A Phase 1/2 Study of the Safety, Tolerability, and Efficacy of Epacadostat Administered in Combination With Nivolumab in Select Advanced Cancers (ECHO-204)
Phase: PHASE1
Conditions: B-cell Malignancies, Colorectal Cancer (CRC), Head and Neck Cancer, Lung Cancer, Lymphoma, Melanoma, Ovarian Cancer, Glioblastoma
Sponsor: Incyte Corporation

Incyte Corporation
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Protocol INCB 24360-204 Amendment 8 
Version 8 
31 MAY 2018 
Clinical Study Protocol 
INCB 24360-204 / NCT02327078
(CA209) 
A Phase 1/2 Study of the Safety, Tolerability, and Efficacy of 
Epacadostat Administered in Combination With Nivolumab in 
Select Advanced Cancers 
Product: 
Epacadostat and Nivolumab 
IND Number: 
122945 
EudraCT Number: 
2016-002423-29 
Phase of Study: 
1/2 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
(In collaboration with Bristol-Myers Squibb) 
Date of Protocol: 
15 AUG 2014 
Date of Amendment 1: 
01 OCT 2014 
Date of Amendment 2: 
03 APR 2015 
Date of Amendment 3: 
16 JUL 2015 
Date of Amendment 4: 
12 FEB 2016 
Date of Amendment 5: 
13 JUL 2016 
Date of Amendment 6:
05 JUL 2017
Date of Amendment (Version) 7:
29 SEP 2017 
Date of Amendment (Version) 8:
31 MAY 2018 
This study will be performed in accordance with ethical principles that have their origin in the Declaration of 
Helsinki and conducted in adherence to the study Protocol, Good Clinical Practices as defined in Title 21 of the US 
Code of Federal Regulations Parts 50, 54 56, 312, and Part 11 as well as ICH GCP consolidated guidelines (E6) and 
applicable regulatory requirements. 
The information in this document is confidential.  No part of this information may be duplicated, referenced, or 
transmitted in any form or by any means (electronic, mechanical, photocopy, recording, or otherwise) without the prior 
written consent of Incyte Corporation. 
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Protocol INCB 24360-204 Amendment 8 
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INVESTIGATOR'S AGREEMENT 
I have received and read the Investigator's Brochures for nivolumab and epacadostat.  I have read 
the INCB 24360-204 Protocol Amendment 8 (Version 8 dated 31 MAY 2018) and agree to 
conduct the study as outlined.  I agree to maintain the confidentiality of all information received 
or developed in connection with this Protocol. 
(Printed Name of Investigator) 
(Signature of Investigator) 
(Date) 
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Protocol INCB 24360-204 Amendment 8 
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SYNOPSIS 
Name of Investigational Products:  Nivolumab and epacadostat 
Title of Study:  A Phase 1/2 Study of the Safety, Tolerability and Efficacy of Epacadostat 
Administered in Combination With Nivolumab in Select Advanced Cancers 
Protocol Number:  INCB 24360-204 
Study Phase:  1/2 
Primary Objectives: 
Phase 1 
• Part 1 Safety:  To assess the safety and tolerability of epacadostat orally in combination with
nivolumab, and to identify dose-limiting toxicities (DLTs) and the recommended Phase 2 dose
(RP2D) of the combination immunotherapy, in subjects with select advanced (metastatic and/or
unresectable) cancers (solid tumors and B-cell non-Hodgkin lymphoma [NHL] or Hodgkin
lymphoma [HL]).
• Part 2 Safety:  To assess the safety and tolerability and to determine a maximum tolerated dose
(MTD) and/or pharmacologically active dose (PAD) of epacadostat in combination with nivolumab
and chemotherapy in subjects with advanced or metastatic squamous cell carcinoma of head and
neck (SCCHN) and in subjects with advanced or metastatic non–small cell lung cancer (NSCLC).
Phase 2 
• Efficacy:
− To assess objective response rate (ORR) and progression-free survival (PFS) at 6 months in
subjects with select solid tumors or subjects with diffuse large B-cell lymphoma (DLBCL).   
− To assess overall survival (OS) at 9 months for subjects with glioblastoma. 
Secondary Objectives: 
Phase 1 
• Part 1 Efficacy:  To assess the preliminary antitumor activity of the combination of epacadostat and
nivolumab in subjects with select advanced solid tumors, B-cell NHL or HL, or glioblastoma by
assessing ORR.
• Part 2 Efficacy:  To explore the preliminary efficacy of epacadostat administered in combination
with nivolumab and chemotherapy in subjects with advanced or metastatic SCCHN and advanced or
metastatic NSCLC by assessing ORR, duration of response (DOR), and PFS.
Phase 2 
• Efficacy:
− To assess the preliminary antitumor activity of the combination of epacadostat and nivolumab in
subjects with select advanced solid tumors and DLBCL by assessing DOR and duration of disease 
control. 
− To evaluate OS in subjects with select solid tumors and DLBCL. 
− To evaluate ORR, PFS, DOR, and duration of disease control for subjects with glioblastoma. 
• Safety:
− To assess the safety and tolerability of epacadostat twice daily (BID) orally when given in
combination with nivolumab 240 mg every 2 weeks. 
− To assess the safety and tolerability of epacadostat BID orally when given in combination with
nivolumab 480 mg every 4 weeks. 
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Protocol INCB 24360-204 Amendment 8 
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Primary Endpoints: 
Phase 1 
• Safety:  In Part 1 and Part 2 of Phase 1 of the study, all subjects who receive at least 1 dose of
epacadostat or nivolumab will be assessed for safety by monitoring the frequency and severity of
adverse events (AEs), serious adverse events (SAEs), and deaths.
Phase 2 
• Efficacy:
− The ORR and PFS at 6 months will be assessed based on RECIST v1.1 criteria for subjects with
select solid tumors or Cheson criteria for subjects with DLBCL. 
− OS will be assessed at 9 months for subjects with glioblastoma as determined by death due to any
cause. 
Secondary Endpoints: 
Phase 1 
• Part 1 Efficacy:  ORR will be assessed per RECIST v1.1 and modified RECIST for subjects with
select advanced solid tumors, Cheson and modified Cheson criteria for B-cell NHL or HL, and
Response Assessment in Neuro-Oncology (RANO) and modified RANO criteria for glioblastoma.
• Part 2 Efficacy:  ORR, DOR, and PFS will be assessed per RECIST v1.1 and modified RECIST for
subjects with advanced or metastatic SCCHN and advanced or metastatic NSCLC treated with
epacadostat in combination with nivolumab and chemotherapy.
Phase 2 
• Efficacy:  The DOR and duration of disease control will be assessed based on RECIST v1.1 criteria
and modified RECIST for select solid tumors, Cheson and modified Cheson criteria for DLBCL, or
RANO and modified RANO criteria for subjects with glioblastoma.  OS will be evaluated for solid
tumors and DLBCL cohorts.  ORR and PFS will be assessed for glioblastoma per modified RANO.
• Safety:  All subjects who receive at least 1 dose of epacadostat or nivolumab will be assessed for
safety by monitoring the frequency and severity of AEs, SAEs, and deaths.
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Overall Study Design: 
This is a Phase 1/2 open-label study that will be conducted in 2 phases.  Phase 1 of the study will 
consist of 2 parts (Part 1 and Part 2).  Part 1 of Phase 1 will consist of a standard dose-escalation 
design to determine the MTD or PAD of epacadostat when coadministered with nivolumab (defined as 
combination immunotherapy) in subjects with select advanced solid tumors and lymphomas, including 
melanoma (MEL), NSCLC, colorectal cancer (CRC), SCCHN, ovarian cancer, glioblastoma, and 
B-cell NHL or HL.  The study design is shown in Figure A1 and Figure A2 below. 
Part 2 of Phase 1 will evaluate the preliminary safety of epacadostat in combination with nivolumab 
and several chemotherapy regimens (defined as combination chemo-immunotherapy) in subjects with 
SCCHN and NSCLC by using a dose de-escalation design.  The starting dose of epacadostat in Part 2 
will be the RP2D of epacadostat selected for the use of combination immunotherapy in Part 1.  Initial 
dose-finding cohorts in Part 2 will be expanded to safety expansion cohorts and will further evaluate 
tolerated dose(s) of epacadostat when given in combination with nivolumab and chemotherapy 
regimens (see Figure A2). 
Phase 2 of the study will include 9 expansion cohorts in tumor types tested in Phase 1 Part 1 (except 
DLBCL will be the only lymphoma permitted) with a) historically high activity under nivolumab 
monotherapy, and b) with historically low activity with nivolumab monotherapy.  In Phase 2 of the 
study, nivolumab will be administered at 240 mg intravenously (IV) every 2 weeks or 480 mg IV 
every 4 weeks for specific tumor types as described in Figure A1. 
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Figure A1:  Study Design for Combination Immunotherapy Cohorts (Phase 1 Part 1 and 
Phase 2) 
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Figure A2:  Study Design for Combination Chemo-Immunotherapy Cohorts (Part 2 of Phase 1 
Only) 
Phase 1 Dose-Finding and Safety Expansion (Part 1 and Part 2) 
In Part 1, for combination immunotherapy cohorts, a 3 + 3 + 3 standard dose-escalation design will be 
used to assess the safety of epacadostat when given in combination with nivolumab. 
In Part 2, for combination chemo-immunotherapy cohorts, a (3 + 3) + 3 dose de-escalation study 
design will be used to evaluate the safety of epacadostat when administered in combination with 
nivolumab and chemotherapy regimen.  Part 2 will be initiated after Phase 1 Part 1 of the study is 
completed and the Phase 2 dose of epacadostat for the combination immunotherapy is determined. 
Combination Immunotherapy Cohorts (Part 1) 
The starting dose of epacadostat when given in combination with nivolumab (3 mg/kg IV every 
2 weeks, Q2W) is 25 mg BID continuous daily dose administration.  The epacadostat dose regimens 
during dose escalation in combination immunotherapy cohorts are provided in Table A1.   
The BID continuous administration cohorts will be tested first.  If epacadostat 50 mg BID continuous 
daily administration is determined as tolerable, the investigators and sponsor may agree to only 
evaluate continuous daily administration.  However, if epacadostat 50 mg BID exceeds the MTD, an 
every-other-week administration schedule of epacadostat administered BID may be tested.  If a dose is 
determined safe for both schedules, a safety expansion cohort may be opened for each dose regimen to 
include approximately 9 subjects in each cohort before selecting the schedule to move to Phase 2.  If at 
least 50 mg BID continuous or every other week cannot be combined safely with nivolumab 3 mg/kg, 
other alternative dose schedules (ie, other intermittent administration) of epacadostat may be tested, if 
needed, following the review of available safety data at the Dose Escalation/Cohort Review meetings.  
If an alternate schedule is tested and determined to be safe, re-escalation of epacadostat according to 
Table A1 will proceed with nivolumab 3 mg/kg every 2 weeks. 
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Table A1: Dose Regimens in Combination Immunotherapy Cohorts During Dose Escalation 
(Part 1) 
Dose 
Level 
Number 
Total Subjects 
(N)a 
Epacadostat 
(Oral) 
Nivolumab/BMS-936558 
(IV; Once Every 2 Weeks) 
1 
Approximately 3-9 
25 mg BID 
3 mg/kg 
2a 
Approximately 3-9 
50 mg BID 
3 mg/kg 
2b 
Approximately 3-9 
50 mg BID every other week 
3 mg/kg 
3a 
Approximately 3-9 
100 mg BID 
3 mg/kg 
3b 
Approximately 3-9 
100 mg BID every other week 
3 mg/kg 
4a 
Approximately 3-9 
300 mg BIDb 
3 mg/kg 
4b 
Approximately 3-9 
300 mg BID every other weekb 
3 mg/kg 
Total 
Approximately 21-63 
a Approximately 3 to 9 subjects will be enrolled during dose escalation.  Additional subjects may be added to any dose level 
after determining the preliminary safety at that dose level for a minimum of 6 and maximum of 9 evaluable subjects per 
dose level.  Dose level numbers marked "a" and "b" may occur in parallel.  Oral administration of epacadostat BID will 
occur on a daily basis unless indicated by the weekly alternating schedule of BID each day for 1 week followed by no doses 
for the following week.  Nivolumab administration will be 3 mg/kg IV every 2 weeks. 
b If 300 mg BID is not tolerated, an intermediate dose of 200 mg BID may be tested on either a continuous schedule or 
every-other-week schedule (see above for RP2D decision process). 
The DLT observation period will last for 6 weeks (42 days).  Three subjects will be treated initially at 
each dose level.  If 0 DLTs occur in a cohort of 3 subjects, a new cohort of 3 subjects will be treated at 
the next higher dose level.  If 1 of 3 subjects experience a DLT, that cohort will be expanded to 
6 subjects.  If 1 of 6 subjects experiences a DLT, a new cohort of 3 subjects will be treated at the next 
higher dose level.  If 2 of 6 DLT subjects experience a DLT, that cohort will be expanded to 9 subjects.  
If ≥ 2/3, 3/6, or 3/9 subjects experience DLTs within a cohort, then that dose level will be determined 
to have exceeded the MTD. 
If epacadostat 100 mg BID is deemed tolerable, up to 6 additional subjects (for a minimum of 
6 evaluable subjects) will be enrolled to confirm the safety of the dose in combination with nivolumab.  
If 1 of 6 or < 3 of 9 subjects experience DLTs, the Phase 2 MEL and NSCLC expansion cohorts will 
open with epacadostat 100 mg BID in combination with nivolumab.  The 300 mg BID dose in Phase 1 
will be tested in parallel to the Phase 2 MEL and NSCLC cohorts opening.  Additional Phase 2 cohorts 
in other tumor types may also be opened to test epacadostat 100 mg BID if it is deemed 
pharmacologically active and safe based on available data from Phase 1 cohorts. 
Note:  Up to 6 additional subjects may be enrolled into each cohort for a total of up to 9 evaluable 
subjects to further explore safety
objectives (original 3-9 subjects from dose escalation 
plus additional subjects required to have a total cohort size of 9). 
If epacadostat 300 mg BID is deemed tolerable, up to 6 additional subjects (for a minimum of 
6 subjects) will be enrolled before opening Phase 2 to further confirm the safety of the dose in 
combination with nivolumab.  If 1 of 6 or < 3 of 9 subjects experience DLTs, the remaining Phase 2 
cohorts may be opened with 300 mg BID as the RP2D after reviewing the emerging data from Phase 2 
cohorts testing 100 mg BID.  
If 300 mg BID is tested and not tolerated, an intermediate dose of 200 mg BID may be tested on either 
a continuous schedule or every-other-week schedule or 100 mg BID may be selected as the RP2D.  
The RP2D decision for the remaining Phase 2 cohorts will be made based on the available data from 
ongoing Phase 2 cohorts administered 100 mg BID.  If an MTD is not determined based on the data 
from Phase 1 and ongoing Phase 2 cohorts, then the remaining Phase 2 cohorts may be opened at a 
PAD of epacadostat (eg, 100 mg BID). 
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Phase 2 Dose Selection for Combination Immunotherapy (Part 1 of Phase 1) 
If 100 mg BID of epacadostat is determined as safe and tolerable in Phase 1 Part 1, Phase 2 of the 
study may begin to enroll in the I/O-naive MEL and NSCLC cohorts in parallel with the Part 1 
evaluation of epacadostat at 300 mg BID.  If 300 mg BID is then selected as the Phase 2 dose (RP2D), 
and either I/O-naive MEL or NSCLC cohort enrolls < 50% of total cohort (≤ 25 subjects) at 100 mg 
BID up to RP2D decision, then any additional subjects in that specific cohort being enrolled will be 
treated with epacadostat 300 mg BID at the sponsor's discretion, in lieu of opening new cohorts of 
I/O-naive MEL and NSCLC with 300 mg BID.  The same rule will apply to any additional Phase 2 
tumor cohorts (ie, CRC, ovarian cancer, etc) that may be opened with epacadostat 100 mg BID before 
RP2D selection.  (Note:  Additional I/O-relapsed and I/O-refractory MEL cohorts will be opened at 
100 mg BID). 
Combination Chemo-Immunotherapy Cohorts (Part 2 of Phase 1) 
The starting dose of epacadostat when given in combination with nivolumab (360 mg IV every 
3 weeks, Q3W) and chemotherapy will be 100 mg BID continuous daily dose administration, which is 
one dose level less than what was determined to be tolerable in Part 1 of Phase 1 and provides an 
adequate safety margin.  Part 2 of Phase 1 will consist of 3 tumor cohorts (1 SCCHN cohort, and 
2 NSCLC cohorts) that will enroll in parallel.  A minimum of 6 evaluable subjects will be enrolled in 
each tumor cohort at epacadostat 100 mg BID, and each cohort will be observed for 42 days for DLTs. 
In a tumor cohort the following rules will be applied to determine dose or dose de-escalation: 
• If ≤ 1 of 6 evaluable subjects has a DLT, then 100 mg BID will be used in a safety expansion cohort
(Cohort A, B, or C) for that specific tumor type.
• If 2 of 6 evaluable subjects have a DLT, 3 additional subjects will be enrolled in the same cohort
(Cohort 1, 2, or 3).  If there are no additional DLTs (≤ 2 DLTs occurred in a total of 9 evaluable
subjects), then a safety expansion cohort (Cohort A or B or C) will start to enroll in that specific dose
level.
• If ≥ 2/3, 3/6, or ≥ 3/9 evaluable subjects have DLTs within a specific tumor cohort, epacadostat will
be de-escalated to 1 lower dose level, 50 mg BID, and that tumor cohort will enroll 6 subjects to test
this dose level as described above.
• Note:  If different MTDs are determined for the 2 NSCLC cohorts (combination
chemo-immunotherapy), 3 to 6 additional subjects may be enrolled in each NSCLC cohort to further
evaluate the safety profile before dose selection for safety expansion.
The doses of epacadostat to be evaluated and scenarios for de-escalation are summarized in Table A2. 
Table A2: Epacadostat Dose De-Escalation Scenarios for Combination Chemo-Immunotherapy 
Cohorts in Part 2 
Combination Chemo-Immunotherapy Cohort 
Epacadostat Dose 
Dose Level 1 (starting dose) 
100 mg BIDa 
Dose Level -1 
50 mg BID 
a If epacadostat 100 mg BID is not tolerated within a specific cohort, the dose of epacadostat will be de-escalated to 50 mg 
BID for evaluation.  Alternate doses may be evaluated at the sponsor discretion 
 and 
safety results. 
Epacadostat dose regimens in combination chemo-immunotherapy cohorts by tumor types are 
provided in Table A3. 
Once 100 mg BID or 50 mg BID of epacadostat in combination chemo-immunotherapy cohorts is 
determined as the MTD or PAD, each of the tumor cohorts will be expanded for safety evaluation at 
that dose level of epacadostat.  Each of the safety expansion cohorts with combination 
chemo-immunotherapy will enroll up to 30 evaluable subjects. 
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Table A3: Summary of Treatment Regimens for Each Possible Epacadostat Dose-Finding 
Scenario for Combination Chemo-Immunotherapy Cohorts in Part 2 
Tumor Typesa 
Cohortb 
Total 
Subjects, N 
Epacadostat 
(Oral) 
Nivolumab 
(IV, Once Every 
3 Weeks) 
Chemotherapy Regimen 
SCCHN 
1 
~6-9 
100 mg BID 
360 mg 
Cisplatin (100 mg/m2 IV Q3W 
for up to 6 cycles) 
or 
Carboplatin AUC 5 IV Q3W for 
up to 6 cycles 
5-FU (1000 mg/m2 continuous IV 
for 4 days Q3W for up to 
6 cycles, on Day 1 of each cycle 
starting C1D1) 
1a 
~6-9 
50 mg BID 
360 mg 
Same as  above 
Nonsquamous 
NSCLC 
2 
~6-9 
100 mg BID 
360 mg 
Pemetrexed (500 mg/m2 IV Q3W 
for up to 6 cycles but no less than 
4 cycles, on D1of each cycle 
starting C1D1) 
Carboplatin (AUC 5 IV Q3W up 
to 6 cycles but no less than 
4 cycles, on Day 1 of each cycle 
starting C1D1) 
or 
Cisplatin (100 mg/m2 IV Q3W up 
to 6 cycles but no less than 
4 cycles) 
2a 
~6-9 
50 mg BID 
360 mg 
Same as above 
NSCLC 
3 
~6-9 
100 mg BID 
360 mg 
Paclitaxel (200 mg/m2 IV Q3W 
for up to 6 cycles but no less than 
4 cycles, on Day 1 of each cycle 
starting C1D1) 
Carboplatin (AUC 6 IV Q3W up 
to 6 cycles but no less than 
4 cycles, on Day 1 of each cycle 
starting C1D1) 
or 
Cisplatin (100 mg/m2 IV Q3W up 
to 6 cycles but no less than 
4 cycles) 
3a 
~6-9 
50 mg BID 
360 mg 
Same as above 
Total 
~18-54 
a Cohort 1, Cohort 2, and Cohort 3 will enroll in parallel. 
b If Cohort 1, Cohort 2, Cohort 3 with epacadostat 100 mg BID proves intolerable, then Cohort 1a, Cohort 2a, or Cohort 3a 
may be evaluated with epacadostat 50 mg BID.  If the epacadostat 100 mg BID is determined to be safe and tolerable at a 
specific tumor type, then the safety expansion cohort for that specific tumor type will enroll at 100 mg BID.  Alternative 
doses of epacadostat may be investigated at the sponsor discretion. 
In Phase 1, no intrasubject dose escalation is allowed.  In Phase 1 Part 1, additional subjects will be 
enrolled in a cohort to achieve the minimum of 3 evaluable subjects if discontinuations or dose 
interruptions or reductions occur that result in a subject being nonevaluable for DLTs.  In Phase 1 
Part 2, additional subjects will be enrolled in a cohort to achieve the minimum of 6 evaluable subjects.  
In both Part 1 and Part 2, subjects who withdraw from the study during the DLT period for reasons 
other than a DLT may be replaced within the same dose level. 
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For the purpose of making decisions on dose of epacadostat  from a safety perspective, subjects will be 
considered evaluable if they meet 1 of the following criteria: 
• In Part 1, in the combination immunotherapy cohorts, subjects must have received at least 2 out of 
the 3 scheduled nivolumab doses of 3 mg/kg through the 6-week (42-day) DLT observation period 
(only if the 1 missed dose was secondary to nonmedical reasons) and must have received at least 
75% of the cohort-specified dose of epacadostat during the DLT observation period. 
• In Part 2, in combination chemo-immunotherapy cohorts, subjects must have received 2 doses of 
nivolumab and chemotherapy regimen and must have received at least 75% of the cohort-specified 
dose of epacadostat in during the 42 day DLT observation period. 
• In addition, subjects with dose delays during the 42-day DLT observation period of > 1 week for 
non-DLT events will be considered not evaluable for making decisions on dose escalation or dose 
de-escalation and should be replaced. 
Dose escalation in Part 1 or dose de-escalation in Part 2 of epacadostat will be based on the number of 
dose limiting toxicities (DLTs) experienced during the DLT observation period.  Dose modifications 
should not be made during the DLT observation period without discussion with the medical monitor. 
Phase 2 Combination Immunotherapy Cohort Expansions 
The purpose of the cohort expansions in Phase 2 is to gather additional safety, tolerability, preliminary 
efficacy, 
 information regarding the combination of epacadostat and nivolumab.  
Once the safety profile of active doses is characterized and the RP2D has been defined, the cohort 
expansions will be initiated at the RP2D.  However, the I/O-naive MEL and NSCLC cohorts may be 
opened using epacadostat 100 mg BID in parallel to testing 300 mg BID if the 100 mg BID dose of 
epacadostat is deemed tolerable in Phase 1 Part 1.  Treatment doses in the cohort expansion groups 
will not exceed the MTD.  Nine expansion cohorts in Phase 2 will be restricted to the same tumor 
types tested in Phase 1 Part 1 (except DLBCL will be the only lymphoma permitted in Phase 2), and 
Phase 2 will also include a cohort for glioblastoma.  The NSCLC and I/O-naive MEL cohorts, which 
have demonstrated activity with nivolumab monotherapy and are in Phase 3 evaluation in these 
indications, will be used to assess increased activity of the combination.  In Phase 2, there will be 
2 additional MEL cohorts to explore the activity of combination immunotherapy; one cohort will 
enroll subjects who relapsed on or after anti–programmed death receptor-1(PD-1)/PD-L1 therapy (I/O 
relapsed) and the other cohort will enroll subjects who were refractory to prior anti–PD-1/PD-L1 
therapy (I/O refractory) (for I/O relapsed MEL cohort and I/O refractory MEL cohort definitions, see 
eligibility section below).  Subjects who are enrolled in these 2 new MEL cohorts will be administered 
nivolumab 480 mg IV every 4 weeks whereas, subjects who are enrolled in I/O-naive MEL, NSCLC, 
CRC, SCCHN, ovarian cancer, DLBCL and glioblastoma cohorts will be administered nivolumab 
240 mg IV every 2 weeks.  Subjects enrolled in I/O MEL cohorts will be administered epacadostat 
100 mg BID; however, if there is no or minimal activity in tumor responses in these cohorts, 
alternative doses of epacadostat may be explored at the sponsor discretion.  The CRC, SCCHN, 
ovarian cancer, DLBCL, and glioblastoma cohorts will explore activity of the combination in tumors 
with preliminary, unknown, or historically low responses to nivolumab monotherapy.  Continuous 
evaluation of toxicity events in the cohort expansions will be performed throughout enrollment in the 
expansion cohorts.  If the cumulative incidence of Grade 3 or Grade 4 study treatment-related AEs 
exceeds 40% after enrolling the first 6 subjects in any of these cohorts, the findings will be reviewed 
and further enrollment will be interrupted until the sponsor(s), investigators, and regulatory authorities, 
if applicable, have determined the appropriate course of action.  If an expansion cohort is discontinued 
due to toxicity, a new cohort may be initiated at a previously tested lower dose level of epacadostat. 
In each of the NSCLC and I/O-naive MEL cohorts, approximately 50 subjects will be enrolled to allow 
for a more precise estimate of the ORR in these tumors where activity for nivolumab as monotherapy 
has been established.  The sample size for the I/O-relapsed MEL, I/O-refractory MEL, CRC, ovarian, 
SCCHN, and DLBCL cohorts will be approximately 25 subjects each.  The sample size for the 
glioblastoma cohort will be approximately 28 (Table A4). 
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Table A4: Tumor Types Eligible for Combination Immunotherapy Cohort Expansion 
Tumor Type 
No. of Subjects to be Enrolled 
(Phase 2 Only) 
NSCLC 
50 
I/O-naive MEL 
50 
I/O-relapsed MEL 
25 
I/O-refractory MEL 
25 
CRC 
25 
Ovarian cancer 
25 
SCCHN 
25 
DLBCL 
25 
Glioblastoma 
28 
Totals 
~278 
Dose-Limiting Toxicity:  For the purpose of guiding dose escalation, DLTs will be defined separately 
and will be determined based on the incidence, intensity, and duration of AEs that occur within the 
first 42 days (6 weeks) after the initiation of epacadostat dosing.  Adverse events will be graded 
according to the National Cancer Institute (NCI) CTCAE v4. 
For all subjects enrolled in Part 1 and Part 2 of Phase 1 and in Phase 2, participation has following 
main periods: 
Screening:  Up to 28 days. 
Treatment:  The treatment period with the combination immunotherapy (nivolumab + epacadostat) 
will continue every 56 days and with the combination chemo-immunotherapy (nivolumab + 
epacadostat + chemotherapy) will continue every 21 days as long as the subjects are receiving benefit 
from treatment and have not met any criteria for study withdrawal.  
End of Treatment (EOT):  + 5 days of withdrawal from study treatment. 
Safety Follow-Up:  Safety follow-up visits will occur at 30 and 100 days after EOT (or after the last 
dose of study drug if the EOT visit was not performed). 
Combination Immunotherapy and Chemo-Immunotherapy, Regimen, and Mode of 
Administration: 
Epacadostat is an investigational agent and will be self-administered BID orally without regard to 
food and continued BID continuous or every other week during the 8-week cycle for an every-2-week 
dose schedule of nivolumab in combination immunotherapy cohorts.  In combination 
chemo-immunotherapy cohorts, epacadostat will be administered BID continuously during 21-day 
cycle (3 weeks) for as long as subject is deriving benefit and has not met any of the Protocol-defined 
conditions for treatment withdrawal.  Intrasubject dose escalation of epacadostat is not permitted.   
The RP2D defined during Phase 1 will be used for Phase 2.  (Note:  Subjects enrolled into 
I/O-refractory and I/O-relapsed MEL cohorts in Phase 2 will be administered epacadostat 100 mg 
BID).  Intrasubject dose escalation of epacadostat is not allowed.  All BID doses will be taken morning 
and evening, approximately 12 hours apart.  If a dose is missed by more than 4 hours, that dose should 
be skipped and the next scheduled dose should be taken at the usual time. 
Nivolumab will be administered 3 mg/kg as a 60-minute infusion every 2 weeks on Days 1, 15, 29, 
and 43 of each 8-week cycle of study therapy in Phase 1 Part 1.  In Phase 1 Part 2, for the combination 
chemo-immunotherapy cohorts, the dose of nivolumab will be 360 mg as a 30-minute infusion every 
3 weeks on Day 1 of each 21-day cycle. 
In the Phase 2 dose expansion of the combination immunotherapy cohorts, the dose of nivolumab will 
be 240 mg  as a 30-minute infusion every 2 weeks on Days 1, 15, 29, and 43 of each 8-week cycle.  
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For I/O-relapsed and I/O-refractory MEL cohorts in Phase 2, the dose of nivolumab will be 480 mg as 
a 30-minute infusion every 4 weeks on Day 1 and Day 29 of each 8-week cycle.  Subjects will 
continue to receive nivolumab for up to 2 years as long as the subject is deriving benefit and have not 
met any protocol-defined criteria for study treatment withdrawal.  Intrasubject dose escalation of 
nivolumab is not permitted.  Nivolumab doses and schedules are summarized in Table A5. 
Table A5:  Nivolumab Doses and Schedules in Phase 1 and Phase 2 
Study Phases 
and Cohorts 
Phase 1 
Phase 2 
Part 1 – dose finding 
for combination 
immunotherapy 
cohorts 
Part 2 – dose finding for 
combination chemo-
immunotherapy cohorts and 
safety expansion cohorts 
Select tumor 
cohorts for 
combination 
immunotherapy 
I/O-relapsed 
and 
I/O-refractory 
MEL cohorts 
Nivolumab 
(Dose, schedule, 
infusion duration, 
cycle length) 
3 mg/kg, Q2W 
60 min IV 
8-week cycle 
360 mg, Q3W 
30 min IV 
21-day cycle 
240 mg, Q2W 
30 min IV 
8-week cycle 
480 mg Q4W 
30 min IV 
8-week cycle 
Paclitaxel/Platinum (Carboplatin or Cisplatin) will be administered on Day 1 of each 21-day cycle 
for a minimum of 4 cycles and up to 6 cycles.  Subjects will receive paclitaxel 200 mg/m2 IV over 
3 hours (± 15 min) with either AUC 6 carboplatin or 100 cisplatin mg/m2 IV over 30 minutes 
(± 5 min).  Premedications include the following:  1) dexamethasone 20 mg PO 12 hours and 6 hours 
before or dexamethasone 16 mg to 20 mg IV 30 minutes before, 2) chlorphenamine 10 mg IV 
30 minutes before, and 3) ranitidine 50 mg IV 30 minutes before paclitaxel administration.  
Premedications may be adjusted based on institutional guidelines, study investigator practice, or 
availability of similar medications on the investigative site's formulary.  Subjects may receive 
prophylactic G-CSF support after completion of Cycle 1. 
Pemetrexed/Platinum (Carboplatin or Cisplatin) will be administered on Day 1 of each 21-day 
cycle for a minimum of 4 cycles and up to 6 cycles.  Subjects will receive pemetrexed 500 mg/m2 IV 
over 10 minutes (± 5 min) with either AUC 5 carboplatin or 100 mg/m2 cisplatin IV over 30 minutes 
(± 5 min).  Pemetrexed may continue as maintenance therapy after 6 cycles as long as the subject is 
deriving benefit and has not met any of the Protocol-defined conditions for treatment withdrawal.  
Premedications include the following: 1) dexamethasone 4 mg orally (PO) BID (or equivalent) taken 
the day before, the day of, and the day after pemetrexed administration; 2) folic acid 400 μg to 1000 μg 
PO once daily beginning 7 days before first dose of pemetrexed and continued through the full course 
of therapy and for 21 days after the last dose of pemetrexed; and 3) vitamin B12 1 mg intramuscularly 
1 week before the first dose of pemetrexed and every 3 cycles thereafter.  Premedications may be 
adjusted based on institutional guidelines, study investigator practice, or availability of similar 
medications on the investigative site's formulary.  Subjects may receive prophylactic G-CSF support 
after the completion of Cycle 1. 
5-Fluorouracil (5-FU) and Platinum (cisplatin or carboplatin) will be administered beginning on 
Day 1 of each 21-day cycle for up to 6 cycles.  5-FU will be administered on Day 1 of each cycle.  
Subjects will receive 100 mg/m2 cisplatin IV over 30 minutes (± 5 min) or carboplatin AUC 5 IV over 
30 minutes (± 5 min) followed by 5-FU 1000 mg/m2 per day as continuous IV infusion over 4 days.  
Premedications, including corticosteroids, may be given based on institutional guidelines, study 
investigator practice, or availability of similar medications on the investigative site's formulary.  
Subjects may receive prophylactic granulocyte-colony stimulating factor (G-CSF) support after 
completion of Cycle 1. 
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Duration of Participation:  Subject participation is continuous 8-week cycles in the combination 
immunotherapy cohorts or 21-day cycles in the combination chemo-immunotherapy cohorts.  Subjects 
may continue on epacadostat and/or nivolumab for up to 2 years as long as they are receiving benefit 
and do not meet other treatment withdrawal criteria. 
Study Population: 
Subjects with Stage IIIB, Stage IV, or recurrent NSCLC; unresectable or Stage IV MEL; recurrent 
(unresectable) or metastatic CRC; recurrent (unresectable) or metastatic SCCHN; International 
Federation of Gynecology and Obstetrics (FIGO) Stage Ic, II, III, or IV recurrent ovarian cancer 
(unresectable);  B-cell NHL or HL; and relapsed or refractory glioblastoma after standard-of-care 
therapy may enroll.  Subjects with select cancers must have had disease progression on treatment or 
intolerance to treatment, or subjects who have refused currently approved treatment may enroll with 
medical monitor approval (except for subjects with MEL, who may be enrolled as initial treatment for 
their advanced cancer). 
Key Inclusion Criteria: 
• Male or female subjects, age 18 years or older.
• Subjects with histologically or cytologically confirmed NSCLC, MEL, CRC, SCCHN, ovarian
cancer, recurrent B-cell NHL or HL, or glioblastoma.
• Subjects with Stage IIIB, Stage IV, or recurrent NSCLC; unresectable or Stage IV MEL; recurrent
(unresectable) or metastatic CRC; recurrent (unresectable) or metastatic SCCHN; FIGO Stage Ic, II,
III, or IV recurrent ovarian cancer (unresectable); relapsed or refractory B-cell NHL or HL
(including relapsed or refractory DLBCL); or relapsed or refractory glioblastoma and meet the
following tumor-specific criteria:
− Subjects with Stage IIIB, Stage IV, or recurrent NSCLC:
o For all NSCLC subjects (Phase 1 and Phase 2):
Subjects with nonsquamous NSCLC must be screened for epidermal growth factor receptor
(EGFR) and anaplastic lymphoma kinase (ALK) fusion oncogene status.
Tumors with driver mutations (EGFR mutation–positive or ALK fusion oncogene–positive)
previously treated with an approved tyrosine kinase inhibitor (TKI) must have progressed on
or been intolerant to the TKI therapy.  (Note:  For subjects with driver mutations and treated
with a prior TKI therapy, up to 2 additional lines of therapy that include a TKI therapy are
permitted.)
Maintenance or switch maintenance therapy after first line chemotherapy is acceptable.
Malignancy must be deemed unresectable.
o For combination immunotherapy cohorts (Part 1 of Phase 1 and Phase 2), subjects with
nonsquamous, squamous, or adenosquamous NSCLC, or NSCLC NOS histology who have
received up to 1 prior systemic regimen for Stage IIIB, Stage IV, or recurrent NSCLC.  Prior
systemic regimen must have contained a platinum-based therapy (at least 2 cycles with or
without bevacizumab).
Subjects ineligible for platinum-based therapy who have received alternative chemotherapy
regimens or are intolerant of platinum-based therapy may enroll with medical monitor
approval.
Subjects who completed and progressed on a platinum-containing regimen as adjuvant,
neoadjuvant, or part of a course of chemoradiation therapy within the 6 months before
screening would be counted as having received 1 prior platinum-containing regimen and,
therefore, would not require re-treatment with a platinum-containing regimen for advanced or
metastatic disease.
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o For combination chemo-immunotherapy cohorts (Part 2 of Phase 1 only), subjects with 
nonsquamous or squamous NSCLC must have no more than 1 prior line of therapy for 
Stage IIIB, Stage IV, or recurrent NSCLC. 
 Subjects must not have received previous platinum-based doublet chemotherapy for 
Stage IIIB, Stage IV, or recurrent NSCLC. 
 Subjects who completed a platinum-based chemotherapy doublet regimen as adjuvant, 
neoadjuvant, or part of a course of chemoradiation therapy and progressed ≥ 6 months after 
completing therapy will be eligible for combination chemo-immunotherapy only.  If 
progression occurred < 6 months after completing therapy, the subject will not be eligible. 
 In the dose-finding cohorts, subjects may have received a prior TKI for tumors with any driver 
mutation (EGFR mutation positive or ALK fusion oncogene positive). 
 In the safety expansion cohorts, subjects must not have any prior therapy for advanced or 
metastatic disease, except TKI for driver mutations. 
− Subjects with unresectable or Stage IV MEL.  Note:  There will be 3 MEL cohorts in Phase 2, 
which will include I/O-naive, I/O-relapsed, and I/O-refractory cohorts as defined below: 
o For all MEL subjects (Phase 1 and Phase 2): 
 Documentation of V600E-activating BRAF mutation status or consent to BRAF V600E 
mutation testing during the screening period.  Testing should be performed in a Clinical 
Laboratory Improvement Amendments–certified laboratory.  BRAF mutation status 
determined as part of a panel of genetic tests performed in a gene expression analysis will also 
satisfy the inclusion criteria for BRAF mutation testing. 
 No nitrosoureas (eg, carmustine or lomustine) within the past 6 weeks and during study 
treatment.  
 Must not have any prior ocular toxicity on any prior therapy, including immune checkpoint 
inhibitors.  
 No more than 2 prior lines of therapy for advanced/metastatic disease, only 1 of which can be 
a prior anti–PD-1/PD-L1 therapy with or without anti–cytotoxic T-lymphocyte-associated 
antigen-4 (CTLA-4) therapy.  Prior anti–CTLA-4 monotherapy is not permitted. 
 Must not have ocular melanoma. 
o For subjects with advanced or metastatic I/O-naive MEL (Part 1 of Phase 1 and Phase 2): 
 Subjects must be treatment-naive or have received only 1 prior treatment for advanced or 
metastatic disease, including targeted therapy. 
 Subjects must not have received any prior anti–PD-1/PD-L1 therapy. 
Note:  Anti–CTLA-4 given as in the adjuvant setting or as first-line treatment for advanced or 
metastatic disease will be permitted.  These subjects must have discontinued anti–CTLA-4 
therapy at least 12 weeks before first dose of epacadostat.   
o For subjects with advanced or metastatic MEL who were relapsed on or after the previous anti–
PD-1/PD-L1 therapy following an initial response to PD-1 pathway–targeted therapy 
(I/O-relapsed MEL; Phase 2 only): 
 Relapsed is defined as having a best response CR, partial response (PR), or stable disease with 
a subsequent confirmed radiographic progression per RECIST v1.1 on or after anti–
PD-1/PD-L1 therapy with or without anti–CTLA-4 therapy. 
Note:  Disease progression may be confirmed based on study investigator's certification at 
screening assessment). 
 If with known BRAF mutations, subjects may have had prior BRAF/MEK inhibitors following 
the last anti–PD-1/PD-L1 therapy (with or without anti–CTLA-4 therapy). 
 No more than 2 prior lines of therapy for advanced/metastatic disease, only 1 of which can be 
a prior anti–PD-1/PD-L1 therapy, with or without anti–CTLA-4 therapy.  Prior anti–CTLA-4 
monotherapy is not permitted. 
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o For subjects with advanced or metastatic MEL who were refractory to previous anti–
PD-1/PD-L1 therapy (I/O-refractory MEL; Phase 2 only): 
 Refractory is defined as having a best response of confirmed radiographic progression per 
RECIST v1.1 to a prior anti-PD–1/PD-L1 therapy with or without anti–CTLA-4 therapy. 
Note:  Disease progression may be confirmed based on study investigator's certification at 
screening assessment. 
 If with known BRAF mutations, may have had prior BRAF/MEK inhibitors following the last 
anti–PD-1/PD-L1 therapy (with or without anti–CTLA-4 therapy). 
 No more than 2 prior lines of therapy for advanced/metastatic disease, only 1 of which can be a 
prior anti–PD-1/PD-L1 therapy, with or without anti–CTLA-4 therapy.  Prior anti–CTLA-4 
monotherapy is not permitted. 
− Subjects with recurrent (unresectable) or metastatic CRC: 
o Histologically or cytologically confirmed adenocarcinoma of the colon or rectum. 
o Prior treatment:  Previous treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based 
chemotherapy; an anti–vascular endothelial growth factor (VEGF) therapy (if no 
contraindication); and, if KRAS wild type and no contraindication, an anti-EGFR therapy and 
progressed following the last administration of approved therapy. 
o Subjects who have discontinued treatment due to unacceptable toxicity may enroll.  
− Subjects with recurrent (unresectable) or metastatic SCCHN: 
o Histologically confirmed metastatic or recurrent squamous cell carcinoma not amenable to local 
therapy with curative intent (surgery or radiation with or without chemotherapy).  Histologically 
confirmed recurrent or metastatic carcinoma of the nasopharynx and salivary gland or 
nonsquamous histologies will be excluded. 
o For combination immunotherapy cohorts in Phase 1 Part 1 and Phase 2:  No more than 2 prior 
systemic regimens for advanced disease.  Prior systemic regimens must include a 
platinum-based therapy.  Investigational agents used in combination with standard therapies are 
allowed.  Subjects who relapsed within 6 months of adjuvant therapy, including a 
platinum-containing regimen, may enroll. 
o For combination chemo-immunotherapy cohorts in Phase 1 Part 2:  Subjects must not have 
received a previous platinum-based chemotherapy for recurrent or metastatic SCCHN. 
Note:  Subjects who completed a platinum based chemotherapy as adjuvant, neoadjuvant, or part 
of a course of chemoradiation therapy and progressed ≥ 6 months after completing therapy will 
be eligible.  If progression occurred < 6 months after completing the therapy, the subject will not 
be eligible. 
o Documentation of human papillomavirus status (eg, p16-status) of tumor. 
− Subjects with FIGO Stage Ic, Stage II, Stage III, Stage IV, recurrent, or persistent (unresectable) 
histologically confirmed epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube 
carcinoma: 
o Subjects must have received a platinum-taxane–based regimen as frontline therapy. 
o Subjects who received maintenance paclitaxel, bevacizumab, or alternative maintenance therapy 
(eg, vaccines) are eligible for enrollment provided they have discontinued therapy at least 
4 weeks for prior taxane and at least 8 weeks for bevacizumab, or they have received medical 
monitor approval for time lapse from alternative maintenance therapy before enrollment and 
recovered from toxicities to less than Grade 2. 
o Borderline, low malignant potential epithelial carcinoma per histopathology is excluded. 
− Subjects with relapsed or recurrent B-cell NHL or HL (including relapsed or refractory  DLBCL, 
excluding Burkitt's lymphoma and precursor B-lymphoblastic leukemia/lymphoma): 
o Prior allogeneic stem-cell transplantation is excluded. 
o Not a candidate for curative therapy or hematopoietic stem cell transplantation (due to disease 
burden, fitness, or preference). 
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o Subjects must have relapsed or have had refractory DLBCL specifically for Phase 2 but may
have any B-cell NHL or HL as noted above for Phase 1 dose escalation.
o Subjects with HL:  must be brentuximab vedotin refractory or intolerant.
− Subjects with histologically confirmed diagnosis of relapsed or refractory glioblastoma: 
o Previous first-line treatment with at least radiotherapy and temozolomide.
o Documented first recurrence of glioblastoma by diagnostic biopsy or contrast enhanced
magnetic resonance imaging (MRI) per RANO criteria.
Note:  Relapse is defined as progression following initial line of therapy (ie, radiation ±
chemotherapy).  If the participant had a surgical resection for relapsed disease and no antitumor
therapy was instituted for up to 12 weeks, this is considered 1 relapse or recurrence.
o MRI within 14 days before start of study drug.  MRIs should include vascular imaging when
possible.  Corticosteroid dose must be stable or decreasing for at least 5 days before the scan.  If
steroids are added or the steroid dose is increased between the date of the screening MRI and the
start of treatment, a new baseline MRI is required.
o An interval of at least 12 weeks after the end of prior radiation therapy is required unless there is
either 1) histopathologic confirmation of recurrence of tumor or 2) new enhancement on MRI
outside of the radiotherapy treatment field.
o An interval of ≥ 21 days and full recovery (ie, no ongoing safety issues) from surgical resection
before enrollment.
• Presence of measurable disease per RECIST v1.1 for solid tumors or Response Criteria for
Lymphoma (Cheson et al 2007) B-cell NHL (including DLBCL) or HL.  For subjects with
glioblastoma, presence of measurable disease is not required.
• ECOG performance status 0 to 1.
• Fresh baseline tumor biopsies (defined as a biopsy specimen taken since completion of the most
recent prior systemic regimen) are required for all cohorts except glioblastoma.  For I/O-relapsed
MEL and I/O-refractory MEL cohorts (Phase 2) as well as all combination chemo-immunotherapy
cohorts (Part 2 of Phase 1), biopsies will be confirmed to contain adequate tumor tissue by a local
pathology review.  If a subject has inaccessible lesions, such as in ovarian cancer, the subject may be
enrolled with medical monitor approval.  In this case, submission of archived tumor tissue may be
acceptable.
For archived tumor tissue, a formalin fixed paraffin-embedded tumor tissue block is preferred.  If a
block is not available, a minimum of 20 unstained freshly cut slides may be submitted to the testing
laboratory as specified in the Laboratory Manual.
Note:  Unstained slides must have been prepared from a formalin fixed paraffin-embedded block
obtained within 6 months before screening).
• Female subjects of childbearing potential (defined as women who have not undergone surgical
sterilization with a hysterectomy and/or bilateral oophorectomy, and are not postmenopausal as
defined as ≥ 12 months of amenorrhea) must have a negative serum pregnancy test at screening.  All
female (and male as appropriate for Protocol) subjects of childbearing potential must agree to take
appropriate precautions to avoid pregnancy (or fathering children), with at least 99% certainty, from
screening through 150 days after the last dose of epacadostat.  Permitted methods that are at least
99% effective in preventing pregnancy should be communicated to the subject and their
understanding confirmed.
Key Exclusion Criteria: 
• Laboratory and medical history parameters not within Protocol-defined range unless directly
resulting from the bone marrow infiltration of the underlying malignancy.  All screening laboratory
tests should be performed within 7 days of  the first dose of epacadostat (Cycle 1 Day 1) and must be
independent of  hematopoietic growth factor support:
− Absolute neutrophil count < 1.5 × 109/L (in no case < 1.0 × 109/L).
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− Platelets < 100 × 109/L (in no case < 50 × 109/L). 
− Hemoglobin < 9 g/dL or ≤ 5.6 mmol/L (transfusion is acceptable to meet this criterion). 
− Serum creatinine ≥ 1.5 × institutional upper limit of normal (ULN), or measured or calculated 
creatinine clearance (CrCl) < 50 mL/min for subjects with creatinine levels > 1.5 × institutional 
ULN. 
− Aspartate aminotransferase, alanine aminotransferase > 2.5 × ULN OR ≥ 5 × ULN for subjects 
with liver metastases. 
− Total bilirubin ≥ 1.5 × ULN or conjugated (direct) bilirubin ≥ ULN (need only be tested if total 
bilirubin exceeds ULN).  If an institutional ULN for conjugated bilirubin is not available, then 
conjugated bilirubin should be < 40% of total bilirubin to be considered eligible. 
− International normalized ratio (INR) or prothrombin time (PT) > 1.5 × ULN unless subject is 
receiving anticoagulant therapy as long as PT or INR is within therapeutic range of intended use of 
anticoagulants. 
− Activated partial thromboplastin time (aPTT) > 1.5 × ULN unless subject is receiving 
anticoagulant therapy, as long as PTT is within therapeutic range of intended use of anticoagulants. 
• Current pregnancy or breastfeeding.
• Participation in any other study in which receipt of an investigational study drug occurred within
28 days or 5 half-lives (whichever is longer) before Cycle 1 Day 1.  For investigational agents with
long half-lives (eg, 5 days), enrollment before the fifth half-life requires medical monitor approval.
• Subjects who have received prior immune checkpoint inhibitors (eg, anti–CTLA-4, anti–PD-1,
anti–PD-L1, and any other antibody or drug specifically targeting T-cell costimulation) or an IDO
inhibitor (except as required for I/O-relapsed and I/O-refractory MEL cohorts [Phase 2], see
inclusion criteria above).  Subjects who have received experimental vaccines or other immune
therapies should be discussed with the medical monitor to confirm eligibility.
• Any prior immune-related adverse events (irAEs) must have resolved to ≤ Grade 1 before first dose
of epacadostat and nivolumab (Cycle 1 Day 1).  Any ≥ Grade 3 irAEs (except lymphopenia or
asymptomatic amylase/lipase elevations) from prior immunotherapies, including CTLA-4 treatment,
are excluded.
Note:  Subjects with history of ≥ Grade 3 endocrinopathies must be discussed with the medical
monitor to determine eligibility.
• Subjects who are receiving an immunologically based treatment for any reason, including chronic
use of systemic steroid or prednisone equivalent at doses ≥ 10 mg/day within 7 days before the first
dose of epacadostat and nivolumab (Cycle 1 Day 1).  Use of inhaled or topical steroids or systemic
corticosteroids < 10 mg is permitted.
Note:  There are some exceptions in use of systemic corticosteroids or physiological replacement
doses of steroids for subjects with glioblastoma)
• Subjects who have received any anticancer medication in the 21 days before Cycle 1 Day 1 or has
any unresolved toxicity greater than Grade 1 from previous anticancer therapy, except for stable
chronic toxicities not expected to resolve, such as peripheral neurotoxicity, alopecia, and fatigue.
• Prior monoclonal antibody within 4 weeks before starting Cycle 1 Day 1 or not recovered (≤ Grade 1
or at baseline) from AEs due to agents administered more than 4 weeks earlier.  Exception to this
rule would be use of denosumab.
• Untreated central nervous system (CNS) metastases or CNS metastases that have progressed
(eg, evidence of new or enlarging CNS metastasis or new neurological symptoms attributable to
CNS metastases or cerebral edema).  Subjects with previously treated and clinically stable CNS
metastases (without evidence of radiographic progression shown by imaging at least 28 days before
Cycle 1 Day 1) and off all corticosteroids for at least 2 weeks before Cycle 1 Day 1 are eligible.
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• Subjects with any active or inactive autoimmune process (eg, rheumatoid arthritis, moderate or 
severe psoriasis, multiple sclerosis, inflammatory bowel disease) or who are receiving systemic 
therapy for an autoimmune or inflammatory disease.   
− Exceptions include subjects with vitiligo, hypothyroidism stable on hormone replacement, 
controlled asthma, Type I diabetes, Graves' disease, Hashimoto's disease, or with medical monitor 
approval. 
• Evidence of interstitial lung disease or active, noninfectious pneumonitis including symptomatic 
and/or pneumonitis requiring treatment. 
• Subjects who have had prior radiotherapy within 2 weeks of Cycle 1 Day 1.  Subjects must have 
recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation 
pneumonitis.  A 1-week wash out is permitted for palliative radiation to non-CNS disease with 
medical monitor approval. 
• Any history of serotonin syndrome (SS) after receiving 1 or more serotonergic drugs. 
• History or presence of an abnormal electrocardiogram (ECG) that, in the investigator's opinion, is 
clinically meaningful.  Screening QTc interval > 480 milliseconds is excluded (corrected by 
Fridericia or Bazett formula).  In the event that a single QTc is > 480 milliseconds, the subject may 
enroll if the average QTc for the 3 ECGs is < 480 milliseconds.  For subjects with an intraventricular 
conduction delay (QRS interval > 120 milliseconds), the JTc interval may be used in place of the 
QTc with sponsor approval.  The JTc must be < 340 milliseconds if JTc is used in place of the QTc.  
Subjects with left bundle branch block are excluded. 
• History or current evidence of any condition, therapy, or laboratory abnormality that might confound 
the results of the study, interfere with the subject's participation for the full duration of the study, or 
is not in the best interest of the subject to participate, in the opinion of the treating investigator. 
• Known allergy or reaction to any component of epacadostat, nivolumab, 5-FU, cisplatin, carboplatin, 
paclitaxel, pemetrexed, or their formulation components or mannitol. 
• Exclusion criteria for subjects enrolled with glioblastoma: 
− More than 1 recurrence of glioblastoma. 
− Presence of extracranial metastatic or leptomeningeal disease. 
− Diagnosis of secondary glioblastoma (ie, glioblastomas that progress from low-grade diffuse 
astrocytoma or anaplastic astrocytoma). 
− Previous radiation therapy with anything other than standard therapy (ie, focally directed 
radiation). 
− Subjects requiring escalating (within 7 days of Cycle 1 Day 1) or chronic supraphysiologic doses 
(to be more than 2 mg of Decadron® or biologic equivalent per day) of corticosteroids for control 
of their disease. 
− Treatment with carmustine wafer except when administered as first-line treatment and at least 
6 months before Cycle 1 Day 1. 
− Evidence of > Grade 1 CNS hemorrhage on the baseline MRI. 
− History or evidence upon physical/neurological examination of CNS disease (eg, seizures) 
unrelated to cancer unless adequately controlled by medication or potentially interfering with 
Protocol treatment. 
− Subjects unable (due to existent medical condition, eg, pacemaker or implantable cardioverter 
defibrillator device) or unwilling to have a head contrast-enhanced MRI. 
− History of intracranial abscess within 6 months before enrollment. 
− Prior VEGF or VEGF-receptor directed therapy (ie, bevacizumab). 
• Use of any prohibited medication. 
• Has a known history of or is positive for hepatitis B (HBsAg reactive) or has active hepatitis C 
(HCV RNA).  Note:  Testing must be performed to determine eligibility.  
− HBV DNA must be undetectable and HBsAg negative at screening visit. 
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− Hepatitis C Ab testing is allowed for screening purposes in countries where HCV RNA is not part 
of SOC.  In these cases, HCV antibody positive participants will be excluded.   
− Participants who have had definitive treatment for HCV are permitted if HCV RNA is 
undetectable at screening visit.  (Includes serology testing shown in the laboratory analytes.) 
• Subjects with bleeding associated with tumors that invade or are adjacent to major blood vessels, as 
shown unequivocally by imaging studies, or history of bleeding related to disease under study within 
3 months of Cycle 1 Day 1. 
Study Schedule/Procedures: 
Subjects will have regularly scheduled study visits at the clinical site on Day 1 of every cycle (CXD1) 
and at designated timepoints within each cycle, as noted in the Schedule of Assessments.  Safety 
assessments will include laboratory assessments, vital sign collection, ECGs, and physical 
examinations.  Adverse events will be assessed continuously during the study and for 100 days after 
the last dose of combination treatment.  Adverse events will be coded using the most current version of 
MedDRA at Protocol initiation and reviewed for potential significance and importance.  Subjects 
should be followed until all treatment related AEs have recovered to baseline or are deemed 
irreversible by the investigator.  Both AEs and laboratory tests will be graded using the NCI CTCAE 
v4. 
Efficacy measures will be assessed 8 and 16 weeks after the start of treatment for subjects in the 
combination chemo-immunotherapy cohorts (Phase 1 Part 2) and then every 12 weeks thereafter.  All 
other subjects (Phase 1 Part 1 and Phase 2) will have efficacy assessments every 12 weeks.  All 
subjects will continue to have efficacy assessments until the end of treatment; no efficacy assessments 
are required during the safety follow-up period.  Tumor responses will be derived for appropriate 
populations of subjects as defined by RECIST v1.1 for solid tumors, Cheson criteria for lymphoma, or 
RANO criteria for subjects with glioblastoma based on recorded tumor measurements as well as based 
on investigator assessment of response.   
The decision to treat a subject with additional cycles of study therapy will be based on tumor 
assessment (evaluation completed before the first dose in the next cycle):  1) radiographic progression, 
2) clinical deterioration suggesting that no further benefit from treatment is likely, 3) intolerability to 
therapy, 4) the subject meets criteria for discontinuation of study therapy, or 5) the subject has received 
2 years of nivolumab therapy.  
Subjects will enter the safety follow-up period upon discontinuation of treatment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Planned Number of Subjects:   
Up to approximately 485 subjects may be enrolled in the overall study.  There will be approximately 
up to 207 subjects enrolled in the Phase 1, which will include subjects enrolled in both dose escalation 
in combination immunotherapy cohorts as well as in combination chemo-immunotherapy cohorts and 
combination chemo-immunotherapy safety expansion cohorts.  In Phase 2, there will be up to 
approximately 278 subjects enrolled. 
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Principal Coordinating Investigator:  TBD 
Statistical Methods: 
Selection of Sample Size 
Phase 1 (Part 1 and Part 2):  Dose Finding and Safety Expansion:  For Part 1 of Phase 1 
dose-escalation of combination immunotherapy cohorts, the sample size at each dose depends on the 
number of observed toxicities (3 + 3 + 3 design) during DLT observation period.  Between 3 and 
9 subjects are expected to be treated during dose escalation in each cohort.  
For Part 2 of Phase 1 dose finding (dose de-escalation) of combination chemo-immunotherapy cohorts, 
the sample size at each dose also depends on the number of observed toxicities during DLT 
observation period.  Between 6 and 9 subjects are expected to be treated in each individual cohort.  For 
safety expansion cohorts of combination chemo-immunotherapy, up to 30 subjects will be enrolled in 
each tumor /combination chemo-immunotherapy specific cohorts. 
Phase 2 Cohort Expansion:  During cohort expansion, approximately 25 subjects are expected to be 
enrolled in each of the 4 low historic response expansion cohorts (CRC, SCCHN, ovarian cancer, and 
DLBCL) and in the 2 MEL cohorts (I/O relapsed and I/O refractory).  Approximately 50 subjects are 
expected in each of the 2 higher historic ORR cohorts (NSCLC and I/O-naive MEL).  For these 
cohorts, ORR and PFS will be analyzed as dual primary endpoints.  The sample size yields a power of 
80% to detect either an increase in ORR by 17% to 26% from historical response rate of each tumor 
type, or a PFS rate at 6 months increased by 17% to 22% from historical survival probability.  This 
assumes a 1-sided alpha of 2.5% (based on Bonferroni adjustment due to dual primary endpoints for 
each independent cohort), 10% lost to follow-up, enrollment period of 6 to 10 months (depends on 
cohort), and 6 to 10 months of follow-up (depends on cohort) after last subject enrolled.  Twenty-eight 
subjects are expected to be enrolled in the glioblastoma cohort.  This yields a power of 80% to detect 
an OS rate at 9 months of 25% increase (Ha) from historical survival probability (H0).  This assumes a 
1-sided alpha of 5%, 10% lost to follow-up, enrollment period of 4 months, and 9 months of follow-up 
after last subject enrolled. 
Statistical Analysis: 
Primary Analyses: 
Phase 1 (Part 1 and Part 2) and Phase 2:  Subject enrollment, disposition, demographics, and medical 
history will be summarized at baseline.  DLTs will be summarized for each cohort.  Dose exposure and 
density will be calculated for Phase 1.  AEs will be coded by MedDRA, and incidences will be 
tabulated by preferred term and system organ class for all events, related events, and events ≥ Grade 3.  
Severity of AEs will be based on the CTCAE scale.  Quantitative safety variables and their changes 
from baseline (laboratory, vital signs) will be summarized with descriptive statistics.  Clinically 
significant abnormal values will be flagged and tabulated based on predefined criteria. 
Phase 2:  The proportion of subjects with objective response (ORR) will be tabulated by tumor type 
(cohort).  The PFS and OS will be analyzed by the Kaplan-Meier method.  The PFS/OS rate and the 
corresponding confidence interval using log-log transformation will be provided by tumor type 
(cohort) at 6 months for PFS and 9 months for OS.  
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Safety Monitoring Committee:   Due to the complexity of combination chemo-immunotherapy 
cohorts, a Safety Monitoring Committee (SMC) will review safety data at regular intervals throughout 
Phase 1 Part 2.  Details regarding SMC membership, roles and responsibilities of the committee will 
be specified in the SMC charter. 
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TABLE OF CONTENTS 
SYNOPSIS ......................................................................................................................................3 
LIST OF ABBREVIATIONS ........................................................................................................33 
1. 
INTRODUCTION ......................................................................................................37 
1.1. 
Pharmaceutical and Therapeutic Background ............................................................37 
1.1.1. 
Inhibition of PD-1 as a Target for Cancer ..................................................................37 
1.1.2. 
Inhibition of Indoleamine 2,3-Dioxygenase as a Target for Cancer ..........................39 
1.1.3. 
Combined Immune Checkpoint Inhibition .................................................................40 
1.1.4. 
Rationale for Studying Immunotherapy in Advanced or Metastatic Cancers ............42 
1.1.5. 
Overview of 5-Fluorouracil and Cisplatin in Squamous Cell Carcinoma of 
Head and Neck ............................................................................................................44 
1.1.6. 
Overview of Platinum-Based Doublet Chemotherapy Compared With 
Immunotherapy in Squamous and Nonsquamous Non–Small Cell Lung 
Cancer .........................................................................................................................44 
1.2. 
Study Rationale ...........................................................................................................46 
1.2.1. 
Rationale for Combining PD-1 Inhibitor and IDO1 Inhibitor 
 
