Endpoints; 
Section 3, Subject Eligibility; Section 4, Investigational Plan; Section 5, Treatment; 
Section 6, Study Assessments; Section 7, Conduct  of Study Assessments and 
Procedures; Section 9, Statistics 
 
Description of change:  Two additional treatment groups were added to include new 
epigenetic p1iming regimens with a BET inhibitor (INCB057643) and LSDI  inhibitor 
(INCB059872).  All relevant Protocol sections, tables, and figures have been updated 
accordingly. 
 
Rationale for change: To evaluate the addition of2  novel epigenetic agents to the 
combination  of pembrolizumab and epacadostat. 
 
2.   Synopsis; Section 2, Study Objectives and Endpoints; Section 3.1, Subject Inclusion 
Criteria; Section 9, Statistics 
 
Description of change:  The inclusion criteria were updated to enroll non-small-cell 
lung cancer (NSCLC) subjects with metastatic (Stage IV) or recurrent disease and to 
clarify that subjects with NSCLC, head and neck squamous cell carcinoma (HNSCC), 
and urothelial carcinoma should have documented disease progression while on a 
programmed death receptor-I (PD-1) pathway-targeted agent.  Progression following 
cessation of PD-1 pathway-targeted therapy is not sufficient.  All relevant Protocol 
sections were updated accordingly. 
 
Rationale for change: To clarify that the disease progression on a PD-1 pathway- 
targeted therapy should have occmTed while receiving PD-1 therapy, not upon relapse. 
 
3.   Synopsis; Section 3.2, Exclusion  Criteria; Section 6, Study Assessments 
 
Description of change:  A new exclusion crite1ion was added to exclude subjects with 
semm albumin < 3 g/dL. Additionally, a new exclusion criterion was added to exclude 
subjects with uncontrolled type I or type II diabetes mellitus (defined as HgbA1c > 8). 
All relevant Protocol sections, including tables, were updated accordingly. 
 
Rationale for change: To include new measures to confnm perfmmance status of 
subjects. 


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Synopsis; Section  4.1, Overall Study Design; Section  7.6.2, Tumor Biopsy 
 
Description of change: A note was added to clarify that tumor tissue will be fmmalin- 
fixed and paraffin-embedded locally and further assessed with hematoxylin and eosin 
staining. A pathologist will complete a quality control fmm to document  tissue quality. 
 
Rationale for change: To specify the cunent tumor biopsy collection procedures. 
 
5.   Section 1.7.3.3, Treatment Sequencing Tumor Biopsy Cohort Indications 
 
Description of change: Rationale for the treatment of HNSCC, melanoma, and 
urothelial carcinoma was added based on the most recent prescribing information for 
nivolumab, pembrolizumab, and atezolizumab and prelimina1y clinical data from the 
ongoing clinical study INCB 24360-202. 
 
Rationale for change: To provide rationale for the inclusion of the 3 additional tumor 
types that will be enrolled in the treatment sequencing tumor biopsy cohmts during 
Pait 2, dose expansion. 
 
6.   Section  5.4.1.3.7, Procedures for Immune-Mediated Myocarditis 
 
Description of change: Dose modification and management guidelines were added for 
immune-mediated myocarditis. 
 
Rationale for change: To provide guidance for potential immune-related myocarditis. 
 
7.   Section  5.6.3, Prohibited Medications 
 
Description of change: Melatonin and propofol were removed from the list of 
prohibited medications, as they are now pe1mitted. 
 
Rationale for change: After a review of the cunent literature,  there is no longer a need 
to exclude melatonin supplements. Propofol  was removed as it is not a significant 
UGTIA9 inhibitor. 
 
8.   Section  6.2, Treatment 
 
Description of change: Clarification that possible re-treatment with pembrolizumab or 
the combination may be allowed wat it has been discussed and 
approved by the medical monitor.  
mandatmy biopsies will not be 
perfmmed. 
 
Rationale for change: To provide details for possible re-treatment with pembrolizumab 
or the combination. 
 
9.   Section  9, Statistics (Table 55: Probability of Dose De-Escalation for Various 
Dose-Limiting Toxicity  Rates) 
 
Description of change:   Probabilities of dose de-escalation for various dose-liiniting 
toxicity (DLT) rates were updated in Table 55. 
 
Rationale for change: To provide conect probabilities of dose de-escalation for various 
DLT rates. 


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10. Incorporation  of administrative changes.  Other minor, administrative changes have 
been incorporated  throughout  the Protocol and are noted in the redline version of the 
amendment, including the addition of summary of changes for all amendments to 
Appendix E. 


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"'"
 
 
Amendment 2 (02 JUN 2017) 
 
Overall Rationale for the Amendment: 
 
The prima1y purpose of this amendment is to extend the length of azacitidine treatment and add 
new expansion cohmts to evaluate different  sequences of treatment for the 3 study dmgs. 
 
This amendment includes the changes to Protocol INCB 24360-206 Amendment 1 
(04 NOV 2016) summarized below.  A redline version of the amendment depicting the updated 
and previous text is also provided. 
 
1.   Synopsis; Section  2.1.1, Primary Ob  '"'.,,,.,C! 
Section  2.2.1, Primary Endpoints; 
Section  9.4.1, Primary Analyses; ""'"' 1 
Other Analyses 
 
Description of change: The p1imary and seconda1y efficacy objectives and endpoints 
were revised so that  
·ective  
rate  
is evaluated  
standard 
RECIST v1.1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.   Synopsis; Section  4.1, Overall Study Design; Section  4.4, Duration of Treatment and 
Subject Participation; Section  5.2.3.1, Azacitidine Description and Administration; 
Section  6, Study Assessments (Tables 18, 20, 22, and  24, Schedules of Assessments); 
Section  6.2, Treatment 
 
Description of change: The number of cycles of azacitidine was increased from a 
maximum of 2 to 6.  All subjects will receive 5 doses of azacitidine  in Cycles 1 through 
3.  Subjects who remain on treatment  beyond the Week 9 scan should continue to receive 
azacitidine until the second on-study scan (up to the Week 18 scan, for a maximum of 
3 additional cycles). 
 
Rationale for change: Recent research suggests that the response time for epigenetic 
agents may va1y. The combination of azacitidine with pembrolizumab and epacadostat 
has been well tolerated to date, and additional cycles of azacitidine have been added to 
maximize potential efficacy. 


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4.   Synopsis; Section 1, Introduction; Section 3.1, Subject Inclusion Criteria; Section 
4.1, Overall Study Design; Section 4.1.2 Part  2: Expansion; Section 4.3.1, Number 
of Subjects; Section 6, Study Assessments (Tables 18-25, Schedules of Assessments 
and Laboratory Assessments); Section 7.8.1, Blood Sample Collection 
 
Description of change:  The safety/efficacy expansion cohmt for non-small-celllung 
cancer (NSCLC) subjects  who are PD-1-naive has been removed.  Safety/efficacy 
expansion cohmts remain for subjects with NSCLC who have had disease progression on 
a PD-1-targeted therapy (A-1)  and microsatellite stable colorectal cancer (MSS CRC; 
A-2). Additional treatment sequencing tumor biopsy cohmts  (A-3 through A-5) will 
emoll 4 specific tumor types and include 3 tumor  biopsies.  Inclusion c1iteria were added 
for each specific tumor type, and Protocol sections have been updated throughout. 
 
Rationale for change: The PD-1-naive NSCLC expansion cohort was removed because 
of expected emollment difficulty.  The additional treatment sequencing tumor biopsy 
cohmts (A-3 through A-5) have been added to identify epigenetic changes and changes in 
the tumor microenvironment induced by each of the components of the regimen  in each 
of the additional tumor types. 
 
5.   Synopsis; Section 3.1, Subject Inclusion Criteria; Section 4.1, Overall Study Design; 
Section 6, Study Assessments (Tables 18, 20, 22, and 24, Schedules of Assessments); 
Section 7.6.2, Tumor  Biopsy 
 
Description of change:  The tumor biopsy requirements were updated to require fresh 
baseline tumor biopsies rather than archival. 
 
Rationale for change: The tumor biopsy study procedures were amended  to require 
fresh biopsies to more precisely evaluate changes in the tumor microenvironment. 
 
6.   Synopsis; Section 3.1, Subject Inclusion Criteria 
Description of change:  Added a note in the inclusion criteria for Pa1t 2 to specify that 
subjects must have failed available therapies that confer  clinical benefit as indicated for 
each of the specific tumor types, unless they are ineligible, intolerant, or refused standard 
treatment. 
Rationale for change: To specify that all subjects should have failed available approved 
therapies with the exception of being ineligible, intolerant, or refused standard-of-care 
therapies. 
7.   Synopsis; Section 4.1.1, Part 1:  Dose Escalation 
Description of change:  Text has been added to allow for determination of a dose- 
limiting toxicity (DLT) by the principal investigators and medical monitor in ce1tain 
cases where toxicities due to the combination agent may be indistinguishable from 
toxicities due to immunotherapy. 
Rationale for change: To allow for flexibility with dete1mining a DLT in situations 
where there are overlapping toxicities and the subject has received < 75% dose intensity. 


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8.   Synopsis; Section  9, Statistics 
 
Description of change: The statistical sections were updated to reflect  the changes of 
the Part 2 expansion. Detail on the interim analysis was provided, and other minor 
changes were made. 
 
Rationale for change: To update the planned analyses based on the changes to the 
expansion cohmts and provide additional  detail for the inte1im analysis. 
 
9.   Section 1.4, Overview of Azacitidine 
 
Description of change: Azacitidine background was updated to include fmther details 
from the European Union  Summmy of Product Characteristics (SmPC). 
 
Rationale for change: To add specific details from the SmPC. 
 
10. Section 1.6.1, Risks from Epacadostat; Section  5.4.3, Procedures for Subjects 
Exhibiting Serotonin Syndrome; Section 8.4, Adverse  Events of Special Interest 
 
Description of change: The sections were updated to clarify that serotonin syndrome is 
an uncommon risk, provide data from the cunent clinical studies, and provide an 
ove1view of the existing preclinical data. 
 
Rationale for change: Updated in alignment  with cunent epacadostat program 
infmmation. 
 
11. Section  6.4.1, Safety Follow-Up 
 
Description of change: The repmting requirements for AEs and SAEs were conected to 
specify that AEs should be repmted up until at least 42 days after the last dose of study 
dmg and 90 days for SAEs. 
 
Rationale for change: Conected to be in alignment  with Sections 8.1.2 and 8.3.2. 
 
12. Incorporation of administrative changes. Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version  of the 
amendment. 


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Amendment 1(04 NOV 2016) 
 
Overall Rationale for the Amendment: 
 
The prima1y purpose of this amendment is to address FDA's October 20, 2016, clinical 
infmmation request. 
 
This amendment includes the changes to Protocol INCB 24360-206 (30 SEP 2016) summarized 
below.  A redline version of the amendment depicting the updated and previous text is also 
provided. 
 
1.  Synopsis, Part 1: Dose Escalation, Estimated Number of Subjects, Statistical 
Methods; Section 4.1.1, Part 1: Dose Escalation; Section 4.3.1, Planned  Number of 
Subjects; Section 9.2.1, Sample Size in Part 1 
Description of change:  The study was switched from a 3 + 3 to a 3 + 3 + 3 dose- 
escalation design. The description of the dose-escalation scheme and estimated number 
of subjects was updated to reflect this change. 
 
Rationale for change: To provide a more thorough assessment of the maximum 
tolerated dose (MTD). 
 
2.   Synopsis, Part 1:  Dose Escalation; Section 4.1.1, Part 1: Dose Escalation, Table 1 
(Dose Levels: Treatment Group A) 
 
Description of change:  Additional clarification was added to specify the crite1ia for 
dose escalation from Cohmt 1 to Cohmt 2. The tables showing the planned dose levels 
were updated to present the 2 options for escalation  of the second cohmt. 
 
Rationale for change: FDA request. 
 
3.   Synopsis, Key Inclusion  Criteria; Section 3.1, Subject Inclusion Criteria 
 
Description of change:  Revised inclusion criterion #7 to specify that the contraception 
period for males and female must extend until 120 days after the last dose of study dmg. 
fuclusion c1iterion #10 was conected to state that subjects in Cohmt A1 must be 
checkpoint inhibitor-naive.  Added clarification to inclusion c1iterion #12 to specify that 
microsatellite instability testing should be perfmmed locally. 
 
Rationale for change: FDA request. The bi1th control requirements have been updated 
to 120 days after the last dose of study dmg to be consistent with the pembrolizumab 
package inse1t. 
 
4.   Synopsis, Key Exclusion Criteria; Section 3.2, Subject Exclusion  Criteria 
 
Description of change:  fu exclusion crite1ion #14, a note was added to specify that in 
Part 2, subjects with treated hepatitis B are eligible as long as they have no evidence of 
active infection.  A new exclusion crite1ion (#28) was added to specify that subjects with 
bleeding associated with tumors in proximity to major blood vessels are excluded except 
with medical monitor approval. 
 
Rationale for change: FDA request to consider expanding the eligibility crite1ia. The 
new crite1ion #28 was added to exclude subjects who are at high risk for early 
progression and bleeding. 


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5.   Section 1.5.2, Justification for the Treatment Regimen 
 
Description of change:  Background infmmation on the epacadostat combination dose 
from the INCB 24360-202 and INCB 24360-301 studies was added. 
 
Rationale for change: To provide infmmation regarding the clinical experience with an 
epacadostat 300 mg BID dose. 
 
6.   Section 5.4.1.1, Dose-Limiting Toxicity and Determination  of Maximum Tolerated 
Dose 
 
Description of change:  Three new DLTs were added to specify that Grade 4 vomiting 
and dianhea, Grade 4 electrolyte abnmmalities, and Grade 4 systemic reactions would be 
considered DLTs. The Grade 4 thrombocytopenia and neutropenia DLT definition was 
revised to define Grade 4 thrombocytopenia of any duration  and Grade 4 neutropenia 
lasting > 3 days as DLTs. 
 
Rationale for change: FDA request. 
 
7.   Incorporation  of administrative changes.  Other minor administrative changes and 
inconsistencies  in the protocol have been incorporated. 


 
Signature Manifest 
 
Document Number: IC-DEV-PROT-AMEND-0384 
Title: INCB 24360-206 Protocol Amendment 4 
 
All dates and times are in Eastern Standard Time. 
 