 
............................................46 
1.2.2. 
Rationale for Combining PD-1 Inhibitor and IDO1 Inhibitor With 
Chemotherapy
.............................47 
1.2.3. 
Preclinical and Clinical Study Data for Epacadostat and Nivolumab ........................49 
1.3. 
Potential Risks and Benefits of the Treatment Regimen ............................................49 
 
49 
1.3.2. 
Risks From Nivolumab ...............................................................................................50 
1.3.3. 
Risks for the Combination of Epacadostat and Nivolumab ........................................50 
1.3.4. 
Risks From 5-Fluorouracil/Platinum (Cisplatin or Carboplatin) ................................50 
1.3.5. 
Risks From Paclitaxel/Carboplatin .............................................................................51 
1.3.6. 
Risks From Paclitaxel/Cisplatin .................................................................................51 
1.3.7. 
Risks From Pemetrexed/Carboplatin ..........................................................................51 
1.3.8. 
Risks From Pemetrexed/Cisplatin ..............................................................................52 
1.3.9. 
Risks From Combining an IDO Inhibitor With Chemotherapy .................................52 
1.3.10. 
Risks From Combining a PD-1 Inhibitor With Chemotherapy ..................................52 
1.4. 
Justification for Treatment Regimens .........................................................................52 
1.4.1. 
Rationale for 2-Year Duration of Treatment ..............................................................55 
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2. 
STUDY OBJECTIVES AND PURPOSE ..................................................................56 
2.1. 
Primary Objectives .....................................................................................................56 
2.1.1. 
Phase 1 ........................................................................................................................56 
2.1.2. 
Phase 2 ........................................................................................................................56 
2.2. 
Secondary Objectives .................................................................................................56 
2.2.1. 
Phase 1 ........................................................................................................................56 
2.2.2. 
Phase 2 ........................................................................................................................56 
 
57 
3. 
SUBJECT ELIGIBILITY ...........................................................................................58 
3.1. 
Study Population .........................................................................................................58 
3.2. 
Subject Inclusion Criteria ...........................................................................................58 
3.3. 
Subject Exclusion Criteria ..........................................................................................63 
4. 
INVESTIGATIONAL PLAN .....................................................................................67 
4.1. 
Overall Study Design ..................................................................................................67 
4.1.1. 
Phase 1 Dose-Finding and Safety Expansion (Part 1 and Part 2) ...............................69 
4.1.1.1. 
Combination Immunotherapy Cohorts (Part 1) ..........................................................69 
4.1.1.2. 
Combination Chemo-Immunotherapy Cohorts (Part 2 of Phase 1) ............................71 
4.1.2. 
Phase 2 Combination Immunotherapy Cohort Expansions ........................................74 
4.2. 
Study Endpoints ..........................................................................................................76 
4.2.1. 
Primary Endpoint ........................................................................................................76 
4.2.1.1. 
Phase 1 ........................................................................................................................76 
4.2.1.2. 
Phase 2 ........................................................................................................................76 
4.2.2. 
Secondary Endpoints ..................................................................................................76 
4.2.2.1. 
Phase 1 ........................................................................................................................76 
4.2.2.2. 
Phase 2 ........................................................................................................................76 
 
77 
4.3. 
Measures Taken to Avoid Bias ...................................................................................77 
4.4. 
Number of Subjects ....................................................................................................77 
4.5. 
Study Termination ......................................................................................................78 
5. 
TREATMENT OF SUBJECTS ..................................................................................78 
5.1. 
Administration of Study Drugs ...................................................................................78 
5.1.1. 
Epacadostat .................................................................................................................78 
5.1.2. 
Nivolumab ..................................................................................................................78 
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5.1.2.1. 
Timing of Dose Administration of Nivolumab ..........................................................79 
5.2. 
Background Therapies ................................................................................................80 
5.2.1. 
Paclitaxel/Platinum (Carboplatin or Cisplatin) ...........................................................80 
5.2.1.1. 
Description and Administration ..................................................................................80 
5.2.1.2. 
Supply, Packaging, and Labeling ...............................................................................80 
5.2.2. 
Pemetrexed/Platinum (Carboplatin or Cisplatin) ........................................................80 
5.2.2.1. 
Description and Administration ..................................................................................80 
5.2.2.2. 
Supply, Packaging, and Labeling ...............................................................................81 
5.2.3. 
Platinum (Carboplatin or Cisplatin)/5-Fluorouracil ...................................................81 
5.2.3.1. 
Description and Administration ..................................................................................81 
5.2.3.2. 
Supply, Packaging, and Labeling ...............................................................................82 
5.3. 
Treatment Compliance ................................................................................................82 
5.4. 
Randomization and Blinding ......................................................................................82 
5.5. 
Duration of Treatment and Subject Participation .......................................................82 
5.6. 
Rationale for Dose Modifications ...............................................................................83 
5.6.1. 
Definition of Dose-Limiting Toxicities ......................................................................83 
5.6.1.1. 
Procedures for Cohort Review and Dose Escalation ..................................................84 
5.6.1.2. 
Follow-Up for Dose-Limiting Toxicities ....................................................................84 
5.7. 
Dose Modification of Study Drugs .............................................................................85 
5.7.1. 
Planned Dose Modifications .......................................................................................85 
5.7.2. 
Criteria and Procedures for Interruption .....................................................................85 
5.7.3. 
Procedures for Subjects Exhibiting Immune-Related Adverse Events ......................89 
5.7.3.1. 
Procedures and Guidelines for Pneumonitis ...............................................................91 
5.7.3.2. 
Procedures and Guidance for Enterocolitis ................................................................91 
5.7.3.3. 
Procedures and Guidance for Hepatitis ......................................................................92 
5.7.3.4. 
Procedures for Immune-Mediated Dermatitis ............................................................93 
5.7.3.5. 
Procedures for Immune-Mediated Neuropathies ........................................................94 
5.7.3.6. 
Procedures for Immune-Mediated Endocrinopathies .................................................95 
5.7.3.7. 
Procedures for Other Immune-Mediated Adverse Reactions, Including 
Ocular Manifestations .................................................................................................96 
5.7.4. 
Procedures for Subjects Exhibiting Serotonin Syndrome ..........................................97 
5.8. 
Criteria for Permanent Discontinuation of Study Drug(s) ..........................................98 
5.9. 
Study Completion .......................................................................................................99 
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5.9.1. 
Study Completion Criteria ..........................................................................................99 
5.9.2. 
Withdrawal Procedures .............................................................................................100 
5.10. 
Beginning and End of the Study ...............................................................................100 
5.11. 
Concomitant Medications and Measures ..................................................................100 
5.11.1. 
Acceptable Concomitant Medications ......................................................................100 
5.11.2. 
Supportive Care Guidelines ......................................................................................101 
5.11.3. 
Management of Infusion Reactions From Nivolumab .............................................101 
5.12. 
Restricted Medications and Measures ......................................................................103 
5.13. 
Prohibited Medications and Measures ......................................................................103 
6. 
STUDY ASSESSMENTS ........................................................................................104 
6.1. 
Screening Period .......................................................................................................115 
6.2. 
Treatment Period ......................................................................................................116 
6.3. 
End of Treatment ......................................................................................................116 
6.4. 
Follow-Up Period .....................................................................................................116 
6.4.1. 
Safety Follow-Up ......................................................................................................116 
6.5. 
Unscheduled Visits ...................................................................................................116 
6.6. 
Early Termination .....................................................................................................116 
7. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES .........................117 
7.1. 
Study Procedures ......................................................................................................117 
7.2. 
Administration of Informed Consent Form ..............................................................117 
7.3. 
Demography and History ..........................................................................................117 
7.3.1. 
Demographics and Medical History .........................................................................117 
7.3.2. 
Prior Medications ......................................................................................................117 
7.3.3. 
Concomitant Medications .........................................................................................118 
7.3.4. 
Post-Treatment Anticancer Therapy Status ..............................................................118 
7.4. 
Safety Assessments ...................................................................................................118 
7.4.1. 
Adverse Events .........................................................................................................118 
7.4.2. 
Comprehensive Physical Examination .....................................................................118 
7.4.3. 
Targeted Physical Examination ................................................................................118 
7.4.4. 
Vital Signs ................................................................................................................119 
7.4.5. 
Twelve-Lead Electrocardiograms .............................................................................119 
7.4.6. 
Laboratory Assessments ...........................................................................................119 
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7.4.6.1. 
Chemistry, Hematology, Coagulation Panel, Serology, and Endocrine 
Function Testing .......................................................................................................119 
7.4.6.2. 
Urinalysis ..................................................................................................................119 
7.4.6.3. 
Liver Chemistry Tests ...............................................................................................120 
7.4.6.4. 
Pregnancy Testing ....................................................................................................120 
7.5. 
Efficacy Assessments ...............................................................................................120 
7.5.1. 
Initial Tumor Imaging ...............................................................................................120 
7.5.2. 
Tumor Imaging During the Study.............................................................................121 
7.5.3. 
Assessment of Disease by Cheson Criteria for Lymphomas ....................................121 
7.5.3.1. 
CT Scan or MRI for Lymphoma Evaluation ............................................................122 
7.5.3.2. 
FDG-PET or Combined PET-CT .............................................................................122 
7.5.4. 
Assessment of Disease by RANO Criteria for Glioblastoma ...................................122 
 
125 
 
125 
 
127 
 
.127 
7.7. 
Other Study Procedures ............................................................................................127 
7.7.1. 
Study Compliance .....................................................................................................127 
7.7.2. 
Administration of Nivolumab and Compliance ........................................................127 
7.7.3. 
Administration of Epacadostat and Compliance ......................................................128 
7.7.4. 
Dispensing of Epacadostat ........................................................................................128 
7.7.5. 
Dispensing of Nivolumab .........................................................................................128 
7.7.6. 
Distribution of Subject Reminder Cards ...................................................................128 
7.7.7. 
Withdrawal or Discontinuation .................................................................................128 
8. 
SAFETY MONITORING AND REPORTING .......................................................129 
8.1. 
Adverse Events .........................................................................................................129 
8.1.1. 
Definitions ................................................................................................................129 
8.1.2. 
Reporting ..................................................................................................................129 
8.2. 
Laboratory Test Abnormalities .................................................................................131 
8.2.1. 
Definitions and Reporting .........................................................................................131 
8.2.2. 
Potential Drug-Induced Liver Injury ........................................................................131 
8.3. 
Serious Adverse Events ............................................................................................132 
8.3.1. 
Definitions ................................................................................................................132 
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8.3.2. 
Reporting ..................................................................................................................132 
8.4. 
Emergency Unblinding of Treatment Assignment ...................................................133 
8.5. 
Pregnancy .................................................................................................................133 
8.6. 
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor ...............................................................................................................134 
8.7. 
Warnings and Precautions ........................................................................................134 
8.8. 
Safety Monitoring Committee ..................................................................................135 
8.9. 
Adverse Events of Special Interest ...........................................................................135 
8.10. 
Product Complaints ..................................................................................................136 
9. 
STATISTICS ............................................................................................................136 
9.1. 
Study Populations .....................................................................................................136 
9.2. 
Selection of Sample Size ..........................................................................................137 
9.2.1. 
Cohort Size in Part 1 and Part 2 of Phase 1 Study ....................................................137 
9.2.2. 
Sample Size for the Dose-Expansion Portion (Phase 2) of the Study ......................137 
9.3. 
Level of Significance ................................................................................................138 
9.4. 
Statistical Analyses ...................................................................................................138 
9.4.1. 
Primary Analyses ......................................................................................................138 
9.4.2. 
Secondary Analyses ..................................................................................................139 
 
140 
9.4.4. 
Safety Analyses ........................................................................................................140 
9.4.5. 
Clinical Laboratory Tests .........................................................................................140 
9.5. 
Analyses for the Safety Monitoring Committee .......................................................140 
9.6. 
Interim Analysis ........................................................................................................141 
10.
STUDY DRUG MATERIALS AND MANAGEMENT .........................................142
10.1. 
Investigational Products Description ........................................................................142 
10.1.1. 
Packaging, Labeling, and Preparation of Study Drug or Placebo ............................142 
10.1.1.1. 
Epacadostat ...............................................................................................................142 
10.1.1.2. 
Nivolumab ................................................................................................................142 
10.1.2. 
Storage and Stability of Study Drugs .......................................................................142 
10.1.2.1. 
Epacadostat ...............................................................................................................142 
10.1.2.2. 
Nivolumab ................................................................................................................142 
10.2. 
Accountability, Handling, and Disposal of Epacadostat and Nivolumab ................143 
10.2.1. 
Disposal of Epacadostat and Nivolumab ..................................................................143 
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11.
STUDY ADMINISTRATION .................................................................................144
11.1. 
Data Management .....................................................................................................144 
11.1.1. 
Data Collection .........................................................................................................144 
11.1.2. 
Data Management .....................................................................................................144 
11.2. 
Study Monitoring ......................................................................................................144 
11.3. 
Protocol Adherence ..................................................................................................145 
11.4. 
Financial Disclosure .................................................................................................145 
11.5. 
Compliance With Study Registration and Results Posting Requirements ...............146 
12.
QUALITY CONTROL AND QUALITY ASSURANCE .......................................146
12.1. 
Sponsor Audits..........................................................................................................146 
12.2. 
Inspection by Regulatory Authorities .......................................................................146 
13.
ETHICS ....................................................................................................................147
13.1. 
Ethical Conduct of the Study ....................................................................................147 
13.2. 
Written Informed Consent ........................................................................................147 
13.3. 
Ethics Review ...........................................................................................................147 
13.4. 
Data Privacy ..............................................................................................................148 
14.
DATA HANDLING AND RECORDKEEPING .....................................................149
14.1. 
Inspection of Records ...............................................................................................149 
14.2. 
Retention of Records ................................................................................................149 
14.3. 
Confidentiality ..........................................................................................................149 
15.
PUBLICATION POLICY ........................................................................................150
16.
REFERENCES .........................................................................................................151
APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS .............................................................................161 
162 
APPENDIX C. MANAGEMENT ALGORITHMS .................................................................163 
APPENDIX D. PROHIBITED MONOAMINE OXIDASE INHIBITORS AND 
DRUGS ASSOCIATED WITH SIGNIFICANT MONOAMINE OXIDASE 
INHIBITORY ACTIVITY .......................................................................................171 
APPENDIX E. RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) VERSION 1.1..........................................................................................172 
APPENDIX F. RESPONSE CRITERIA FOR LYMPHOMA .................................................173 
APPENDIX G. RESPONSE ASSESSMENT FOR WALDENSTRÖM'S 
MACROGLOBULEMIA .........................................................................................176 
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APPENDIX H. RESPONSE CRITERIA FOR GLIOBLASTOMA ........................................177 
APPENDIX I. DOSE MODIFICATIONS FOR PACLITAXEL/PLATINUM 
(CARBOPLATIN OR CISPLATIN) ........................................................................180 
APPENDIX J. DOSE MODIFICATIONS FOR PEMETREXED/PLATINUM 
(CARBOPLATIN OR CISPLATIN) ........................................................................184 
APPENDIX K. DOSE MODIFICATIONS FOR PLATINUM (CARBOPLATIN OR 
CISPLATIN)/5-FLUOROURACIL .........................................................................187 
APPENDIX L. PROTOCOL AMENDMENT SUMMARY OF CHANGES ..........................191 
LIST OF TABLES 
Table 1: 
Phase 1 Part 1 Dose-Escalation Schema for Epacadostat in Combination 
With Nivolumab Once Every 2 Weeks (Combination Immunotherapy 
Cohorts) ......................................................................................................................70 
Table 2: 
Epacadostat Dose De-Escalation Scenarios for Combination 
Chemo-Immunotherapy Cohorts ................................................................................72 
Table 3: 
Summary of Treatment Regimens for Each Possible Epacadostat 
Dose-Finding Scenario for Combination Chemo-Immunotherapy Cohorts in 
Part 2 ...........................................................................................................................73 
Table 4: 
Tumor Types Eligible for Combination Immunotherapy Cohort Expansion .............75 
Table 5: 
Nivolumab Doses and Schedules in Phase 1 and Phase 2 ..........................................79 
Table 6: 
Criteria for Defining Dose-Limiting Toxicities ..........................................................84 
Table 7: 
Dose Reductions of Epacadostat ................................................................................85 
Table 8: 
Dose Modification Guidelines for Drug-Related Adverse Events for 
Combination Immunotherapy .....................................................................................87 
Table 9: 
General Approach to Handling Immune-Related Adverse Events .............................90 
Table 10: Recommended Approach to Handling Noninfectious Pneumonitis ...........................91 
Table 11: Recommended Approach for Handling Enterocolitis .................................................92 
Table 12: Recommended Approach for Handling Hepatitis .......................................................93 
Table 13: Recommended Approach for Handling Dermatitis ....................................................94 
Table 14: Recommended Approach for Handling Neuropathies ................................................95 
Table 15: Recommended Approach for Handling Endocrinopathies .........................................96 
Table 16: Signs and Symptoms of Serotonin Syndrome ............................................................98 
Table 17: Warfarin Dose Adjustment Recommendation When Initiating Concurrent 
Epacadostat Treatment ..............................................................................................103 
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Table 18: Schedule of Assessments for Screening Through Treatment Period 
(Combination Immunotherapy Cohorts With Nivolumab Q2W Dosing 
Schedule) ..................................................................................................................105 
Table 19: Schedule of Assessments for Screening Through Treatment Period 
(Combination Immunotherapy Cohorts With Nivolumab Q4W Dosing 
Schedule) ..................................................................................................................106 
Table 20: Schedule of Assessments End of Treatment Through Safety Follow-Up 
(Combination Immunotherapy Cohorts With Both Q2W and Q4W 
Nivolumab Dosing Schedules) .................................................................................107 
Table 21: Laboratory Assessments for Screening Through Treatment Period 
(Combination Immunotherapy Cohorts With Nivolumab Q2W Dosing 
Schedule) ..................................................................................................................108 
Table 22: Laboratory Assessments for Screening Through Treatment Period 
(Combination Immunotherapy Cohorts With Nivolumab Q4W Dosing 
Schedule) ..................................................................................................................109 
Table 23: Laboratory Assessments for End of Treatment Through Safety Follow-Up 
(Combination Immunotherapy Cohorts With Both Nivolumab Q2W and 
Q4W Dosing Schedules) ...........................................................................................110 
Table 24: Schedule of Assessments for Phase 1 Part 2 Subjects Treated With 
Epacadostat + Nivolumab (Q3W) + Platinum/Paclitaxel or Epacadostat + 
Nivolumab + Platinum/Pemetrexed or Epacadostat + Nivolumab + 
Platinum/5-FU (Combination Chemo-Immunotherapy Cohorts) .............................111 
Table 25: Laboratory Assessments for Phase 1 Part 2 Subjects Treated With 
Epacadostat + Nivolumab (Q3W) + Platinum/Paclitaxel, Epacadostat + 
Nivolumab + Platinum/Pemetrexed or Epacadostat + Nivolumab + 
Platinum/5-FU (Combination Chemo-Immunotherapy Cohorts) .............................113 
Table 26: Laboratory Tests:  Required Analytes ......................................................................115 
Table 27: RANO Criteria for Response Assessment Incorporating MRI and Clinical 
Factors .......................................................................................................................123 
Table 28: Assessment of Best Overall Response ......................................................................124 
 
 
 
125 
 
 
 
126 
 
 
 
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126 
Table 32: Probability of Observing a Toxicity for Various Safety Event Rates ......................137 
Table 33: Sample Size Calculation for Each Cohort:  Comparing With a Known 
Proportion .................................................................................................................138 
Table 34: Sample Size Calculation for Glioblastoma Cohort:  Comparing With a 
Known Proportion ....................................................................................................138 
Table 35: Probability of Early Termination for Various Safety Event Rates ...........................141 
Table 36: Nivolumab Product Description ...............................................................................142 
LIST OF FIGURES 
Figure 1: 
Study Design for Combination Immunotherapy Cohorts (Phase 1 Part 1 and 
Phase 2) .......................................................................................................................68 
Figure 2: 
Study Design for Combination Chemo-Immunotherapy Cohorts (Phase 1 
Part 2 Only) .................................................................................................................69 
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LIST OF ABBREVIATIONS 
The following abbreviations and special terms are used in this clinical study Protocol. 
Term 
Explanation 
5-FU 
5-fluorouracil 
ACTH 
adrenocorticotropic hormone 
 