 
 
 
 
APPROVAL: 24360-206 Amendment 4 
 
 
 
Approval and Release 
 
Date 
Meaning/Reason 
 
 
Revision: 0 
 
30 Aug 2018, 114815 AM 
 
30 Aug 2018, 12:0943 PM 
 
30 Aug 2018, 121657 PM 
 
Approved 
Approved 
Approved 

SAP_000.pdf: 
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INCB 24360-206 SAP Amendment 1 
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CONFIDENTIAL 
STATISTICAL ANALYSIS PLAN 
INCB 24360-206 / NCT02959437   
A Phase 1/2 Study Exploring the Safety, Tolerability, Effect on the 
Tumor Microenvironment, and Efficacy of Azacitidine in 
Combination With Pembrolizumab and Epacadostat in Subjects 
With Advanced Solid Tumors and Previously Treated Stage IIIB or 
Stage IV Non–Small Cell Lung Cancer and Stage IV 
Microsatellite-Stable Colorectal Cancer 
IND Number: 
132,309 
EudraCT Number: 
2016-004289-25 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
Protocol Version: 
Protocol Amendment 3 dated 20 OCT 2017 
CRF Approval Date: 
30 APR 2018 
SAP Version: 
Amendment 1 
SAP Author: 
 
 
Date of Plan: 
18 JUL 2018 
This study is being conducted in compliance with good clinical practice, 
including the archiving of essential documents. 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
INTRODUCTION ........................................................................................................8 
2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS.................................9 
2.1. 
Protocol and Case Report Form Version ......................................................................9 
2.2. 
Study Objectives ...........................................................................................................9 
2.2.1. 
Primary Objectives .......................................................................................................9 
2.2.2. 
Secondary Objectives ...................................................................................................9 
 
10 
2.3. 
Study Endpoints ..........................................................................................................10 
2.3.1. 
Primary Endpoints ......................................................................................................10 
2.3.2. 
Secondary Endpoints ..................................................................................................10 
 
11 
3. 
STUDY DESIGN .......................................................................................................12 
3.1. 
Overall Study Design ..................................................................................................12 
3.1.1. 
Treatment Groups .......................................................................................................12 
3.1.1.1. 
Treatment Group A .....................................................................................................12 
3.1.1.2. 
Treatment Groups B and C .........................................................................................14 
3.1.2. 
Dose-Escalation Phase (All Treatment Groups) .........................................................17 
3.1.2.1. 
Treatment Group A:  Azacitidine ...............................................................................18 
3.1.2.2. 
Treatment Group B: INCB057643 .............................................................................18 
3.1.2.3. 
Treatment Group C:  INCB059872 ............................................................................19 
3.1.3. 
Dose-Expansion Phase ................................................................................................20 
3.1.3.1. 
Treatment Group A .....................................................................................................20 
3.1.3.2. 
Treatment Group B .....................................................................................................22 
3.1.3.3. 
Treatment Group C .....................................................................................................24 
3.1.4. 
Re-Treatment ..............................................................................................................26 
3.1.4.1. 
Re-Treatment With Pembrolizumab or the Combination ...........................................26 
3.1.4.2. 
Re-Treatment With Azacitidine, INCB057643, or INCB059872 ..............................27 
3.2. 
Randomization ............................................................................................................27 
3.3. 
Control of Type I Error ...............................................................................................27 
3.4. 
Sample Size Considerations .......................................................................................27 


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3.4.1. 
Sample Size in Part 1 ..................................................................................................27 
3.4.1.1. 
Part 1 Dose Escalation ................................................................................................27 
3.4.1.2. 
Part 1 Dose Expansion ................................................................................................27 
3.4.2. 
Sample Size in Part 2 Safety/Efficacy Expansion Cohorts ........................................27 
3.4.2.1. 
Part 2 Simon 2-Stage Cohorts.....................................................................................27 
3.4.2.2. 
Part 2 Treatment Sequencing Tumor Biopsy Cohorts ................................................28 
3.5. 
Schedule of Assessments ............................................................................................28 
4. 
DATA HANDLING DEFINITIONS AND CONVENTIONS ..................................29 
4.1. 
General Considerations ...............................................................................................29 
4.2. 
Scheduled Study Evaluations and Study Periods .......................................................29 
4.2.1. 
Day 1 ...........................................................................................................................29 
4.2.2. 
Study Day ...................................................................................................................29 
4.2.3. 
Baseline Value ............................................................................................................29 
4.2.4. 
Handling of Missing and Incomplete Data .................................................................29 
4.2.5. 
Cycle Length and Duration .........................................................................................31 
4.3. 
Variable Definitions ....................................................................................................31 
4.3.1. 
Age ..............................................................................................................................31 
4.3.2. 
Body Mass Index ........................................................................................................31 
4.3.3. 
Prior and Concomitant Medication .............................................................................31 
5. 
STATISTICAL METHODOLOGY ...........................................................................32 
5.1. 
General Methodology .................................................................................................32 
5.2. 
Treatment Groups .......................................................................................................32 
5.3. 
Analysis Populations ..................................................................................................32 
5.3.1. 
Response Evaluable Population ..................................................................................32 
5.3.2. 
Safety Population ........................................................................................................32 
6. 
BASELINE, EXPOSURE, AND DISPOSITION VARIABLES AND 
ANALYSES ...............................................................................................................33 
6.1. 
Baseline and Demographics, Physical Characteristics, and Disease History .............33 
6.1.1. 
Demographics .............................................................................................................33 
6.1.2. 
Baseline Disease Characteristics and Disease History ...............................................33 
6.1.3. 
Prior Therapy ..............................................................................................................33 
6.1.4. 
Medical History ..........................................................................................................33 
6.2. 
Disposition of Subjects ...............................................................................................34 


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6.3. 
Protocol Deviations and Violations ............................................................................34 
6.4. 
Exposure .....................................................................................................................34 
6.4.1. 
Exposure for Epacadostat ...........................................................................................34 
6.4.2. 
Exposure for Pembrolizumab .....................................................................................34 
6.4.3. 
Exposure for Azacitidine ............................................................................................35 
6.5. 
Study Drug Compliance .............................................................................................35 
6.6. 
Prior and Concomitant Medication .............................................................................36 
7. 
EFFICACY .................................................................................................................36 
7.1. 
General Considerations ...............................................................................................36 
7.2. 
Analysis of the Efficacy Parameters ...........................................................................36 
7.2.1. 
Response Criteria ........................................................................................................36 
7.2.2. 
Objective Response Rates and Best Overall Response ..............................................36 
7.2.3. 
Duration of Response .................................................................................................37 
7.2.4. 
Largest Percentage Reduction in Sum of Diameters of Target Lesions .....................37 
7.2.5. 
Progression-Free Survival ..........................................................................................37 
 
38 
8. 
SAFETY AND TOLERABILITY ..............................................................................39 
8.1. 
General Considerations ...............................................................................................39 
8.2. 
Adverse Events ...........................................................................................................39 
8.2.1. 
Adverse Event Definitions ..........................................................................................39 
8.2.2. 
Dose-Limiting Toxicities ............................................................................................39 
8.2.3. 
Maximum Tolerated Dose ..........................................................................................39 
8.2.4. 
Adverse Events of Special Interest .............................................................................40 
8.2.5. 
Adverse Event Summaries ..........................................................................................40 
8.3. 
Clinical Laboratory Tests ...........................................................................................41 
8.3.1. 
Laboratory Value Definitions .....................................................................................41 
8.3.2. 
Laboratory Value Summaries .....................................................................................42 
8.4. 
Vital Signs ..................................................................................................................42 
8.5. 
Electrocardiograms .....................................................................................................43 
9. 
INTERIM ANALYSES ..............................................................................................43 
10. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN ........................44 
10.1. 
Changes to Protocol-Defined Analyses ......................................................................44 
10.1.1. 
Efficacy Analyses .......................................................................................................44 


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44 
10.1.3. 
Interim Analyses .........................................................................................................44 
10.2. 
Changes to the Statistical Analysis Plan .....................................................................44 
11. 
REFERENCES ...........................................................................................................45 
APPENDIX A. PLANNED TABLES AND LISTINGS ............................................................46 
 
LIST OF TABLES 
Table 1: 
Dose Levels:  Treatment Group A ..............................................................................18 
Table 2: 
Dose Levels:  Treatment Group B ..............................................................................19 
Table 3: 
Dose Levels: Treatment Group C ...............................................................................19 
Table 4: 
Treatment Group A Safety/Efficacy Expansion Cohorts (Part 2) ..............................20 
Table 5: 
Treatment Group A Treatment Sequencing Tumor Biopsy Cohorts (Part 2) .............21 
Table 6: 
Treatment Group B Safety/Efficacy Expansion Cohorts (Part 2) ..............................23 
Table 7: 
Treatment Group B Treatment Sequencing Tumor Biopsy Cohorts (Part 2) .............24 
Table 8: 
Treatment Group C Safety/Efficacy Expansion Cohorts (Part 2) ..............................25 
Table 9: 
Treatment Group C Treatment Sequencing Tumor Biopsy Cohorts (Part 2) .............26 
Table 10: Simon 2-Stage Design ................................................................................................28 
Table 11: RECIST Evaluation Criteria for Overall Response:  Measurable Disease at 
Baseline .......................................................................................................................37 
Table 12: Evaluation and Censoring of Progression-Free Survival ............................................38 
Table 13: Criteria for Clinically Notable Vital Sign Abnormalities ...........................................43 
Table 14: Criteria for Clinically Notable Electrocardiogram Abnormalities .............................43 
Table 15: Statistical Analysis Plan Versions ..............................................................................44 
 
LIST OF FIGURES 
Figure 1: 
Study Design:  Treatment Group A ............................................................................13 
Figure 2: 
Study Design:  Treatment Group B ............................................................................15 
Figure 3: 
Study Design:  Treatment Group C ............................................................................16 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
adverse event 
BET 
bromodomain and extra-terminal 
BID 
twice daily 
BMI 
body mass index 
CI 
confidence interval 
CR 
complete response 
CRC 
colorectal cancer 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
dose-limiting toxicity 
DNMT 
deoxyribonucleic acid methyltransferase 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
HNSCC 
head and neck squamous cell carcinoma 
IDO1 
indoleamine 2,3-deoxygenase 1 
IHC 
immunohistochemistry 
irAE 
immune-related adverse event 
IV 
intravenously 
KM 
Kaplan-Meier 
LSD1 
lysine-specific demethylase 1A 
MedDRA 
Medical Dictionary for Regulatory Activities  
 
 
mRNA 
messenger ribonucleic acid 
MSS 
microsatellite stable 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NE 
not evaluable 
NSCLC 
non–small-cell lung cancer 
ORR 
objective response rate 
 
 


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Abbreviation 
Term 
PAD 
pharmacologically active dose 
PD 
progressive disease 
PD-1 
programmed death receptor-1 
PFS 
progression-free survival 
PO 
orally 
 
 
PR 
partial response 
PT 
preferred term 
Q3W 
every 3 weeks 
QD 
every day 
QoD 
every other day 
QTcF 
QT interval corrected by Fridericia 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RP2D 
recommended Phase 2 dose 
SC 
subcutaneously 
SD 
stable disease 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TIL 
tumor-infiltrating lymphocyte 
TNM 
malignant tumors 
Treg 
T regulatory cell 
UC 
urothelial carcinoma 
WHO 
World Health Organization  


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1. 
INTRODUCTION 
This is an open-label, multicenter, Phase 1/2 study evaluating the addition of 3 different 
epigenetic priming regimens to an immunotherapy doublet in subjects with advanced or 
metastatic solid tumors.  This study will use a suite of tissue 
 technologies to 
evaluate the immune activity of the DNMT inhibitor, azacitidine; the BET inhibitor, 
INCB057643; or the LSD1 inhibitor, INCB059872, in combination with the PD-1 inhibitor 
pembrolizumab and the IDO1 inhibitor epacadostat.  The first part of the study will consist of a 
dose-escalation assessment of the safety and tolerability of the treatments in subjects with 
advanced or metastatic solid tumors.  Part 2 of the study will be an open-label Phase 2 
assessment with Simon 2-stage design (Simon 1989) to evaluate ORR and TIL infiltration in 
previously treated NSCLC and MSS CRC.  Separate treatment sequencing tumor biopsy cohorts 
are also included in the expansion to further evaluate epigenetic changes and changes in the 
tumor microenvironment in subjects with HNSCC, melanoma, UC, and MSS CRC. 
The purpose of this SAP is to provide details of the statistical analyses that have been outlined in 
the Study INCB 24360-206 Protocol.  The scope of this plan includes the final analyses that are 
planned and will be executed by the Department of Biostatistics or designee. 
 
 
 


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2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS 
2.1. 
Protocol and Case Report Form Version 
This SAP is based on Study INCB 24360-206 Protocol Amendment 3 dated 20 OCT 2017 and 
CRFs approved 30 APR 2018.  Unless superseded by an amendment, this SAP will be effective 
for all subsequent Protocol amendments and eCRF versions. 
2.2. 
Study Objectives 
2.2.1. 
Primary Objectives 
• Part 1:  To evaluate the safety and tolerability and to determine the MTD, maximum 
tested dose, or PAD of the combinations in subjects with advanced or metastatic solid 
tumors. 
• Part 2:  To evaluate the efficacy of the combinations in subjects with previously 
treated Stage IV or recurrent NSCLC, Stage IV MSS CRC, and select solid tumors by 
assessing ORR per RECIST v1.1 at the MTD, maximum tested dose, or PAD. 
2.2.2. 
Secondary Objectives 
• Part 1:  To evaluate the efficacy of the combination in subjects with advanced or 
metastatic solid tumors by assessing ORR per RECIST v1.1 at the MTD, maximum 
tested dose, or PAD. 
• Part 2:  To evaluate the safety and tolerability of the combinations in subjects with 
previously treated Stage IV or recurrent NSCLC, Stage IV MSS CRC, and select 
solid tumors at the MTD, maximum tested dose, or PAD. 
• Parts 1 and 2:  To evaluate changes in T-cell infiltration in the tumor 
microenvironment with the combinations in subjects with advanced or metastatic 
solid tumors, previously treated Stage IV or recurrent NSCLC, and Stage IV MSS 
CRC. 
• Parts 1 and 2:  To evaluate the efficacy of the combinations in subjects with advanced 
or metastatic solid tumors, previously treated Stage IV or recurrent NSCLC, and 
Stage IV MSS CRC by assessing PFS. 
• Parts 1 and 2:  To evaluate the efficacy of the combinations in subjects with advanced 
or metastatic solid tumors, previously treated Stage IV or recurrent NSCLC, and 
Stage IV MSS CRC by assessing DOR. 