 
AE 
adverse event 
ALK 
anaplastic lymphoma kinase 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AT 
aminotransferase 
BCG 
Bacillus Calmette–Guérin 
BID 
twice daily 
BMS 
Bristol-Myers Squibb 
BOR 
best overall response 
BRAF 
B-Raf proto-oncogene, serine/threonine kinase 
CA 
cancer antigen 
Cave 
time-averaged concentration 
CD 
cluster of differentiation 
CFR 
Code of Federal Regulations 
cHL 
classical Hodgkin lymphoma 
CHMP 
Committee for Medicinal Products for Human Use 
CI 
confidence interval 
Cmax,ss 
steady-state peak concentration 
Cmin,ss 
steady-state trough concentration 
CNS 
central nervous system 
CR 
complete response 
CRC 
colorectal cancer 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T-lymphocyte-associated antigen-4 
CV% 
coefficient of variation 
DC 
dendritic cell 
DLBCL 
diffuse large B-cell lymphoma 
DLCO 
diffusing capacity of the lung for carbon monoxide 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DoR 
duration of response 
eCRF 
electronic case report form 
ECG 
. lectrocardiogram 
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Term 
Explanation 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
epidermal growth factor receptor 
eIB 
epacadostat Investigator's Brochure 
EOI 
end of infusion 
EOT 
end-of-treatment 
FDA 
Food and Drug Administration 
FDG 
fluorodeoxyglucose 
FEF 
forced expiratory flow 
FIGO 
International Federation of Gynecology and Obstetrics 
FL 
follicular lymphoma 
FLAIR 
fluid-attenuated inversion recovery 
FoxP3 
forkhead box P3 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HL 
Hodgkin lymphoma 
HPV 
human papilloma virus 
HR 
hazard ratio 
ICD 
immunogenic cell death 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IDO1 
indoleamine 2,3-dioxygenase-1 
IEC 
independent ethics committee 
Ig 
immunoglobulin 
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
IHC 
immunohistochemistry 
IN 
Investigator Notification 
INR 
international normalized ratio 
I/O 
immuno-oncology 
irAE 
immune-related adverse event 
IRB 
institutional review board 
irRC 
immune-related response criteria 
ITT 
intent to treat 
IV 
intravenously 
LFT 
liver function (chemistry) test 
LH 
luteinizing hormone 
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Term 
Explanation 
MAOI 
monoamine oxidase inhibitors 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEL 
. elanoma 
MRI 
magnetic resonance imaging 
MSI 
microsatellite instability testing 
MTD 
maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NHL 
non-Hodgkin lymphoma 
nIB 
nivolumab Investigator's Brochure 
NSCLC 
non−small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PAD 
pharmacologically active dose 
PD 
progressive disease 
PD-1 
programmed death receptor-1 
PD-L1 
programmed death ligand-1 
PEF 
peak expiratory flow 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetics 
PR 
partial response 
PT 
prothrombin time 
PT-DC 
platinum-based doublet chemotherapy 
Q2W 
once every 2 weeks 
Q3W 
once every 3 weeks 
Q4W 
once every 4 weeks 
RANO 
Response Assessment in Neuro-Oncology 
RCC 
renal cell carcinoma 
RECIST v1.1 
Response Evaluation Criteria In Solid Tumors Version 1.1 
RNA 
ribonucleic acid 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SCCHN 
squamous cell carcinoma of the head and neck 
SD 
stable disease 
SMC 
Safety Monitoring Committee 
SmPC 
Summary of Product Characteristics 
SNRI 
serotonin/norepinephrine reuptake inhibitors 
SS 
serotonin syndrome 
SSRI 
serotonin reuptake inhibitors 
TKI 
tyrosine kinase inhibitor 
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Term 
Explanation 
Treg 
regulatory T cell 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
USPI 
United States Package Insert 
VA 
alveolar volume 
VEGF 
vascular endothelial growth factor 
WHO 
World Health Organization 
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1.
INTRODUCTION
The INCB 24360-204 study is a Phase 1/2 dose-escalation and cohort expansion study of the 
safety, tolerability, and efficacy of epacadostat administered in combination with nivolumab.  
Epacadostat (INCB024360) is a novel, potent, and selective inhibitor of indoleamine 
2,3-dioxygenase 1 (IDO1), and nivolumab is a fully human immunoglobulin (Ig) G4 antibody 
that blocks the programmed death receptor-1 (PD-1), that is, an anti–PD-1.  
Targeting the immune system is a proven and effective approach for the treatment of cancer, and 
immunotherapy is now an accepted standard of care in several tumor types.  The blocking of 
immune cell co-inhibitory receptors such as cytotoxic T-lymphocyte–associated protein 4 
(CTLA-4) by ipilimumab; PD-1 by pembrolizumab or nivolumab; and programmed cell death 
ligand-1 (PD-L1) by atezolizumab or avelumab provides a critical mechanism for redirecting the 
host immune response against the tumor (Chen and Mellman 2013).  It is anticipated that the 
combination of the oral IDO1 inhibitor (epacadostat) with anti–PD-1 (nivolumab) or with 
nivolumab and cytotoxic agents (chemotherapy regimens) will demonstrate adequate safety and 
tolerability at pharmacologically-relevant doses so as to permit further clinical testing. 
For a thorough discussion of the pharmacology of epacadostat and nivolumab, refer to the 
Investigator's Brochure (eIB) and the nivolumab Investigator's Brochure (nIB). 
1.1. 
Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades (Dimery and Hong 1993, 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 immune destruction 
despite displaying recognizable antigens on their surface and despite the presence of high-avidity 
T cells that are specific for these antigens (Boon and van der Bruggen 1996, Ercolini et al 2005).  
Histologic evaluation of many human cancers show extensive infiltration by inflammatory and 
immune cells (Gadgeel et al 2016, Galon et al 2006), suggesting that the immune system 
responds less effectively to malignancy.  These observations have led to the hypothesis that 
dominant mechanisms of immune tolerance or immune suppression are responsible for the 
immune system's inability to effectively respond in a way that consistently results in rejection. 
There are a number of inhibitory mechanisms that have been identified to be involved in 
tumor-mediated immune suppression and include expression of the programmed death ligand-1 
(PD-L1), which can engage the inhibitory receptor PD-1 on activated T cells; the presence of the 
tryptophan-catabolizing enzyme IDO1, which exploits the exquisite sensitivity of T cells to 
tryptophan depletion and tryptophan metabolites; and infiltration with FoxP3+ regulatory T cells 
(Treg), which can mediate extrinsic suppression of effector T-cell function.  Therefore, agents 
that target these negative regulatory pathways, and thereby allow the expansion of effector 
T cells present in the tumor, may be beneficial in the clinic. 
1.1.1. 
Inhibition of PD-1 as a Target for Cancer 
The PD-1 receptor-ligand interaction is a major pathway stimulated by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T cells 
under healthy conditions, is to down-modulate unwanted or excessive immune responses, 
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including autoimmune reactions.  Programmed death receptor-1 (encoded by the gene 
Pdcd1) is an Ig superfamily member related to CD28 and CTLA-4, which has been shown to 
negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or 
PD-L2; Talmadge et al 2007, Usubütün et al 1998).  The mechanism by which PD-1 
down-modulates T-cell responses is similar to but distinct from that of CTLA-4, as both 
molecules regulate an overlapping set of signaling proteins (Hiraoka 2010, Nobili et al 2008). 
Programmed death receptor-1 has been shown to be expressed on activated lymphocytes, 
including peripheral CD4+ and CD8+ T cells, B cells, Tregs, and natural killer cells (Hodi and 
Dranoff 2010, Kloor 2009).  Expression has also been shown during thymic development on 
CD4-CD8- (double negative) T cells as well as on subsets of macrophages and dendritic cells 
(DCs; Hillen et al 2008).  The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed 
or can be induced in a variety of cell types, including nonhematopoietic tissues as well as in 
various tumors (Lee et al 2008, Leffers et al 2009, Nishimura et al 2000, Hiraoka 2010).  
Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell 
receptor.  PD-L1 is expressed at low levels on various nonhematopoietic tissues, most notably on 
vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting 
cells found in lymphoid tissue or chronic inflammatory environments.  Programmed death 
ligand-2 is thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 
serves to dampen unwarranted T-cell function in peripheral tissues (Hiraoka 2010).  Although 
healthy organs express little (if any) PD-L1, a variety of cancers were demonstrated to express 
abundant levels of this T-cell inhibitor.  Programmed death receptor-1 has been suggested to 
regulate tumor-specific T-cell expansion in subjects with melanoma (MEL; Liotta et al 2010).  
This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and 
should be considered as an attractive target for therapeutic intervention. 
Nivolumab is a fully human Ig G4 antibody that blocks PD-1, blocks interaction with PD-L1 and 
PD-L2, and restores T-cell antitumor function (Brahmer et al 2010).  Nivolumab has been 
approved as monotherapy in the United States for metastatic NSCLC that has progressed on or 
after platinum-based chemotherapy, for advanced RCC after previous antiangiogenic therapy, for 
classical Hodgkin lymphoma that has relapsed or progressed after autologous hematopoietic 
stem cell transplantation and post-transplantation brentuximab vedotin, for recurrent or 
metastatic SCCHN with disease progression on or after platinum-based therapy, for locally 
advanced metastatic urothelial carcinoma with disease progression during or after 
platinum-containing chemotherapy or disease progression within 12 months of neoadjuvant or 
adjuvant treatment with platinum-containing chemotherapy, for microsatellite instability-high or 
mismatch repair deficient metastatic colorectal cancer and for melanoma in both the adjuvant 
and advanced/metastatic setting (Opdivo 2018).  Nivolumab is approved in the European Union 
as monotherapy or in combination with ipilimumab for advanced (unresectable or metastatic) 
melanoma, as monotherapy for locally advanced or metastatic NSCLC after prior chemotherapy, 
for advanced RCC after prior therapy, for recurrent or metastatic SCCHN, for metastatic 
urothelial carcinoma with disease progression during or after platinum-containing chemotherapy, 
and for Hodgkin lymphoma following autologous stem cell transplant and treatment with 
brentuximab vedotin (Opdivo SmPC 2018). 
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1.1.2. 
Inhibition of Indoleamine 2,3-Dioxygenase as a Target for Cancer 
Recent interest has focused on the role of IDO1 as a mechanism of induction of tolerance to 
malignancy (Godin-Ethier et al 2011).  Indoleamine 2,3-dioxygenase is a heme-containing 
monomeric oxidoreductase that catalyzes the degradation of the essential amino acid tryptophan 
to N-formyl-kynurenine.  Kynurenine can be subsequently metabolized through a series of 
enzymatic steps to nicotinamide adenine dinucleotide.  Indoleamine 2,3-dioxygenase is the first 
rate-limiting enzyme in one of the breakdown pathways of tryptophan.  In another pathway, 
tryptophan hydroxylase catalysis of tryptophan leads to the formation of serotonin and 
melatonin. 
The expression and activity profiles of IDO1 are distinct from those of tryptophan dioxygenase, 
an enzyme predominantly expressed in the liver that catalyzes the same enzymatic reaction as 
IDO1 and maintains proper tryptophan balance in response to dietary uptake.  In contrast to 
tryptophan dioxygenase, IDO1 is expressed in a variety of tissues, with particularly high levels 
found in areas of contact with potential sources of immune challenge (eg, gut, respiratory tract, 
placenta, spleen), consistent with a role for regulating tryptophan metabolism in a local 
microenvironment (Mellor and Munn 2004).  Within the immune system, IDO1 activity is 
specifically induced in cells such as DCs and macrophages at localized sites of inflammation 
(Munn and Mellor 2007). 
IDO1-driven oxidation of tryptophan results in a strong inhibitory effect on the development of 
T-cell−mediated responses by blocking T-cell activation and inducing T-cell apoptosis 
(Mellor et al 2003).  Both the reduction in local tryptophan levels and the production of 
tryptophan catabolites that are inhibitory to cell proliferation contribute to the 
immunosuppressive effects (Frumento et al 2002).  IDO1 activity also promotes the 
differentiation of naive T cells to cells with a regulatory phenotype (Treg; Fallarino et al 2006).  
Since increased Treg activity has been shown to promote tumor growth, and Treg depletion has 
been shown to allow an otherwise ineffectual antitumor immune response to occur (Zou 2006), 
IDO1 expansion of Tregs may provide an additional mechanism whereby IDO1 could promote 
an immunosuppressive environment. 
The biological relevance of IDO1 inhibition to immune tolerance was first demonstrated when it 
was shown that treating mice with a small molecule inhibitor of the IDO1 pathway, 
1-methyl-tryptophan, could break the tolerogenic state that protects allogeneic concepti from the 
maternal immune system (Munn et al 1998).  A critical role for IDO1 in immunomodulation has 
been confirmed in numerous animal models, including models of allograft tolerance, 
inflammation, and cancer (Mellor and Munn 2004).  While IDO1 inhibition can exacerbate 
disease in models of autoimmune disorders (Mellor and Munn 2004), IDO1 null mice show no 
evidence of susceptibility to developing spontaneous autoimmunity or alterations in immune 
system development (Mellor et al 2003), suggesting that IDO1 inhibition in a therapeutic setting 
may produce minimal side effects in subjects without pre-existing autoimmune conditions. 
Within the context of cancer, there are several lines of evidence to suggest that IDO1 is a key 
regulator of the immunosuppressive mechanisms responsible for tumor escape from immune 
surveillance.  Several groups have demonstrated that blockade of IDO1 activity can directly 
influence the ability of tumor-bearing animals to reject tumors (Uyttenhove et al 2003, 
Muller et al 2005).  In addition, studies with 1-methyl-tryptophan demonstrate that IDO1 
inhibition dramatically increases the efficacy of various chemotherapeutic agents (eg, platinum 
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compounds, taxane derivatives, and cyclophosphamide) without increased toxicity 
(Muller et al 2005).  Although the specific mechanisms responsible for this potentiation remain 
to be fully elucidated, the effects were not observed in T-cell−deficient animals, suggesting that 
the results may be the consequence of the disablement of immunosuppressive mechanisms that 
exist within the tumor microenvironment. 
Based on studies examining serum levels of tryptophan and kynurenine, IDO1 appears to be 
chronically activated in subjects with cancer, and IDO1 activation correlates with more extensive 
disease (Huang et al 2010, Weinlich et al 2007).  IDO1 has subsequently been found to be 
overexpressed by a wide variety of human tumor cell types, as well as by the DCs that localize to 
the tumor-draining lymph nodes (Uyttenhove et al 2003, Munn et al 2004).  Increased expression 
of IDO1 in tumor cells has been shown to be an independent prognostic variable for reduced 
overall survival (OS) in subjects with MEL and ovarian, colorectal, and pancreatic cancer 
(Okamoto et al 2005, Brandacher et al 2006, Ino et al 2006, Nakamura et al 2007, 
Witkiewicz et al 2008, Hamid et al 2009). 
Together, these results suggest that the IDO1 pathway is a key regulatory element responsible for 
the induction and maintenance of tumor immune tolerance.  Small molecule inhibitors of IDO1 
may provide an innovative and tractable method to treat advanced malignancies, either alone or 
in combination with chemotherapeutics and/or immunotherapy-based strategies. 
1.1.3. 
Combined Immune Checkpoint Inhibition 
Blockade of immune inhibitory 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-L1.  Ipilimumab, a fully human IgG1 monoclonal antibody blocking 
CTLA-4, improved OS in patients with advanced MEL (Hodi et al 2010, Robert et al 2011).  
Nivolumab, a fully human IgG4 antibody blocking PD-1, produced durable objective responses 
in patients with MEL, RCC, and NSCLC (Topalian et al 2012, Hamid et al 2013, Wolchok 
et al 2013).  Although these single agents have antitumor activity, multiple immune inhibitory 
mechanisms are present concurrently within the tumor microenvironment, suggesting that 
combination therapies may be required for optimal therapeutic effect (Quezada and Peggs 2013). 
For example, CTLA-4 and PD-1 appear to play complementary roles in regulating adaptive 
immunity.  Whereas PD-1 contributes to T-cell exhaustion in peripheral tissues, CTLA-4 inhibits 
at earlier points in T-cell activation.  In preclinical models, combined blockade of PD-1 and 
CTLA-4 achieved more pronounced antitumor activity than blockade of either pathway alone 
(Curran et al 2010, Selby et al 2013). 
On the basis of these observations, a Phase 1 study was conducted to investigate the safety and 
efficacy of combined CTLA-4 and PD-1 blockade (with the use of ipilimumab and nivolumab, 
respectively) in subjects with advanced MEL.  The objective response rate (ORR; according to 
modified WHO criteria) for all subjects in the concurrent regimen group was 40%.  Evidence of 
clinical activity (conventional, unconfirmed, or immune-related response or stable disease [SD] 
for ≥ 24 weeks) was observed in 65% of subjects.   
In 17 subjects treated at the maximum doses associated with an acceptable level of adverse 
events (AEs), 53% had an objective response compared with ipilimumab monotherapy (10.9%), 
all with a tumor reduction of ≥ 80%.  Grade 3 or 4 AEs related to therapy occurred in 53% of 
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subjects in the concurrent regimen group but were qualitatively similar to previous experience 
with monotherapy and were generally reversible.  Among subjects in the sequenced-regimen 
group, 18% had Grade 3 or 4 AEs related to therapy, and the ORR was 20%.  Grade 3 or 4 AEs, 
regardless of attribution, were observed in 72% of subjects, and Grade 3 or 4 treatment-related 
AEs were noted in 53% of subjects.  Serious AEs (SAEs) related to the treatment were reported 
in 49% of subjects in the concurrent regimen group.  Common Grade 3 or 4 selected AEs that 
were related to therapy included hepatic events (15%), gastrointestinal events (9%), and renal 
events (6%).  Isolated cases of pneumonitis and uveitis were observed.  In both regimen groups, 
treatment-related AEs were manageable and generally reversible with the use of 
immunosuppressants (or hormone-replacement therapy for endocrinopathies) according to 
previously-established algorithms (Yervoy 2012). 
As described above, IDO1 is another negative regulatory mechanism that contributes to 
tumor-derived immune suppression.  In preclinical models, IDO1 inhibition has been shown to 
synergize with blockade of either anti−CTLA-4 or anti−PD-1/PD-L1 in delaying tumor growth 
and increasing OS (Holmgaard et al 2013, Spranger et al 2013).  This effect was shown to be 
T-cell dependent, leading to enhanced T-cell proliferation and interleukin-2 production within 
the tumor and to a marked increase in the effector-to-regulatory T-cell ratios in the tumor. 
In 119 diffuse large B-cell lymphoma (DLBCL) patients treated with first-line (rituximab, 
cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy, IDO expression 
on lymphoma cells and DCs was associated with both a decrease in complete remission and a 
decrease in OS rate (Ninomiya et al 2011).  In a survey of 57 newly diagnosed non-Hodgkin 
lymphoma (NHL) patients with diverse histologies including DLBCL, mantle cell lymphoma, 
and follicular lymphoma (FL), expression of IDO, mRNA, and protein were higher in the NHL 
tissues than in reactive lymph node tissues, and upregulation of IDO1 was correlated with 
advanced clinical stage, larger tumors, and poor prognosis (Liu et al 2014), suggesting a 
fundamental contribution of the local crosstalk between malignant lymphocytes and their 
microenvironment to lymphomagenesis.  In a Phase 1 study of subjects with relapsed FL treated 
with the combination of the PD-1 inhibitor pidilizumab and rituximab, of 29 evaluable subjects, 
19 achieved ORs for an ORR of 66%, 15 (52%) had CRs, and 4 (14%) had partial responses 
(PRs), and the median progression-free survival (PFS) was 21.1 months (Westin et al 2012).  A 
recent study suggests that PD-1 blockade in high risk DLBCL subjects after autologous stem cell 
transplantation resulted in a longer than expected PFS as well as increases in circulating 
activated lymphocytes, suggesting an on-target effect (Armand et al 2013).  These promising 
data suggest a strong foundation for immunomodulatory combinations. 
In an ongoing, Phase 1, open-label, dose-escalation study of epacadostat with ipilimumab 
(3 mg/kg intravenously [IV]), daily doses of epacadostat have been evaluated in 21-day cycles in 
3 cohorts thus far (300 mg, 100 mg, and 25 mg twice daily [BID]).  Seven subjects were enrolled 
at 300 mg BID.  When 5 subjects developed clinically significant alanine aminotransferase 
(ALT) elevations after 30 to 76 days on treatment, enrollment was stopped.  The ALT elevations 
were reversible with corticosteroids and treatment discontinuation.  Six of 7 subjects had 
evaluable scans either before discontinuation or within a few weeks of discontinuation of one or 
both agents, and all showed immune-related SD.  Enrollment was restarted at 25 mg BID (n = 8), 
where 1 subject with progression of prior extensive liver metastases had a dose-limiting toxicity 
(DLT; Grade 3 aspartate aminotransferase [AST] elevation).  Immune-related AEs (irAEs) were 
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generally Grade 1/2 and manageable with continued administration or temporary dose 
interruption; 1 subject each discontinued for Grade 3 colitis and Grade 3 salivary amylase 
elevation.  Six of 8 subjects had tumor reduction by the first evaluation.  Confirmed disease 
control rate was 75% (6/8 subjects).  Three subjects had confirmed immune-related PR 
(2 occurred by the first or second scan).  A 50 mg BID cohort is enrolling and to date has 1 PR 
and 1 complete response (CR).  Epacadostat 25 mg BID with ipilimumab was generally 
well-tolerated, and irAEs previously observed with ipilimumab were reversible with appropriate 
management.  Tumor response and duration data suggest the potential for enhanced MEL patient 
outcomes compared with ipilimumab monotherapy. 
Programmed death ligand-1 has been shown to be expressed in the tumor microenvironment of 
SCCHN.  Programmed death ligand-1 staining by IHC is seen in both human papilloma virus 
(HPV)-positive tumors and HPV-negative tumors, although HPV positivity does appear to 
correlate with a higher probability of PD-L1 expression in the tumor microenvironment 
(Lyford-Pike et al 2013).  In early clinical studies, a subject with metastatic SCCHN was treated 
with the anti–PD-L1 monoclonal antibody MDPL3280A and experienced a response by the 
second cycle of treatment (Herbst et al 2013).  Additional studies of anti–PD-1 and anti–PD-L1 
agents in the setting of metastatic SCCHN are ongoing. 
In summary, both IDO1 and PD-1 have been shown to suppress T-cell−mediated antitumor 
immunity, and IDO1 and the PD-1 ligand PD-L1 have been shown to be co-expressed in 
multiple cancer types and to correlate with poor prognosis.  Combined inhibition of both 
pathways may therefore lead to greater suppression of antitumor immunity and to increased 
efficacy.  Preclinical and clinical data indicate that these pathways are important in MEL as well 
as in other cancers. 
1.1.4. 
Rationale for Studying Immunotherapy in Advanced or Metastatic Cancers 
Cancer immunotherapies have demonstrated promising data in the NSCLC patient population.  
In 38 subjects with previously treated advanced NSCLC administered 10 mg/kg nivolumab every 
2 weeks, an ORR of 24% as measured by the immune response criteria (irRC; Wolchok 
et al 2009) was observed, with similar results using RECIST v1.1 criteria (21%).  Most responses 
were observed by the first planned assessment at Week 9.  Median duration of response (DOR) 
by irRC has not been reached with a median duration of follow-up of 9 months (minimum, 
6 months).  Pretreatment tumor PD-L1 expression was a statistically significant predictor of 
response.  In subjects with evaluable tumor PD-L1 expression, the majority of confirmed 
responses by RECIST v1.1 criteria (and irRC) occurred in subjects with tumors strongly positive 
for PD-L1.  The most common AEs were fatigue, rash, and pruritus (16% each).  The incidence 
of diarrhea was 13% (only Grade 1 or 2 reported).  Only 1 drug-related Grade 3 or 4 AE 
(Grade 3 pulmonary edema; 3%) was seen (Garon et al 2013). 
In a Phase 1 study of nivolumab, 42% and 24% of heavily pretreated subjects with NSCLC were 
alive at 1 and 2 years, respectively, based on Kaplan-Meier estimates, and median survival was 
9.9 months.  In all treated subjects, the ORR was 17% as measured by RECIST v1.1 criteria.  
Drug-related select AEs with potential immunologic etiologies, defined as AEs that require more 
frequent monitoring and/or specific interventions, included rash, diarrhea, and pruritus 
(Brahmer et al 2013).  In addition to PD-1 inhibition, drugs targeting PD-L1 have also shown 
promising data.  Atezolizumab, a humanized monoclonal antibody that blocks PD-L1 from 
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binding to its receptors, including PD-1 and B7.1, has shown similar efficacy.  In a Phase 1 study 
that included subjects with both squamous and nonsquamous NSCLC, ORR was 
24% (9/37 subjects), and at the time of the abstract, all responses were ongoing and improving.  
The 24-week PFS was 46%.  Analysis of biomarker data from archival tumor samples 
demonstrated a correlation between PD-L1 status and efficacy.  Subjects with PD-L1−positive 
tumors showed an ORR of 100% (4/4), while subjects who were PD-L1 tumor status−negative 
had an ORR of 15% (4/26).  The response rate in former or current smokers was 25% of subjects 
(8/37) versus 16% of subjects (1/6) who were never smokers.  The incidence of Grade 3/4 AEs, 
regardless of attribution, was 34%, including pericardial effusion (6%), dehydration (4%), 
dyspnea (4%), and fatigue (4%).  No Grade 3 to Grade 5 pneumonitis or diarrhea was reported 
(Soria et al 2013).  Targeting the IDO1 enzyme has been studied in subjects with metastatic 
NSCLC as well in the form of vaccination with an epitope derived from IDO1.  In the Phase 1 
study, no severe toxicities occurred.  One of 15 HLA-A2−positive subjects treated developed a 
PR after 1 year of vaccine treatment, and SD of ≥ 8.5 months was reported in another 6 subjects.  
The median survival was 25.9 months, and long-lasting PR and SD were seen in 47% of the 
subjects.  Expression of IDO1 was detected in 9 of 10 tumor biopsy specimens by 
immunohistochemistry (Iversen et al 2014). 
Given the recent benefits in OS achieved with immunotherapeutics in MEL and prostate cancer, 
researchers have posited that immunotherapy approaches may offer promise in other 
difficult-to-treat cancers such as glioblastoma (Heimberger and Sampson 2011).  Immunologic 
factors have clinically been associated with glioblastomas:  a reduced risk of malignant gliomas 
and longer survival is observed in patients with elevated IgE levels compared with those with 
normal levels (Schwartzbaum et al 2012, Turner 2012, Lin et al 2011, Schlehofer et al 2011).  In 
addition, immune checkpoint receptors such as PD-L1/B7-H1/CD274, a transmembrane receptor 
ligand and negative regulator of T-cell signaling, have been reported to be upregulated in 
glioblastoma (Parsa et al 2007, Jacobs et al 2009, Berghoff et al 2014).  Studies have also 
suggested an association between malignancy grade of astrocytic tumors and tumor cell PD-L1 
expression (Wilmotte et al 2005, Yao et al 2009).  
Currently for glioblastoma, bevacizumab is approved as single agent for patients with 
progressive disease (PD) following prior therapy.  This approval was based on demonstration of 
durable ORRs observed in 2 single-arm studies (AVF3708g and NCI 06-C-0064E; 
Avastin 2014).  The ORR was 25.9% in Study AVF3708g, with a median DOR of 4.2 months, 
and was 19.6% in Study NIC 06-C-0064E, with a median DOR of 3.9 months.  Another 
multicenter, randomized, noncomparative Phase 2 study evaluating bevacizumab alone or in 
combination with irinotecan in recurrent glioblastoma reported 6-month PFS rates of 42.6% and 
50.3%, respectively and median OS rates of 9.2 months and 8.7 months, respectively 
(Friedman et al 2009). 
Although the efficacy of checkpoint inhibitors such as nivolumab and ipilimumab have not 
previously been studied in glioblastoma, a multicenter Phase 2 study to evaluate the response of 
brain tumor metastases to ipilimumab was previously performed (CA184-042; Margolin 
et al 2012).  Subjects (N = 71) with advanced Stage IV MEL and measurable active brain 
metastases were randomized to ipilimumab monotherapy.  The study demonstrated that 
ipilimumab had clinical activity in subjects with MEL brain metastases, with some subjects 
showing prolonged clinical responses, disease control, and prolonged survival.  Ipilimumab did 
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not cause unexpected neurological toxicity in subjects with brain metastases.  The DOR observed 
in the corticosteroid-free arm (Arm A; median of 10.4 months both by mWHO and irRC) was 
consistent with that observed in other ipilimumab studies and longer than that observed for other 
therapies commonly used to treat brain metastases in patients with MEL metastatic to the brain:  
temozolomide (median DOR = 2 months).  The OS rates observed in Arm A of this study (26% 
at Year 2) are consistent with survival data observed in other ipilimumab monotherapy 
(10 mg/kg) studies and appear favorable to the survival recorded in historical studies, where 
2-year survival is approximately 10% (Parsa et al 2007). 
1.1.5. 
Overview of 5-Fluorouracil and Cisplatin in Squamous Cell Carcinoma of Head 
and Neck 
Cisplatin-based combination therapy has become one of the major cornerstones for treatment of 
subjects with recurrent/metastatic SCCHN with approximately 35% response rates 
(Jacobs et al 1992).  Responses are often short lasting, and recurrent disease is often resistant to 
second-line chemotherapy (Dimery and Hong 1993).  Further investigation led to combination 
therapies with other cytotoxic agents (Gibson et al 2005, Bourhis et al 2006, Vermorken et al 
2008).  5-FU, cisplatin, and cetuximab have become the standard of care for treatment of 
recurrent and/or metastatic head and neck cancer due to higher response rate being achieved in 
chemotherapy combination regimen compared to single agents (Sacco and Cohen 2015). 
Despite the recent advances in treatment of SCCHN patients, OS in advanced and recurrent 
SCCHN requires further investigations with new combination therapies for an improved 
outcome.  In 2016, the approval of nivolumab by the FDA for the treatment of subjects with 
recurrent or metastatic SCCHN has changed the therapeutic landscape in the investigation of 
treatment options for SCCHN subjects by introducing new alternatives with the addition of 
immune checkpoint inhibitors.  Chemotherapy and checkpoint inhibitor combinations may be 
crucial for the broadest applications to achieve improved patient outcomes. 
1.1.6. 
Overview of Platinum-Based Doublet Chemotherapy Compared With 
Immunotherapy in Squamous and Nonsquamous Non–Small Cell Lung Cancer 
Platinum-based doublet chemotherapy (PT-DC), such as paclitaxel and pemetrexed, has become 
the standard of care first-line therapy for NSCLC patients (without sensitizing epidermal growth 
factor receptor [EGFR] mutations or anaplastic lymphoma kinase [ALK] translocation) with 
squamous and nonsquamous histologies, respectively (NCCN 2016, Novello et al 2016).  
However, most patients survive less than a year, and there are limited treatment options for 
squamous NSCLC (NCCN 2016). 
Randomized studies comparing various PT-DC regimens in NSCLC have shown similar efficacy 
results, with ORRs ranging from 15% to 32%, median PFS ranging from 4.0 to 5.1 months, and 
median OS ranging from 8.1 to 10.3 months.  One- and 2-year OS rates ranged from 30% to 44% 
and 10% to 19%, respectively (Kelly et al 2001, Sandler et al 2006, Scagliotti et al 2002, 
Scagliotti et al 2008, Schiller et al 2002).  Bevacizumab and maintenance therapy with 
pemetrexed have improved clinical outcomes (Barlesi et al 2014, Scagliotti et al 2014, 
Patel et al 2013), but most subjects will eventually progress (Chang 2011).  
A recent multicenter Phase 1 study has been conducted to explore the safety and efficacy of 
nivolumab as monotherapy or combined with current standard-of-care treatment PT-DC in 
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first-line advanced NSCLC.  Preliminary data from this study show that confirmed ORRs with 
nivolumab plus PT-DC ranged from 33% to 47% across arms, which compare favorably with 
previously reported rates of 15% to 32% for PT-DC alone (Rizvi et al 2016).  Median OS was 
longer than expected in subjects on PT-DC alone (8.1-10.3 months).  OS for nivolumab 5 mg/kg 
administered in combination with paclitaxel and carboplatin was particularly notable; median OS 
was not reached at the time of the reporting period (8.8-30.1 months), and 57% of subjects were 
still alive after a median follow-up time of more than 2 years.  Although sample sizes were 
small, 1-year OS rates (50% to 87%) seemed similar to those seen with nivolumab monotherapy 
(73%) in NCT01454102 (CHECKMATE-012; Gettinger et al 2016).  Overall, the safety profile 
of the combination arm was similar to the PT-DC monotherapy arm.  Most treatment-related 
AEs reported during combination cycles were those associated with PT-DC and managed by 
chemotherapy dose delays and reductions, rather than discontinuation. 
Activity of PD-1 monotherapy over a platinum-based chemotherapy regimen in subjects with 
previously untreated advanced NSCLC with PD-L1+ (expression ≥ 50% on tumor cells) was 
demonstrated in an open-label Phase 3 study (Reck et al 2016).  The pembrolizumab 
monotherapy group showed a significantly longer median PFS of 10.3 months compared with 
6.0 months with chemotherapy group hazard ratio (HR = 0.50; 95% confidence interval [CI], 
0.37 to 0.68; p < 0.001).  OS at 6 months was 80.2% in the pembrolizumab group versus 72.4% 
in the chemotherapy group (HR for death = 0.60; 95% CI, 0.41 to 0.89; p = 0.005).  The ORR 
was greater in subjects treated with PD-1 inhibitor versus investigator-choice chemotherapy 
(45% vs 28%).  Treatment-related AEs of any grade were less frequent (occurring in 73.4% vs 
90.0% of subjects), as were ≤ Grade 3 treatment-related AEs (26.6% vs 53.3%).  Collectively, 
these results may provide the basis for PD-1 monotherapy to become more effective than 
chemotherapy in the first-line setting for advanced NSCLC without any overlapping toxicity 
profile. 
Another Phase 2 study investigated the efficacy of the combination of pembrolizumab and 
pemetrexed/carboplatin versus pemtrexed/carboplatin alone in subjects with advanced 
nonsquamous NSCLC in the first-line setting.  With a median follow-up of 19 months, the 
chemo-immunotherapy combination showed a significant improvement in ORR of 57% versus 
32% and median PFS of 19.0 months versus 8.9 months (Borghaei et al 2017).  This combination 
received accelerated approval from the FDA in May 2017. 
Collectively, all these data show that the immunogenic effects of conventional chemotherapy and 
rapid emergence of chemotherapy resistance may present as a good rationale to combine 
chemotherapy doublets with immunotherapy, particularly checkpoint inhibitors 
(Schvartsman et al 2016, Rizvi et al 2016).  Combining immune checkpoint inhibitors with 
platinum-based doublets may also provide a rapid and large initial response through the action of 
the cytotoxic chemotherapy, thus releasing tumor antigens in the tumor microenvironment to be 
recognized by the immune system.  This may later be durable and trigger a response with 
checkpoint inhibition. 
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1.2. 
Study Rationale 
1.2.1. 
Rationale for Combining PD-1 Inhibitor and IDO1 Inhibitor 
 
 
The goal of cancer immunotherapy is to initiate or reinitiate a self-sustaining cycle of cancer 
immunity, enabling it to amplify and propagate.  Cancer immunotherapies must overcome the 
negative feedback mechanisms inherent in most cancers.  The current approach will attempt to 
further amplify an immune response by targeting multiple nonredundant immune checkpoints.  
Expression of IDO1 represents an early checkpoint that results in a diminished immune response 
and tolerance to tumor antigen. 
Another common rate-limiting step is the expression of PD-L1 as a distal immune modulator 
expressed in 20% to 50% of human cancers (Hiraoka 2010, Herbst et al 2013), including, but not 
limited to, the ones selected for investigation in this study:  advanced or metastatic NSCLC, 
MEL, ovarian cancer, colorectal cancer (CRC), SCCHN, and DLBCL.  Expression of IDO and 
PD-1/L1 have been found to be increased in NSCLC as the disease progresses, and expression of 
these markers in tumor cells has been associated with shorter subject survival (Iversen 
et al 2014).  Anti−PD-1 monotherapy response rates of 17% to 24% have been reported in 
refractory NSCLC (Garon et al 2013, Brahmer et al 2013) with survival medians of 8 to 
18 months. 
There is an urgent need for novel treatment interventions to improve clinical response for 
patients suffering from glioblastoma.  Use of an inhibitor of PD-L1 in mouse glioblastoma 
models suggests benefit when given in combination with radiation therapy (Zeng et al 2013).  In 
similar studies using an orthotopic, immunocompetent murine glioblastoma model, Reardon et al 
(2014) recently demonstrated that anti–PD-1 therapy eradicated established tumors in 
approximately 50% of treated animals.  Long-term survivors did not grow tumors upon 
intracranial rechallenge, suggesting the generation of tumor-specific immune memory responses 
(Reardon et al 2014).  Furthermore, in recent studies combining an IDO1 inhibitor with  
anti–PD-1 therapy increased the long-term survival rate to approximately 75% of treated animals 
(Wainwright et al 2014, Reardon et al 2016). 
Although many studies have evaluated the efficacy of anti–PD-1, anti–PD-L1, and anti–CTLA-4 
as first-line treatments for metastatic MEL (Redman et al 2016), the available data are limited for 
the efficacy of a combination of checkpoint inhibitors as the second-line treatment following 
anti–PD-1 or anti–PD-L1 monotherapy.  There is currently no effective therapy for metastatic 
MEL that is relapsed or refractory after anti–PD-1/PD-L1 treatment; thus it remains as a 
substantial unmet medical need for advanced or metastatic MEL.  Early data from a Phase 2 
study of nivolumab (anti–PD-1) versus chemotherapy (CHECKMATE-037) in subjects with 
advanced MEL who progressed after anti–CTLA-4 therapy showed activity with an improved 
ORR in subjects who were administered nivolumab compared with subjects who were 
administered chemotherapy (Weber et al 2015).  Additionally, a Phase 1/2 study of 
pembrolizumab (anti–PD-1) versus investigator-choice chemotherapy for ipilimumab-refractory 
MEL (KEYNOTE-002) also demonstrated clinical activity with improved ORR, PFS, and OS in 
subjects who progressed after anti–CTLA-4 therapy and were administered pembrolizumab, 
compared with subjects who were administered chemotherapy (Ribas et al 2015) .  Most 
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recently, a Phase 1/2 study of pembrolizumab with epacadostat (KEYNOTE-037) also showed 
an improved ORR and disease control rate in advanced MEL (Gangadhar et al 2016).  These data 
support promising activity of epacadostat in combination with an anti–PD-1 inhibitor in subjects 
with advanced MEL and likely activity of the combination immunotherapy in subjects who 
progressed after previous PD-1/PD-L1 therapy. 
In APR 2018, an eDMC review of  ECHO-301/KEYNOTE-252 study, a Phase 3 study 
evaluating the anti–PD-1 antibody pembrolizumab in combination with epacadostat versus 
pembrolizumab with placebo as first-line treatment in subjects with unresectable or metastatic 
melanoma, concluded that the coprimary endpoint of improvement in PFS was not met 
(HR = 1.00; 95% CI:  0.83, 1.21) and that the coprimary endpoint of improvement in OS was 
also not expected to reach statistical significance (HR = 1.13; 95% CI:  0.86, 1.49).  Based on 
these results, and on the recommendation of the eDMC, the study was stopped.  The safety 
profile observed in the ECHO-301/KEYNOTE-252 study was consistent with that observed in 
previously reported studies of epacadostat in combination with pembrolizumab.  The purpose of 
this study is to test the combination of different mechanisms for overcoming tumor tolerance.  
Targeting PD-1 pathway assumes that the T cells are essentially exhausted (and thus tolerant of 
the tumor) and that this exhaustion may be reversed by blocking PD-1 signaling.  Targeting 
IDO1 pathway will concurrently decrease infiltration of regulatory CD4+ cells and 
immune-suppressive cytokines.  
 
 
 
 
 
 
1.2.2. 
Rationale for Combining PD-1 Inhibitor and IDO1 Inhibitor With 
Chemotherapy
While chemotherapy has largely been thought to be immunosuppressive and exert its effect via 
direct cytotoxicity, there is an emerging body of evidence to suggest that some chemotherapies 
may influence an immune response to tumors via induction of immunogenic cell death (ICD), 
elimination of immunosuppressive cells, or sensitization of tumor cells to immune effector cells 
(Apetoh et al 2015).  Platinum agents have demonstrated immunogenic effects via ICD and 
enhancement of effector immune response through PD-L1 receptor expression (Hato et al 2014).  
Paclitaxel and 5-FU have been shown to restore antitumor activity of CD8+ T cells (Sevko et al 
2013, Vincent et al 2010).  Given these findings, the combination of chemotherapy with 
immunotherapy is a rational choice, especially in patients for whom these chemotherapies are the 
accepted standard of care.  Initial treatment options for patients with recurrent or metastatic solid 
tumors include various chemotherapy agents (platinum agent [cisplatin or carboplatin], 5-FU, or 
taxanes), either alone or in combination, and the biologic agent cetuximab (NCCN 2016).  In 
patients with non-nasopharyngeal SCCHN, the addition of cetuximab to a platinum agent 
[cisplatin or carboplatin] and 5-FU (EXTREME regimen) prolonged median OS from 7.4 to 
10.1 months (hazard ratio [HR] = 0.80; p = 0.04) and median PFS from 3.3 to 5.6 months 
(HR = 0.54; p < 0.001) compared with a platinum agent−5-FU doublet.  Additionally, ORR 
increased from 20% with platinum/5-FU to 36% with the EXTREME regimen (p < 0.001; 
Vermorken et al 2008).  Based on these results, the EXTREME regimen has become the standard 
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of care for subjects with non-nasopharyngeal SCCHN in the recurrent and metastatic setting 
(NCCN 2016). 
While AEs of ≥ Grade 3 were comparable between the treatment groups (EXTREME:  82%; 
platinum/5-FU:  76%), the most common AEs observed with EXTREME (anemia, neutropenia, 
thrombocytopenia) and cetuximab-specific AEs (Grade 3 skin toxicities, Grade 3/4 
infusion-related reactions) limit the use of this regimen to younger patients with good 
performance status.  In those who are eligible to receive this regimen, many will stop therapy 
prematurely due to toxicity, as demonstrated by a 20% discontinuation rate due to AEs in the 
pivotal Phase 3 study (Vermorken et al 2008).  Common comorbidities in patients with SCCHN 
such as diminished hepatic, cardiac, and pulmonary function from previous alcohol and tobacco 
use and poor nutritional status from the clinical manifestations of the cancer and/or previous 
radiation can further limit the use of EXTREME.  Second-line treatment regimens are limited 
and primarily palliative, resulting in very poor long-term survival rates for this patient 
population.  There remains a substantial unmet need for well-tolerated therapies that offer 
sustained responses and prolonged survival compared with EXTREME in the first-line setting 
for recurrent or metastatic SCCHN.  
PD-1 and PD-L1 blocking agents have currently been investigated in several clinical trials in 
subjects with recurrent/metastatic SCCHN.  A Phase 1b study with anti–PD-1 in recurrent and 
metastatic SCCHN (KEYNOTE-012) showed 18% (34 out of 192 subjects) best ORR regardless 
of HPV status (25% HPV[+] and 14% HPV[-]).  Duration of response was approximately 
12 months.  In a recent Phase 2 study (KEYNOTE-055) evaluating anti–PD-1 antitumor activity 
after platinum and cetuximab failure in SCCHN showed 16% (95% CI, 11%-23%) ORR 
(Bauml et al 2017).  The preliminary efficacy and safety results were consistent with 
KEYNOTE-012, and anti–PD-1 was well-tolerated among heavily pretreated recurrent or 
metastatic SCCHN subjects.  A preliminary analysis from Phase 3 (CHECKMATE-141) study to 
evaluate anti–PD-1 activity against single-agent chemotherapy of the investigator’s choice 
(docetaxel, methotrexate, or cetuximab) in recurrent or metastatic SCCHN subjects also 
demonstrated a significant OS benefit with anti–PD-1 treatment (with an increase from 16% to 
36% in 1-year OS) (Ferris et al 2016). 
PD-1/PD-L1 blockade is being investigated in combination with chemotherapeutic agents in 
various tumor types.  In a Phase 1 study (n = 56), nivolumab in combination with PT-DC in 
chemotherapy-naive NSCLC showed ORR ranging from 33% to 50% and PFS ranging from 
4.8 to 6.1 months, and ≥ Grade 3 treatment-related AEs were observed in 45% of subjects 
(Rizvi et al 2016).  More promising efficacy signals have been observed in the KEYNOTE-021 
study of pembrolizumab in combination with PT-DC from open-label cohorts (n = 74, ORR 
48%-71%, PFS ~10 months, ≥ Grade 3 treatment-related AEs 56%-71%; Gadgeel et al 2016) 
and a randomized cohort of pembrolizumab/PT-DC versus PT-DC (n = 123, ORR 55% vs 29%, 
respectively, PFS 13 vs 8.9 months, respectively, ≥ Grade 3 treatment-related AEs 39% vs 26%, 
respectively; Langer et al 2016) as well as a Phase 1 study of atezolizumab (n = 58 safety 
evaluable, n = 41 efficacy evaluable, ORR 50%-77%, PFS immature at time of analysis; 
Giaccone et al 2015).  Confirmatory Phase 3 clinical studies in advanced/metastatic NSCLC are 
ongoing for these 3 therapies. 
The IDO pathway inhibitor indoximod has been evaluated in combination with chemotherapy in 
clinical studies.  In a Phase 1 study (n = 27), indoximod in combination with docetaxel in 
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pretreated subjects with metastatic solid tumors was well-tolerated with no unexpected toxicities 
and had a modest ORR of 18% (Soliman et al 2014).  Based on encouraging activity observed in 
subjects with breast cancer from this study, a Phase 2 study of indoximod in combination with 
docetaxel or paclitaxel was initiated.  Preliminary safety data showed AEs were similar to those 
typically seen with taxanes, and no unexpected AEs were observed (Tang et al 2015).  
Indoximod in combination with gemcitabine and nab-paclitaxel in subjects with metastatic 
pancreatic cancer was also well-tolerated in a Phase 1/2 study, and preliminary efficacy results 
showed durable responses in 42% of subjects (Bahary et al 2016). 
Overall, the data suggest that combining the IDO1 inhibitor epacadostat, a PD-1 inhibitor, and 
chemotherapy may result in a further increase of immunomodulatory effects in the tumor 
microenvironment and ultimately improve the overall clinical benefit in patients with advanced 
or metastatic solid tumors without overlapping toxicity profiles. 
1.2.3. 
Preclinical and Clinical Study Data for Epacadostat and Nivolumab 
Refer to the eIB and the nIB. 
1.3. 
Potential Risks and Benefits of the Treatment Regimen 
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1.3.2. 
Risks From Nivolumab 
Potential safety concerns and recommended management guidelines regarding pulmonary 
toxicities, GI toxicities, hepatotoxicity, endocrinopathies, dermatologic toxicities, and other 
toxicities of concern are summarized in the nIB, and details regarding immune-related toxicities 
can be found in Section 5.7.3, Table 9, and Appendix C. 
1.3.3. 
Risks for the Combination of Epacadostat and Nivolumab 
The combination of epacadostat and nivolumab has the potential to precipitate more frequent, 
more severe, and/or new immune-related toxicities as compared with each individually. 
1.3.4. 
Risks From 5-Fluorouracil/Platinum (Cisplatin or Carboplatin) 
The most common adverse reactions (occurring in greater than 30%) with 5-FU are diarrhea, 
nausea with occasional vomiting, mucositis, loss of appetite, photophobia, dysgeusia, phlebitis, 
and low blood cell counts.  Nephrotoxicity is dose dependent and is the DLT of cisplatin.  
Ototoxicity has been observed in up to 31% of patients treated with a single dose of cisplatin.  
Myelosuppression occurs in 25% to 30% of patients treated with cisplatin, with leukopenia and 
thrombocytopenia more pronounced at higher doses (> 50mg/m2).  Elderly patients may be more 
susceptible to myelosuppression.  When 5-FU is used in combination with cisplatin, 
hematological AEs were observed more often (> 40%) and mainly consisted of 
granulocytopenia, anemia, thrombocytopenia, and infection.  Nausea and vomiting rates were 
similar in frequency (18% and 11%, respectively).  Stomatitis was also common (> 25%) in the 
patients taking the combination regimen.  Neurological toxicities were similar to single-agent 
regimens (< 5%; Gibson et al 2005). 
In a retrospective clinical study conducted to determine and to compare the efficacy of palliative 
chemotherapy with carboplatin plus 5-FU versus cisplatin plus 5-FU for subjects with recurrent 
and metastatic SCCHN, no Grade 3/4 adverse reactions were reported in subjects who received 
cisplatin in combination with 5-FU.  Grade 3/4 hematologic toxicities were more common with 
the carboplatin plus 5-FU group (granulocytopenia [41.6%], anemia [37.5%], and 
thrombocytopenia [16.6%]).  Nausea, vomiting, and diarrhea were the most frequent events 
reported.  Nonhematological toxicities were more pronounced in the cisplatin plus 5-FU group.  
The most common Grade 1/2 adverse reactions were nausea (94.1%) and vomiting (82.4%) in 
the cisplatin plus 5-FU group.  Grade 1 peripheral neuropathy and ototoxicity were more likely 
to develop in subjects who used carboplatin plus 5-FU (16.7% and 12.5 %, respectively) 
compared with those who used cisplatin plus 5-FU (11.8% and 0%, respectively; Kua et al 
2013). 
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Renal toxicities are more likely to develop in subjects treated with cisplatin plus 5-FU and are 
least common in subjects treated with carboplatin plus 5-FU (Forastiere et al 1992).  Also, in rare 
cases, fatal reactions may develop with either cisplatin or carboplatin and 5-FU combination 
regimens. 
1.3.5. 
Risks From Paclitaxel/Carboplatin 
Bone marrow suppression (leukopenia, neutropenia, and thrombocytopenia) is dose-dependent 
and is also the DLT of carboplatin.  Anaphylactic reactions to carboplatin may occur within 
minutes of administration.  Carboplatin can induce emesis, which can be more severe in patients 
who have previously received emetogenic therapy.  Although peripheral neurotoxicity is 
infrequent, its incidence is increased in patients older than 65 years and in patients previously 
treated with cisplatin. 
Bone marrow suppression (primarily neutropenia) is dose-dependent and is the DLT of 
paclitaxel.  Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and 
hypotension requiring treatment, angioedema, and generalized urticaria have occurred in 2% to 
4% of subjects receiving paclitaxel in clinical trials.  Fatal reactions have occurred in subjects 
despite premedication. 
1.3.6. 
Risks From Paclitaxel/Cisplatin 
In a randomized Phase 3 study conducted to determine the response rate, survival, and toxicity of 
cisplatin and fluorouracil (CF) versus cisplatin and paclitaxel (CP) in subjects with advanced 
SCCHN, the most common Grade 3/4 adverse reactions were hematologic events, which were 
more common in the CF group than in the CP group (leukopenia, 63% vs 35%; 
granulocytopenia, 67% vs 55%; thrombocytopenia, 23% vs 4%, respectively).  Infection rate 
(≥ Grade 3) was 21% in the CF group versus 13% in the CP group.  Grade 3/4 anemia and 
thrombocytopenia occurred in 33% and 23% of subjects in the CF group, respectively, versus in 
13% and 4% of subjects in the CP group, respectively.  Nausea and vomiting rates were similar 
in frequency (19% and 18%, respectively, in the CF group; 18% and 10%, respectively, in the 
CP group).  Grade 3/4 stomatitis was more frequent in the group that received infusional 
fluorouracil (31% in the CF group; 0% in the CP group).  Neurotoxicity and metabolic events 
were equivalent between groups.  The Kruskal-Wallis test for comparing the distribution of 
worst degree (≤ Grade 3) toxicities between 2 treatment groups indicated no significant 
difference between the groups treated with CF and CP (Gibson et al 2005). 
1.3.7. 
Risks From Pemetrexed/Carboplatin 
The most common events (incidence ≥ 20% with single-agent use) with pemetrexed are fatigue, 
nausea, and anorexia.  When pemetrexed is used in combination with a platinum agent, common 
AEs include the following:  vomiting (40%), nausea (56%), neutropenia (29%), leukopenia 
(18%), anemia (33%), stomatitis/pharyngitis (14%), thrombocytopenia (10%), and constipation 
(21%).  Refer to the US prescribing information (Alimta 2013) or the EU SmPC (Alimta 2016) 
for pemetrexed for full details. 
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1.3.8. 
Risks From Pemetrexed/Cisplatin 
Use of pemetrexed and cisplatin in combination has been approved by the FDA for patients with 
nonsquamous NSCLC as first-line therapy.  The most common AEs (incidence ≥ 20%) during 
pemetrexed monotherapy were fatigue, nausea, and anorexia.  The most common AEs (incidence 
≥ 20%) when pemetrexed was administered in combination with cisplatin include vomiting, 
neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation 
(Alimta 2013). 
1.3.9. 
Risks From Combining an IDO Inhibitor With Chemotherapy 
In a Phase I study of the IDO pathway inhibitor indoximod with docetaxel in advanced solid 
tumors, the most frequent AEs were fatigue (58.6%), anemia (51.7%), hyperglycemia, (48.3%), 
infection (44.8%), and nausea (41.4%; Soliman et al 2014).  In a Phase 2 study of indoximod 
with docetaxel in subjects with metastatic breast cancer, the most common indoximod-related 
AEs of any grade occurring in ≥ 10% of subjects were fatigue (21%), nausea (20%), diarrhea 
(13%), and headache (12%).  Twenty-eight percent of subjects treated with indoximod and 
docetaxel experienced at least 1 Grade 3 or 4 AE.  The safety profile of indoximod with 
docetaxel was compatible with the safety profile of taxane monotherapy (Tang et al 2015). 
Recently presented safety data from a Phase 1/2 study evaluating the combination of indoximod 
with gemcitabine/nab-paclitaxel in subjects with metastatic pancreatic cancer showed that the 
most frequently reported any grade AEs (regardless of attribution) occurring in ≥ 10% of 
subjects were fatigue (40%); weight loss, diarrhea, peripheral edema, and asthenia (20% each); 
and anemia, decreased appetite, nausea, myalgia, rash, decreased neutrophil count, and decreased 
platelet count (13.3% each; Bahary et al 2016). 
1.3.10. 
Risks From Combining a PD-1 Inhibitor With Chemotherapy 
In an investigator-initiated Phase 1 study of subjects with metastatic CRC, common AEs when 
pembrolizumab was combined with mFOLFOX6 were neutropenia (40%) and hyponatremia 
(30%; Stenehjem et al 2016).  The most common AE in 11 subjects with metastatic pancreatic 
cancer treated with gemcitabine/nab-paclitaxel plus nivolumab was anemia (33%; 
George et al 2016). 
Recently updated safety data from a randomized cohort of the KEYNOTE-021 study where 
subjects with nonsquamous NSCLC were treated with carboplatin/pemetrexed with 
pembrolizumab showed the most common ≥ Grade 3 treatment-related AEs were anemia (12%), 
decreased neutrophil count (7%), and fatigue (3%; Papadimitrakopoulou et al 2017).  Overall, 
treatment-related AEs ≥ Grade 3 occurred in 39% subjects treated with the PD-1/chemotherapy 
combination versus 29% with chemotherapy alone. 
1.4. 
Justification for Treatment Regimens 
The goal of the present study is to explore doses of the IDO1 inhibitor epacadostat that may 
synergize or otherwise augment the efficacy observed with the PD-1 inhibitor nivolumab in 
subjects with advanced cancer.  In Phase 1 of the study for combination immunotherapy 
(epacadostat + nivolumab), the established regimen of nivolumab (3 mg/kg every 2 weeks) will 
be combined with doses of epacadostat that provide partial and more complete IDO1 inhibition 
based on observations from the Phase 1 study INCB 24360-101.  The starting dose selected for 
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epacadostat in combination with nivolumab is 25 mg BID with escalation up to 300 mg BID.  
This is based on the preliminary observation that the average kynurenine inhibition for 
epacadostat 25 mg BID and 100 mg BID is 66% and 89%, respectively, and on the safety of 
these doses, as well as doses up to 700 mg BID in the Phase 1 study INCB 24360-201 as 
monotherapy and in combination with ipilimumab.  Pharmacokinetic (PK) and 
pharmacodynamic (PD) observations from Studies INCB 24360-101 and INCB 24360-201 in 
cancer subjects support these doses, which provide a differential pharmacologic effect.  Based on 
a 6-hour observation period at steady state on Day 15 after administration of epacadostat, 
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. 
Doses of epacadostat ≥ 300 mg BID are associated with > 94% average inhibition of kynurenine, 
and based on this small difference in the average kynurenine inhibition, a final escalation of 
epacadostat to 300 mg BID may be evaluated.  Target coverage at 25 mg BID is consistent with 
the level needed to achieve maximal efficacy as well as to demonstrate synergy with an  
anti–PD-1 in preclinical models. 
In general, as single agents, epacadostat and ipilimumab have been well-tolerated in the subjects 
who had significant comorbidities.  Initial evaluation of epacadostat 300 mg BID in combination 
with ipilimumab (3 mg/kg IV every 3 weeks, up to 4 doses) in this study was terminated because 
of the occurrence of Grade 3 or 4 ALT/AST elevations in 5 of 7 subjects treated at this dose.  
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.  However, subsequent cohorts with lower doses of epacadostat in 
combination with ipilimumab (25 mg BID, 50 mg BID, and 50 mg once every morning/25 mg 
once every evening) were well-tolerated (Gibney et al 2015).  In addition, early safety analysis of 
epacadostat in combination with another PD-1 inhibitor (pembrolizumab) achieved dose 
combinations of 300 mg BID (Gangadhar et al 2015).  It is expected that achieving similar dose 
combinations with nivolumab will result in a clinically active combination regimen.  Complete 
inhibition of the IDO1 target is not required for maximally effective activity in preclinical 
models, and as monotherapy, maximally effective doses in preclinical models result in exposures 
that are comparable to doses of 50 to 300 mg BID in humans. 
Population PK (PPK) analyses using data from various tumor types including NSCLC, MEL, 
RCC, classical HL, and UC have shown that the PK of nivolumab is linear with proportional 
exposures over a dose range of 0.1 to 10 mg/kg; no differences in PK across ethnicities and solid 
tumor types were observed.  To provide additional flexibility and convenience when combining 
with other anticancer agents, such as chemotherapy, the PPK model was used to simulate dosing 
regimens with less frequent administration (Q3W and Q4W).  These regimens were selected 
such that they would provide similar exposures to those following administration of the approved 
q2w dosing regimens. 
Using the PPK model, the exposures following the administration of nivolumab 360 mg Q3W 
and 480 mg Q4W were simulated.  Based on this analysis, it is predicted that steady state 
average concentrations (Cave) of nivolumab 240 mg q2w or nivolumab 3 mg/kg q2w are similar 
following the administration in subjects who have an approximate median weight of 80 kg.  The 
steady state peak concentrations (Cmax,ss) following the administration of nivolumab 360 mg 
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Q3W and 480 mg Q4W are predicted to be approximately 26% and 40% higher than following 
the administration of nivolumab 3 mg/kg, respectively.  However, Cmax,ss of nivolumab 360 mg 
Q3W and 480 Q4W is predicted to be less than those following the administration of nivolumab 
10 mg/kg q2w, and this provides sufficient safety margins for these dosing regimens 
(Zhao et al 2017). 
Both nivolumab 360 mg Q3W and 480 mg Q4W dosing regimens are currently being 
investigated in multiple tumor types, such as NSCLC and MEL, as monotherapy and in 
combination with other agents, including the combination with platinum-doublet chemotherapy 
in Phase 2 and Phase 3 studies (ie, Studies NCT03041181 and NCT02713867). 
In Part 2 of the Phase 1 study, the dosing regimen and schedule of nivolumab in combination 
chemo-immunotherapy cohorts will be a flat dose of 360 mg IV infusion administered Q3W.  
Since nivolumab 240 mg q2w and 480 mg Q4W dosing regimens and schedules have been 
supported by the safety, efficacy, and exposure-response analyses results (Zhao et al 2017), these 
dosing regimens and schedules of nivolumab will be used in Phase 2 for the dose expansion of 
combination immunotherapy cohorts. 
Nivolumab has been administered safely over 60 minutes at doses ranging up to 10 mg/kg over a 
long treatment duration.  In Study CA209010 (a Phase 2, randomized, double-blinded, 
dose-ranging study of nivolumab in subjects with advanced/metastatic clear cell RCC), a dose 
association was observed for infusion site reactions and hypersensitivity reactions (1.7% at 
0.3 mg/kg, 3.7% at 2 mg/kg, and 18.5% at 10 mg/kg).  All of the events were either Grade 1 or 
Grade 2 and were manageable.  An infusion duration of 30 minutes for a 240 mg dose, 360 mg 
dose, and 480 mg dose (30% of the dose provided at 10 mg/kg) is not expected to present any 
safety concerns compared to the prior experience with 10 mg/kg nivolumab dose infused over a 
60-minute duration.  For Phase 2 of the study, nivolumab infusion time will be 30 minutes.  For 
those experiencing an infusion reaction, infusion time may be increased to 60 minutes. 
In the present study, epacadostat has been studied in subjects at both 100 mg BID and 300 mg 
BID with nivolumab 240 mg IV Q2W.  In Part 1 of Phase 1, 13 subjects were treated at 300 mg 
BID, and no DLTs were observed during a 42-day observation period, and an MTD was not 
defined.  As of 13 FEB 2017, 174 subjects were treated at 300 mg BID (13 subjects in Part 1 of 
Phase 1; 161 subjects in Phase 2).  The most common treatment-related AEs (≥ 10%) were rash, 
fatigue, nausea, diarrhea, pruritus, AST increased, and decreased appetite.  The pooled safety 
data from Part 1 of Phase 1 and Phase 2 demonstrated that there were fewer dose reductions 
(4% [n = 3] in 100 mg BID and 5% [n = 8] in 300 mg BID) and study treatment discontinuations 
(6% [n = 4] in 100 mg BID and 12% [n = 20] in 300 mg BID) in subjects treated with 
epacadostat 100 mg BID compared to 300 mg BID in combination with nivolumab (Perez et al 
2017).  There were no treatment-related deaths.  The overall frequency of all-grade 
treatment-related AEs in subjects treated with epacadostat 100 mg BID or 300 mg BID in 
combination with nivolumab was 83% and 73%, respectively.  Treatment-related Grade 3 or 4 
AEs were 25% in 100 mg BID and 27% in 300 mg BID.  The frequency of dose interruptions 
due to any grade treatment-related AEs were 26% (n = 18) in 100 mg BID and 30% (n = 48) in 
300 mg BID. 
Based on the published safety and PK profiles for both epacadostat and nivolumab, the starting 
dose of epacadostat will be 100 mg BID in combination with nivolumab 360 mg Q3W and 
chemotherapy regimen in Part 2 of Phase 1.  For I/O-relapsed and I/O-refractory MEL cohorts in 
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Phase 2, epacadostat dose will also be 100 mg BID in combination with nivolumab 480 mg 
Q4W.  Alternative doses of epacadostat may be explored 
 and 
safety results at the sponsor discretion. 
1.4.1. 
Rationale for 2-Year Duration of Treatment 
Accumulating data suggest that 2 years of PD-1 checkpoint inhibitor treatment may be sufficient 
for long-term benefit.  CA209003, a dose-escalation cohort expansion study evaluating the safety 
and clinical activity of nivolumab in subjects with previously treated advanced solid tumors 
(including 129 subjects with NSCLC), specified a maximum treatment duration of 2 years.  
Among 16 subjects with NSCLC who discontinued nivolumab after completing 2 years of 
treatment, 12 subjects were alive after > 5 years and remained progression-free without any 
subsequent therapy.  In the CA209003 NSCLC cohort, the OS curve begins to plateau after 
2 years, with an OS rate of 25% at 2 years and 18% at 3 years (Brahmer et al 2017).  These 
survival outcomes are similar to Phase 3 studies in previously treated NSCLC, in which 
nivolumab treatment was continued until progression or unacceptable toxicity (2-year OS rates 
of 23% and 29%, and 3-year OS rates of 16%-18% for squamous and nonsquamous NSCLC, 
respectively; Felip et al 2017).  Similar results have been reported in clinical studies of 
pembrolizumab, another PD-1 inhibitor.  Keynote-010 was a randomized Phase 3 study of 
pembrolizumab (at either 2 mg/kg or 10 mg/kg every 3 weeks) versus docetaxel in subjects with 
previously treated, PD-L1–positive, advanced NSCLC that specified a maximum treatment 
duration of 2 years for pembrolizumab.  Overall survival was significantly longer with both 
pembrolizumab 2 mg/kg (HR 0.72, p = 0.00017) and pembrolizumab 10 mg/kg (HR 0.60, 
p < 0.00001) compared with docetaxel, with an OS plateau developing beyond 2 years in both 
pembrolizumab arms.  Among 690 patients who received pembrolizumab, 47 patients completed 
2 years of pembrolizumab and stopped treatment.  Most were able to maintain their response, 
including those with stable disease, with only 2 patients (4%) having confirmed progression after 
stopping at 2 years (Herbst et al 2016).  Keynote-006 was a randomized Phase 3 study of 
pembrolizumab versus ipilimumab in patients with advanced melanoma, which also specified a 
maximum 2-year duration of pembrolizumab treatment.  One hundred four (19%) of 556 patients 
randomized to pembrolizumab completed 2 years of treatment.  With a median follow-up of 
9 months after completion of pembrolizumab, the estimated risk of progression or death was 9% 
in these patients (Robert et al 2017). 
Taken together, these data suggest that treatment beyond 2 years is unlikely to confer additional 
clinically meaningful benefit and that the risk of progression after discontinuing treatment at 
2 years is low.  
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2. 
STUDY OBJECTIVES AND PURPOSE 
2.1. 
Primary Objectives 
2.1.1. 
Phase 1 
• Part 1 Safety:  To assess the safety and tolerability of epacadostat BID orally in 
combination with nivolumab and to identify DLTs and the recommended Phase 2 
dose (RP2D) of the combination immunotherapy, in subjects with select advanced 
(metastatic and/or unresectable) cancers (solid tumors and B-cell NHL or HL). 
• Part 2 Safety:  To assess the safety and tolerability and to determine a maximum 
tolerated dose (MTD) and/or pharmacologically active dose (PAD) of epacadostat in 
combination with nivolumab and chemotherapy in subjects with advanced or 
metastatic SCCHN and in subjects with advanced or metastatic NSCLC. 
2.1.2. 
Phase 2 
• Efficacy: 
− To assess ORR and PFS at 6 months in subjects with select solid tumors or 
subjects with DLBCL). 
− To assess OS at 9 months for subjects with glioblastoma. 
2.2. 
Secondary Objectives 
2.2.1. 
Phase 1 
• Part 1 Efficacy:  To assess the preliminary antitumor activity of the combination of 
epacadostat and nivolumab in subjects with select advanced solid tumors, B-cell NHL 
or HL, or glioblastoma by assessing ORR. 
• Part 2 Efficacy:  To explore the preliminary efficacy of epacadostat administered in 
combination with nivolumab and chemotherapy in subjects with advanced or 
metastatic SCCHN and advanced or metastatic NSCLC by assessing ORR, DOR, and 
PFS. 
2.2.2. 
Phase 2 
• Efficacy: 
− To assess the preliminary antitumor activity of the combination of epacadostat 
and nivolumab in subjects with select advanced solid tumors and DLBCL by 
assessing DOR and duration of disease control. 
− To evaluate OS in subjects with select solid tumors and DLBCL. 
− To evaluate ORR, PFS, DOR, and duration of disease control for subjects with 
glioblastoma. 
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•
Safety:
− To assess the safety and tolerability of epacadostat BID orally when given in
combination with nivolumab 240 mg every 2 weeks. 
− To assess the safety and tolerability of epacadostat BID orally when given in 
combination with nivolumab 480 mg every 4 weeks. 
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3.
SUBJECT ELIGIBILITY
3.1. 
Study Population
Subjects with Stage IIIB, Stage IV, or recurrent NSCLC; unresectable or Stage IV MEL; 
recurrent (unresectable) or metastatic CRC; recurrent (unresectable) or metastatic SCCHN; 
International Federation of Gynecology and Obstetrics (FIGO) Stage Ic, II, III, or IV recurrent 
ovarian cancer (unresectable); relapsed or refractory B-cell NHL or HL (including relapsed or 
refractory DLBCL); and relapsed or refractory glioblastoma after standard-of-care therapy may 
enroll.  Subjects with these select tumors must have had disease progression on treatment or 
intolerance to treatment, or subjects who have refused currently approved treatment may enroll 
with medical monitor approval (except for subjects with MEL, who may be enrolled as described 
in the inclusion/exclusion criteria in Sections 3.2 and 3.3). 
3.2. 
Subject Inclusion Criteria 
The following criteria are required for inclusion in the study: 
1. Male or female subjects, age 18 years or older.
2. Ability to comprehend and willingness to sign an informed consent form (ICF).
3. Subjects with histologically or cytologically confirmed NSCLC, MEL, CRC, SCCHN,
ovarian cancer, recurrent B-cell NHL or HL, or glioblastoma.
4. Subjects with Stage IIIB, Stage IV, or recurrent NSCLC; unresectable or Stage IV MEL;
recurrent (unresectable) or metastatic CRC; recurrent (unresectable) or metastatic
SCCHN; FIGO Stage Ic, II, III, or IV recurrent ovarian cancer (unresectable); relapsed or
refractory B-cell NHL or HL (including relapsed or refractory DLBCL); and relapsed or
refractory glioblastoma and meet the following tumor-specific criteria:
a.
Subjects with Stage IIIB, Stage IV, or recurrent NSCLC:
− For all NSCLC subjects (Phase 1 and Phase 2):
− Subjects with nonsquamous NSCLC must be screened for EGFR and ALK 
fusion oncogene status. 
− Tumors with driver mutations (EGFR mutation–positive or ALK fusion 
oncogene–positive) previously treated with an approved tyrosine kinase 
inhibitor (TKI) must have progressed on or been intolerant to the TKI therapy.  
(Note:  For subjects with driver mutations and treated with a prior TKI 
therapy, up to 2 additional lines of therapy that include a TKI therapy are 
permitted.) 
− Maintenance or switch maintenance therapy after first-line chemotherapy is 
acceptable. 
− Malignancy must be deemed unresectable. 
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− For combination immunotherapy cohorts (Part 1 of Phase 1 and Phase 2), 
subjects with nonsquamous, squamous, or adenosquamous NSCLC, or NSCLC 
NOS histology who have received up to 1 prior systemic regimen for Stage IIIB, 
Stage IV, or recurrent NSCLC.  Prior systemic regimen must have contained a 
platinum-based therapy (at least 2 cycles with or without bevacizumab). 
− Subjects ineligible for platinum-based therapy who have received alternative 
chemotherapy regimens or are intolerant of platinum-based therapy may 
enroll with medical monitor approval. 
− Subjects who completed and progressed on a platinum-containing regimen as 
adjuvant, neoadjuvant, or part of a course of chemoradiation therapy within 
the 6 months before screening would be counted as having received 1 prior 
platinum-containing regimen and, therefore, would not require re-treatment 
with a platinum-containing regimen for advanced or metastatic disease. 
− For combination chemo-immunotherapy cohorts (Part 2 of Phase 1 only), 
subjects with nonsquamous or squamous NSCLC must have received no more 
than 1 prior line of therapy for Stage IIIB, Stage IV, or recurrent NSCLC. 
− Subjects must not have received previous PT-DC for Stage IIIB, Stage IV, or 
recurrent NSCLC.  
− Subjects who completed a platinum-based chemotherapy doublet regimen as 
adjuvant, neoadjuvant, or part of a course of chemoradiation therapy and 
progressed ≥ 6 months after completing therapy will be eligible for 
combination chemo-immunotherapy only.  If progression occurred < 6 months 
after completing therapy, the subject will not be eligible. 
− In the dose-finding cohorts, subjects may have received a prior TKI for 
tumors with any driver mutation (EGFR mutation–positive or ALK fusion 
oncogene–positive). 
− In the safety expansion cohorts, subjects must not have received any prior 
therapy for advanced or metastatic disease, except TKI for driver mutations. 
b. Subjects with unresectable or Stage IV MEL.  Note:  There will be 3 MEL cohorts in 
Phase 2, which will include I/O-naive, I/O-relapsed, and I/O-refractory cohorts as 
defined below: 
− For all MEL subjects (Phase 1 and Phase 2): 
− Documentation of V600E-activating BRAF mutation status or consent to 
BRAF V600E mutation testing during the screening period.  Testing should be 
performed in a Clinical Laboratory Improvement Amendments–certified 
laboratory.  BRAF mutation status determined as part of a panel of genetic 
tests performed in a gene expression analysis will also satisfy the inclusion 
criteria for BRAF mutation testing. 
− No nitrosoureas (eg, carmustine or lomustine) within the past 6 weeks and 
during study treatment. 
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− Must not have any prior ocular toxicity on any prior therapy, including 
immune checkpoint inhibitors. 
No more than 2 prior lines of therapy for advanced/metastatic disease, only 
1 of which can be a prior anti–PD-1/PD-L1 therapy with or without anti–
CTLA-4 therapy.  Prior anti–CTLA-4 monotherapy is not permitted. 
− Must not have ocular melanoma. 
− For subjects with advanced or metastatic I/O-naive MEL (Part 1 of Phase 1 and 
Phase 2): 
− Subjects must be treatment-naive or have received only 1 prior treatment for 
advanced or metastatic disease, including targeted therapy. 
− Subjects must not have received any prior anti–PD-1/PD-L1 therapy. 
Note:  Anti–CTLA-4 given as in the adjuvant setting or as first-line treatment 
for advanced or metastatic disease will be permitted.  These subjects must 
have discontinued anti–CTLA-4 therapy at least 12 weeks before first dose of 
epacadostat. 
− For subjects with advanced or metastatic MEL who were relapsed on or after the 
previous anti–PD-1/PD-L1 therapy following an initial response to PD-1 
pathway–targeted therapy (I/O-relapsed MEL; Phase 2 only): 
− Relapsed is defined as having a best response of CR, PR, or SD with a 
subsequent confirmed radiographic progression per RECIST v1.1 on or after 
anti–PD-1/PD-L1 therapy with or without anti–CTLA-4 therapy. 
Note:  Disease progression may be confirmed based on study investigator's 
certification at screening assessment. 
− If with known BRAF mutations, subjects may have had prior BRAF/MEK 
inhibitors following the last anti–PD-1/PD-L1 therapy (with or without 
anti–CTLA-4 therapy). 
− No more than 2 prior lines of therapy for advanced/metastatic disease, only 
1 of which can be a prior anti–PD-1/PD-L1 therapy, with or without  
anti–CTLA-4 therapy.  Prior anti–CTLA-4 monotherapy is not permitted. 
− For subjects with advanced or metastatic MEL who were refractory to previous 
anti–PD-1/PD-L1 therapy (I/O-refractory MEL; Phase 2 only): 
− Refractory is defined as having a best response of confirmed radiographic 
progression per RECIST v1.1 to a prior anti–PD-1/PD-L1 therapy with or 
without anti–CTLA-4 therapy. 
Note:  Disease progression may be confirmed based on study investigator's 
certification at screening assessment. 
− If with known BRAF mutations, may have had prior BRAF/MEK inhibitors 
following the last anti–PD-1/PD-L1 therapy (with or without anti–CTLA-4 
therapy). 
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− No more than 2 prior lines of therapy for advanced/metastatic disease, only 
1 of which can be a prior anti–PD-1/PD-L1 therapy, with or without  
anti–CTLA-4 therapy.  Prior anti–CTLA-4 monotherapy is not permitted. 
c. Subjects with recurrent (unresectable) or metastatic CRC: 
− Histologically or cytologically confirmed metastatic or recurrent adenocarcinoma 
of the colon or rectum. 
− Prior treatment:  Previous treatment with fluoropyrimidine-, oxaliplatin-, and 
irinotecan-based chemotherapy; an anti–vascular endothelial growth factor 
(VEGF) therapy (if no contraindication); and, if KRAS wild type and no 
contraindication, an anti-EGFR therapy and progressed following the last 
administration of approved therapy. 
− Subjects who have discontinued treatment due to unacceptable toxicity may 
enroll. 
d. Subjects with recurrent (unresectable) or metastatic SCCHN: 
− Histologically confirmed squamous cell carcinoma not amenable to local therapy 
with curative intent (surgery or radiation with or without chemotherapy).  
Histologically confirmed recurrent or metastatic carcinoma of the nasopharynx 
and salivary gland or nonsquamous histologies will be excluded. 
− For combination immunotherapy cohorts in Phase 1 Part 1 and Phase 2:  No more 
than 2 prior systemic regimens for advanced disease.  Prior systemic regimens 
must include a platinum-based therapy.  Investigational agents used in 
combination with standard therapies are allowed.  Subjects who relapsed within 
6 months of adjuvant therapy, including a platinum-containing regimen, may 
enroll. 
− For combination chemo-immunotherapy cohorts in Phase 1 Part 2:  Subjects must 
not have received a previous platinum-based chemotherapy for recurrent or 
metastatic SCCHN. 
Note:  Subjects who completed a platinum based chemotherapy as adjuvant, 
neoadjuvant, or part of a course of chemoradiation therapy and progressed 
≥ 6 months after completing therapy will be eligible.  If progression occurred 
< 6 months after completing the therapy, the subject will not be eligible. 
− Documentation of HPV status (eg, p16-status) of tumor. 
e. Subjects with FIGO Stage Ic, Stage II, Stage III, Stage IV, recurrent, or persistent 
(unresectable) histologically confirmed epithelial ovarian cancer, primary peritoneal 
cancer, or fallopian tube carcinoma: 
− Subjects must have received a platinum-taxane–based regimen as frontline 
therapy. 
− Subjects who received maintenance paclitaxel, bevacizumab, or alternative 
maintenance therapy (eg, vaccines) are eligible for enrollment provided that they 
have discontinued therapy at least 4 weeks for prior taxane and at least 8 weeks 
for bevacizumab, or they have received medical monitor approval for time lapse 
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from alternative maintenance therapy before enrollment and recovered from 
toxicities to ≤ Grade 2. 
− Borderline, low malignant potential epithelial carcinoma per histopathology is 
excluded. 
f.
Subjects with relapsed or recurrent B-cell NHL or HL (including relapsed or
refractory  DLBCL, excluding Burkitt's lymphoma and precursor B-lymphoblastic
leukemia/lymphoma):
− Prior allogeneic stem cell transplantation is excluded.
− Not a candidate for curative therapy or hematopoietic stem cell transplantation
(due to disease burden, fitness, or preference). 
− Subjects must have relapsed or have had refractory DLBCL specifically for 
Phase 2 but may have any B-cell NHL or HL as noted above for Phase 1 dose 
escalation. 
− Subjects with HL must be brentuximab vedotin–refractory or intolerant. 
g. Subjects with histologically confirmed diagnosis of relapsed or refractory
glioblastoma:
− Previous first-line treatment with at least radiotherapy and temozolomide.
− Documented first recurrence of glioblastoma by diagnostic biopsy or
contrast-enhanced magnetic resonance imaging (MRI) per Response Assessment 
in Neuro-Oncology (RANO) criteria. 
Note:  Relapse is defined as progression following initial line of therapy 
(ie, radiation ± chemotherapy).  If the participant had a surgical resection for 
relapsed disease and no antitumor therapy was instituted for up to 12 weeks, this 
is considered 1 relapse or recurrence. 
− MRI within 14 days before start of study drug.  MRIs should include vascular 
imaging when possible.  Corticosteroid dose must be stable or decreasing for at 
least 5 days before the scan.  If steroids are added or the steroid dose is increased 
between the date of the screening MRI and the start of treatment, a new baseline 
MRI is required. 
− An interval of at least 12 weeks after the end of prior radiation therapy is required 
unless there is either 1) histopathologic confirmation of recurrence of tumor or 
2) new enhancement on MRI outside of the radiotherapy treatment field.
− An interval of ≥ 21 days and full recovery (ie, no ongoing safety issues) from 
surgical resection before enrollment. 
5. Presence of measurable disease per RECIST v1.1 (Appendix E) for solid tumors or
Response criteria for Lymphoma (Cheson et al 2007; Appendix F) for B-cell NHL
(including DLBCL) or HL.  For subjects with glioblastoma, presence of measurable
disease is not required.
6. ECOG performance status 0 to 1.
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7. Fresh baseline tumor biopsies (defined as a biopsy specimen taken since completion of 
the most recent prior systemic regimen) are required for all cohorts except glioblastoma.  
For I/O-relapsed MEL and I/O-refractory MEL cohorts (Phase 2) as well as all 
combination chemo-immunotherapy cohorts (Part 2 of Phase 1), biopsies will be 
confirmed to contain adequate tumor tissue by a local pathology review.  If a subject has 
inaccessible lesions, such as in ovarian cancer, the subject may be enrolled with medical 
monitor approval.  In this case, submission of archived tumor tissue may be acceptable. 
For archived tumor tissue, a formalin fixed paraffin-embedded tumor tissue block is 
preferred.  If a block is not available, a minimum of 20 unstained freshly cut slides may 
be submitted to the testing laboratory as specified in the Laboratory Manual. 
Note:  Unstained slides must have been prepared from a formalin-fixed 
paraffin-embedded block obtained within 6 months before screening. 
8. Female subjects of childbearing potential (defined as women who have not undergone 
surgical sterilization with a hysterectomy and/or bilateral oophorectomy and are not 
postmenopausal as defined as ≥ 12 months of amenorrhea) must have a negative serum 
pregnancy test at screening.  All female (and male as appropriate for Protocol) subjects of 
childbearing potential must agree to take appropriate precautions to avoid pregnancy (or 
fathering children), with at least 99% certainty, from screening through 150 days after the 
last dose of epacadostat.  Permitted methods that are at least 99% effective in preventing 
pregnancy (Appendix A) should be communicated to the subject and their understanding 
confirmed. 
3.3. 
Subject Exclusion Criteria 
If met, any of the following criteria will lead to subject exclusion from the study: 
1. Laboratory and medical history parameters not within Protocol-defined range unless 
directly resulting from the bone marrow infiltration of the underlying malignancy.  All 
screening laboratory tests should be performed within 7 days of the first dose of 
epacadostat (C1D1) and must be independent of  hematopoietic growth factor support: 
a. Absolute neutrophil count < 1.5 × 109/L (in no case < 1.0 × 109/L). 
b. Platelets < 100 × 109/L (in no case < 50 × 109/L). 
c. Hemoglobin < 9 g/dL or ≤ 5.6 mmol/L (transfusion is acceptable to meet this 
criterion). 
d. Serum creatinine ≥ 1.5 × institutional upper limit of normal (ULN), or measured or 
calculated creatinine clearance (CrCl) < 50 mL/min for subjects with creatinine levels 
> 1.5 × institutional ULN. 
e. AST, ALT > 2.5 × ULN OR ≥ 5 × ULN for subjects with liver metastases. 
f. Total bilirubin ≥ 1.5 × ULN or conjugated (direct) bilirubin ≥ ULN (need only be 
tested if total bilirubin exceeds ULN).  If an institutional ULN for conjugated 
bilirubin is not available, then conjugated bilirubin should be < 40% of total bilirubin 
to be considered eligible. 
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g. International normalized ratio (INR) or prothrombin time (PT) > 1.5 × ULN unless
subject is receiving anticoagulant therapy as long as PT or INR is within therapeutic
range of intended use of anticoagulants.
h. Activated partial thromboplastin time (aPTT) > 1.5 × ULN unless subject is receiving
anticoagulant therapy, as long as PTT is within therapeutic range of intended use of
anticoagulants.
2. Current pregnancy or breastfeeding.
3. Participation in any other study in which receipt of an investigational study drug occurred
within 28 days or 5 half-lives (whichever is longer) before C1D1.  For investigational
agents with long half-lives (eg, 5 days), enrollment before the fifth half-life requires
medical monitor approval.
4. Subjects who have received prior immune checkpoint inhibitors (eg, anti–CTLA-4,
anti–PD-1, anti–PD-L1, and any other antibody or drug specifically targeting T-cell
costimulation) or an IDO inhibitor (except as required for I/O-relapsed and I/O-refractory
MEL cohorts [Phase 2], see inclusion criteria above).  Subjects who have received
experimental vaccines or other immune therapies should be discussed with the medical
monitor to confirm eligibility.
5. Any prior irAEs must have resolved to ≤ Grade 1 before first dose of epacadostat and
nivolumab (C1D1).  Any ≥ Grade 3 irAEs (except lymphopenia or asymptomatic
amylase/lipase elevations) from prior immunotherapies, including CTLA-4 treatment, are
excluded.
Note:  Subjects with history of ≥ Grade 3 endocrinopathies must be discussed with the
medical monitor to determine eligibility.
6. Subjects who are receiving an immunologically based treatment for any reason, including
chronic use of systemic steroid or prednisone equivalent at doses ≥ 10 mg/day within
7 days before the first dose of epacadostat and nivolumab (C1D1).  Use of inhaled or
topical steroids or systemic corticosteroids < 10 mg is permitted.  (Note:  There are some
exceptions in use of systemic corticosteroids or physiological replacement doses of
steroids for subjects with glioblastoma; see Section 5.13).
7. Subjects who have received any anticancer medication in the 21 days before C1D1 or has
any unresolved toxicity greater than Grade 1 from previous anticancer therapy, except for
stable chronic toxicities not expected to resolve, such as peripheral neurotoxicity,
alopecia, and fatigue.
8. Prior monoclonal antibody within 4 weeks before starting C1D1 or not recovered
(≤ Grade 1 or at baseline) from AEs due to agents administered more than 4 weeks
earlier.  Exception to this rule would be use of denosumab.
9. If subject received major surgery, they must have recovered adequately from the toxicity
and/or complications from the intervention before starting therapy.  For subjects with
glioblastoma, it must be ≥ 21 days since prior surgery and full recovery (ie, no ongoing
safety issues) from surgical resection before enrollment.
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10. Has a history of other malignancy within 2 years of study entry, with the exception of
cured basal cell or squamous cell carcinoma of the skin, superficial bladder cancer,
prostate intraepithelial neoplasm, carcinoma in situ of the cervix, or other noninvasive or
indolent malignancy, or cancers from which the subject has been disease-free for
≥ 1 year, following treatment with curative intent.
11. Untreated central nervous system (CNS) metastases or CNS metastases that have
progressed (eg, evidence of new or enlarging CNS metastasis or new neurological
symptoms attributable to CNS metastases or cerebral edema).  Subjects with previously
treated and clinically stable CNS metastases (without evidence of radiographic
progression shown by imaging at least 28 days before C1D1) and off all corticosteroids
for at least 2 weeks before C1D1 are eligible.
12. Subjects with any active or inactive autoimmune process (eg, rheumatoid arthritis,
moderate or severe psoriasis, multiple sclerosis, inflammatory bowel disease) or who are
receiving systemic therapy for an autoimmune or inflammatory disease.
a.
Exceptions include subjects with vitiligo, hypothyroidism stable on hormone
replacement, controlled asthma, Type I diabetes, Graves' disease, Hashimoto's
disease, or with medical monitor approval.
13. Evidence of interstitial lung disease or active, noninfectious pneumonitis including
symptomatic and/or pneumonitis requiring treatment.
14. Subjects who have had prior radiotherapy within 2 weeks of C1D1.  Subjects must have
recovered from all radiation-related toxicities, not require corticosteroids, and not have
had radiation pneumonitis.  A 1-week wash out is permitted for palliative radiation to
non-CNS disease with medical monitor approval.
15. Presence of a gastrointestinal condition that may affect drug absorption.
16. Active infection requiring systemic therapy
17. Has a known history of or is positive for hepatitis B (HBsAg reactive) or has active
hepatitis C (HCV RNA).  Note:  Testing must be performed to determine eligibility.
a.
HBV DNA must be undetectable and HBsAg negative at screening visit.
b. Hepatitis C Ab testing is allowed for screening purposes in countries where HCV
RNA is not part of SOC.  In these cases, HCV antibody positive participants will be
excluded.
c.
Participants who have had definitive treatment for HCV are permitted if HCV RNA is
undetectable at screening visit.  (Includes serology testing shown in the laboratory
analytes; see Table 26).
18. Known history of human immunodeficiency virus.
19. Subjects receiving MAOIs within the 21 days before screening.
20. Any history of SS after receiving 1 or more serotonergic drugs.
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21. Receipt of live attenuated vaccine within 30 days before C1D1.  Examples of live 
vaccines include, but are not limited to, the following:  measles, mumps, rubella, chicken 
pox, yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine.  
Seasonal influenza vaccines for injection are generally killed virus vaccines and are 
allowed; however, intranasal influenza vaccines are live attenuated vaccines and are not 
allowed. 
22. History or presence of an abnormal electrocardiogram (ECG) that, in the investigator's 
opinion, is clinically meaningful.  Screening QTc interval > 480 milliseconds is excluded 
(corrected by Fridericia or Bazett formula).  In the event that a single QTc is 
> 480 milliseconds, the subject may enroll if the average QTc for the 3 ECGs is 
< 480 milliseconds.  For subjects with an intraventricular conduction delay (QRS interval 
> 120 milliseconds), the JTc interval may be used in place of the QTc with sponsor 
approval.  The JTc must be < 340 milliseconds if JTc is used in place of the QTc.  
Subjects with left bundle branch block are excluded (see Section 7.4.5 for details). 
23. Use of any UGT1A9 inhibitor from screening through follow-up period, including the 
following:  diclofenac, imipramine, ketoconazole, mefenamic acid, and probenecid.  See 
Section 5.13 for more details. 
24. Clinically significant cardiac disease, including unstable angina, acute myocardial 
infarction within 6 months from Day 1 of study drug administration, New York Heart 
Association Class III or IV congestive heart failure, and arrhythmia requiring therapy. 
25. History or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the study, interfere with the subject's participation for the 
full duration of the study, or is not in the best interest of the subject to participate, in the 
opinion of the treating investigator. 
26. Known allergy or reaction to any component of epacadostat, nivolumab, 5-FU, cisplatin, 
carboplatin, paclitaxel, pemetrexed, or their formulation components or mannitol. 
27. Exclusion criteria for subjects with glioblastoma: 
a. More than 1 recurrence of glioblastoma. 
b. Presence of extracranial metastatic or leptomeningeal disease. 
c. Diagnosis of secondary glioblastoma (ie, glioblastomas that progress from low-grade 
diffuse astrocytoma or anaplastic astrocytoma). 
d. Previous radiation therapy with anything other than standard therapy (ie, focally 
directed radiation). 
e. Subjects requiring escalating (within 7 days of C1D1) or chronic supra physiologic 
doses (to be more than 2 mg of Decadron® or biologic equivalent per day) of 
corticosteroids for control of their disease. 
f. Treatment with carmustine wafer except when administered as first-line treatment and 
at least 6 months before C1D1. 
g. Evidence of > Grade 1 CNS hemorrhage on the baseline MRI. 
h. History or evidence upon physical/neurological examination of CNS disease 
(eg, seizures) unrelated to cancer unless adequately controlled by medication or 
potentially interfering with Protocol treatment. 
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i.
Subjects unable (due to existent medical condition, eg, pacemaker or implantable
cardioverter defibrillator device) or unwilling to have a head contrast-enhanced MRI.
j.
History of intracranial abscess within 6 months before enrollment.
k. Prior VEGF or VEGF-receptor directed therapy (ie, bevacizumab).
28. Use of any prohibited medication listed in Section 5.13.
29. Subjects with bleeding associated with tumors that invade or are adjacent to major blood
vessels, as shown unequivocally by imaging studies, or history of bleeding related to
disease under study within 3 months of Cycle 1 Day1.
4.
INVESTIGATIONAL PLAN
4.1. 
Overall Study Design 
This is a Phase 1/2 open-label study that will be conducted in 2 phases.  Phase 1 of the study will 
consist of 2 parts (Part 1 and Part 2).  Part 1 of Phase 1 will consist of a standard dose-escalation 
design to determine the MTD or PAD of epacadostat when coadministered with nivolumab 
(defined as combination immunotherapy) in subjects with select advanced solid tumors and 
lymphomas, including MEL, NSCLC, CRC, SCCHN, ovarian cancer, glioblastoma, and B-cell 
NHL or HL.  The study design for Part 1 of Phase 1 is shown in Figure 1. 
Part 2 of Phase 1 will evaluate the preliminary safety of epacadostat in combination with 
nivolumab and several chemotherapy regimens (defined as combination chemo-immunotherapy) 
in subjects with SCCHN and NSCLC by using a dose de-escalation design.  The starting dose of 
epacadostat in Part 2 will be the RP2D of epacadostat selected for the use of combination 
immunotherapy in Part 1.  Initial dose-finding cohorts in Part 2 will be expanded to safety 
expansion cohorts and will further evaluate tolerated dose(s) of epacadostat when given in 
combination with nivolumab and chemotherapy regimens (see Figure 2 for study design of 
Phase 1 Part 2). 
Phase 2 of the study will include 9 expansion cohorts in tumors types tested in Phase 1 Part 1 
(except DLBCL will be the only lymphoma permitted) with a) historically high activity under 
nivolumab monotherapy and b) with historically low activity with nivolumab monotherapy.  In 
Phase 2 of the study, nivolumab will be administered at 240 mg IV every 2 weeks or 480 mg IV 
every 4 weeks for specific tumor types as described in Figure 1.  (Note:  In Phase 2, subjects 
enrolled into I/O-relapsed and I/O-refractory MEL cohorts will be administered epacadostat 
100 mg BID.) 
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Figure 1: 
Study Design for Combination Immunotherapy Cohorts (Phase 1 Part 1 and 
Phase 2) 
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Figure 2: 
Study Design for Combination Chemo-Immunotherapy Cohorts (Phase 1 
Part 2 Only) 
 