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2.3. 
Study Endpoints 
2.3.1. 
Primary Endpoints 
• Part 1:  Safety and tolerability will be assessed by monitoring the frequency, duration, 
and severity of AEs; through physical examinations; by evaluating changes in vital 
signs and ECGs; and through clinical laboratory blood and urine sample evaluations. 
• Part 2:  Objective response rate, defined as the percentage of subjects having a CR or 
PR, will be determined by investigator assessment of radiographic disease as per 
RECIST v1.1. 
2.3.2. 
Secondary Endpoints 
• Part 1:  Objective response rate, defined as the percentage of subjects having a CR or 
PR, will be determined by investigator assessment of radiographic disease as per 
RECIST v1.1. 
• Part 2:  Safety and tolerability will be assessed by monitoring the frequency, duration, 
and severity of AEs; through physical examinations; by evaluating changes in vital 
signs and ECGs; and through clinical laboratory blood and urine sample evaluations. 
• Parts 1 and 2:  Percentage of responders, where a responder is defined as an increase 
in the number of TILs or the ratio of CD8+ lymphocytes to Tregs infiltrating tumor 
post-treatment versus pretreatment with pembrolizumab and epacadostat in 
combination with azacitidine, INCB057643, or INCB059872 evaluated by IHC, will 
be determined. 


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• Parts 1 and 2:  Progression-free survival, defined as the time from date of first dose of 
study drug until the earliest date of disease progression, will be determined by 
investigator assessment of objective radiographic disease assessments per 
RECIST v1.1, or death due to any cause, if occurring sooner than progression. 
• Parts 1 and 2:  Duration of response determined by radiographic disease assessment, 
defined as the time from earliest date of disease response until the earliest date of 
disease progression as per RECIST v1.1, or death due to any cause, if occurring 
sooner than progression, will be determined. 


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3. 
STUDY DESIGN 
3.1. 
Overall Study Design 
This is an open-label, multicenter, Phase 1/2 study evaluating the addition of 3 different 
epigenetic priming regimens to an immunotherapy doublet in subjects with advanced or 
metastatic solid tumors. 
Part 1 of the study will be an open-label Phase 1 assessment to evaluate the safety and 
tolerability and to determine the MTD, maximum tested dose, or PAD of the combinations in 
subjects with advanced or metastatic solid tumors. 
Part 2 of the study will be an open-label Phase 2 assessment with Simon 2-stage design to 
evaluate ORR and TIL infiltration in previously treated NSCLC and MSS CRC.  Separate 
treatment sequencing tumor biopsy cohorts are also included in Part 2 to further evaluate 
epigenetic changes and changes in the tumor microenvironment in subjects with select solid 
tumors. 
3.1.1. 
Treatment Groups 
3.1.1.1. 
Treatment Group A 
In Treatment Group A, subjects will receive the DNMT inhibitor azacitidine in combination with 
the PD-1 inhibitor pembrolizumab and the IDO1 inhibitor epacadostat.  Part 1 of Treatment 
Group A will consist of a dose-escalation assessment of the safety and tolerability of the 
treatments in subjects with advanced or metastatic solid tumors.  In Part 1 of Treatment Group A, 
pembrolizumab and epacadostat will be administered in 21-day cycles from Cycle 1 Day 1 in 
combination with azacitidine.  Subjects in Treatment Group A will receive up to 6 cycles of 
azacitidine as long as the subject is receiving benefit from treatment and has not met any criteria 
for study withdrawal (except for Expansion Cohorts A-4 and A-5, which will receive up to 
5 cycles).  In Part 2 of Treatment Group A will consist of Simon 2-Stage cohorts in previously 
treated NSCLC and MSS CRC.  Separate treatment sequencing tumor biopsy cohorts are also 
included in Part 2 to further evaluate epigenetic changes and changes in the tumor 
microenvironment in subjects with select solid tumors.  In Treatment Group A, subjects who 
have an initial response or SD for greater than 6 months but later relapse while receiving 
pembrolizumab and epacadostat will have the opportunity to repeat the epigenetic priming 
regimen to which they were originally assigned.  Study treatment may continue as long as the 
subject is receiving benefit and has not met any criteria for study withdrawal or until the subject 
has received 35 administrations of pembrolizumab (approximately 2 years), whichever occurs 
first.  See Figure 1 for study design illustration. 


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Figure 1: 
Study Design:  Treatment Group A 
Part 1 Dose Escalation
Azacitidine
75 mg to 100 mg SC or IV
for 5 days in Cycles 1 and 2
+
Pembrolizumab 
200 mg IV Q3W
+
Epacadostat
100 to 300 mg PO BID 
Dose Selected 
Azacitidine 
+ 
Pembrolizumab
+ 
Epacadostat
MTD or PAD 
Part 2 Expansion
Simon 2-Stage Cohorts
Cohort A-1
Up to 27 subjects with Stage IV or 
recurrent NSCLC with prior PD-1
pathway–targeted treatment
Cohort A-2
Up to 27 subjects with Stage IV MSS CRC
Part 2 Expansion
Treatment Sequencing Tumor 
Biopsy Cohorts
Cohort A-3
Azacitidine monotherapy lead-in for
1 week prior to Pembrolizumab and 
Epacadostat
Cohort A-4
Pembrolizumab and Epacadostat
for 1 cycle;
Azacitidine added at Cycle 2
Cohort A-5
Pembrolizumab monotherapy for 1 cycle; 
Epacadostat and Azacitidine added at 
Cycle 2


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3.1.1.2. 
Treatment Groups B and C 
In Treatment Group B, subjects will receive the BET inhibitor INCB057643 as a monotherapy 
priming regimen in Cycle 1 and then will add pembrolizumab and epacadostat on Cycle 2 Day 1.  
In Treatment Group C, subjects will receive the LSD1 inhibitor INCB059872 as a monotherapy 
priming regimen in Cycle 1 and then will add pembrolizumab and epacadostat on Cycle 2 Day 1.  
Part 1 of Treatment Groups B and C will consist of a dose-escalation assessment of the safety 
and tolerability of the treatments in subjects with advanced or metastatic solid tumors.  Part 1 
will also contain dose-expansion cohorts in previously treated NSCLC and MSS CRC.  
Following enrollment of Part 1, there will be an optional study hold for evaluation of safety, 
efficacy
to facilitate a go/no-go decision regarding enrollment of 
Part 2.  Part 2 of Treatment Groups B and C will consist of Simon 2-stage cohorts in previously 
treated NSCLC and MSS CRC.  Separate treatment sequencing tumor biopsy cohorts are also 
included in Part 2 to further evaluate epigenetic changes and changes in the tumor 
microenvironment in subjects with select solid tumors.  Enrollment of the treatment sequencing 
tumor biopsy cohorts is contingent upon passing Stage 1 in 1 of the 2 cohorts, for each respective 
treatment group.  Study treatment may continue as long as the subject is receiving benefit and 
has not met any criteria for study withdrawal or until the subject has received 35 administrations 
of pembrolizumab (approximately 2 years), whichever occurs first.  See Figure 2 and Figure 3 
for study design illustration for Treatment Groups B and C, respectively. 


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Figure 2: 
Study Design:  Treatment Group B 
 


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Figure 3: 
Study Design:  Treatment Group C 
 
 


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3.1.2. 
Dose-Escalation Phase (All Treatment Groups) 
A 3 + 3 + 3 design will be used to assess the MTD, maximum tested dose, or PAD of the triplet 
combination of azacitidine, INCB057643, or INCB059872 with pembrolizumab and epacadostat 
in 21-day treatment cycles.  The MTD will be defined as the highest dose at which less than 
one-third of the subjects (with a minimum of 6 subjects) have a DLT.  When the MTD, 
maximum tested dose, or PAD has been determined or reached, the dose will be recommended 
for Part 2.  The Part 2 expansion will begin after the determination of the MTD, maximum tested 
dose, or PAD; however, enrollment priority will be given to the open Part 1 dose-escalation 
cohort. 
A minimum of 3 subjects will initially be enrolled in Cohort 1, and each subject will be observed 
for 21 days from the start of triplet combination therapy before enrollment in the next cohort 
begins.  The dose of azacitidine, INCB057643, or INCB059872 (or epacadostat) will be 
escalated if 0 of the first 3 evaluable subjects enrolled has a DLT.  If 1 of 3 subjects in Cohort 1 
has a DLT, the cohort will be expanded to 6 subjects.  If 1 of 6 subjects in Cohort 1 has a DLT, a 
new cohort of 3 subjects will be treated at the next higher dose level (Cohort 2).  If 2 of 
6 subjects in Cohort 1 have a DLT, that cohort will be further expanded to a total of 9 subjects.  
If ≤ 2/9 subjects have a DLT, 3 subjects will be treated at the next higher dose level.  If ≥ 2/3, 
3/6, or 3/9 subjects have a DLT within a cohort, dose de-escalation will be required, and 
Cohorts -1 or -2 will be tested.  The MTD is defined as the highest dose level at which ≤ 1/6 or 
≤ 2/9 subjects experience a DLT. 
Subjects must have received ≥ 75% of planned doses of study drug during the 21-day DLT 
(Treatment Group A) or 42-day DLT (Treatment Groups B and C) observation period or have 
had a DLT to be evaluable for dose tolerability (Treatment Group A:  azacitidine [4 doses], 
epacadostat [32 doses], and pembrolizumab [1 dose]; Treatment Group B:  INCB057643 
[32 doses], epacadostat [32 doses], and pembrolizumab [1 dose]; Treatment Group C:  
INCB059872 [QD dosing, 32 doses; QoD dosing, 16 doses], epacadostat [32 doses], and 
pembrolizumab [1 dose]). 
It is recognized that certain toxicities due to the combination agent (eg, including but not limited 
to gastrointestinal toxicity, including diarrhea; renal insufficiency; high-grade laboratory 
abnormalities; and rash) may initially be clinically indistinguishable from toxicities due to 
immunotherapy.  Epacadostat will be held for these toxicities, and as a result, subjects may not 
receive ≥ 75% of the prescribed dose during Cycle 1.  In these cases, the principal investigators 
and medical monitor may assess subjects who receive dose intensities somewhat below 75% for 
the determination of DLTs, and consider in the adjudication process the specific toxicity 
encountered, the likely cause of the toxicity, and dose intensity and tolerability beyond Cycle 1.  
Additional subjects will be enrolled in a cohort to achieve the minimum of 3 evaluable subjects if 
dropouts or dose interruptions/reductions occur that result in a subject being nonevaluable for 
DLTs. 
During the study, dose interruptions and/or dose modifications may be implemented based on 
toxicity as described in the Protocol, Section 5.4.  However, dose modifications should not be 
made during the DLT observation period without discussion with the medical monitor.  
Intrasubject dose escalation is not permitted. 


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3.1.2.1. 
Treatment Group A:  Azacitidine 
Dose escalation will begin with starting doses of azacitidine 75 mg SC or IV for 5 days (5 doses 
may be administered over the Day 1-7 period) of the first 2 cycles, pembrolizumab 200 mg IV 
Q3W, and epacadostat 100 mg PO BID continuous dose administration.  If the starting dose 
proves intolerable, then azacitidine 50 mg SC or IV for 5 days, pembrolizumab 200 mg IV Q3W, 
and epacadostat 100 mg PO BID will be evaluated.  The cohorts and dose levels are shown in 
Table 1. 
Table 1: 
Dose Levels:  Treatment Group A 
Cohort 
Azacitidine 
Pembrolizumab 
Epacadostat 
-2
a 
50 mg SC or IV for 5 days (5 doses 
over Day 1-7 period) in Cycle 1 & 2 
200 mg IV Q3W 
50 mg PO BID 
-1a 
50 mg SC or IV for 5 days (5 doses 
over Day 1-7 period) in Cycle 1 & 2 
200 mg IV Q3W 
100 mg PO BID 
1 
75 mg SC or IV for 5 days (5 doses 
over Day 1-7 period) in Cycle 1 & 2 
200 mg IV Q3W 
100 mg PO BID 
2A
b 
75 mg SC or IV for 5 days (5 doses 
over Day 1-7 period) in Cycle 1 & 2 
200 mg IV Q3W 
300 mg PO BID 
2Bb 
100 mg SC or IV for 5 days (5 doses 
over Day 1-7 period) in Cycle 1 & 2 
200 mg IV Q3W 
100 mg PO BID 
3 
100 mg SC or IV for 5 days (5 doses 
over Day 1-7 period) in Cycle 1 & 2 
200 mg IV Q3W 
300 mg PO BID 
a If Cohort 1 proves intolerable, Cohort -1 may be evaluated.  If Cohort -1 is not tolerable, Cohort -2 may be evaluated with 
epacadostat 50 mg PO BID.  If a de-escalation cohort is determined to be safe and tolerable, the dose of azacitidine or 
epacadostat may be re-escalated in separate, additional cohorts based on the review of available safety data. 
b For Cohort 2, escalation of azacitidine to 100 mg or epacadostat to 300 mg BID will be dependent on the observation of 
Grade 3 or greater immune-related or non–immune-related toxicities in Cohort 1 (toxicities that were not considered DLTs).  If 
Grade 3 or greater immune-related toxicities are observed in Cohort 1, azacitidine will be escalated first (Cohort 2B).  If 
nonimmune-related Grade 3 or greater toxicities are observed, epacadostat will be preferentially escalated (Cohort 2A).  
Dose-escalation Cohorts 2A and 2B may be opened in parallel if no Grade 3 AEs are observed in Cohort 1. 
3.1.2.2. 
Treatment Group B: INCB057643 
In Treatment Group B, dose escalation will begin with a starting dose of INCB057643 of 4 mg 
PO QD continuous dose administration beginning on Cycle 1 Day 1 for the first 21-day cycle.  
Beginning on Cycle 2 Day 1, pembrolizumab 200 mg IV Q3W and epacadostat 100 mg PO BID 
continuous dose administration will be added to INCB057643.  If the starting dose level proves 
intolerable, INCB057643 4 mg PO QD in combination with pembrolizumab 200 mg IV Q3W 
and epacadostat 50 mg PO BID will be evaluated.  The cohorts and dose levels are shown in 
Table 2. 