4.1.1.
Phase 1 Dose-Finding and Safety Expansion (Part 1 and Part 2) 
In Part 1, for combination immunotherapy cohorts, a 3 + 3 + 3 standard dose-escalation design 
will be used to assess the safety of epacadostat when given in combination with nivolumab. 
In Part 2, for combination chemo-immunotherapy cohorts, a (3 + 3) + 3 dose de-escalation study 
design will be used to evaluate the safety of epacadostat when administered in combination with 
nivolumab and chemotherapy regimen.  Part 2 will be initiated after Phase 1 Part 1 of the study is 
completed and the Phase 2 dose of epacadostat for the combination immunotherapy is 
determined. 
4.1.1.1. 
Combination Immunotherapy Cohorts (Part 1) 
The starting dose of epacadostat when given in combination with nivolumab (3 mg/kg IV every 
2 weeks, Q2W) is 25 mg BID continuous daily dose administration.  The epacadostat dose 
regimens during dose escalation in combination immunotherapy cohorts are provided in Table 1. 
The BID continuous administration cohorts will be tested first.  If epacadostat 50 mg BID 
continuous daily administration is determined as tolerable, the investigators and sponsor may 
agree to only evaluate continuous daily administration.  However, if epacadostat 50 mg BID 
exceeds the MTD, an every-other-week administration schedule of epacadostat administered 
BID may be tested.  If a dose is determined safe for both schedules, a safety expansion cohort 
may be opened for each dose regimen to include approximately 9 subjects in each cohort before 
selecting the schedule to move to Phase 2.  If at least 50 mg BID continuous or every other week 
cannot be combined safely with nivolumab 3 mg/kg, other alternative dose schedules (ie, other 
intermittent administration) of epacadostat may be tested, if needed, following the review of 
available safety data at the Dose Escalation/Cohort Review meetings.  If an alternate schedule is 
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tested and determined to be safe, re-escalation of epacadostat according to Table 1 will proceed 
with nivolumab 3 mg/kg every 2 weeks. 
Table 1: 
Phase 1 Part 1 Dose-Escalation Schema for Epacadostat in Combination 
With Nivolumab Once Every 2 Weeks (Combination Immunotherapy 
Cohorts) 
Dose Level 
Number 
Total Subjects
a
(N) 
Epacadostat 
(Oral) 
Dose of Nivolumab 
(IV, Once Every 2 Weeks) 
1 
Approximately 3-9 
25 mg BID 
3 mg/kg 
2a 
Approximately 3-9 
50 mg BID 
3 mg/kg 
2b 
Approximately 3-9 
50 mg BID every other week 
3 mg/kg 
3a 
Approximately 3-9 
100 mg BID 
3 mg/kg 
3b 
Approximately 3-9 
100 mg BID every other week 
3 mg/kg 
4a 
Approximately 3-9 
300 mg BID
b 
3 mg/kg 
4b 
Approximately 3-9 
300 mg BID every other weekb 
3 mg/kg 
Total 
Approximately 21-
63 
a Approximately 3 to 9 subjects will be enrolled during dose escalation.  Additional subjects may be added to any dose level after 
determining the preliminary safety at that dose level for a minimum of 6 and maximum of 9 evaluable subjects per dose level. 
Dose level numbers marked "a" and "b" may occur in parallel.  Oral administration of epacadostat BID will occur on a daily 
basis unless indicated by the weekly alternating schedule of BID each day for 1 week followed by no doses for the following 
week.  Nivolumab administration will be 3 mg/kg IV every 2 weeks. 
b If 300 mg BID is not tolerated, an intermediate dose of 200 mg BID may be tested on either a continuous schedule or 
every-other-week schedule. 
The DLT observation period will last for 6 weeks (42 days).  Three subjects will be treated 
initially at each dose level.  If 0 DLTs occur in a cohort of 3 subjects, a new cohort of 3 subjects 
will be treated at the next higher dose level.  If 1 of 3 subjects experience a DLT, that cohort will 
be expanded to 6 subjects.  If 1 of 6 subjects experiences a DLT, a new cohort of 3 subjects will 
be treated at the next higher dose level.  If 2 of 6 DLT subjects experience a DLT, that cohort 
will be expanded to 9 subjects.  If ≥ 2/3, 3/6, or 3/9 subjects experience DLTs within a cohort, 
then that dose level will be determined to have exceeded the MTD. 
If epacadostat 100 mg BID is deemed tolerable, up to 6 additional subjects (for a minimum of 
6 evaluable subjects) will be enrolled to confirm the safety of the dose in combination with 
nivolumab.  If 1 of 6 or < 3 of 9 subjects experience DLTs, the Phase 2 MEL and NSCLC 
expansion cohorts will open epacadostat 100 mg BID in combination with nivolumab.  The 
300 mg BID dose in Phase 1 will be tested in parallel to the Phase 2 MEL and NSCLC cohorts 
opening.  Additional Phase 2 cohorts in other tumor types may also be opened to test epacadostat 
100 mg BID if it is deemed pharmacologically active and safe based on available data from 
Phase 1 cohorts. 
Note:  Up to 6 additional subjects may be enrolled into each cohort for a total of up to 
9 evaluable subjects to further explore safety 
 objectives (original 3-9 subjects 
from dose escalation plus additional subjects required to have a total cohort size of 9). 
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If epacadostat 300 mg BID is deemed tolerable, up to 6 additional subjects (for a minimum of 
6 subjects) will be enrolled before opening Phase 2 to further confirm the safety of the dose in 
combination with nivolumab.  If 1 of 6 or < 3 of 9 subjects experience DLTs, the remaining 
Phase 2 cohorts may be opened with 300 mg BID as the RP2D after reviewing the emerging data 
from Phase 2 cohorts testing 100 mg BID. 
If 300 mg BID is tested and not tolerated, an intermediate dose of 200 mg BID may be tested on 
either a continuous schedule or every-other-week schedule or 100 mg BID may be selected as 
the RP2D.  The RP2D decision for the remaining Phase 2 cohorts will be made based on the 
available data from ongoing Phase 2 cohorts administered 100 mg BID.  If an MTD is not 
determined based on the data from Phase 1 and ongoing Phase 2 cohorts, then the remaining 
Phase 2 cohorts may be opened at a PAD of epacadostat (eg, 100 mg BID). 
4.1.1.1.1. Phase 2 Dose Selection for Combination Immunotherapy (Phase 1 Part 1) 
If 100 mg BID of epacadostat is determined as safe and tolerable in Phase 1 Part 1, Phase 2 of 
the study may begin to enroll in the I/O-naive MEL and NSCLC cohorts in parallel with the  
evaluation of epacadostat at 300 mg BID in Part 1.  If 300 mg BID is then selected as the Phase 2 
dose (RP2D), and if either I/O-naive MEL or NSCLC cohort enrolls < 50% of the total cohort 
(≤ 25 subjects) at 100 mg BID up to the RP2D decision, then any additional subjects in that 
specific cohort being enrolled will be treated with epacadostat 300 mg BID at the sponsor's 
discretion, in lieu of opening new cohorts of I/O-naive MEL and NSCLC with 300 mg BID.  The 
same rule will apply to any additional Phase 2 tumor cohorts (ie, CRC, ovarian cancer, etc) that 
may be opened with epacadostat 100 mg BID before RP2D selection.  (Note: Additional 
I/O-relapsed and I/O-refractory MEL cohorts will be opened at 100 mg BID.) 
4.1.1.2. 
Combination Chemo-Immunotherapy Cohorts (Part 2 of Phase 1) 
The starting dose of epacadostat when given in combination with nivolumab (360 mg IV every 
3 weeks, Q3W) and chemotherapy will be 100 mg BID continuous daily dose administration, 
which is 1 dose level less than what was determined to be tolerable in Part 1 of Phase 1 and 
provides an adequate safety margin.  Part 2 of Phase 1 will consist of 3 tumor cohorts (1 SCCHN 
cohort and 2 NSCLC cohorts) that will enroll in parallel.  A minimum of 6 evaluable subjects 
will be enrolled in each tumor cohort epacadostat at 100 mg BID and each cohort will be 
observed for 42 days for DLTs.  
In a tumor cohort the following rules will be applied to determine dose or dose de-escalation: 
•
If ≤ 1 of 6 evaluable subjects has a DLT, then 100 mg BID will be used in a safety
expansion cohort (Cohort A, B, C) for that specific tumor type.
•
If 2 of 6 evaluable subjects have a DLT, 3 additional subjects will be enrolled in the
same cohort (Cohort 1, 2, 3).  If there are no additional DLTs (≤ 2 DLTs occurred in a
total of 9 evaluable subjects), then a safety expansion cohort (Cohort A or B or C)
will start to enroll in that specific dose level.
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•
If ≥ 2 of 3, 3 of 6, or ≥ 3 of 9 evaluable subjects have DLTs within a specific tumor
cohort, epacadostat will be de-escalated to 1 lower dose level, 50 mg BID, and that
tumor cohort will enroll 6 subjects to test this dose level as described above.
•
Note:  If different MTDs are determined for the 2 NSCLC cohorts (combination
chemo-immunotherapy), 3 to 6 additional subjects may be enrolled in each NSCLC
cohort to further evaluate the safety profile before dose selection for safety expansion.
The doses of epacadostat to be evaluated and scenarios for de-escalation are summarized in 
Table 2. 
Table 2: 
Epacadostat Dose De-Escalation Scenarios for Combination 
Chemo-Immunotherapy Cohorts 
Combination Chemo-Immunotherapy Cohort 
Epacadostat Dose 
Dose Level 1 (starting dose) 
100 mg BID
a 
Dose Level -1 
50 mg BID 
a If epacadostat 100 mg BID is not tolerated within a specific cohort, the dose of epacadostat will be de-escalated to 
50 mg BID for evaluation.  Alternate doses may be evaluated at the sponsor discretion 
 
 and safety results. 
Epacadostat dose regimens in combination chemo-immunotherapy cohorts by tumor types are 
provided in Table 3. 
Once 100 mg BID or 50 mg BID of epacadostat in combination chemo-immunotherapy cohorts 
is determined as the MTD or PAD, each of the tumor cohorts will be expanded for safety 
evaluation at that dose level of epacadostat.  Each of the safety expansion cohorts with 
combination chemo-immunotherapy will enroll approximately up to 30 evaluable subjects. 
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Table 3: 
Summary of Treatment Regimens for Each Possible Epacadostat 
Dose-Finding Scenario for Combination Chemo-Immunotherapy Cohorts in 
Part 2 
Tumor Types
a 
Cohort
b 
Total 
Subjects, N 
Epacadostat 
(Oral) 
Nivolumab 
(IV, Once Every 
3 Weeks) 
Chemotherapy Regimen 
SCCHN 
1 
~6-9 
100 mg BID 
360 mg 
Cisplatin (100 mg/m2 IV Q3W 
for up to 6 cycles) 
or 
Carboplatin AUC 5 IV Q3W 
for up to 6 cycles 
5-FU (1000 mg/m2 continuous 
IV for 4 days Q3W for up to 
6 cycles, on Day 1 of each 
cycle starting C1D1) 
1a 
~6-9 
50 mg BID 
360 mg 
Same as  above 
Nonsquamous 
NSCLC 
2 
~6-9 
100 mg BID 
360 mg 
Pemetrexed (500 mg/m2 IV 
Q3W for up to 6 cycles but no 
less than 4 cycles, on D1of 
each cycle starting C1D1) 
Carboplatin (AUC 5 IV Q3W 
up to 6 cycles but no less than 
4 cycles, on Day 1 of each 
cycle starting C1D1) 
or 
Cisplatin (100 mg/m2 IV Q3W 
up to 6 cycles but no less than 
4 cycles) 
2a 
~6-9 
50 mg BID 
360 mg 
Same as above 
NSCLC 
3 
~6-9 
100 mg BID 
360 mg 
Paclitaxel (200 mg/m2 IV Q3W 
for up to 6 cycles but no less 
than 4 cycles, on Day 1 of each 
cycle starting C1D1) 
Carboplatin (AUC 6 IV Q3W 
up to 6 cycles but no less than 
4 cycles, on Day 1 of each 
cycle starting C1D1) 
or 
Cisplatin (100 mg/m2 IV Q3W 
up to 6 cycles but no less than 
4 cycles) 
3a 
~6-9 
50 mg BID 
360 mg 
Same as above 
Total 
~18-54 
a Cohort 1, Cohort 2, and Cohort 3 will enroll in parallel. 
b If Cohort 1, Cohort 2, or Cohort 3 with epacadostat 100 mg BID proves intolerable, then Cohort 1a, Cohort 2a, or Cohort 3a 
may be evaluated with epacadostat 50 mg BID.  If the epacadostat 100 mg BID is determined to be safe and tolerable at a 
specific tumor type, then the safety expansion cohort for that specific tumor type will enroll at 100 mg BID.  Alternative doses 
of epacadostat may be investigated at the sponsor discretion. 
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In Phase 1, no intrasubject dose escalation is allowed.  In Phase 1 Part 1, additional subjects will 
be enrolled in a cohort to achieve the minimum of 3 evaluable subjects if discontinuations or 
dose interruptions or reductions occur that result in a subject being nonevaluable for DLTs.  In 
Phase 1 Part 2, additional subjects will be enrolled in a cohort to achieve the minimum of 
6 evaluable subjects.  In both Part 1 and Part 2, subjects who withdraw from the study during the 
DLT period for reasons other than a DLT may be replaced within the same dose level.   
For the purpose of making decisions on dose of epacadostat from a safety perspective, subjects 
will be considered evaluable if they meet 1 of the following criteria: 
• In Part 1, in the combination immunotherapy cohorts, subjects must have received at 
least 2 out of the 3 scheduled nivolumab doses of 3 mg/kg through the 6-week 
(42-day) DLT observation period (only if the 1 missed dose was secondary to 
nonmedical reasons) and must have received at least 75% of the cohort-specified dose 
of epacadostat during the DLT observation period. 
• In Part 2, in combination chemo-immunotherapy cohorts, subjects must have received 
2 doses of nivolumab and chemotherapy regimen and must have received at least 
75% of the cohort-specified dose of epacadostat during the 42-day DLT observation 
period. 
• In addition, subjects with dose delays during the 42-day DLT observation period of 
> 1 week for non-DLT events will be considered not evaluable for making decisions 
on dose escalation or dose de-escalation and should be replaced. 
Dose escalation in Part 1 or dose de-escalation in Part 2 of epacadostat will be based on the 
number of dose limiting toxicities (DLTs) experienced during the DLT observation period.  Dose 
modifications should not be made during the DLT observation period without discussion with 
the medical monitor. 
4.1.2. 
Phase 2 Combination Immunotherapy Cohort Expansions 
The purpose of the cohort expansions in Phase 2 is to gather additional safety, tolerability, 
preliminary efficacy, 
information regarding the combination of 
epacadostat and nivolumab.  Once the safety profile of active doses is characterized and the 
RP2D has been defined, the cohort expansions will be initiated at the RP2D.  However, the 
I/O-naive MEL and NSCLC cohorts may be opened using epacadostat 100 mg BID in parallel to 
testing 300 mg BID if the 100 mg BID dose of epacadostat is deemed tolerable in Phase 1 Part 1.  
Treatment doses in the cohort expansion groups will not exceed the MTD.  Nine expansion 
cohorts in Phase 2 will be restricted to the same tumor types tested in Phase 1 Part 1 (except 
DLBCL will be the only lymphoma permitted in Phase 2), and Phase 2 will also include a cohort 
for glioblastoma.  The NSCLC and I/O-naive MEL cohorts, which have demonstrated activity 
with nivolumab monotherapy and are in Phase 3 evaluation in these indications, will be used to 
assess increased activity of the combination.  In Phase 2, there will be 2 additional MEL cohorts 
to explore the activity of combination immunotherapy; one cohort will enroll subjects who 
relapsed on or after anti–PD-1/PD-L1 therapy (I/O relapsed) and the other cohort will enroll 
subjects who were refractory to prior anti–PD-1/PD-L1 therapy (I/O refractory) (for I/O relapsed 
MEL cohort and I/O refractory MEL cohort definitions, see Section 3.2).  Subjects who are 
enrolled in these 2 new MEL cohorts will be administered nivolumab 480 mg IV every 4 weeks, 
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whereas subjects who are enrolled in I/O-naive MEL, NSCLC, CRC, SCCHN, ovarian cancer, 
DLBCL and glioblastoma cohorts will be administered nivolumab 240 mg IV every 2 weeks.  
Subjects enrolled in I/O MEL cohorts will be administered epacadostat 100 mg BID; however, if 
there is no or minimal activity in tumor responses in these cohorts, alternative doses of 
epacadostat may be explored at the sponsor discretion.  The CRC, SCCHN, ovarian cancer, 
DLBCL, and glioblastoma cohorts will explore activity of the combination in tumors with 
preliminary, unknown, or historically low responses to nivolumab monotherapy.  Continuous 
evaluation of toxicity events in the cohort expansions will be performed throughout enrollment 
in the expansion cohorts.  If the cumulative incidence of Grade 3 or Grade 4 study treatment–
related AEs exceeds 40% after enrolling the first 6 subjects in any of these cohorts, the findings 
will be reviewed and further enrollment will be interrupted until the sponsor(s), investigators, 
and regulatory authorities, if applicable, have determined the appropriate course of action.  If an 
expansion cohort is discontinued due to toxicity, a new cohort may be initiated at a previously 
tested lower dose level of epacadostat. 
In each of the NSCLC and I/O-naive MEL cohorts, approximately 50 subjects will be enrolled to 
allow for a more precise estimate of the ORR in these tumors where activity for nivolumab as 
monotherapy has been established.  The sample size for the I/O-relapsed MEL, I/O-refractory 
MEL, CRC, ovarian, SCCHN, and DLBCL cohorts will be approximately 25 subjects each.  The 
sample size for the glioblastoma cohort will be approximately 28 (Table 4).  The study schedules 
for Phase 2 are shown in Table 18, Table 19, and Table 20. 
Table 4: 
Tumor Types Eligible for Combination Immunotherapy Cohort Expansion 
Tumor Type 
Approximate Number of Subjects to Be Enrolled 
(Phase 2 Only) 
NSCLC 
50 
I/O-naive MEL 
50 
I/O-relapsed MEL 
25 
I/O-refractory MEL 
25 
CRC 
25 
Ovarian cancer 
25 
SCCHN 
25 
DLBCL 
25 
Glioblastoma 
28 
Totals 
278 
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4.2. 
Study Endpoints 
4.2.1. 
Primary Endpoint 
4.2.1.1. 
Phase 1 
•
Safety:  In Part 1 and Part 2 of Phase 1 of the study, all subjects who receive at least
1 dose of epacadostat or nivolumab will be assessed for safety by monitoring the
frequency and severity of AEs, SAEs, and deaths.
4.2.1.2. 
Phase 2 
•
Efficacy:
− The ORR and PFS at 6 months will be assessed based on RECIST v1.1 criteria for
subjects with select solid tumors or Cheson criteria for subjects with DLBCL. 
− OS will be assessed at 9 months for subjects with glioblastoma as determined by 
death due to any cause. 
4.2.2. 
Secondary Endpoints 
4.2.2.1. 
Phase 1 
•
Part 1 Efficacy:  ORR will be assessed per RECIST v1.1 and modified RECIST for
subjects with select advanced solid tumors, Cheson and modified Cheson criteria for
B-cell NHL or HL, and RANO and modified RANO criteria for glioblastoma.
•
Part 2 Efficacy:  ORR, DOR, and PFS will be assessed per RECIST v1.1 and
modified RECIST for subjects with advanced or metastatic SCCHN and advanced or
metastatic NSCLC treated with epacadostat in combination with nivolumab and
chemotherapy.
4.2.2.2. 
Phase 2 
•
Efficacy:  The DOR and duration of disease control will be assessed based on
RECIST v1.1 criteria and modified RECIST for select solid tumors, Cheson and
modified Cheson criteria for DLBCL, or RANO and modified RANO criteria for
subjects with glioblastoma.  OS will be evaluated for solid tumors and DLBCL
cohorts.  ORR and PFS will be assessed for glioblastoma per modified RANO.
•
Safety:  All subjects who receive at least 1 dose of epacadostat or nivolumab will be
assessed for safety by monitoring the frequency and severity of AEs, SAEs, and
deaths.
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4.3. 
Measures Taken to Avoid Bias 
The measurement of most toxicities using the CTCAE v4.0 and assessment of tumor size using 
the RECIST v1.1 and modified RECIST criteria, Cheson and modified Cheson criteria, or 
RANO and modified RANO criteria represent objective endpoints. 
4.4. 
Number of Subjects 
There will be approximately up to 207 subjects enrolled in Phase 1 of the study and up to 
approximately 278 subjects enrolled in Phase 2 for a total of approximately 485 subjects 
enrolled. 
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4.5. 
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 IRB or IEC in writing of 
the study's completion or early termination, and send a copy of the notification to the sponsor or 
sponsor's designee and retain 1 copy for the site study regulatory file. 
The sponsor may terminate the study electively, or if required by regulatory decision.  If the 
study is terminated prematurely, the sponsor will notify the investigators, the IRBs and IECs, and 
regulatory bodies of the decision and reason for termination of the study.   
5.
TREATMENT OF SUBJECTS
5.1. 
Administration of Study Drugs
5.1.1. 
Epacadostat
Subjects in Phase 1 Part 1 of the study will be administered epacadostat according to cohort 
enrollment (Table 1).  The starting dose of epacadostat for combination immunotherapy cohorts 
is 25 mg BID daily.   
Subjects enrolled in Phase 2 will receive the RP2D epacadostat determined in Phase 1 Part 1.  
(Note:  Subjects enrolled into I/O-refractory and I/O-relapsed MEL cohorts in Phase 2 will be 
administered epacadostat 100 mg BID). 
Subjects enrolled in Phase 1 Part 2 of the study will be administered the starting dose of 
epacadostat 100 mg BID continuously during 21-day cycles (every 3 weeks; Figure 2). 
All BID doses of epacadostat will be taken orally morning and evening, approximately 12 hours 
apart without regard to food.  If the morning or evening dose is missed by more than 4 hours, 
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 7.6.1).  Epacadostat will be given daily in combination with nivolumab 
as long as subjects are receiving benefit from treatment and have not met any criteria for study 
withdrawal.  Intrasubject dose escalation of epacadostat is not permitted. 
5.1.2. 
Nivolumab  
All subjects enrolled in Phase 1 Part 1 will receive nivolumab 3 mg/kg via 60-minute IV infusion 
every 2 weeks on Days 1, 15, 29, and 43 of each 8-week cycle. 
Subjects enrolled in Phase 1 Part 2 will receive nivolumab 360 mg via a 30-minute IV infusion 
on Day 1 of each 21-day cycle.   
Subjects enrolled in Phase 2 will receive nivolumab 240 mg via 30-minute IV infusion every 
2 weeks on Days 1, 15, 29, and 43 of each 8-week cycle. 
Subject enrolled in the I/O-relapsed and I/O-refractory MEL cohorts of Phase 2 will receive 
nivolumab 480 mg via a 30-minute IV infusion every 4 weeks on Days 1 and Day 29 of each 
8-week cycle.  Nivolumab doses and schedules are summarized in Table 5. 
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Subjects will continue to receive nivolumab as long as the subject is deriving benefit and has not 
met any Protocol-defined criteria for study treatment withdrawal.  Intrasubject dose escalation of 
nivolumab is not permitted. 
Table 5: 
Nivolumab Doses and Schedules in Phase 1 and Phase 2 
Study Phases and 
Cohorts 
Phase 1 
Phase 2 
Part 1 – dose-finding 
for combination 
immunotherapy 
cohorts 
Part 2 – dose-finding 
for combination 
chemo-immunotherapy 
cohorts and safety 
expansion cohorts 
Select tumor 
cohorts for 
combination 
immunotherapy 
I/O-relapsed and 
I/O-refractory 
MEL cohorts 
Nivolumab 
(Dose, schedule, 
infusion duration, 
cycle length) 
3 mg/kg, Q2W 
60 min IV 
8-week cycle 
360 mg, Q3W 
30 min IV 
21-day cycle 
240 mg, Q2W 
30 min IV 
8-week cycle 
480 mg Q4W 
30 min IV 
8-week cycle 
In Phase 1 Part 1, the dose amount required to prepare the nivolumab infusion solution will be 
based on the subject's weight in kilograms.  If the subject's weight on the day of administration 
differs by > 10% from the weight used to calculate the dose, the dose must be recalculated.  All 
doses should be rounded to the nearest milligram. 
Details on the dose calculation, preparation, and administration are provided in the Pharmacy 
Manual.  
5.1.2.1. 
Timing of Dose Administration of Nivolumab 
Nivolumab should be administered after all procedures/assessments have been completed as 
detailed in the schedule of assessments (Section 6).  All study treatments will be administered on 
an outpatient basis. 
Nivolumab will be administered as a 30- or 60-minute IV infusion.  Sites should make every 
effort to target infusion timing to be as close to 30 or 60 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 is administered in the clinic, epacadostat should be taken just before beginning the 
infusion of nivolumab.  Subjects who are enrolled in the combination chemo-immunotherapy 
cohorts must take chemotherapy IV after nivolumab infusion is completed.  There should be 
approximately 30 minutes between the completion of nivolumab infusion and start of applicable 
chemotherapy infusion.  Subjects may be administered nivolumab with no less than 11 days 
between doses and no more than 3 days after the scheduled administration date.  Dose given after 
the 3-day window is considered a dose delay.  A maximum delay of 42 days between doses is 
allowed.  If the delay is greater than 42 days, this must be discussed with medical monitor. 
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5.2. 
Background Therapies 
5.2.1. 
Paclitaxel/Platinum (Carboplatin or Cisplatin) 
5.2.1.1. 
Description and Administration 
Subjects will receive paclitaxel 200 mg/m2 IV over 3 hours (± 15 min) and either carboplatin 
AUC 6 IV over 30 minutes (± 5 min) or cisplatin 100 mg/m2 IV on Day 1 of each 21-day cycle 
for a minimum of 4 cycles and up to 6 cycles. 
Subjects must receive the following premedications:  1) dexamethasone 20 mg PO 12 hours and 
6 hours before or dexamethasone 16 mg to 20 mg IV 30 minutes before, 2) chlorphenamine 
10 mg IV 30 minutes before, and 3) ranitidine 50 mg IV 30 minutes before paclitaxel 
administration. 
Epacadostat and nivolumab will be administered before premedications and IV chemotherapy.  
Premedications should be administered approximately 30 minutes (as applicable) following 
completion of the nivolumab infusion.  The infusion of paclitaxel should be completed before 
beginning the infusion of cisplatin or carboplatin.  Premedications may be adjusted based on 
institutional guidelines, investigator practice, or availability of similar medications on the 
investigative site's formulary. 
Subjects must meet minimum criteria for the initiation of each chemotherapy cycle as outlined in 
Appendix I, Section I.1. 
Sites will be instructed to consult local prescribing information for additional information and 
instructions for preparation and infusion of paclitaxel and cisplatin or carboplatin. 
Subjects may receive prophylactic G-CSF support with filgrastim according to investigators 
discretion or per institutional guidelines, or when chemotherapy is held due to neutropenia.  
Granulocyte-colony stimulating factor should not be given in Cycle 1. 
5.2.1.2. 
Supply, Packaging, and Labeling 
In countries where paclitaxel, carboplatin, cisplatin, or their generic equivalents are 
commercially available, investigators are responsible for ensuring that subjects receive 
commercially available supplies of these therapies for the entire duration of study participation.  
Study sponsor may provide certain reference therapies where required by applicable law or 
regulation or under other limited circumstances when a subject may not otherwise have access to 
any study-required therapies.  The contents of the labels will be in accordance with all applicable 
regulatory requirements. 
5.2.2. 
Pemetrexed/Platinum (Carboplatin or Cisplatin) 
5.2.2.1. 
Description and Administration 
Subjects will receive pemetrexed 500 mg/m2 IV over 10 minutes (± 5 min) and either carboplatin 
AUC 5 IV over 30 minutes (± 5 min) or cisplatin 100 mg/m2 IV on Day 1 of each 21-day cycle 
for a minimum 4 cycles and up to 6 cycles.  Pemetrexed may continue as maintenance therapy 
after the 6 cycles. 
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Subjects must also receive 1) dexamethasone 4 mg PO BID (or equivalent) taken the day before, 
the day of, and the day after pemetrexed administration; 2) folic acid 400 μg to 1000 μg PO once 
daily beginning 7 days before the first dose of pemetrexed and continued through the full course 
of therapy and for 21 days after the last dose of pemetrexed; and 3) vitamin B12 1 mg 
intramuscularly 1 week before the first dose of pemetrexed and every 3 cycles thereafter.  
Subsequent vitamin B12 injections may be given the same day as treatment with pemetrexed. 
Epacadostat and nivolumab will be administered before premedications and IV chemotherapy 
regimen.  Premedications should be administered approximately 30 minutes (as applicable) after 
completion of the nivolumab infusion.  
Premedications may be adjusted based on institutional guidelines, investigator practice, or 
availability of similar medications on the investigative site's formulary. 
Subjects must meet minimum criteria for the initiation of each chemotherapy cycle as outlined in 
Appendix J, Section J.1. 
Sites are instructed to consult local prescribing information for additional information and 
instructions for preparation and infusion of pemetrexed with cisplatin or carboplatin. 
Subjects may receive prophylactic G-CSF support with filgrastim according to investigators 
discretion or per institutional guidelines, or when chemotherapy is held due to neutropenia.  
Granulocyte-colony stimulating factor should not be given in Cycle 1. 
5.2.2.2. 
Supply, Packaging, and Labeling 
In countries where pemetrexed, carboplatin, cisplatin, or their generic equivalents are 
commercially available, investigators are responsible for ensuring that subjects receive 
commercially available supplies of these therapies for the entire duration of study participation.  
Study sponsor may provide certain reference therapies where required by applicable law or 
regulation or under other limited circumstances when a subject may not otherwise have access to 
any study-required therapies.  The contents of the labels will be in accordance with all applicable 
regulatory requirements. 
5.2.3. 
Platinum (Carboplatin or Cisplatin)/5-Fluorouracil 
5.2.3.1. 
Description and Administration 
Subjects will receive carboplatin AUC 5 IV over 30 minutes (± 5 min) or cisplatin 100 mg/m2 IV 
on Day 1 of each cycle, followed by 5-FU 1000 mg/m2 IV continuous infusion over 4 days for a 
total dose of 4000 mg/m2.  Subjects will be administered with this chemotherapy regimen for up 
to 6 cycles. 
Epacadostat and nivolumab will be administered before IV chemotherapy regimen.  
Chemotherapy infusion will be initiated approximately 30 minutes following the completion of 
the nivolumab infusion.  Subjects must meet minimum criteria for the initiation of each 
chemotherapy cycle as outlined in Appendix K, Section K.1. 
Premedications, including corticosteroids, may be given based on institutional guidelines, study 
investigator practice, or availability of similar medications on the investigative site's formulary. 
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Sites will be instructed to consult local prescribing information for additional information and 
instructions for preparation and infusion of carboplatin, cisplatin, and 5-FU. 
Subjects may receive prophylactic G-CSF support with filgrastim according to investigators 
discretion or per institutional guidelines, or when chemotherapy is held due to neutropenia.  
Granulocyte-colony stimulating factor should not be given in Cycle 1. 
5.2.3.2. 
Supply, Packaging, and Labeling 
In countries where carboplatin, cisplatin, 5-FU, or their generic equivalents are commercially 
available, investigators are responsible for ensuring that subjects receive commercially available 
supplies of these therapies for the entire duration of study participation.  Study sponsor may 
provide certain reference therapies where required by applicable law or regulation or under other 
limited circumstances when a subject may not otherwise have access to any study-required 
therapies.  The contents of the labels will be in accordance with all applicable regulatory 
requirements. 
5.3. 
Treatment Compliance 
Treatment compliance with all study-related medications should be emphasized to the subject by 
the site personnel, and appropriate steps should be taken to optimize compliance during the 
study.  Subjects will bring all bottles of unopened, empty, and unused study drug with them to 
each study visit.  Investigative site staff will perform a count of returned tablets to assess 
compliance, and this information will be entered into the electronic case report form (eCRF).  
Bottles of study drug, including all bottles of unopened, partially opened, or empty bottles cannot 
be destroyed or returned to the depot until a monitor reviews and verifies all tablet counts for 
compliance.  Compliance with nivolumab will also be documented in the medical record and 
monitored by the sponsor or its designee. 
5-Fluorouracil, carboplatin, cisplatin, paclitaxel, and pemetrexed are administered as an IV 
infusion by site personnel.  Receipt of infusions will be documented by the site staff and 
monitored by the sponsor/designee. 
5.4. 
Randomization and Blinding 
Not applicable. 
5.5. 
Duration of Treatment and Subject Participation 
Each subject enrolled in the study will continue receiving study treatment for up to 2 years in 
continuous 8-week cycles for combination immunotherapy or 21-day cycles for combination 
chemo-immunotherapy and may continue as long as the subject is receiving benefit from 
treatment and has not met any criteria for study withdrawal.  If the subject discontinues all study 
treatment, the treatment period will end, and the subject will enter the safety follow-up period 
(see Section 6.4).   
Individual subject participation will be approximately 12 to 18 months for Phase 1 and 
approximately 42 months for Phase 2 for a total of 60 months.  
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5.6. 
Rationale for Dose Modifications 
The purpose of the dose-escalation in Phase 1 Part 1 is to establish a suitable dose of epacadostat 
in combination with nivolumab.  Thus, toxicities during the first 42 days of treatment will be 
used to define tolerability. 
Modifications to epacadostat dose regimens are planned for Phase 1 Part 2 combination 
chemo-immunotherapy cohorts.  Independent of the determination of tolerability during Phase 1 
Part 1 or Part 2, subjects may require individual modification of epacadostat or nivolumab in 
Part 1 or modifications of epacadostat, nivolumab, or chemotherapy regimen if necessitated by 
drug-related or unrelated AEs, including irAEs or DLTs.  Dose modifications are summarized in 
Section 5.7.1. 
5.6.1. 
Definition of Dose-Limiting Toxicities 
A DLT will be defined as the occurrence of any treatment-emergent AE in Table 6 occurring up 
to and including study Day 42 (6-week observation period) in Phase 1 Parts 1 and 2.  
Dose-limiting toxicities include all treatment-emergent AEs of the specified grades, regardless of 
investigator attribution or relatedness. 
Only toxicities with a clear alternative explanation (eg, due to disease progression); transient 
(≤ 72 hours) abnormal laboratory values without associated clinically significant signs or 
symptoms based on investigator determination; or irAEs of Grade 3 or higher that improve to 
Grade 1 or lower by appropriate care or corticosteroid therapy within 14 days after the initiation 
of supportive care can be deemed a non-DLT. 
For the purpose of making decisions on dose escalation from a safety perspective during the 
DLT observation period, subjects will be considered evaluable for dose tolerability if they meet 
1 of the following criteria: 
• In Phase 1 Part 1, subjects must have received at least 2 out of the 3 scheduled 
nivolumab doses (only if the 1 missed dose was secondary to nonmedical reasons) 
and must have received at least 75% of the cohort-specified dose of epacadostat 
through the 6-week (42-day) DLT observation period. 
• In Phase 1 Part 2, subjects must have received at least 2 doses of the scheduled 
nivolumab doses, 75% of planned doses of chemotherapy regimen (only if the 
1 missed dose was secondary to nonmedical reasons), and at least 75% of the 
cohort-specified dose of epacadostat in C1D1 during the DLT observation period. 
In addition, subjects with dose delays of > 1 week for non-DLT events during the DLT 
observation period will be considered not evaluable for making decisions on dose-escalation 
cohorts or dose de-escalation cohorts and should be replaced. 
Dose escalation (combination immunotherapy) or de-escalation (combination 
chemo-immunotherapy) of epacadostat will be based on the number of DLTs experienced during 
the DLT observation period.  Dose modifications should not be made during the DLT 
observation period without discussion with the medical monitor. 
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Table 6: 
Criteria for Defining Dose-Limiting Toxicities 
Toxicity 
Hematologic Toxicities: 
• Any Grade 4 (life-threatening) thrombocytopenia or neutropenia lasting > 7 days.
• Febrile neutropenia ≥ Grade 3 for 72 hours.
• ≥ Grade 3 hemolysis.
• Grade 4 (life-threatening) anemia not explained by underlying disease.
• ≥ Grade 3 thrombocytopenia with clinically significant bleeding or requirement for a transfusion.
Nonhematologic Toxicities: 
• Any Grade 4 (life-threatening) irAE.
• Grade 4 (life-threatening) nausea, vomiting, or diarrhea.
• Grade 4 (life-threatening) electrolyte abnormality, regardless of duration or response to management.
• Any ≥ Grade 3 AST, ALT, or total bilirubin elevation.
• Grade 2 AST or ALT with symptomatic liver inflammation.
• AST or ALT > 3 × ULN and concurrent total bilirubin > 2 × ULN without initial findings of cholestasis.
• Any other ≥ Grade 3 toxicity EXCLUDING the following:
− Transient (≤ 72 hours) abnormal laboratory values without associated clinically significant signs or
symptoms. 
− Grade 3 nausea/vomiting controlled by medical intervention within 48 hours.
− Episcleritis, uveitis, or iritis of Grade 2 or higher.
− Grade 3 rash in the absence of desquamation, without mucosal involvement, and not requiring systemic
steroids and that resolves to Grade 1 by the next scheduled dose of nivolumab or ≤ 14 days, whichever is 
longer. 
− An event clearly associated with the underlying disease, disease progression, a concomitant medication, or 
comorbidity. 
− Asymptomatic 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). 
− irAEs of Grade 3 or higher that improve to ≤ Grade 1 in ≤ 14 days by appropriate care or with corticosteroid 
therapy. 
5.6.1.1. 
Procedures for Cohort Review and Dose Escalation 
Telephone conferences will be scheduled by the sponsor with Phase 1 investigators in order to 
review cohort-specific data, overall safety data from prior cohorts (if applicable), and to agree on 
dose escalation.  For additional safety oversight, this group will review and adjudicate individual 
high-grade AEs as potentially dose limiting and for guiding the study team on decisions 
regarding dose escalation and cohort expansion.  The same method will be used for reviewing 
data at the end of the dose-escalation portion of the study to determine the recommended dose 
for the dose-expansion portion of the study. 
5.6.1.2. 
Follow-Up for Dose-Limiting Toxicities 
Subjects whose treatment is discontinued because of a DLT must be followed until resolution or 
stabilization of the DLT event, whichever comes first. 
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5.7. 
Dose Modification of Study Drugs 
5.7.1. 
Planned Dose Modifications 
Intrasubject dose escalations are not permitted.  Subjects will remain on their cohort-assigned 
dose, or a lower dose of epacadostat if required because of AEs, throughout the treatment and 
extension phases.  Table 7 describes epacadostat dose reductions that may occur due to any 
related AEs. 
There will be no dose reductions of nivolumab allowed for the management of toxicities of 
individual subjects.  Doses of nivolumab may be delayed for toxicity management.  
In combination chemo-immunotherapy cohorts, if cisplatin is selected as a part of a specific 
chemotherapy regimen, then the cisplatin starting dose will be 100 mg/m2 at C1D1.  However, if 
a subject develops ≥ Grade 3 nausea and/or vomiting that prevents administration of the daily 
epacadostat doses for more than 3 days within that cycle, then the cisplatin dose may be 
de-escalated to 75 mg/mg2 starting on C2D1, with the medical monitor's approval.  Once the 
cisplatin dose is reduced to 75 mg/m2, it should remain reduced at subsequent doses and cycles.  
No dose escalation of cisplatin and/or any other chemotherapy drugs is permitted. 
Table 7: 
Dose Reductions of Epacadostat 
Current Dose 
Dose Reduction 
300 mg BID 
100 mg BID 
100 mg BID 
50 mg BID 
50 mg BID 
25 mg BID 
5.7.2. 
Criteria and Procedures for Interruption 
In some circumstances, it may be necessary to temporarily interrupt study treatments as a result 
of AEs that may have an unclear relationship to the study drug(s).  If an interruption is necessary, 
both study treatments should be interrupted. 
Any dose interruptions of > 2 weeks for LFT abnormalities must be discussed with the medical 
monitor before resuming treatment.  Treatment with both study drugs should be withheld for 
drug-related Grade 4 hematologic toxicities, nonhematological toxicity ≥ Grade 3 (including 
laboratory abnormalities), and severe or life-threatening AEs.  
Table 8 summarizes the dose administration guidance for nivolumab and epacadostat that should 
be implemented with the indicated drug-related AEs.  Additional information related to dose 
changes for epacadostat and nivolumab for specific AEs can be found in Section 5.7.3 for irAEs 
and Section 5.7.4 for an AE of SS.  Additional guidance for the management and follow-up for 
specific irAE can be found in Appendix C.  For all dose decisions for nivolumab, Appendix C 
should be followed for those specific events of clinical interest.  In the event guidance in 
Appendix C differs from Section 5.7.3, then Appendix C should be followed for any decision on 
dose administration for nivolumab and Section 5.7.3 should be followed for decisions on dose 
administration for epacadostat. 
Except in cases of emergency, it is recommended that the investigator consult with the sponsor's 
medical monitor (or other representative of the sponsor) before temporarily interrupting therapy 
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for reasons other than Protocol-mandated medication hold.  Additionally, the investigator must 
notify the sponsor's medical monitor and study project manager via email or during safety 
teleconferences before restarting study drug that was temporarily interrupted because of an AE. 
Dose modifications for hematologic and nonhematologic AEs related to chemotherapy may be 
managed per institutional guidelines.  In the absence of these guidelines, recommendations for 
dose modifications for epacadostat, nivolumab, and applicable chemotherapy doublet regimen in 
the event of hematologic and nonhematologic AEs are provided in the Protocol appendices: 
•
Appendix I for subjects who receive paclitaxel/platinum
•
Appendix J for subjects who receive pemetrexed/platinum
•
Appendix K for subjects who receive platinum/5-FU
It is important to note that some AEs will overlap with potential irAEs.  In these cases, both the 
AE and irAE guidance within the applicable appendix should be reviewed to determine the most 
appropriate management of study medications. 
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Table 8: 
Dose Modification Guidelines for Drug-Related Adverse Events for Combination Immunotherapy 
Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing for 
Treatment 
Restart 
Dose/Schedule for Treatment Restart 
Discontinue Subject  
(After Medical Monitor 
Consultation) 
Epacadostat 
Nivolumab 
Hematologic toxicity 
1, 2, 3 
No 
N/A 
N/A 
N/A 
N/A 
4 
Yes 
Toxicity 
resolves to 
≤ Grade 1 or 
baseline 
Reduce dose by 
1 dose level. 
Restart at same dose for 
the following events:  
Grade 4 neutropenia 
lasting ≤ 7 days, Grade 4 
lymphopenia or 
leukopenia.  For all other 
Grade 4 Hematologic 
toxicities, treatment with 
nivolumab may not be 
restarted.  (Note:  In case 
nivolumab is discontinued 
permanently, epacadostat 
should be discontinued as 
well.) 
Toxicity does not resolve 
within 6 weeks of last 
infusion.  Permanent 
discontinuation should be 
considered for any severe or 
life-threatening event. 
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Table 8: 
Dose Modification Guidelines for Drug-Related Adverse Events for Combination Immunotherapy  (Continued) 
Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing for 
Treatment 
Restart 
Dose/Schedule for Treatment Restart 
Discontinue Subject  
(After Medical Monitor 
Consultation) 
Epacadostat 
Nivolumab 
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
desquamation, without
mucosal involvement, and not
requiring systemic steroids and
that resolves to Grade 1 within
14 days
For additional information 
regarding AE with potential 
immune etiology, see 
Section 5.7.3. 
1 
No 
N/A 
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. 
Toxicity does not resolve 
within 6 weeks of last 
infusion. 
3
a
Yesa
Toxicity 
resolves to 
≤ Grade 1 or 
baseline 
Restart at 1 dose 
level lower. 
Restart at same dose.a
Toxicity does not resolve 
within 6 weeks of last 
infusion.  Permanent 
discontinuation should be 
considered for any severe or 
life-threatening event. 
4 
Yes 
Toxicity 
resolves to 
≤ Grade 1 or 
baseline 
Restart at 1 dose 
level lower. 
Restart only as noted.
b   
For all other Grade 4 
nonhematologic toxicities, 
treatment with nivolumab 
may not be restarted.  
(Note:  In case nivolumab 
is discontinued 
permanently, epacadostat 
should be discontinued as 
well.) 
Toxicity does not resolve 
within 6 weeks of last 
infusion.  Permanent 
discontinuation should be 
considered for any severe or 
life-threatening event. 
Note:  Subjects who experience a recurrence of the same severe or life-threatening AE at the same grade or greater treatment should be discontinued from study treatment. 
a The following exceptions for asymptomatic 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 recommended to consult with the medical monitor for Grade 3 amylase or lipase abnormalities. 
b Isolated Grade 4 lipase or amylase abnormalities not associated with symptoms or clinical manifestations of pancreatitis.  Medical monitor should be consulted for any G4 
amylase or lipase abnormality. 
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5.7.3. 
Procedures for Subjects Exhibiting Immune-Related Adverse Events 
This section is meant to apply to suspected irAEs from epacadostat, nivolumab or the 
combination. 
Immune-related AEs may be defined as an AE of unknown etiology, associated with drug 
exposure and consistent with an immune phenomenon.  Immune-related AEs may be predicted 
based on the nature of the nivolumab or epacadostat compounds, their mechanism of action, and 
reported 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 
shortly after the first dose or several months after the last dose of treatment. 
If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, toxin 
or other etiologic causes before labeling an AE as an irAE.  Subjects who develop a ≥ Grade 2 
irAE should be discussed immediately with the sponsor. 
General recommendations to managing irAEs not detailed elsewhere in the Protocol are detailed 
in Table 9.  Recommendations for management of specific immune-mediated AEs such as 
pneumonitis (Section 5.7.3.1), enterocolitis (Section 5.7.3.2), hepatitis (Section 5.7.3.3), 
dermatitis (Section 5.7.3.4), neuropathies (Section 5.7.3.5), endocrinopathies (Section 5.7.3.6), 
and other immune-mediated AEs (Section 5.7.3.7) are detailed in the sections below and  
specific guidance related to immune toxicity management and follow-up related to nivolumab 
can be found in Appendix C. 
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Table 9: 
General Approach to Handling Immune-Related Adverse Events 
irAE 
Withhold/Discontinue 
Nivolumab and 
Epacadostat 
Guidance for Restarting Study 
Treatment 
Supportive Care 
Grade 1 
No action. 
Not applicable. 
Provide symptomatic 
treatment. 
Grade 2 
May withhold 
nivolumab and 
epacadostat per 
investigator's discretion. 
May return to treatment if improves to 
Grade 1 or resolves within 6 weeks.  If AE 
resolves within 4 weeks, subject may restart 
at the same dose and schedule for both 
nivolumab and epacadostat. 
For an AE that does not resolve within 
4 weeks, epacadostat should be reduced 
1 dose level, but nivolumab 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. 
Consider systemic 
corticosteroids in addition 
to appropriate 
symptomatic treatment. 
Grade 3  
Withhold or discontinue 
nivolumab and 
epacadostat. 
Discontinue if unable to 
reduce corticosteroid 
dose to < 10 mg/day of 
prednisone or equivalent 
within 6 weeks of 
toxicity. 
Any restart of study treatment must be 
discussed with medical monitor before 
restarting treatment. 
Systemic corticosteroids 
are indicated in addition 
to appropriate 
symptomatic treatment.  
May use 1 to prednisone 
2 mg/kg 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. 
Grade 4 
Discontinue nivolumab 
and/or epacadostat. 
Not applicable.  Any exceptions require 
medical monitor approval. 
Systemic corticosteroids 
are indicated in addition 
to appropriate 
symptomatic treatment.  
May use 1 to prednisone 
2 mg/kg 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. 
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5.7.3.1. 
Procedures and Guidelines for Pneumonitis 
Subjects with symptomatic pneumonitis should immediately stop receiving nivolumab and 
epacadostat and have an evaluation.  The evaluation may include bronchoscopy to rule out other 
causes such as infection.  If the subject is determined to have study drug−associated pneumonitis, 
the suggested treatment plan is detailed in Table 10. 
Table 10: 
Recommended Approach to Handling Noninfectious Pneumonitis 
Study Drug(s) 
Associated 
Pneumonitis 
Withhold/Discontinue 
Nivolumab and 
Epacadostat 
Guidance for Restarting Study 
Treatment 
Supportive Care 
Grade 1 
(asymptomatic) 
No action. 
Not applicable. 
Intervention not 
indicated.
a 
Grade 2 
Withhold nivolumab and 
epacadostat. 
First episode of pneumonitis: 
• If improves to near baseline:
- Decrease the dose of epacadostat by
1 dose level, and for nivolumab, 
restart at same dose and schedule for 
subsequent cycles. 
• If not improved after 2 weeks or
worsening permanently, discontinue
nivolumab.  Discuss with medical
monitor if restart with epacadostat is
permitted.  (Note:  In case nivolumab is
discontinued permanently, epacadostat
should be discontinued as well.)
Second episode of pneumonitis: 
• Permanently discontinue nivolumab and
epacadostat if upon rechallenge subject
develops pneumonitis ≥ Grade 2.
Systemic 
corticosteroids are 
indicated.  Taper if 
necessary.a 
Grades 3 and 4 
Discontinue nivolumab 
and epacadostat. 
Not applicable.  Any exceptions require 
medical monitor approval. 
Systemic 
corticosteroids are 
indicated.  The use 
of infliximab may 
be indicated as 
appropriate.  See 
Appendix C for 
additional 
recommendations. 
a See Appendix C for additional guidance. 
5.7.3.2. 
Procedures and Guidance for Enterocolitis 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, 
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 ruled out 
and endoscopic evaluation should be considered for persistent or severe symptoms.  
Recommendations for management of enterocolitis are shown in Table 11 as well as additional 
information in Appendix C. 
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Table 11: 
Recommended Approach for Handling Enterocolitis 
Study Drug(s) 
Associated 
Enterocolitis 
Withhold/Discontinue 
Nivolumab and 
Epacadostat 
Guidance for Restarting Study 
Treatment 
Supportive Care 
Grade 1 
No action. 
Not applicable. 
All subjects who experience 
diarrhea should be advised to 
drink liberal quantities of clear 
fluids.  If sufficient oral fluid 
intake is not feasible, fluid and 
electrolytes should be 
substituted via IV infusion.  
An antidiarrheal can be 
started. 
Grade 2 
Withhold nivolumab 
and epacadostat. 
May return to treatment if 
improves to Grade 1.  If AE 
resolves within 4 weeks, subject 
may restart at the same dose and 
schedule for both nivolumab and 
epacadostat.   
For an AE that does not resolve 
within 4 weeks, epacadostat 
should be reduced 1 dose level, 
but nivolumab 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. 
An antidiarrheal should be 
started.  If symptoms are 
persistent for > 1 week, 
systemic corticosteroids 
should be initiated 
(eg, 0.5-1 mg/kg per day of 
prednisone or equivalent).  
When symptoms improve to 
≤ Grade 1, corticosteroid taper 
should be started and 
continued over at least 
1 month. 
Grades 3 and 4 
Discontinue nivolumab 
and epacadostat. 
Not applicable.  Any exceptions 
require medical monitor approval. 
Treatment with systemic 
corticosteroids should be 
initiated at a dose of 1 to 
2 mg/kg per day of prednisone 
or equivalent.  Systemic 
corticosteroids are indicated.  
The use of infliximab may be 
indicated as appropriate.  
When symptoms improve to 
≤ Grade 1, corticosteroid taper 
should be started and 
continued over at least 
1 month. 
5.7.3.3. 
Procedures and Guidance for Hepatitis 
Liver chemistry tests (hepatic transaminase and bilirubin levels) should be monitored and signs 
and symptoms of hepatotoxicity should be assessed before each dose of nivolumab and 
epacadostat.  In subjects with hepatotoxicity, infectious or malignant causes should be ruled out 
and frequency of LFT monitoring should be increased until resolution.  Recommendations for 
management of hepatitis are shown in Table 12 as well as additional information for 
management and follow-up in Appendix C.  See Section 8.2.2 for reporting requirements for 
certain cases that may be considered SAEs. 
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Table 12: 
Recommended Approach for Handling Hepatitis 
Study Drug(s) 
Associated 
Hepatitis 
Withhold/Discontinue 
Nivolumab and 
Epacadostat 
Guidance for Restarting Study 
Treatment 
Supportive Care 
Grade 1 
No action. 
Not applicable. 
Increase frequency of LFT 
monitoring to twice per week 
until LFTs return to baseline. 
Grade 2 
Withhold nivolumab 
and epacadostat. 
If AE resolves to ≤ Grade 1 or 
baseline within 4 weeks, subject 
may restart at the same dose and 
schedule for both nivolumab and 
epacadostat.  For an AE that does 
not resolve within 4 weeks, 
epacadostat should be reduced 
1 dose level, but nivolumab 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. 
Increase frequency of LFT 
monitoring to twice per week 
until LFTs return to baseline.  
If elevation persists for 
> 1 week, systemic 
corticosteroids should be 
initiated (eg, 0.5 mg/kg per 
day of prednisone or 
equivalent).  When symptoms 
improve to ≤ Grade 1, 
corticosteroid taper should be 
started and continued over at 
least 1 month. 
Grades 3 and 4 
Discontinue nivolumab 
and epacadostat. 
Not applicable.  Any exceptions 
require medical monitor approval. 
Increase frequency of LFT 
monitoring to every 1-2 days. 
Treatment with systemic 
corticosteroids should be 
initiated at a dose of 1 to 
2 mg/kg per day of prednisone 
or equivalent.  When 
symptoms improve to 
≤ Grade 1, corticosteroid taper 
should be started and 
continued over at least 
1 month. 
5.7.3.4. 
Procedures for Immune-Mediated Dermatitis 
Monitor subjects for signs and symptoms of dermatitis such as rash and pruritus.  Unless an 
alternate etiology has been identified, signs or symptoms of dermatitis should be considered 
immune mediated.  Recommendations for management of dermatitis are shown in Table 13 as 
well as additional information for management and follow-up in Appendix C. 
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Table 13: 
Recommended Approach for Handling Dermatitis 
irAE 
Withhold/Discontinue 
Nivolumab and Epacadostat 
Guidance for Restarting 
Study Treatment 
Supportive Care 
Grade 1 
No action. 
Not applicable. 
For mild to moderate 
dermatitis, such as 
localized rash and 
pruritus, treat 
symptomatically.  
Administer topical or 
systemic corticosteroids if 
there is no improvement 
of symptoms within 
1 week. 
Grade 2 
No action. 
Not applicable. 
For mild to moderate 
dermatitis, such as 
localized rash and 
pruritus, treat 
symptomatically.  
Administer topical or 
systemic corticosteroids if 
there is no improvement 
of symptoms within 
1 week. 
Grades 3 and 4 
Withhold epacadostat and /or 
nivolumab in subjects with 
moderate to severe signs and 
symptoms of rash.   
Permanently discontinue 
epacadostat and nivolumab in 
subjects with Stevens-Johnson 
syndrome, toxic epidermal 
necrolysis, or rash complicated by 
full thickness dermal ulceration or 
by necrotic, bullous, or 
hemorrhagic manifestations.  
If AE resolves to baseline 
within 4 weeks, subject may 
restart at the same dose and 
schedule for both nivolumab 
and epacadostat.  For an AE 
that does not resolve within 
4 weeks, epacadostat should 
be reduced 1 dose level, but 
nivolumab 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 
corticosteroids at a dose 
of 1 to 2 mg/kg per day of 
prednisone or equivalent.  
When dermatitis is 
controlled, corticosteroid 
tapering should occur over 
a period of at least 
1 month. 
5.7.3.5. 
Procedures for Immune-Mediated Neuropathies 
Subjects should be monitored for symptoms of motor or sensory neuropathy such as unilateral or 
bilateral weakness, sensory alterations, or paresthesia.  Recommendations for management of 
neuropathies are shown in Table 14 as well as additional information for management and 
follow-up in Appendix C.  
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Table 14: 
Recommended Approach for Handling Neuropathies 
irAE 
Withhold/Discontinue 
Nivolumab and 
Epacadostat 
Guidance for Restarting 
Study Treatment 
Supportive Care 
Grade 1 
No action. 
Not applicable. 
Provide symptomatic 
treatment. 
Grade 2 
May withhold nivolumab 
and epacadostat. 
If AE resolves to ≤ Grade 1 or 
baseline within 4 weeks, 
subject may restart at the same 
dose and schedule for both 
nivolumab and epacadostat.  
For an AE that does not 
resolve within 4 weeks, 
epacadostat should be reduced 
1 dose level, but nivolumab 
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. 
Consider systemic 
corticosteroids in addition to 
appropriate symptomatic 
treatment. 
Grades 3 and 
4 
Discontinue nivolumab and 
epacadostat. 
Not applicable.  Any 
exceptions require medical 
monitor approval. 
Consider initiation of systemic 
corticosteroids at a dose of 1 
to 2 mg/kg per day prednisone 
or equivalent for severe 
neuropathies.   
Institute medical intervention 
as appropriate for 
management of severe 
neuropathy.   
5.7.3.6. 
Procedures for Immune-Mediated Endocrinopathies 
Subjects should be monitored for clinical signs and symptoms of hypophysitis, adrenal 
insufficiency (including adrenal crisis), and hyper- or hypothyroidism.  Subjects may present 
with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and 
hypotension or with nonspecific symptoms which may resemble other causes such as brain 
metastasis or underlying disease.  Unless an alternate etiology has been identified, signs or 
symptoms of endocrinopathies should be considered immune-mediated. 
Thyroid function tests and clinical chemistries should be monitored at the start of treatment, 
before each dose, and as clinically indicated based on symptoms.  In a limited number of 
subjects, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary 
gland.  Recommendations for management of endocrinopathies are shown in Table 15.  For 
additional information on detailed management of asymptomatic thyroid-stimulating hormone 
(TSH) elevation versus symptomatic endocrinopathy, see Appendix C. 
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Table 15: 
Recommended Approach for Handling Endocrinopathies 
irAE 
Withhold/Discontinue 
Nivolumab and 
Epacadostat 
Guidance for Restarting Study 
Treatment 
Supportive Care 
Grade 1 
No action. 
Not applicable. 
Provide symptomatic 
treatment. 
Grade 2 
May withhold 
nivolumab and 
epacadostat. 
If AE resolves within 4 weeks, subject 
may restart at the same dose and 
schedule for both nivolumab and 
epacadostat.  For an AE that does not 
resolve within 4 weeks, epacadostat 
should be reduced 1 dose level, but 
nivolumab 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. 
Initiate systemic 
corticosteroids treatment at a 
dose of 1 to 2 mg/kg per day 
of prednisone or equivalent, 
and initiate appropriate 
hormone replacement therapy. 
Grade 3 
Withhold or discontinue 
both nivolumab and 
epacadostat. 
If AE resolves or is controlled within 
4 weeks, subject may restart at the same 
dose and schedule for both nivolumab 
and epacadostat.  For an AE that does 
not resolve within 4 weeks, epacadostat 
should be reduced 1 dose level, but 
nivolumab 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. 
Consider initiating systemic 
corticosteroids treatment at a 
dose of 1 to 2 mg/kg per day 
of prednisone or equivalent, 
and initiate appropriate 
hormone replacement therapy. 
Grade 4 
Discontinue both 
nivolumab and 
epacadostat. 
Not applicable.  Any exceptions require 
medical monitor approval. 
Consider initiation of systemic 
corticosteroids at a dose of 
1 to 2 mg/kg per day of 
prednisone or equivalent, and 
initiate appropriate hormone 
replacement therapy.   
5.7.3.7. 
Procedures for Other Immune-Mediated Adverse Reactions, Including Ocular 
Manifestations 
Epacadostat and nivolumab should be permanently discontinued for severe immune-mediated 
adverse reactions.  Systemic corticosteroids 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. 
Corticosteroid eye drops should be administered to subjects who develop uveitis, iritis, or 
episcleritis.  Epacadostat and nivolumab should be permanently discontinued for 
immune-mediated ocular disease that is unresponsive to local immunosuppressive therapy.  
For additional management and follow-up guidance for renal immune events see Appendix C. 
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5.7.4. 
Procedures for Subjects Exhibiting Serotonin Syndrome 
As noted in Section 1.3, there is a chance that epacadostat could cause an increase in serotonin 
levels in the brain that might trigger SS (Boyer and Shannon 2005) when administered in 
combination with other serotonergic agents.  This syndrome has been most closely associated 
with use of MAOIs, meperidine/pethidine, linezolid, or methylene blue; all of these agents are 
prohibited during the study.  Serotonin reuptake inhibitors and SNRIs are permitted in the study.  
Serotonin syndrome usually manifests with autonomic changes, mental status changes, and 
neurological findings.  These mild, moderate, and severe signs and symptoms of SS (summarized 
in Table 16) should be evaluated in the context of possible comorbid conditions as well.  
The following procedures will be implemented if subjects exhibit the signs/symptoms of SS 
described in Table 16, including tremor, hyperreflexia, spontaneous, ocular, or inducible clonus, 
together with agitation, fever, diaphoresis, or muscle rigidity: 
•
Immediately interrupt study treatment administration.
•
Immediately interrupt any SSRI or SNRI administration.
•
Provide appropriate medical management of the subject until all signs/symptoms are
resolved (eg, IV fluids and/or sympathomimetic amines for hypotension,
benzodiazepines for agitation, administration of 5-hydroxytryptamine antagonists
such as cyproheptadine).
•
If etiologies other than serotonin syndrome are excluded, nivolumab administration
may be resumed unless other AE management guidelines apply for the specific event.
•
If subject chooses to remain in the study, restart treatment with epacadostat after the
SSRI or SNRI has been discontinued, no sooner than 5 half-lives have elapsed for the
specific SSRI or SNRI in question and after resolution of signs/symptoms of SS.  The
SSRI or SNRI treatment MAY NOT be restarted.
•
If subject chooses to withdraw from the study, or must restart treatment with SSRI or
SNRI, the subject should be scheduled for a follow-up visit.  Treatment with SSRI or
SNRI may be initiated 2 weeks after resolution of signs and symptoms of SS.
•
If a subject has experienced moderate or severe unconfounded SS in the opinion of
the investigator, without concomitant SSRI or SNRI usage, or serotonergic
concomitant medications, only nivolumab administration may be resumed;
epacadostat treatment should be permanently discontinued.
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Table 16: 
Signs and Symptoms of Serotonin Syndrome 
Seriousness 
Autonomic Signs 
Neurological Signs 
Mental Status 
Other 
Mild 
Afebrile or low-grade 
fever 
Tachycardia 
Mydriasis 
Diaphoresis or 
shivering 
Intermittent tremor 
Akathisia 
Myoclonus 
Mild hyperreflexia 
Restlessness 
Anxiety 
 