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Table 2: 
Dose Levels:  Treatment Group B 
Cohort 
INCB057643 
Pembrolizumab 
Epacadostat 
-1
a 
4 mg PO QD 
beginning C3D1 
200 mg IV Q3W 
beginning C2D1 
50 mg PO BID 
beginning C2D1 
1 
4 mg PO QD 
beginning C1D1 
200 mg IV Q3W 
beginning C2D1 
100 mg PO BID 
beginning C2D1 
2 
8 mg PO QD 
beginning C1D1 
200 mg IV Q3W 
beginning C2D1 
100 mg PO BID 
beginning C2D1 
3 
12 mg PO QD 
beginning C1D1 
200 mg IV Q3W 
beginning C2D1 
100 mg PO BID 
beginning C2D1 
a If Cohort 1 proves intolerable, Cohort -1 may be evaluated.  If Cohort -1 is not tolerable, lower doses or alternative dose 
schedules of INCB057643 may be tested; however, at this time, 4 mg tablets are the lowest dose formulation available.  Any 
dose reduction in INCB057643 would be combined with pembrolizumab 200 mg IV Q3W and epacadostat 50 mg PO BID.  If 
a de-escalation cohort is determined to be safe and tolerable, the dose of INCB057643 or epacadostat may be re-escalated in 
separate, additional cohorts based on the review of available safety data. 
3.1.2.3. 
Treatment Group C:  INCB059872 
In Treatment Group C, dose escalation will begin with a starting dose of INCB059872 of 1 mg 
PO QoD continuous dose administration beginning on Cycle 1 Day 1 for the first 21-day cycle.  
Beginning on Cycle 2 Day 1, pembrolizumab 200 mg IV Q3W and epacadostat 100 mg PO BID 
continuous dose administration will be added to INCB059872.  If the starting dose level proves 
intolerable, INCB059872 1 mg PO QoD in combination with pembrolizumab 200 mg IV Q3W 
and epacadostat 50 mg PO BID will be evaluated.  The cohorts and dose levels are shown in 
Table 3. 
Table 3: 
Dose Levels: Treatment Group C 
Cohort 
INCB059872 
Pembrolizumab 
Epacadostat 
-1
a 
1 mg PO QoD 
beginning C1D1 
200 mg IV Q3W 
beginning C2D1 
50 mg PO BID 
beginning C2D1 
1 
1 mg PO QoD 
beginning C1D1 
200 mg IV Q3W 
beginning C2D1 
100 mg PO BID 
beginning C2D1 
2A
b 
2 mg PO QoD 
beginning C1D1 
200 mg IV Q3W 
beginning C2D1 
100 mg PO BID 
beginning C2D1 
2Bb 
1 mg PO QD 
beginning C1D1 
200 mg IV Q3W 
beginning C2D1 
100 mg PO BID 
beginning C2D1 
3
c 
3 mg PO QoD 
beginning C1D1 
200 mg IV Q3W 
beginning C2D1 
100 mg PO BID 
beginning C2D1 
a If Cohort 1 proves intolerable, Cohort -1 may be evaluated.  If Cohort -1 is not tolerable, lower doses or alternative dose 
schedules of INCB059872 may be tested.  Any dose reduction in INCB059872 would be combined with pembrolizumab 
200 mg IV Q3W and epacadostat 50 mg PO BID.  If a de-escalation cohort is determined to be safe and tolerable, the dose of 
INCB059872 or epacadostat may be re-escalated in separate, additional cohorts based on the review of available safety data. 
b Dose-escalation Cohorts 2A and 2B may be opened in parallel if no Grade 3 AEs are observed in Cohort 1. 
c Cohort 3 will be enrolled once Cohort 2A clears the DLT period.  Enrollment into Cohort 3 is not dependent upon clearing the 
DLT period from Cohort 2B. 


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3.1.3. 
Dose-Expansion Phase 
3.1.3.1. 
Treatment Group A 
Once the safety profile of all doses tested has been characterized and the RP2D of the 
combination has been defined, the cohort expansion will be initiated at the RP2D.  The doses 
selected for expansion will not exceed the MTD or maximum tested dose in Part 1. 
The purpose of Phase 2 is to gather additional safety, tolerability
 and 
preliminary efficacy information regarding the triplet combination in select tumor types where 
there is substantial room for improvement over mono- and doublet immunotherapies.  The 
expansion will include: 
1. Safety/efficacy cohorts in NSCLC (A-1) and MSS CRC (A-2) (2 tumor biopsies are 
required) 
2. Treatment sequencing biopsy cohorts (3 tumor biopsies are required) 
a. A-3:  azacitidine monotherapy followed by the pembrolizumab/epacadostat doublet 
b. A-4:  pembrolizumab/epacadostat doublet followed by azacitidine 
c. A-5:  pembrolizumab monotherapy followed by epacadostat and azacitidine 
Note:  Only subjects with untreated (first-line) melanoma will be treated in the 
pembrolizumab monotherapy cohort (A-5). 
3.1.3.1.1. Treatment Group A Safety/Efficacy Expansion Cohorts (Part 2) 
Two cohorts will be evaluated as part of the safety/efficacy expansion.  The eligible tumor types 
are NSCLC and MSS CRC.  Subjects enrolled in the NSCLC tumor cohort must have had 
disease progression on a prior PD-1 pathway–targeted agent. 
A Simon 2-stage design will be used 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, 8 NSCLC subjects who progressed on a PD-1 pathway–targeted agent and 8 MSS CRC 
subjects will be enrolled.  If no responses are observed in the NSCLC PD-1 failure and MSS 
CRC cohorts, the cohort(s) will be discontinued.  If at least 1 response is observed in the NSCLC 
PD-1 failure or MSS CRC cohort, 19 additional NSCLC PD-1 failure or MSS CRC subjects will 
be enrolled (Stage 2), for a maximum of 27 subjects per cohort (see Table 4). 
Table 4: 
Treatment Group A Safety/Efficacy Expansion Cohorts (Part 2) 
Cohort 
Treatment 
Tumor Type (n) 
Expansion Cohort A-1 
MTD or maximum tested dose for the 
azacitidine + pembrolizumab + 
epacadostat combination. 
A maximum of 27 subjects with 
previously treated Stage IV or recurrent 
NSCLC with progression on a prior PD-1 
pathway–targeted agent. 
Expansion Cohort A-2 
MTD or maximum tested dose for the 
azacitidine + pembrolizumab + 
epacadostat combination. 
A maximum of 27 subjects with 
previously treated Stage IV MSS CRC. 


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Continuous evaluation of toxicity events will be performed throughout the expansion.  In the 
expansion, after the sixth subject in Stage 1 has been enrolled, if > 40% of subjects have an AE 
≥ Grade 3 that is attributable to the investigational agents, further enrollment of subjects will be 
suspended until the sponsor, investigators, and regulatory authorities (if applicable) have 
determined the appropriate course of action.  If an expansion cohort is discontinued because of 
toxicity, a new cohort may be initiated at a previously tested lower dose level. 
3.1.3.1.2. Treatment Group A Treatment Sequencing Tumor Biopsy Cohorts (Part 2) 
The sequencing biopsy cohorts require 3 tumor biopsies to identify epigenetic changes and 
changes in the tumor microenvironment induced by each of the components of the regimen.  All 
subjects will have tumor biopsies at baseline and 2 additional biopsies while on study treatment. 
Approximately 25 subjects will be enrolled in Expansion Cohorts A-3 and A-4, and 
approximately 10 subjects will be enrolled in Expansion Cohort A-5.  The eligible tumor types 
for Expansion Cohorts A-3, A-4, and A-5 are HNSCC, melanoma, UC, and MSS CRC.  In 
Expansion Cohorts A-3 and A-4, subjects with tumor types other than MSS CRC must have had 
disease progression on a prior PD-1 pathway–targeted agent. 
Five to 8 evaluable subjects per tumor type in Expansion Cohorts A-3 and A-4, and 10 subjects 
in Expansion Cohort A-5 will initiate treatment and have tumor biopsies performed as indicated 
in Table 5. 
Table 5: 
Treatment Group A Treatment Sequencing Tumor Biopsy Cohorts (Part 2) 
Cohort 
Treatment Sequence 
Biopsy Sequence 
Tumor Type (n) 
Expansion Group A-3 
Azacitidine monotherapy 
during Week -1 (5 doses), 
initiate pembrolizumab and 
epacadostat on C1D1 (after 
biopsy #2), 5 doses of 
azacitidine will be 
administered in Cycles 2 and 3. 
Biopsy #1 at baseline. 
Biopsy #2 on C1D1 (window 
Day -5 to C1D1, biopsy before 
pembrolizumab/epacadostat 
administration). 
Biopsy #3 during Week 5 or 6. 
HNSCC (5-8) 
Melanoma (5-8) 
UC (5-8) 
MSS CRC (5-8) 
Expansion Group A-4 
Pembrolizumab and 
epacadostat for 1 cycle, initiate 
azacitidine after biopsy #2, 
5 doses of azacitidine will be 
administered in Cycles 2 and 3. 
Biopsy #1 at baseline. 
Biopsy #2 on C2D1 (window 
C1D20 to C2D1, biopsy before 
azacitidine administration). 
Biopsy #3 during Week 8 or 9.   
HNSCC (5-8) 
Melanoma (5-8) 
UC (5-8) 
MSS CRC (5-8) 
Expansion Group A-5 
Pembrolizumab monotherapy 
for 1 cycle, initiate epacadostat 
and azacitidine after biopsy #2, 
5 doses of azacitidine will be 
administered in Cycles 2 and 3. 
Biopsy #1 at baseline. 
Biopsy #2 on C2D1 (window 
C1D20 to C2D1, biopsy before 
epacadostat/azacitidine 
administration). 
Biopsy #3 during Week 8 or 9. 
First-line melanoma 
(10) 
Subjects in Expansion Cohort A-3 will receive up to 6 cycles of azacitidine.  Subjects in 
Expansion Cohorts A-4 and A-5 will receive up to 5 cycles of azacitidine.  The sponsor will 
manage enrollment so that there are approximately 5 to 8 evaluable subjects for a given tumor 
type.  Subjects may be replaced if they have not completed all of the biopsy requirements. 


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3.1.3.2. 
Treatment Group B 
3.1.3.2.1. Treatment Group B Dose Expansion Cohorts (Part 1) 
Because higher doses of epigenetic priming regimens may be deleterious to immune function, 
expansion cohorts at each dose level tested that cleared the DLT window will be opened for 
signal detection 
 analysis to guide an RP2D.  Once an RP2D is determined, 
this dose will be used in Part 2 in the Simon 2-stage and treatment sequencing tumor biopsy 
cohorts.  During dose expansion, 5 NSCLC subjects who progressed on a PD-1 pathway–
targeted agent and 5 MSS CRC subjects will be enrolled at each dose level with DLT clearance 
as detailed below. 
The expansion will include: 
1. Safety/efficacy cohorts in NSCLC (2 tumor biopsies are required) 
a. B-1:  INCB057643 4 mg QD followed by the pembrolizumab/epacadostat doublet 
b. B-3:  INCB057643 8 mg QD followed by the pembrolizumab/epacadostat doublet 
c. B-5:  INCB057643 12 mg QD followed by the pembrolizumab/epacadostat doublet 
2. Safety/efficacy cohorts in MSS CRC (2 tumor biopsies are required) 
a. B-2:  INCB057643 4 mg QD followed by the pembrolizumab/epacadostat doublet 
b. B-4:  INCB057643 8 mg QD followed by the pembrolizumab/epacadostat doublet 
c. B-6:  INCB057643 12 mg QD followed by the pembrolizumab/epacadostat doublet 
The following cohorts will be expanded only under certain circumstances, as listed below: 
1. Cohorts B-1 and B-2:  Objective responses have been seen in subjects dosed with 
INCB057643 at 8 and 12 mg QD and, as such, are known PADs.  However, 4 mg QD 
dosing has not been evaluated in humans.  To ensure 4 mg QD is a PAD, Cohorts B-1 
and B-2 will only be enrolled if > 1/3 of the subjects in the dose-escalation cohort have a 
25% drop in platelet count from Cycle 1 Day 1 to Cycle 2 Day 1. 
Continuous evaluation of toxicity events will be performed throughout the expansion cohorts.  
After the dose-expansion cohorts have been enrolled, beginning with the sixth patient for a 
specific regimen, if > 40% of subjects have an AE ≥ Grade 3 that is attributable to the 
investigational agents, further enrollment of subjects will be suspended until the sponsor, 
investigators, and regulatory authorities (if applicable) have determined the appropriate course of 
action.  If an expansion cohort is discontinued because of toxicity, a new cohort may be initiated 
at a previously tested lower dose level. 
Following completed enrollment of the safety/efficacy expansion cohorts, there will be an 
optional 8-week pause to utilize 
 data for RP2D determination.  During this time 
period, no subject enrollment may be allowed.  If there is no evidence of clinical efficacy 
 
 in the dose-expansion cohorts, enrollment in the respective treatment 
group will be stopped prior to Part 2. 


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3.1.3.2.2. Treatment Group B Simon 2-Stage Cohorts (Part 2) 
Following safety, efficacy, 
 data evaluation, an RP2D will be determined.  A 
Simon 2-stage design will be used 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, 8 NSCLC subjects who progressed on a PD-1 pathway–targeted agent and 8 MSS CRC 
subjects will be enrolled.  If no responses are observed in the NSCLC PD-1 failure and MSS 
CRC cohorts, the cohort(s) will be discontinued.  If at least 1 response is observed in the NSCLC 
PD-1 failure or MSS CRC cohort, 19 additional NSCLC PD-1 failure or MSS CRC subjects will 
be enrolled (Stage 2), for a maximum of 27 subjects per cohort (see Table 6). 
Table 6: 
Treatment Group B Safety/Efficacy Expansion Cohorts (Part 2) 
Cohort 
Treatment 
Tumor Type (n) 
Expansion Cohort B-7 
MTD, maximum tested dose, or PAD for 
the INCB057643 + pembrolizumab + 
epacadostat combination. 
A maximum of 27 subjects with 
previously treated Stage IV or recurrent 
NSCLC with progression on a prior PD-1 
pathway-targeted agent. 
Expansion Cohort B-8 
MTD, maximum tested dose, or PAD for 
the INCB057643 + pembrolizumab + 
epacadostat combination. 
A maximum of 27 subjects with 
previously treated Stage IV MSS CRC. 
3.1.3.2.3. Treatment Group B Treatment Sequencing Tumor Biopsy Cohorts (Part 2) 
The sequencing biopsy cohorts require 3 tumor biopsies (except for Cohort B-11, which requires 
2 tumor biopsies) to identify epigenetic changes and changes in the tumor microenvironment 
induced by each of the components of the regimen.  All subjects will have tumor biopsies at 
baseline and 2 additional biopsies while on study treatment. 
If Stage 1 is passed in Cohort B-7 or B-8, approximately 25 subjects will be enrolled in 
Expansion Cohorts B-9, B-10, and B-11.  The eligible tumor types for Expansion Cohorts B-9, 
B-10, and B-11 are HNSCC, melanoma, UC, and MSS CRC.  In Expansion Cohorts B-9, B-10, 
and B-11, subjects with tumor types other than MSS CRC must have had disease progression on 
a prior PD-1 pathway–targeted agent. 
Five to 8 evaluable subjects per tumor type in Expansion Cohorts B-9, B-10, and B-11 will 
initiate treatment and have tumor biopsies performed as indicated in Table 7. 


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Table 7: 
Treatment Group B Treatment Sequencing Tumor Biopsy Cohorts (Part 2) 
Cohort 
Treatment Sequence 
Biopsy Sequence 
Tumor Type (n) 
Expansion Cohort B-9 
INCB057643 continuous 
monotherapy during C1, 
initiate pembrolizumab and 
epacadostat on C2D1 after 
biopsy #2. 
Biopsy #1 at baseline. 
Biopsy #2 on C2D1 (window 
C1D15 to C2D1, biopsy before 
pembrolizumab/ epacadostat 
administration). 
Biopsy #3 during Week 8 or 9. 
HNSCC (5-8) 
Melanoma (5-8) 
UC (5-8) 
MSS CRC (5-8) 
Expansion Cohort B-10 
INCB057643 and epacadostat 
for 1 cycle, initiate 
pembrolizumab after 
biopsy #2. 
Biopsy #1 at baseline. 
Biopsy #2 on C2D1 (window 
C1D15 to C2D1, biopsy before 
pembrolizumab 
administration). 
Biopsy #3 during Week 8 or 9.   
HNSCC (5-8) 
Melanoma (5-8) 
UC (5-8) 
MSS CRC (5-8) 
Expansion Cohort B-11 
INCB057643, epacadostat, 
and pembrolizumab beginning 
C1. 
Biopsy #1 at baseline. 
Biopsy #2 during Week 5 or 6. 
HNSCC (5-8) 
Melanoma (5-8) 
UC (5-8) 
MSS CRC (5-8) 
The sponsor will manage enrollment so that there are 5 to 8 evaluable subjects for a given tumor 
type.  Subjects may be replaced if they have not completed all of the biopsy requirements. 
3.1.3.3. 
Treatment Group C 
3.1.3.3.1. Treatment Group C Dose Expansion Cohorts (Part 1) 
Because higher doses of epigenetic priming regimens may be deleterious to immune function, 
expansion cohorts at each dose level tested that clear the DLT window will be opened for signal 
detection 
 analysis to guide an RP2D.  Once an RP2D is determined, this 
dose will be used in Part 2 in the Simon 2-stage and treatment sequencing tumor biopsy cohorts.  
During dose expansion, 5 NSCLC subjects who progressed on a PD-1 pathway–targeted agent 
and 5 MSS CRC subjects will be enrolled at each dose level with DLT clearance as detailed 
below. 
The expansion will include: 
1. Safety/efficacy cohorts in NSCLC (2 tumor biopsies are required) 
a. C-1:  INCB059872 1 mg QoD followed by the pembrolizumab/epacadostat doublet 
b. C-3:  INCB059872 2 mg QoD followed by the pembrolizumab/epacadostat doublet 
c. C-5:  INCB059872 1 mg QD followed by the pembrolizumab/epacadostat doublet 
d. C-7:  INCB059872 3 mg QoD followed by the pembrolizumab/epacadostat doublet 
2. Safety/efficacy cohorts in MSS CRC (2 tumor biopsies are required) 
a. C-2:  INCB059872 1 mg QoD followed by the pembrolizumab/epacadostat doublet 
b. C-4:  INCB059872 2 mg QoD followed by the pembrolizumab/epacadostat doublet 
c. C-6:  INCB059872 1 mg QD followed by the pembrolizumab/epacadostat doublet 
d. C-8:  INCB059872 3 mg QoD followed by the pembrolizumab/epacadostat doublet 


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The following cohorts will be expanded only under certain circumstances, as listed below: 
1. Cohorts C-1, C-2, C-5, and C-6:  Objective responses have been seen in subjects dosed 
with INCB059872 2 and 3 mg QoD and above and, as such, are PADs.  However, 1 mg 
QoD has not been evaluated in humans, and there is no objective data to show that 1 mg 
QD is a PAD.  To ensure that 1 mg QD and 1 mg QoD are PADs, Cohorts C-1, C-2, C-5, 
and C-6 will only be enrolled if > 1/3 of the subjects in the dose-escalation cohorts have a 
25% drop in platelet count from Cycle 1 Day 1 to Cycle 2 Day 1. 
2. Cohorts C-3 and C-4 will only be expanded if both of the following occur: 
a. The INCB059872 1 mg QD cohort does not clear its DLT window or is deemed not 
tolerated for reasons outside of strict DLT criteria. 
b. The INCB059872 2 mg QoD cohort clears its DLT window and is deemed to have 
acceptable tolerability. 
Continuous evaluation of toxicity events will be performed throughout the expansion cohorts.  
After the dose-expansion cohorts have been enrolled, beginning with the sixth patient for a 
specific regimen, if > 40% of subjects have an AE ≥ Grade 3 that is attributable to the 
investigational agents, further enrollment of subjects will be suspended until the sponsor, 
investigators, and regulatory authorities (if applicable) have determined the appropriate course of 
action.  If an expansion cohort is discontinued because of toxicity, a new cohort may be initiated 
at a previously tested lower dose level. 
Following completed enrollment of the safety/efficacy expansion cohorts, there will be an 
optional 8-week pause to utilize 
 data for RP2D determination.  During this time 
period, no subject enrollment may be allowed.  If there is no evidence of clinical efficacy 
 
 in the dose-expansion cohorts, enrollment in the respective treatment 
group will be stopped prior to Part 2. 
3.1.3.3.2. Treatment Group C Simon 2-Stage Cohorts (Part 2) 
Following safety, efficacy,
 data evaluation, an RP2D will be determined.  A 
Simon 2-stage design will be used 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, 8 NSCLC subjects who progressed on a PD-1 pathway–targeted agent and 8 MSS CRC 
subjects will be enrolled.  If no responses are observed in the NSCLC PD-1 failure and MSS 
CRC cohorts, the cohort(s) will be discontinued.  If at least 1 response is observed in the NSCLC 
PD-1 failure or MSS CRC cohort, 19 additional NSCLC PD-1 failure or MSS CRC subjects will 
be enrolled (Stage 2), for a maximum of 27 subjects per cohort (see Table 8). 
Table 8: 
Treatment Group C Safety/Efficacy Expansion Cohorts (Part 2) 
Cohort 
Treatment 
Tumor Type (n) 
Expansion Cohort C-9 
MTD, maximum tested dose, or PAD for 
the INCB059872 + pembrolizumab + 
epacadostat combination. 
A maximum of 27 subjects with 
previously treated Stage IV or recurrent 
NSCLC with progression on a prior PD-1 
pathway–targeted agent. 
Expansion Cohort C-10 
MTD, maximum tested dose, or PAD for 
the INCB059872 + pembrolizumab + 
epacadostat combination. 
A maximum of 27 subjects with 
previously treated Stage IV MSS CRC. 


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3.1.3.3.3. Treatment Group C Treatment Sequencing Tumor Biopsy Cohorts (Part 2) 
The sequencing biopsy cohorts require 3 tumor biopsies (except for Cohort C-13, which requires 
2 tumor biopsies) to identify epigenetic changes and changes in the tumor microenvironment 
induced by each of the components of the regimen. 
If Stage 1 is passed in Cohort C-9 or C-10, approximately 25 subjects will be enrolled in 
Expansion Cohorts C-11, C-12, and C-13.  The eligible tumor types for Expansion Cohorts C-11, 
C-12, and C-13 are HNSCC, melanoma, UC, and MSS CRC.  In Expansion Cohorts C-11, C-12, 
and C-13, subjects with tumor types other than MSS CRC must have had disease progression on 
a prior PD-1 pathway–targeted agent. 
Five to 8 evaluable subjects per tumor type in Expansion Cohorts C-11, C-12, and C-13 will 
initiate treatment and have tumor biopsies performed as indicated in Table 9. 
Table 9: 
Treatment Group C Treatment Sequencing Tumor Biopsy Cohorts (Part 2) 
Cohort 
Treatment Sequence 
Biopsy Sequence 
Tumor Type (n) 
Expansion Cohort C-11 
INCB059872 continuous 
monotherapy during C1, 
initiate pembrolizumab and 
epacadostat on C2D1 (after 
biopsy #2). 
Biopsy #1 at baseline. 
Biopsy #2 on C2D1 (window 
C1D15 to C2D1, biopsy before 
pembrolizumab/epacadostat 
administration). 
Biopsy #3 during Week 8 or 9. 
HNSCC (5-8) 
Melanoma (5-8) 
UC (5-8) 
MSS CRC (5-8) 
Expansion Cohort C-12 
INCB059872 and epacadostat 
for 1 cycle, initiate 
pembrolizumab after 
biopsy #2. 
Biopsy #1 at baseline. 
Biopsy #2 on C2D1 (window 
C1D15 to C2D1, biopsy before 
pembrolizumab 
administration). 
Biopsy #3 during Week 8 or 9.   
HNSCC (5-8) 
Melanoma (5-8) 
UC (5-8) 
MSS CRC (5-8) 
Expansion Cohort C-13 
INCB059872, epacadostat and 
pembrolizumab beginning C1. 
Biopsy #1 at baseline. 
Biopsy #2 during Week 5 or 6 
HNSCC (5-8) 
Melanoma (5-8) 
UC (5-8) 
MSS CRC (5-8) 
The sponsor will manage enrollment so that there are 5 to 8 evaluable subjects for a given tumor 
type.  Subjects may be replaced if they have not completed all of the biopsy requirements. 
3.1.4. 
Re-Treatment 
3.1.4.1. 
Re-Treatment With Pembrolizumab or the Combination 
Subjects who stop pembrolizumab or the combination with SD, PR, or CR may be eligible for up 
to an additional 17 cycles (approximately 1 year) of additional combination therapy or 
pembrolizumab if they experience disease progression after stopping the combination treatment 
or pembrolizumab.  Re-treatment with pembrolizumab or the combination must be discussed and 
approved by the medical monitor.  
 
 


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3.1.4.2. 
Re-Treatment With Azacitidine, INCB057643, or INCB059872 
Re-treatment with azacitidine, INCB057643, or INCB059872 (based on original treatment 
assignment) along with pembrolizumab and epacadostat may be administered for subjects who 
had a CR, PR, or SD (for > 6 months) and later had evidence of PD while receiving 
pembrolizumab and epacadostat.  Three additional cycles of azacitidine are permitted (for 
subjects originally enrolled in Treatment Group A).  Cycle 1 Day 1 (or Day 1 of Week -1 for 
Expansion Cohort A-3) must be no more than 28 days after the subject has signed the ICF. 
3.2. 
Randomization 
Not applicable. 
3.3. 
Control of Type I Error 
For the primary efficacy endpoint in the Part 2 Simon 2-stage cohorts, the 1-sided Type I error 
will be controlled at 0.05 for each individual cohort expansion.  For other endpoints, CIs will be 
reported at a 95% confidence level.  Note that this level of significance does not account for the 
multiple expansion cohorts. 
3.4. 
Sample Size Considerations 
3.4.1. 
Sample Size in Part 1 
3.4.1.1. 
Part 1 Dose Escalation 
In Part 1, a 3 + 3 + 3 design will be used to assess the primary objective of determining the 
MTD, maximum tested dose, or PAD of the triplet combination of azacitidine, INCB057643, or 
INCB059872 with pembrolizumab and epacadostat in 21-day treatment cycles.  Based on the 3 + 
3 + 3 design algorithm, a minimum of 3 subjects and up to 9 subjects will be enrolled at each 
dose level.  The total number of subjects will depend on the frequency of DLTs and number of 
dose levels tested before the MTD, maximum tested dose, or PAD is established. 
3.4.1.2. 
Part 1 Dose Expansion 
In addition to the dose-escalation cohorts, dose-expansion cohorts for Treatment Groups B and C 
in 5 NSCLC subjects who progressed on a PD-1 pathway–targeted agent and 5 MSS CRC 
subjects will be opened at each dose level tested that clears the DLT window for signal detection 
 analysis to guide an RP2D.  See Sections 3.1.3.2.1 and 3.1.3.3.1 for 
Treatment Group B and C dose-expansion cohorts, respectively. 
3.4.2. 
Sample Size in Part 2 Safety/Efficacy Expansion Cohorts 
3.4.2.1. 
Part 2 Simon 2-Stage Cohorts 
The safety/efficacy expansion in Part 2 will include 2 cohorts per treatment group, subjects with 
NSCLC who have had disease progression on a prior PD-1 pathway–targeted agent and subjects 
with MSS CRC.  A Simon 2-stage design will be used for each of the cohorts (Simon 1989).  
The response rates for the historical control (p0), desired response rates for the combination (p1), 
number of subjects needed in Stage 1 (n1) and Stage 2 (n2), total number of subjects (n), first 


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stage threshold declaring cohort undesirable (r1), and the upper limit of the number of responses 
in n subjects such that futility of the drug is concluded (r) are provided for each expansion cohort 
in Table 10.  The calculation is based on a 1-sided Type I error of 0.05 and power of 80%. 
Table 10: 
Simon 2-Stage Design 
Cohort 
Tumor Type 
 
 
 
 
 
 
r 
Expansion Cohort A-1 
NSCLC subjects who 
have had disease 
progression on a prior 
PD-1 pathway-targeted 
agent 
3% 
20% 
8 
19 
27 
0 
2 
Expansion Cohort A-2 
MSS CRC 
3% 
20% 
8 
19 
27 
0 
2 
Expansion Cohort B-7 
NSCLC subjects who 
have had disease 
progression on a prior 
PD-1 pathway–targeted 
agent 
3% 
20% 
8 
19 
27 
0 
2 
Expansion Cohort B-8 
MSS CRC 
3% 
20% 
8 
19 
27 
0 
2 
Expansion Cohort C-9 
NSCLC subjects who 
have had disease 
progression on a prior 
PD-1 pathway–targeted 
agent 
3% 
20% 
8 
19 
27 
0 
2 
Expansion Cohort C-10 
MSS CRC 
3% 
20% 
8 
19 
27 
0 
2 
3.4.2.2. 
Part 2 Treatment Sequencing Tumor Biopsy Cohorts 
Three treatment sequencing tumor biopsy cohorts per treatment group will be enrolled to 
evaluate epigenetic and tumor microenvironment changes.  Five to 8 evaluable subjects per each 
tumor type will be enrolled in Expansion Cohorts A-3, A-4, B-9 through B-11, and C-11 through 
C-13.  The eligible tumor types are HNSCC, melanoma, UC, and MSS CRC.  Subjects with 
tumor types other than MSS CRC must have had disease progression on a prior PD-1 pathway–
targeted agent.  Ten subjects with first-line melanoma will be enrolled in Expansion Cohort A-5.  
See Table 5, Table 7, and Table 9 for more details regarding treatment sequences and biopsy 
sequences for Treatment Groups A, B, and C, respectively. 
Assuming the true rate of subjects positive for the biomarker is 70%, the probability of observing 
16 or more subjects out of 25 subjects with the biomarker is 81% for Expansion Cohorts A-3, 
A-4, B-9 through B-11, and C-11 through C-13, and the probability of observing 6 or more 
subjects out of 10 subjects with the biomarker is 85% for Expansion Cohort A-5. 
3.5. 
Schedule of Assessments 
See Protocol Amendment 3 dated 20 OCT 2017 for a full description of all study procedures and 
assessment schedules for this study. 


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4. 
DATA HANDLING DEFINITIONS AND CONVENTIONS 
4.1. 
General Considerations 
Due to the early termination of the study, only subjects in Treatment Group A have been 
enrolled.  No analyses on Treatment Groups B and C will be conducted. 
4.2. 
Scheduled Study Evaluations and Study Periods 
4.2.1. 
Day 1 
For Expansion Group A-3, Day 1 is the date that the first dose of epacadostat or pembrolizumab 
is administered to subjects. 
For all other treatment groups, Day 1 is the date that the first dose of any study drug 
(epacadostat, pembrolizumab, or azacitidine) is administered to subjects. 
4.2.2. 
Study Day 
If a visit/reporting date is on or after Day 1, then the study day at the visit/reporting date will be 
calculated as  
Day # = (Visit/Reporting Date – Day 1 date + 1).  
If the visit/reporting date is before Day 1, then the study day at the visit/reporting date will be 
calculated as 
Day # = (Visit/Reporting Date – Day 1 date).  
A study day of -1 indicates 1 day before Day 1. 
4.2.3. 
Baseline Value 
Baseline is the last nonmissing measurement obtained before the first administration of any study 
drug (epacadostat, pembrolizumab, or azacitidine) is administered to subjects. 
When scheduled assessments and unscheduled assessments occur on the same day and time of 
the assessment or time of first dose is not available, use the following convention to determine 
baseline: 
• If both a scheduled and an unscheduled visit are available on the day of the first dose 
and the time is missing, use the scheduled assessment as baseline. 
• If all scheduled assessments are missing on the day of the first dose and an 
unscheduled assessment is available, use the unscheduled assessment as baseline. 
4.2.4. 
Handling of Missing and Incomplete Data  
In general, values for missing data will not be imputed unless methods for handling missing data 
are specified in this section or relevant sections.  


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Partial disease/cancer diagnosis date will be handled as follows:  
• If only the day is missing, then the imputed day will be the first of the month. 
• If both the month and day are missing, then the imputed day and month will be 
01 JAN. 
• No imputation will be done if the date is completely missing. 
Missing or partial date of last dose will be handled as follows:  
• If only the day is missing, then the imputed date of the last dose will be the earlier 
date of the first day of the month or the date that the subject discontinued treatment.  
• Otherwise, the date that the subject discontinued treatment will be used as the date of 
the last dose.  
For relevant efficacy endpoints, partial death date will be imputed as follows:  
• If mmyyyy for the last contact date = mmyyyy for the death date, then the death date 
will be set to the day after the last contact date.  
• If mmyyyy for the last contact date < mmyyyy for the death date, then the death date 
will be set to the first day of the death month.  
• Otherwise, the partial death date will not be imputed. 
For prior and concomitant medications: 
The start/stop dates recorded in the eCRF by the investigator and his or her research staff will be 
used to identify when a concomitant medication was taken during the study.  Any missing start 
date must be queried for resolution.  Unresolved missing start dates will be handled as follows: 
• If the date is completely missing, the medication will be considered both prior and 
concomitant. 
• If only the day is missing, and the last day of the month is before the first dose date 
on Day 1, then the concomitant medication will be considered as starting before 
Day 1, and the incomplete date will be imputed as the last day of the month. 
• If only the day is missing, and the first day of the month is after the first dose date on 
Day 1, then the concomitant medication will be considered as starting after Day 1, 
and the incomplete date will be imputed as the first day of the month. 
• If only the day is missing, and the month is equal to the month of the first dose date 
on Day 1, then the incomplete date will be imputed as the first day of the month. 
• If both the month and day are missing, and the last day of the year is before the first 
dose date on Day 1, then the concomitant medication will be considered as starting 
before Day 1, and the incomplete date will be imputed as if it is the last day of the 
year.  Otherwise, the incomplete date will be imputed as if it is the first day of the 
year. 


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4.2.5. 
Cycle Length and Duration 
For Treatment Group A, Cycle 1 Day 1 is the day that the first dose of pembrolizumab is 
administered.  Scheduled cycle length is 21 days.  Actual Day 1 of subsequent cycles will 
correspond with the first day of administration of pembrolizumab for Treatment Group A in that 
cycle; thus, treatment cycles may become out of sync with the originally planned schedule, and 
cycle length may be different from 21 days (± 3-day window for subsequent cycles).  The date of 
Day 1 of subsequent cycles recorded on the eCRF will be used as Day 1 of the subsequent 
cycles. 
4.3. 
Variable Definitions 
The following variables will only be calculated if not reported on the eCRF.  
4.3.1. 
Age 
Subject age will be calculated as the integer part of the number of years from date of birth to the 
date of signing the informed consent form, using the following formula: 
Age = integer part of (date of informed consent – date of birth + 1) / 365.25. 
When date of birth was not collected for a subject, and the age of the subject was reported in the 
eCRF, the reported age will substitute for the calculated age. 
4.3.2. 
Body Mass Index 
Body mass index will be calculated as follows: 
BMI (kg/m2) = [weight (kg)] / [height (m)]2. 
4.3.3. 
Prior and Concomitant Medication 
Prior medication is defined as any nonstudy medication started before the first dose of 
epacadostat, pembrolizumab, or azacitidine. 
Concomitant medication is defined as any nonstudy medication that is started accordingly:  
• Before the date of first administration of epacadostat, pembrolizumab, or azacitidine, 
and is ongoing throughout the study or ends on/after the date of first study drug 
administration. 
• On/after the date of first administration of epacadostat, pembrolizumab, or azacitidine 
and is ongoing or ends during the course of study drug. 
A prior medication could also be classified as "both prior and concomitant medication" if the end 
date is on or after first dose of epacadostat, pembrolizumab, or azacitidine.  In the listing, it will 
be indicated whether a medication is prior-only, concomitant-only, or both prior and concomitant 
medication. 
For the purposes of analysis, all medications will be considered concomitant medications unless 
the medications can unequivocally be defined as not concomitant. 


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5. 
STATISTICAL METHODOLOGY 
5.1. 
General Methodology 
Unless otherwise noted, SAS® software (SAS Institute Inc, Cary, NC; v9.4 or later) will be used 
for the generation of all tables, figures, and statistical analyses.  Descriptive summaries for 
continuous variables will include, but not be limited to, the number of observations, mean, 
standard deviation, median, minimum, and maximum.  Descriptive summaries for categorical 
variables will include the number and percentage of subjects in each category.  Summary tables 
and figures will be provided only for initial treatment phase.  Only listings will be provided for 
re-treatment phase, if applicable. 
5.2. 
Treatment Groups 
This is an open-label, multicenter, Phase 1/2 study evaluating the addition of an epigenetic 
priming regimen to an immunotherapy doublet in subjects with advanced or metastatic solid 
tumors.  The study will be conducted in 2 parts. 
Due to the stop of study enrollment, only subjects in Treatment Group A have been enrolled into 
Parts 1 and 2.  Data from Parts 1 and 2 for Treatment Group A will be summarized together by 
dose level.  The dose levels for Treatment Group A are shown in Table 1. 
5.3. 
Analysis Populations 
5.3.1. 
Response Evaluable Population 
The response evaluable population includes all subjects enrolled in the study who received at 
least 1 dose of study drug (epacadostat, pembrolizumab, or azacitidine), completed a baseline 
scan, and met at least 1 of the following criteria: 
• The subject has ≥ 1 postbaseline scan. 
• The subject has been on study for a minimum of 70 days of follow-up. 
• The subject has discontinued from treatment. 
All RECIST-based response analyses will be conducted using the response evaluable population. 
5.3.2. 
Safety Population 
The safety population includes all subjects enrolled in the study who received at least 1 dose of 
study drug (epacadostat, pembrolizumab, or azacitidine).  All safety analyses will be conducted 
using the safety population. 
Specific safety analysis populations to be used for study drug–specific tables include the 
following subgroups: 
• Epacadostat safety population  
• Pembrolizumab safety population  
• Azacitidine safety population 


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6. 
BASELINE, EXPOSURE, AND DISPOSITION VARIABLES AND 
ANALYSES 
Appendix A provides a list of planned tables and listings. 
6.1. 
Baseline and Demographics, Physical Characteristics, and Disease 
History 
6.1.1. 
Demographics 
The following demographics will be summarized for the safety population by dose level for 
Treatment Group A in Parts 1 and 2 combined:  age, sex, race, and ethnicity. 
6.1.2. 
Baseline Disease Characteristics and Disease History 
Primary diagnosis, TNM staging, stage at diagnosis, current stage, disease histology, and 
primary site of disease will be summarized for all subjects in the safety population by dose level 
for Treatment Group A in Parts 1 and 2 combined. 
ECOG performance status will be summarized for all subjects in the safety population by dose 
level for Treatment Group A in Parts 1 and 2 combined. 
6.1.3. 
Prior Therapy 
Number of prior systemic cancer therapy regimens will be summarized for all subjects in the 
safety population by dose level for Treatment Group A in Parts 1 and 2 combined.  Regimen 
name, component drugs, start and stop date, purpose of the regimen, best response, reason for 
discontinuation, and date of relapse/progression will be listed. 
Number of subjects who received prior radiation will be summarized for all subjects in the safety 
population by dose level for Treatment Group A in Parts 1 and 2 combined.  Radiotherapy type, 
body site, start and stop date, reason for regimen, number of fractions, total dose, and best 
response will be listed. 
Number of subjects who had prior surgery or surgical procedure for the malignancies under 
study will be summarized for all subjects in the safety population by dose level for Treatment 
Group A in Parts 1 and 2 combined.  Date and description of the surgery/procedure will be listed. 
6.1.4. 
Medical History 
Medical history will be summarized for all subjects in the safety population by dose level for 
Treatment Group A in Parts 1 and 2 combined.  This summation will include the number and 
percentage of subjects with significant medical history for each body SOC as documented on the 
eCRF. 


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6.2. 
Disposition of Subjects 
The number and percentage of subjects who entered the initial treatment phase, the initial 
follow-up phase, the re-treatment phase, and the re-treatment follow-up phase will be 
summarized.  Under each phase (initial treatment phase and re-treatment phase), the number and 
percentage of subjects who discontinued study treatment with primary reason for discontinuation 
and withdrew from the study with a primary reason for study withdrawal will be summarized for 
all subjects in the safety population by dose level for Treatment Group A in Parts 1 and 2 
combined.  The number of subjects enrolled by site will also be provided for the safety 
population by dose level for Treatment Group A in Parts 1 and 2 combined. 
6.3. 
Protocol Deviations and Violations 
Protocol deviations and violations recorded on the eCRF will be presented in the subject data 
listings.  If data warrant, protocol deviations and violations will be summarized descriptively. 
6.4. 
Exposure 
For subjects in the safety population, exposure to epacadostat, pembrolizumab, and azacitidine 
will be summarized descriptively. 
6.4.1. 
Exposure for Epacadostat 
Exposure for epacadostat will be summarized as follows: 
• Duration of treatment (days):  Date of last dose of epacadostat – date of first dose 
of epacadostat + 1. 
• Average daily dose (mg/day):  Total dose administered (mg) / duration of treatment 
(days). 
• Number and percentage of subjects with 0 to 3, > 3, > 6, and > 9 months duration of 
exposure. 
6.4.2. 
Exposure for Pembrolizumab 
Exposure for pembrolizumab will be summarized as follows: 
• Total number of infusions:  Total number of infusions per subject with a nonzero 
dose of pembrolizumab. 
• Total dose administered (mg):  Sum of the cumulative dose of pembrolizumab that 
has been administered. 
For an infusion , let 
be the concentration (mg/mL) of pembrolizumab and 
 be the 
total volume administered (in mL) reported on the pembrolizumab dosing eCRF; let 
 be the total number of infusions 
Total dose administered (mg) = 
 
• Duration of treatment (days):  Date of last dose of pembrolizumab – date of first 
dose of pembrolizumab + 1. 


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6.4.3. 
Exposure for Azacitidine 
Exposure for azacitidine will be summarized as follows: 
• Total number of administrations:  Total number of infusions and injections per 
subject with a nonzero dose of azacitidine. 
• Total dose administered (mg):  Sum of the cumulative dose of azacitidine that has 
been administered. 
For an infusion/injection i, let 
be the concentration (mg/mL) of azacitidine and 
 
be the total volume administered (mL) reported on the azacitidine dosing eCRF if the 
th administration is through IV; let Mi be the actual dose administered (mg) if the th 
administration is through SC.  Let 
 , 
, 
Suppose N is the total number of infusions and injections,  
Total dose administered (mg) = 
 
• Average dose (mg):  Total dose administered (mg) / total number of injections and 
infusions. 
• Duration of treatment (days):  Date of last dose of azacitidine – date of first dose of 
azacitidine + 1. 
6.5. 
Study Drug Compliance 
For subjects in the safety population, overall compliance (%) for epacadostat will be calculated 
for all subjects as 
Compliance (%) = 100 × [total dose actually taken] / [total prescribed dose]. 
The total prescribed dose is defined as the sum of the doses prescribed by the investigator 
accounting for dose modifications. 
The total actual dose taken will be calculated based on information entered on the drug 
accountability eCRF.  If there is dispensed drug that has not been returned yet, this dispensed 
drug kit will not be considered. 
Compliance calculations are not necessary for IV or SC administered agents (eg, pembrolizumab 
and azacitidine). 


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6.6. 
Prior and Concomitant Medication 
For subjects in the safety population, prior medications and concomitant medications will be 
coded using the WHO Drug Dictionary and summarized by WHO drug class and WHO drug 
term.  Results will be summarized as number and percentage of subjects with prior and 
concomitant medications by PT and WHO drug class. 
7. 
EFFICACY 
A list of planned tables and listings is provided in Appendix A. 
7.1. 
General Considerations 
Efficacy endpoints of this study include ORR, DOR, PFS and OS by investigator assessment 
based on RECIST v1.1.  Listings of response assessment at each visit will be provided. 
7.2. 
Analysis of the Efficacy Parameters 
7.2.1. 
Response Criteria 
Overall disease status will be categorized using RECIST v1.1.  Subjects will have their overall 
response evaluated as CR, PR, SD, PD, or NE at each postbaseline radiological assessment based 
on changes in target lesions, nontarget lesions, and appearance of new lesions. 
7.2.2. 
Objective Response Rates and Best Overall Response 
A subject is defined as an objective responder if the subject has an overall response of CR or PR 
at any postbaseline visit prior to first PD.  Objective responders will be assessed based on 
RECIST v1.1. 
Objective response rate is defined as the proportion of subjects with objective responses.  
Objective response rate will be estimated with 95% CIs overall by cohort-specific tumor type.  
CIs will be calculated based on the method for Simon 2-stage CIs of response rates outlined in 
Koyama and Chen (2008).  Subjects who do not have sufficient baseline data to ascertain 
response will be included in the denominators in the calculation of ORR. 
In general, the best response is determined on subject level using the highest overall response 
achieved postbaseline prior to and including the first PD, in the order of CR, PR, SD, PD, and 
NE.  Responses of CR, PR, or SD after a response of PD will not be considered in determining 
best response by RECIST v1.1 criteria.  In the case of SD, measurements must meet the SD 
criteria at least after the date of first dose at a minimum of 56 days (9 weeks – 7-day window).  
Subjects who fail to meet this criterion will have best overall response of PD if the next available 
assessment indicated PD, or NE if there is no additional assessment available.   
Under RECIST v1.1, the best response is determined by subject using the highest overall 
response achieved postbaseline prior to and including the first PD, in the order of CR, PR, SD, 
PD, and NE.  Responses of CR, PR, or SD after a response of PD will not be considered in 
determining best response by RECIST v1.1 criteria.  In the case of SD, measurements must meet 
the SD criteria at least after the date of first dose of study drug at a minimum of 56 days 
(9 weeks – 7-day window).  Subjects who fail to meet this criterion will have best overall 


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response of PD if the next available assessment indicated PD, or NE if there is no additional 
assessment available. 
For subjects with measurable disease at baseline, the RECIST v1.1 assessment criteria presented 
in Table 11 can be used to determine the overall disease status at a given time point based on the 
target lesion, nontarget lesion, and new lesion assessment. 
Table 11: 
RECIST Evaluation Criteria for Overall Response:  Measurable Disease at 
Baseline 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non-PD or NE 
No 
PR 
SD 
Non-PD or NE 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
7.2.3. 
Duration of Response 
Duration of response will be assessed by RECIST v1.1. 
Censoring of DOR will follow the same algorithm as the censoring of PFS.  The KM estimate of 
median DOR will be presented with its 95% CI.  The 95% CI will be calculated using 
Brookmeyer and Crowley's method (1982). 
7.2.4. 
Largest Percentage Reduction in Sum of Diameters of Target Lesions 
For each subject in the response evaluable population with target lesions at baseline, target lesion 
sizes will be measured by sum of diameters.  The best percent change from baseline, defined as 
the largest decrease in target lesion size for each subject, will be summarized descriptively. 
Per RECIST v1.1, target lesions considered "too small to measure" will be assigned a default 
value of 5 mm for purposes of this analysis.  Likewise, target lesions identified as "not present" 
at postbaseline assessments will be assigned 0 mm for this analysis.  In the event a target lesion 
is unaccounted for in a particular postbaseline timepoint (ie, assessment missing or NE), then the 
overall sum of diameters for target lesions will not be evaluable for that postbaseline timepoint. 
7.2.5. 
Progression-Free Survival 
Progression-free survival will be assessed by RECIST v1.1. 
Censoring for PFS will follow the algorithm outlined in Table 12, which is based on the FDA 
Guidance for Industry:  Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics 
(FDA 2007). 


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The KM estimate of median PFS will be presented with its 95% CI.  The 95% CI will be 
calculated using Brookmeyer and Crowley's method (1982). 
Table 12: 
Evaluation and Censoring of Progression-Free Survival 
Situation 
Outcome 
Date of Progression or Censoring 
No baseline tumor assessments 
Censored 
Date of Day 1 
No valid postbaseline response 
assessments 
Censored 
Date of Day 1 
Progression documented between 
scheduled response assessments 
Progressed 
Date of first overall response of PD 
No progression 
Censored 
Date of last valid radiologic 
assessment (not NE and not missing) 
Study discontinuation for 
undocumented progression 
Censored 
Date of last valid radiologic 
assessment (not NE and not missing) 
Study discontinuation for toxicity or 
other reason 
Censored 
Date of last valid radiologic 
assessment (not NE and not missing) 
New anticancer treatment started 
Censored 
Date of last valid radiologic 
assessment (not NE and not missing) 
on/before starting a new anticancer 
treatment. 
Death before first progressive 
response assessment 
Progressed 
Date of death 
Death between adequate response 
assessments 
Progressed 
Date of death 
Death or progression after more than 
1 missed assessment 
Censored 
Date of last valid radiologic 
assessment (not NE and not missing) 
prior to death 
Under RECIST v1.1, PFS is defined as the length of time between the baseline visit (Day 1) and 
the earlier of death or first assessment of PD.  Date of death will be determined using the Death 
Report, Survival Follow-Up, and Subject Status eCRFs. 


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8. 
SAFETY AND TOLERABILITY 
A list of planned tables and listings is provided in Appendix A. 
8.1. 
General Considerations 
Summary tables may be replaced with listings when appropriate.  For instance, an AE frequency 
table may be replaced with a listing if it only contains a few unique PTs reported on relatively 
few subjects. 
8.2. 
Adverse Events 
8.2.1. 
Adverse Event Definitions 
A TEAE is any AE either reported for the first time or worsening of a pre-existing event after the 
first dose of study drug (epacadostat, pembrolizumab, and azacitidine).  Analysis of AEs (as 
discussed below) will be limited to TEAEs, but data listings will include all AEs regardless of 
their timing in relation to study drug administration. 
Adverse events will be tabulated by MedDRA PT and SOC.  Severity of AEs will be graded 
using the NCI CTCAE.  The CTCAE v4.03 is used for this study.  The CTCAE reporting 
guidelines and grading details are available on the Cancer Therapy Evaluation Program website. 
The subset of AEs considered by the investigator to be related to study drug will be considered to 
be treatment-related AEs.  If the investigator does not specify the relationship of the AE to study 
drug, the AE will be considered to be treatment-related.  The incidence of AEs and treatment-
related AEs will be tabulated.  In addition, SAEs will also be tabulated. 
Any missing onset date, causality, or severity must be queried for resolution.  Unresolved 
missing causality and severity will be handled according to the following rules: 
• An unresolved missing causality will be considered treatment-related. 
• An unresolved missing severity will be identified as an unknown severity.  
For purposes of analysis, all AEs will be considered TEAEs unless the AE can unequivocally be 
defined as not treatment-emergent. 
8.2.2. 
Dose-Limiting Toxicities 
The number of subjects with DLTs and the type of DLT will be listed by dose level. 
8.2.3. 
Maximum Tolerated Dose 
In Part 1, the MTD is defined as the highest dose level at which ≤ 1/6 or ≤ 2/9 subjects 
experience a DLT. 


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8.2.4. 
Adverse Events of Special Interest 
Adverse events of special interest include irAEs that are seen with immunotherapy and any other 
observed autoimmune phenomenon. 
An overall summary of irAEs will include number (%) of subjects reporting any irAEs, any 
Grade 3 or 4 irAEs, any treatment-related irAEs, any fatal irAEs, and any irAEs leading to 
treatment interruption/dose reduction/discontinuation. 
8.2.5. 
Adverse Event Summaries 
An overall summary of AEs by dose level in Treatment Group A will include: 
• Number (%) of subjects reporting any TEAEs 
• Number (%) of subjects reporting any DLTs 
• Number (%) of subjects reporting any SAEs 
• Number (%) of subjects reporting any Grade 3 or 4 TEAEs 
• Number (%) of subjects reporting any TEAEs related to epacadostat 
• Number (%) of subjects reporting any TEAEs related to azacitidine 
• Number (%) of subjects reporting any TEAEs related to pembrolizumab 
• Number (%) of subjects who temporarily interrupted epacadostat because of TEAEs 
• Number (%) of subjects who temporarily interrupted azacitidine because of TEAEs 
• Number (%) of subjects who temporarily interrupted pembrolizumab because of 
TEAEs 
• Number (%) of subjects who permanently discontinued epacadostat because of 
TEAEs 
• Number (%) of subjects who permanently discontinued azacitidine because of TEAEs 
• Number (%) of subjects who permanently discontinued pembrolizumab because of 
TEAEs 
• Number (%) of subjects with epacadostat dose reductions because of TEAEs  
• Number (%) of subjects with azacitidine dose reductions because of TEAEs  
• Number (%) of subjects who had a fatal TEAE 
• Number (%) of subjects who withdrew from study because of TEAEs 


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The following summaries will be produced by MedDRA term (if 10 or fewer subjects appear in a 
table, a listing may be appropriate): 
• Summary of TEAEs by SOC and PT 
• Summary of TEAEs by PT in decreasing order of frequency 
• Summary of TEAEs by SOC, PT, and maximum severity 
• Summary of Grade 3 or 4 TEAEs by SOC and PT 
• Summary of epacadostat treatment-related AEs by SOC and PT 
• Summary of pembrolizumab treatment-related AEs by SOC and PT 
• Summary of azacitidine treatment-related AEs by SOC and PT 
• Summary of TEAEs with a fatal outcome by SOC and PT 
• Summary of serious TEAEs by SOC and PT 
• Summary of serious TEAEs by PT in descending order of frequency 
• Summary of nonserious TEAEs by SOC and PT 
• Summary of TEAEs leading to epacadostat dose reduction by SOC and PT 
• Summary of TEAEs leading to azacitidine dose reduction by SOC and PT 
• Summary of TEAEs leading to epacadostat dose interruption by SOC and PT 
• Summary of TEAEs leading to pembrolizumab dose interruption by SOC and PT 
• Summary of TEAEs leading to azacitidine dose interruption by SOC and PT 
• Summary of TEAEs leading to discontinuation of epacadostat by SOC and PT 
• Summary of TEAEs leading to discontinuation of pembrolizumab by SOC and PT 
• Summary of TEAEs leading to discontinuation of azacitidine by SOC and PT 
• An overall summary of treatment-emergent irAEs 
8.3. 
Clinical Laboratory Tests 
8.3.1. 
Laboratory Value Definitions 
Laboratory values and change from baseline values will be summarized descriptively by visit.  
Baseline will be determined according to Section 4.2.3.  If there are multiple values that meet the 
criteria for baseline, additional rules may be provided after consultation with the medical monitor 
to delineate which value will be defined as baseline. 
Laboratory test values outside the normal range will be assessed for severity based on CTCAE 
grade or similar criteria where clinical intervention is required for CTCAE grading.  The 
incidence of abnormal laboratory values and shift tables relative to baseline will be tabulated. 


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8.3.2. 
Laboratory Value Summaries 
All test results and associated normal ranges from central laboratories will be reported in SI 
units.  All tests with numeric values will have a unique unit per test.  Any laboratory test results 
and associated normal ranges from local laboratories will be converted to SI units.  For the 
limited number of cases where the associated normal ranges from a local laboratory cannot be 
obtained despite due diligence, associated central laboratory normal ranges will be applied.  In 
the event that central laboratory normal ranges are not available, a set of standard normal ranges 
based on documented reference ranges will be applied to facilitate reporting the test results. 
When there are multiple laboratory nonmissing values for a subject's particular test at a 
scheduled visit, central laboratory values have higher priority over local laboratory values.  If a 
tie still exists, the laboratory value with the smallest laboratory sequence number will be used in 
by-visit summaries. 
Numeric laboratory values will be summarized descriptively in SI units, and non-numeric test 
values will be tabulated when necessary. 
For test results that will be summarized with available normal ranges, the number and percentage 
of subjects with the laboratory values being low (but never high), normal, high (but never low), 
and both low and high will be calculated for each test.  This shift summary will be produced for 
each test for the safety population.  The denominator for the percentage calculation will use the 
number of subjects in the baseline category (ie, low, high, normal, missing) as the denominator 
for the percentage in each of the categories during the treatment period. 
Shift tables will be presented showing change in CTCAE grade from baseline to worst grade 
postbaseline.  Separate summaries for abnormally high and abnormally low laboratory values 
will be provided when the laboratory parameter has both high and low grading criteria.  The 
denominator for the percentage calculation will be the number of subjects in the baseline 
category. 
In cases where differentials of hematology parameters are obtained without corresponding 
absolute count data, efforts will be made to investigate if the conversion to an absolute value will 
lead to additional abnormalities.  This will be discussed with the clinical team regarding 
appropriate documentation and action. 
8.4. 
Vital Signs 
Values at each scheduled visit, change, and percent change from baseline for vital signs, 
including pulse, systolic blood pressure, diastolic blood pressure, respiration rate, body 
temperature, and weight will be summarized descriptively. 
Criteria for clinically notable vital sign abnormalities are defined in Table 13.  The abnormal 
values for subjects exhibiting clinically notable vital sign abnormalities will be listed along with 
their assigned treatment group.  Alert vital signs are defined as an absolute value outside the 
defined range and percentage change from baseline greater than 25%.  The abnormal values for 
subjects exhibiting alert vital sign abnormalities will be listed. 


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Table 13: 
Criteria for Clinically Notable Vital Sign Abnormalities 
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure 
> 155 mmHg 
< 85 mmHg 
Diastolic blood pressure 
> 100 mmHg 
< 40 mmHg 
Pulse 
> 100 bpm 
< 45 bpm 
Temperature 
> 38ºC 
< 35.5ºC 
Respiratory rate 
> 24/min 
< 8/min 
8.5. 
Electrocardiograms 
Twelve-lead ECGs including RR, QRS, QT, QTcF, QTcB, and JTc intervals will be obtained for 
each subject during the study.  Values at each scheduled visit, change, and percent change from 
baseline will be summarized for each ECG parameter.  Baseline will be determined as the 
average of all nonmissing values before the first administration of epacadostat, pembrolizumab, 
or azacitidine. 
Criteria for clinically notable ECG abnormalities are defined in Table 14.  Subjects exhibiting 
clinically notable ECG abnormalities will be listed with study visit and assigned treatment group.  
Abnormal values for subjects with alert ECG values, defined as both the absolute value and the 
percentage change from baseline being outside normal ranges, will be identified and listed. 
Table 14: 
Criteria for Clinically Notable Electrocardiogram Abnormalities 
Parameter 
High Threshold 
Low Threshold 
QTcF  
> 460 ms 
< 295 ms 
PR  
> 220 ms 
< 75 ms 
QRS  
> 120 ms 
< 50 ms 
QT  
> 500 ms 
< 300 ms 
RR 
> 1330 ms 
< 600 ms 
QTcF = Fridericia correction. 
Twelve-lead ECGs will be obtained for each subject during the study.  Electrocardiogram 
abnormalities, both at baseline and postbaseline visits, will be tabulated by dose level for 
Treatment Group A in Parts 1 and 2 combined.  Incidences of abnormalities will be listed with 
study visit, assigned treatment group, and a description of the abnormality. 
9. 
INTERIM ANALYSES 
There are no planned, formal interim analyses for Part 1.  Periodic review of accrued clinical 
data will be conducted by the sponsor and provided to study investigators via teleconferences.  
Based on review of the most current safety data, the sponsor (in consultation with the study 
investigators and using the dose-escalation/de-escalation rules) will determine if and at what 
dose additional subjects should be treated in the study. 
Since the study was terminated prior to the interim analyses, no interim analyses will be 
conducted for Part 2. 


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10. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN 
All versions of the SAP are listed in Table 15. 
Table 15: 
Statistical Analysis Plan Versions 
SAP Version 
Date 
Original 
12 JAN 2018 
Amendment 1 
18 JUL 2018 
10.1. 
Changes to Protocol-Defined Analyses 
10.1.1. 
Efficacy Analyses 
• The efficacy endpoints will only be summarized per RECIST v1.1.  
 
 
• The confirmation of responses will not be included. 
10.1.3. 
Interim Analyses 
• Simon 2-stage design will not be performed due to the early termination of the study.  
No interim analyses will be conducted for Part 2. 
10.2. 
Changes to the Statistical Analysis Plan 
• All planned figures will be eliminated. 
• The analyses of Treatment Groups B and C will be eliminated due to the early 
termination of the study. 
• Please see Section 10.1 for other changes from the original SAP. 


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11. 
REFERENCES 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 
1982;38:29-41. 
Food and Drug Administration (FDA). Guidance for Industry: Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics. 2007. 
www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM07
1590.pdf. Accessed January 4, 2016. 
Koyama T, Chen H. Proper inference from Simon's two-stage designs. Stat Med 2008;27:3145-
3154. 
Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989;10:1-10. 


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APPENDIX A. PLANNED TABLES AND LISTINGS 
Tables 
Table No. 
Title 
Population 
Standard 
In-Text 
Baseline and Demographic Characteristics 
1.1  Disposition 
1.1.1 
Analysis Populations 
Safety  
X 
X 
1.1.2 
Summary of Subject Disposition 
Safety  
X 
X 
1.1.3 
Summary of Number of Subjects Enrolled by Site 
Safety  
X 
 
1.2  Demography 
1.2.1 
Summary of Demographics 
Safety  
X 
X 
1.3  Baseline Characteristics 
1.3.1 
Summary of Cancer History and Baseline Disease 
Characteristics 
Safety  
 
X 
1.4  Prior Medication and Concomitant Medication 
1.4.1 
Summary of Prior Cancer Therapy 
Safety  
 
X 
1.4.2 
Summary of Prior Medications 
Safety  
X 
 
1.4.3 
Summary of Concomitant Medications 
Safety  
X 
 
1.5  Others 
1.5.1 
Summary of General Medical History 
Safety  
X 
 
2  Efficacy 
2.1.1 
Summary of Best Response, Duration of Response 
Under RECIST v1.1 for Subjects in the Initial 
Treatment Phase  
Response 
Evaluable 
 
X 
2.2.1 
Summary of Progression-Free Survival Under 
RECIST v1.1 for Subjects in the Initial Treatment 
Phase  
Response 
Evaluable 
 
X 
 
 
 
 
 
 
2.3.2 
Summary of Largest Percentage Reduction in Sum of 
Diameters of Target Lesions 
Response 
Evaluable 
 
 
Safety 
3.1  Dose Exposure 
3.1.1.1 
Summary of Exposure to Epacadostat for Subjects in 
the Initial Treatment Phase 
Epacadostat Safety 
 
X 
3.1.1.2 
Summary of Exposure to Pembrolizumab for Subjects 
in the Initial Treatment Phase 
Pembrolizumab 
Safety 
 
X 
3.1.1.3 
Summary of Exposure to Azacitidine for Subjects in 
the Initial Treatment Phase 
Azacitidine Safety 
 
X 
3.1.2.1 
Summary of Epacadostat Compliance 
Epacadostat Safety 
 
X 
3.2  Adverse Events 
3.2.1 
Overall Summary of Treatment-Emergent Adverse 
Events 
Safety 
X 
X 
3.2.2 
Summary of Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term 
Safety 
X 
X 
3.2.3 
Summary of Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of 
Frequency 
Safety 
X 
X 
3.2.4 
Summary of Treatment-Emergent Adverse Events by 
MedDRA System Organ Class, Preferred Term, and 
Maximum Severity 
Safety 
X 
 


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Table No. 
Title 
Population 
Standard 
In-Text 
3.2.5 
Summary of Grade 3 or 4 Treatment-Emergent 
Adverse Events by MedDRA System Organ Class and 
Preferred Term 
Safety 
X 
X 
3.2.6.1 
Summary of Epacadostat Treatment-Related Adverse 
Events by MedDRA System Organ Class and Preferred 
Term 
Epacadostat 
Safety 
X 
 
3.2.6.2 
Summary of Pembrolizumab Treatment-Related 
Adverse Events by MedDRA System Organ Class and 
Preferred Term 
Pembrolizumab 
Safety 
X 
 
3.2.6.3 
Summary of Azacitidine Treatment-Related Adverse 
Events by MedDRA System Organ Class and Preferred 
Term 
Azacitidine Safety 
X 
 
3.2.7 
Summary of Treatment-Emergent Adverse Events 
With a Fatal Outcome by MedDRA System Organ 
Class and Preferred Term 
Safety 
X 
X 
3.2.8 
Summary of Serious Treatment-Emergent Adverse 
Events by MedDRA System Organ Class and Preferred 
Term 
Safety 
X 
 
3.2.9 
Summary of Serious Treatment-Emergent Adverse 
Events by Preferred Term in Decreasing Order of 
Frequency 
Safety 
X 
X 
3.2.10 
Summary of Nonserious Treatment-Emergent Adverse 
Events by MedDRA System Organ Class and Preferred 
Term 
Safety 
X 
 
3.2.11.1 
Summary of Treatment-Emergent Adverse Events 
Leading to Epacadostat Dose Reduction by MedDRA 
System Organ Class and Preferred Term 
Epacadostat 
Safety 
X 
 
3.2.11.2 
Summary of Treatment-Emergent Adverse Events 
Leading to Azacitidine Dose Reduction by MedDRA 
System Organ Class and Preferred Term 
Azacitidine Safety 
X 
 
3.2.12.1 
Summary of Treatment-Emergent Adverse Events 
Leading to Epacadostat Dose Interruption by MedDRA 
System Organ Class and Preferred Term 
Epacadostat 
Safety 
X 
 
3.2.12.2 
Summary of Treatment-Emergent Adverse Events 
Leading to Pembrolizumab Dose Interruption by 
MedDRA System Organ Class and Preferred Term 
Pembrolizumab 
Safety 
X 
 
3.2.12.3 
Summary of Treatment-Emergent Adverse Events 
Leading to Azacitidine Dose Interruption by MedDRA 
System Organ Class and Preferred Term 
Azacitidine Safety 
X 
 
3.2.13.1 
Summary of Treatment-Emergent Adverse Events 
Leading to Discontinuation of Epacadostat by 
MedDRA System Organ Class and Preferred Term 
Epacadostat 
Safety 
X 
X 
3.2.13.2 
Summary of Treatment-Emergent Adverse Events 
Leading to Discontinuation of Pembrolizumab by 
MedDRA System Organ Class and Preferred Term 
Pembrolizumab 
Safety 
X 
 
3.2.13.3 
Summary of Treatment-Emergent Adverse Events 
Leading to Discontinuation of Azacitidine by 
MedDRA System Organ Class and Preferred Term 
Azacitidine Safety 
X 
 
3.2.14 
An Overall Summary of Treatment-Emergent Immune-
Related Adverse Events 
Safety 
X 
 


Incyte Corporation 
Page 48 of 49 
INCB 24360-206 SAP Amendment 1 
18 JUL 2018 
CONFIDENTIAL 
Table No. 
Title 
Population 
Standard 
In-Text 
3.3  Laboratory 
3.3.1 
Summary of Laboratory Values - Hematology 
Safety 
X 
 
3.3.2 
Shift Summary of Hematology Laboratory Values in 
CTC Grade - to the Worst Abnormal Value  
Safety 
X 
X 
3.3.3 
Summary of Laboratory Values - Chemistry 
Safety 
X 
 
3.3.4 
Shift Summary of Chemistry Laboratory Values in 
CTC Grade - to the Worst Abnormal Value 
Safety 
X 
X 
3.3.5 
Summary of Laboratory Values - Coagulation 
Safety 
X 
 
3.3.6 
Shift Summary of Coagulation Values - to the Worst 
Abnormal Value 
Safety 
X 
 
3.3.7 
Summary of Laboratory Values - Endocrine 
Safety 
X 
 
3.3.8 
Shift Summary of Endocrine Values - to the Worst 
Abnormal Value 
Safety 
X 
 
3.4  Vital Signs 
3.4.1 
Summary of Systolic Blood Pressure 
Safety 
X 
 
3.4.2 
Summary of Diastolic Blood Pressure 
Safety 
X 
 
3.4.3 
Summary of Pulse  
Safety 
X 
 
3.4.4 
Summary of Respiration Rate 
Safety 
X 
 
3.4.5 
Summary of Body Temperature 
Safety 
X 
 
3.4.6 
Summary of Weight 
Safety 
X 
 
3.5  ECGs 
3.5.1 
Summary of PR Interval (ms) From 12-Lead ECG 
Safety 
X 
 
3.5.2 
Summary of QRS Interval (ms) From 12-Lead ECG 
Safety 
X 
 
3.5.3 
Summary of QT Interval (ms) From 12-Lead ECG 
Safety 
X 
 
3.5.4 
Summary of QTcB Interval (ms) From 12-Lead ECG 
Safety 
X 
 
3.5.5 
Summary of QTcF Interval (ms) From 12-Lead ECG 
Safety 
X 
 
3.5.6 
Summary of JTc Interval (ms) From 12-Lead ECG 
Safety 
X 
 
3.5.7 
Summary of Heart Rate From 12-Lead ECG 
Safety 
X 
 
3.5.8 
Summary of Outliers of QT, QTcB, and QTcF Interval 
Values From 12-Lead ECG 
Safety 
X 
X 
Listings 
Listing No. 
Title 
2.1  Discontinued Subjects (Subject Disposition) 
2.1.1 
Subject Enrollment and Disposition Status 
2.1.2 
Subject Inclusion and Exclusion Criteria Violations 
2.2  Protocol Deviations 
2.2 
Protocol Deviations 
2.3  Data Excluded From
 Efficacy, and/or Safety Analyses 
2.3 
Analysis Populations 
2.4  Demography and Baseline (Including Prior and Concomitant Medications) 
2.4.1 
Demographic and Baseline Disease Characteristics 
2.4.2 
Disease History 
2.4.3 
Prior Radiation Treatment 
2.4.4 
Prior Systemic Therapy 
2.4.5 
Prior Surgery or Surgical Procedure 
2.4.6 
Medical History 
2.4.7 
Prior and Concomitant Medications 
2.5  Drug Compliance 
2.5 
Study Drug Compliance 


Incyte Corporation 
Page 49 of 49 
INCB 24360-206 SAP Amendment 1 
18 JUL 2018 
CONFIDENTIAL 
Listing No. 
Title 
2.6  Efficacy 
2.6.1 
Deaths 
2.6.2 
Best Overall Response, Duration of Response, and Progression-Free Survival 
2.6.3 
Overall Response Assessment by Visit  
2.6.4 
Response Assessment:  Target Lesions  
2.6.5 
Response Assessment:  Non-Target Lesions  
2.6.6 
Response Assessment:  New Lesions  
2.6.7 
Largest Percentage Reduction in Sum of Diameters of Target Lesions 
2.6.8 
ECOG Status 
2.7  Adverse Events (and Exposure) 
2.7.1 
Study Drug Administration 
2.7.2 
Adverse Events  
2.7.3 
Dose-Limiting Toxicities 
2.7.4 
Serious Adverse Events 
2.7.5 
Fatal Adverse Events 
2.7.6 
Adverse Events Leading to Discontinuation of Epacadostat, Pembrolizumab, or Azacitidine 
2.8  Laboratory Data 
2.8.1 
Clinical Laboratory Values – Hematology 
2.8.2 
Clinical Laboratory Values – Chemistry 
2.8.3 
Clinical Laboratory Values – Urinalysis  
2.8.4 
Clinical Laboratory Values – Coagulation 
2.8.5 
Clinical Laboratory Values – Endocrine 
2.8.6 
Clinical Laboratory Values – Serology 
2.8.7 
Abnormal Clinical Laboratory Values 
2.9  Vital Signs 
2.9.1 
Vital Signs 
2.9.2 
Abnormal Vital Sign Values 
2.9.3 
Alert Vital Sign Values 
2.10  Electrocardiograms 
2.10.1 
12-Lead ECG Values 
2.10.2 
Abnormal 12-Lead ECG Values 
2.10.3 
Alert 12-Lead ECG Values 
2.11  Physical Examinations 
2.11.1 
Physical Examinations 
2.11.2 
Body Weight 
 


Signature Manifest
Document Number: IC-STS-SAP-0120
Revision: 0
Title: INCB 24360-206 SAP Amendment 1
All dates and times are in Eastern Standard Time.
INCB 24360-206 SAP Amendment 1
Approval
Name/Signature
Title
Date
Meaning/Reason
18 Jul 2018, 12:31:59 PM
Approved
18 Jul 2018, 12:43:31 PM
Approved
23 Jul 2018, 03:33:17 PM
Approved