Moderate 
Increased tachycardia 
Fever (up to 41 °C) 
Diarrhea with 
hyperactive bowel 
sounds 
Diaphoresis with 
normal skin color 
Hyperreflexia 
Inducible clonus 
Ocular clonus (slow 
continuous lateral eye 
movements) 
Myoclonus 
Easily startled 
Increased confusion 
Agitation and 
hypervigilance 
Rhabdomyolysis 
Metabolic acidosis 
Renal failure 
Disseminated 
intravascular 
coagulopathy 
(secondary to 
hyperthermia) 
Severe 
Temperature often 
more than 41°C 
(Secondary to 
increased tone) 
Increased muscle tone 
(lower limb > upper) 
Spontaneous clonus 
Substantial 
myoclonus or 
hyperreflexia 
Delirium 
Coma 
As above 
Source:  Boyer and Shannon 2005. 
5.8. 
Criteria for Permanent Discontinuation of Study Drug(s) 
Subjects may withdraw consent at any time for any reason or be withdrawn from the study at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the sponsor if enrollment into the study is inappropriate, the 
study plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal are provided in Section 7.7.7, Withdrawal or 
Discontinuation. 
Subjects must be withdrawn from the study treatment for the following reasons: 
• In the investigator's medical judgment, further participation would be injurious to the 
subject's health or well-being. 
• The subject becomes pregnant. 
• Consent is withdrawn by the subject or legal representative (such as parent or legal 
guardian). 
• The study is terminated by the sponsor. 
• The study is terminated by the local health authority or IRB/IEC. 
• Radiographic progression of disease per RECIST (Appendix E), Cheson 
(Appendix F), or RANO (Appendix H).  See Section 7.5. 
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•
The subject has experienced an unacceptable toxicity or a toxicity that does not
recover in 6 weeks.  Investigators who wish to continue treatment after a treatment
delay of 4 weeks should consult with the sponsor's medical monitor for approval.
•
Noncompliance with study treatment or procedure requirements.
•
The subject is lost to follow-up.
•
The subject has received study treatment for 2 years (ie, 2 years have elapsed since
Cycle 1 Day 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, then the medical monitor, in collaboration with the investigator, will
determine whether the subject should be withdrawn from the study.
•
If a subject is noncompliant with study procedures or study drug administration in the
investigator's opinion, then the sponsor should be consulted for instruction on
handling the subject.
The EOT and follow-up visit procedures are listed in Section 6 (Table 20 and Table 24).  After 
the EOT, each subject will be followed for 2 safety follow-up visits at 30 and 100 days after the 
last dose of combination treatment for AE and SAE monitoring as described in Section 8.3.2. 
5.9. 
Study Completion 
5.9.1. 
Study Completion Criteria 
Subjects will be considered completing the study if they met any of the following criteria: 
•
Subject dies and a date of death is available.
•
Subject is known to have died; however, the date of death cannot be obtained.
(NOTE:  every effort must be made to obtain the date of death.)
•
Subject completes the 100-day safety follow-up period.
•
Consent is withdrawn for any further 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 otherwise 
entitled.  Every reasonable effort should be made to determine the reason a 
subject withdraws prematurely, and this information should be recorded in the 
eCRF. 
•
The study is terminated by the sponsor.
•
The study is terminated by the local health authority or IRB or IEC.
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5.9.2. 
Withdrawal Procedures 
In the event that any subject discontinues study drug and, subsequently, withdraws from the 
study before completion, regardless of reason, reasonable efforts should be made to have the 
subject return for the EOT procedures to be completed as described in Section 6.3.  The date the 
subject was withdrawn from the study and the specific reason for withdrawal will be recorded in 
the eCRF. 
If a subject is withdrawn from the study: 
•
The study monitor or sponsor must be notified.
•
The reason(s) for withdrawal must be documented in the subject's medical record and
in the eCRF.
•
The EOT or early termination visit should be performed.
•
Subjects must be followed for safety until the time of the follow-up visit or until
study drug–related toxicities resolve, return to baseline, or are deemed irreversible,
whichever is longer.
5.10. 
Beginning and End of the Study 
The study begins when the first subject signs the informed consent.  The end of the study may be 
designated as the timepoint when all subjects have discontinued the study or are a minimum of 
6 months after initial study medication administration.  If by the end of the study there remains at 
least 1 subject still on study treatment for at least 6 months, the subject(s) may enter additional 
treatment cycles.  At this point a database lock of the study may occur to allow the analysis of 
the study data.  Any remaining subjects may continue to receive study medication per Protocol.  
The subject is considered on study until such time that he/she meets any of the study completion 
criteria and written notification is given to the sponsor. 
5.11. 
Concomitant Medications and Measures 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study.  If there is a clinical indication for 1 of these or other medications or 
vaccinations specifically prohibited during the study, discontinuation from study therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this with 
the sponsor.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on study therapy or vaccination schedule requires the mutual agreement of the 
investigator, the sponsor, and the subject. 
5.11.1. 
Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject's welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant 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 drug regimen, frequency, route, and date may 
also be included on the eCRF. 
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All concomitant medications received within 28 days before C1D1 and 30 days after the last 
dose of study treatment should be recorded.  Concomitant medications administered after 
30 days after the last dose of study treatment should be recorded for SAEs and AEs as defined in 
Section 8. 
5.11.2. 
Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator, including, but not limited to, the items outlined below: 
• Nausea/vomiting:  Nausea and vomiting should be treated aggressively, and 
consideration should be given in subsequent cycles to the administration of 
prophylactic antiemetic therapy according to standard institutional practice.  Subjects 
should be strongly encouraged to maintain liberal oral fluid intake. 
• Anti-infectives:  Subjects with a documented infectious complication should receive 
oral or IV antibiotics or other anti-infective agents as considered appropriate by the 
treating investigator for a given infectious condition, according to standard 
institutional practice. 
• Immune-related AEs:  See Section 5.7.3 regarding diagnosis and management of 
adverse experiences of a potential immunologic etiology. 
• Management of infusion reactions from nivolumab (Section 5.11.3). 
5.11.3. 
Management of Infusion Reactions From Nivolumab 
Since nivolumab contains only human Ig protein sequences, it is unlikely to be immunogenic and 
induce infusion or hypersensitivity reactions (current rate of reported infusion reactions for 
nivolumab 3 mg/kg is 6% [3/54] for any Grade, and 0 Grade 3 or 4 infusion reactions have been 
reported).  However, if such a reaction were to occur, it might manifest with fever, chills, rigors, 
headache, rash, pruritus, arthralgias, hypo- or hypertension, bronchospasm, or other symptoms.  
All Grade 3 or 4 infusion reactions should be reported within 24 hours to the medical monitor 
and reported as an SAE if criteria are met.  Infusion reactions should be graded according to 
National Cancer Institute (NCI) CTCAE (version 4.0) guidelines.  In Phase 2, for those 
experiencing an infusion reaction, infusion time may be increased to 60 minutes. 
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines as appropriate: 
For Grade 1 symptoms:  (Mild reaction; infusion interruption not indicated; intervention not 
indicated) 
Remain at bedside and monitor subject until recovery from symptoms.  The following 
prophylactic premedications are recommended for future infusions:  diphenhydramine 50 mg (or 
equivalent) and/or paracetamol 325 to 1000 mg (or acetaminophen) at least 30 minutes before 
additional nivolumab administrations. 
For Grade 2 symptoms:  (Moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [eg, antihistamines, nonsteroidal anti-inflammatory 
drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic medications indicated 
for ≥ 24 hours) 
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Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the subject with 
diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000 mg (or 
acetaminophen); remain at bedside and monitor subject until resolution of symptoms.  
Corticosteroid or bronchodilator therapy may also be administered as appropriate.  If the infusion 
is interrupted, then restart the infusion at 50% of the original infusion rate when symptoms 
resolve; if no further complications ensue after 30 minutes, the rate may be increased to 100% of 
the original infusion rate.  Monitor subject closely.  If symptoms recur, then no further 
nivolumab will be administered at that visit.  Administer diphenhydramine 50 mg IV, and remain 
at bedside and monitor the subject until resolution of symptoms.  The amount of study drug 
infused must be recorded on the eCRF.  The following prophylactic premedications are 
recommended for future infusions:  diphenhydramine 50 mg (or equivalent) and/or paracetamol 
325 to 1000 mg (or acetaminophen) should be administered at least 30 minutes before additional 
nivolumab administrations.  If necessary, corticosteroids (recommended dose:  up to 25 mg of IV 
hydrocortisone or equivalent) may be used. 
For Grade 3 or Grade 4 symptoms:  (Severe reaction, Grade 3:  prolonged [ie, not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical sequelae 
[eg, renal impairment, pulmonary infiltrates].  Grade 4:  life threatening; pressor or ventilatory 
support indicated).  
Immediately discontinue infusion of nivolumab.  Begin an IV infusion of normal saline, and treat 
the subject as follows:  Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution injected 
slowly for IV administration, and/or diphenhydramine 50 mg IV with methylprednisolone 
100 mg IV (or equivalent), as needed.  Subject should be monitored until the investigator is 
comfortable that the symptoms will not recur.  Nivolumab will be permanently discontinued.  
Investigators should follow their institutional guidelines for the treatment of anaphylaxis.  
Remain at bedside and monitor subject until recovery from symptoms.  In the case of 
late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized pruritus 
within 1 week after treatment), symptomatic treatment may be given (eg, oral antihistamine, or 
corticosteroids). 
In order to avoid the occurrence of severe hypersensitivity reactions, all patients treated with 
paclitaxel should be premedicated with corticosteroids (such as dexamethasone), 
diphenhydramine, and H2 antagonists (such as cimetidine or ranitidine) using applicable 
institutional guidelines.  Minor symptoms such as flushing, skin reactions, dyspnea, hypotension, 
or tachycardia do not require interruption of therapy.  However, severe reactions, such as 
hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema, or generalized 
urticaria require immediate discontinuation of paclitaxel and aggressive symptomatic therapy.  
Subjects who have developed severe hypersensitivity reactions should not be rechallenged with 
paclitaxel. 
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5.12. 
Restricted Medications and Measures 
•
Systemic steroids may be used at doses < 10 mg/day, and prednisone or equivalents
with medical monitor approval.
•
Use of coumarin-based anticoagulants (eg, warfarin) is discouraged.  Low-dose
warfarin (1 mg) is acceptable; however, doses that increase the INR are discouraged
and will require dose modification.  If an alternative to coumarin-based
anticoagulants cannot be used, dose modifications of the warfarin may be
needed.  Based on the observed magnitude of epacadostat/warfarin PK interaction and
PK/pharmacodynamic 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 in S- and
R-warfarin oral clearance values.  Close INR monitoring is recommended for subjects
on a stable dose of warfarin who are starting treatment with epacadostat.  Based on
PK/pharmacodynamic modeling, recommendations for warfarin dose modifications
for subjects receiving other epacadostat doses, are summarized in Table 17 based on
the INR before starting epacadostat.
Table 17: 
Warfarin Dose Adjustment Recommendation When Initiating Concurrent 
Epacadostat Treatment 
Stable Baseline INR 
Epacadostat  Dose 
≤ 100 mg BID 
200 mg BID 
300 mg BID 
INR ≤ 2.5 
Close INR monitoring 
Close INR monitoring 
Reduce warfarin by ~33% 
and monitor INR 
INR > 2.5 
Close INR monitoring 
Reduce warfarin by 
20%-25% and monitor INR 
Reduce warfarin by ~33% 
and monitor INR 
•
Use of the anticonvulsant carbamazepine (a UGT1A9 inducer) is discouraged.
Because there is a potential interaction that could result in lower epacadostat
exposures, an alternative to carbamazepine should be used, if possible.
5.13. 
Prohibited Medications and Measures 
Subjects are prohibited from receiving the following therapies during the screening and treatment 
period of this study unless otherwise noted below: 
•
Any investigational medication other than the study drugs.
•
Any anticancer medications, including chemotherapy or biologic therapy other than
the study medications.
•
Any immunological-based treatment for any reason.
− Note:  Inhaled or topical steroids are allowed, and systemic steroids at doses
< 10 mg/day prednisone or equivalents are allowed with medical monitor 
approval, as described in Section 5.12, and immune suppressants are allowed for 
treatment for immune toxicities. 
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− For subjects with glioblastoma:  Systemic corticosteroid use or physiologic 
replacement doses of steroids are permitted, even if > 10 mg/day prednisone 
equivalents, for:  a) treatment-related AEs; b) sequelae of underlying glioblastoma 
treatment; or c) treatment of non-autoimmune conditions (such as prophylaxis for 
contrast dye allergy, delayed-type hypersensitivity reaction caused by contact 
allergen).  Details regarding corticosteroid use before and during the study will be 
collected (name of medication, doses utilized, start and stop dates, frequency of 
use, route of administration).  Information regarding concomitant corticosteroid 
use may be analyzed with regard to study outcome measures. 
•
Radiation therapy
− Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be
allowed after consultation with the sponsor's medical monitor. 
•
Administration of live attenuated vaccines within 30 days before C1D1 and while
participating in the study is prohibited.  Examples of live vaccines include, but are not
limited to, the following:  measles, mumps, rubella, chicken pox, yellow fever, rabies,
BCG, and typhoid vaccine.  Seasonal influenza vaccines for injection are generally
killed virus vaccines and are allowed; however, intranasal influenza vaccines are live
attenuated vaccines and are not allowed.
•
Administration of an injectable influenza vaccine is prohibited during the DLT
observation period (ie, 42 days after C1D1).
•
Any MAOI or drug associated with significant MAO inhibitory activity agents is
prohibited from 21 days before Day 1 through 2 weeks after the final dose of
epacadostat has been taken (see Appendix D).
•
Any UGT1A9 inhibitor, including acitretin, amitriptyline, androsterone, cyclosporine,
dasatinib, diclofenac, diflunisal, efavirenz, erlotinib, flutamide, gefitinib, gemfibrozil,
glycyrrhetinic acid, glycyrrhizin, imatinib, imipramine, ketoconazole (systemic),
linoleic acid supplements, mefenamic acid, mycophenolic acid, niflumic acid,
nilotinib, phenobarbital, phenylbutazone, phenytoin, probenecid, quinidine, ritonavir,
sorafenib, sulfinpyrazone, valproic acid, and verapamil.
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the study.  Subjects may receive 
other medications that the investigator deems to be medically necessary. 
The exclusion criteria (Section 3.3) describe other medications that are prohibited during this 
study.  There are no prohibited therapies during the post-treatment follow-up period. 
6.
STUDY ASSESSMENTS
All study assessments will be performed as indicated in the schedules of assessments in Table 18 
through Table 25.  The order of assessments is suggested by the order of mention within the 
schedules.  For instructions on each assessment, see Section 7.  The required laboratory analytes 
are listed in Table 26. 
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Table 18: 
Schedule of Assessments for Screening Through Treatment Period (Combination Immunotherapy Cohorts With 
Nivolumab Q2W Dosing Schedule) 
Visit Day (Range) 
Screening 
Treatment Period 
C1D1 
C1D8 
Day 15, 29, 
and 43 
C2D1 
C2 Day 15, 
29, 43 
Day 1 All 
Subsequent 
Cycles 
Day 15, 29, 43 
All Subsequent 
Cycles 
Every 
12 Weeks 
Evaluation/Window 
Day -28 to 
Day -1 
Day 1 
± 3 Days 
± 3 Days 
± 3 Days 
± 3 Days 
± 3 Days 
± 3 Days 
± 7 Days 
Informed consent 
X 
Inclusion/exclusion criteria 
X 
X 
Prior medical and cancer history 
X 
Concomitant medications 
review 
X 
X 
X
a 
X 
X 
X 
X 
X 
Laboratory assessments 
X 
X 
X 
X 
X 
X 
X 
Administer epacadostat at clinic
X 
X
b
Administer nivolumab 
X 
X 
X 
X 
X 
X 
Comprehensive physical exam 
X 
Targeted physical exam 
X 
X 
X 
X 
X 
X 
Vital signs and weight (height at 
screening only) 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X
c
Xc 
X
d 
Xd 
Reminder card 
X 
X 
X 
X 
X 
X 
AE assessment 
X 
X 
Xa 
X 
X 
X 
X 
X 
Radiologic tumor assessments
e,f 
X  
Xf 
a Concomitant medication and AE assessments for C1D8 will be collected by phone call. 
b Epacadostat will need to be administered in the clinic on C1D1 and C1D15 only. 
c The ECG should be performed within 60 to 90 minutes (unless emerging 
 data suggest alternate timing) after the first dose of epacadostat on C1D1 and C1D15 only.  In 
addition, a predose ECG will be performed on C1D15. 
d After C1D15, ECG need only be performed as clinically indicated. 
e The same imaging technique should be used in a subject throughout the study.  Local reading will be used to determine eligibility and for subject management. 
f Imaging should be performed every 12 weeks (± 7 days) regardless of any treatment delays for up to 2 years after C1D1 and not be adjusted for delays in cycle starts or extension 
of combination treatment cycle frequencies. 
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Table 19: 
Schedule of Assessments for Screening Through Treatment Period (Combination Immunotherapy Cohorts With 
Nivolumab Q4W Dosing Schedule) 
Visit Day (Range) 
Screening 
Treatment Period 
C1D1 
C1D15 
C1D29 
C2D1 
C2D29 
Day 1 All 
Subsequent 
Cycles 
Day 29 
All 
Subsequent 
Cycles 
Every 
12 Weeks 
Evaluation/Window 
Day -28 to 
Day -1 
Day 1 
± 3 Days 
± 3 Days 
± 3 Days 
± 3 Days 
± 3 Days 
± 3 Days 
± 7 Days 
Informed consent 
X 
Inclusion/exclusion criteria 
X 
X 
Prior medical and cancer history 
X 
Concomitant medications review 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory assessments 
X 
X 
X 
X 
X 
X 
X 
X 
Administer epacadostat at clinic
X 
X
a 
Administer nivolumab 
X 
X 
X 
X 
X 
X 
Comprehensive physical exam 
X 
Targeted physical exam 
X 
X 
X 
X 
X 
X 
Vital signs and weight (height at 
screening only) 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X
b 
Xb 
X
c 
Xc 
Reminder card 
X 
X 
X 
X 
X 
X 
AE assessment 
X 
X 
X 
X 
X 
X 
X 
X 
Radiologic tumor assessments
d,e 
X 
Xe 
a Epacadostat will need to be administered in the clinic on C1D1 and C1D29 only. 
b The ECG should be performed within 60 to 90 minutes (unless emerging 
 data suggest alternate timing) after the first dose of epacadostat on C1D1 and C1D29 only.  In 
addition, a predose ECG will be performed on C1D29. 
c Starting from C2D1, ECG need only be performed as clinically indicated. 
d The same imaging technique should be used in a subject throughout the study.  Local reading will be used to determine eligibility and for subject management.  
e Imaging should always be performed every 12 weeks (± 7 days) regardless of any treatment delays for up to 2 years after C1D1 and should not be adjusted for delays in cycle 
starts. 
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Table 20: 
Schedule of Assessments End of Treatment Through Safety Follow-Up 
(Combination Immunotherapy Cohorts With Both Q2W and Q4W 
Nivolumab Dosing Schedules) 
Visit Day (Range) 
EOT 
Safety Follow-Up Period
a 
30 Days After EOT or 
Last Dose of Nivolumab 
100 Days After Last Dose 
of Nivolumab 
Evaluation/Window 
+ 5 Days 
± 7 Days 
± 7 Days 
Concomitant medications review 
X 
X 
X 
Comprehensive physical exam 
Targeted physical exam 
X 
X 
X 
Vital signs and weight (height at screening only) 
X 
AE assessment 
X 
X 
X 
Laboratory assessments
b 
X 
a Subjects must be followed for AEs and SAEs for 100 days after the last dose of study drug. 
b Safety laboratory assessments will be collected at EOT. 
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Table 21: 
Laboratory Assessments for Screening Through Treatment Period (Combination Immunotherapy Cohorts With 
Nivolumab Q2W Dosing Schedule) 
Visit Day (Range) 
Screening 
Treatment Period 
C1D1 
C1 Day 15, 29, 
and 43
C2D1 
C2 Day 15, 
29, 43
Day 1 
All Subsequent 
Cycles
Day 15, 29, 43 
All Subsequent 
Cycles
Evaluation/Window 
Day -28 to 
Day -1 
Day 1 
± 3 Days
± 3 Days 
± 3 Days 
± 3 Days 
± 3 Days 
Chemistry 
X 
X
a 
X 
X
X 
X 
X 
Hematology 
X 
Xa 
X 
X
X 
X 
X 
Liver chemistry tests 
X 
X 
X
b 
X 
Coagulation panel (PT, aPTT, INR) 
X 
Xa 
Endocrine function testing 
X 
Xa 
X
X
c 
Urinalysis 
X 
Serum pregnancy 
X
d 
Urine pregnancy test
e
X
X 
Serology for hepatitis B and hepatitis C testing
f 
X 
a C1D1 laboratory tests may be omitted if the screening laboratory tests were performed within 7 days before treatment initiation.  If performed more than 7 days before study 
treatment initiation, screening laboratory tests must be repeated to confirm the subject's eligibility on C1D1. 
b If LFTs are abnormal, twice weekly monitoring of LFTs are required until they return to baseline (LFTs include ALT, AST, and total bilirubin). 
c To be repeated every other cycle. 
d Serum pregnancy test required for women of child-bearing potential only and must be performed and confirmed negative within 72 hours before C1D1.  
e Urine pregnancy should be repeated on Day 1 of each cycle or as required by local regulations.  
f Hepatitis B and C serologies should be obtained for subjects without a known history of hepatitis B or C.  Those with a known history are ineligible.  See Table 26 for list of 
laboratory tests. 
 
 
 
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Table 22: 
Laboratory Assessments for Screening Through Treatment Period (Combination Immunotherapy Cohorts With 
Nivolumab Q4W Dosing Schedule) 
Visit Day (Range) 
Screening 
Treatment Period 
C1D1 
C1D15 
C1D29 
C2D1 
C2D29 
Day 1 
All Subsequent 
Cycles
Day 29 
All Subsequent 
Cycles
Evaluation/Window 
Day -28 to 
Day -1 
Day 1 
Day 1 
± 3 Days 
± 3 
Days 
± 3 Days 
± 3 Days 
± 3 Days 
Chemistry 
X 
X
a 
X 
X 
X 
X 
X 
X 
Hematology 
X 
Xa 
X 
X 
X 
X 
X 
X 
Liver chemistry tests 
X 
X 
X 
X
b 
X 
Coagulation panel (PT, aPTT, INR) 
X 
Xa 
Endocrine function testing 
X 
Xa 
X 
X
c 
Urinalysis 
X 
Serum pregnancy
d 
X 
Urine pregnancy test
e 
X 
X 
Serology for hepatitis B and hepatitis C testing
f 
X 
a C1D1 laboratory tests may be omitted if the screening laboratory tests were performed within 7 days before treatment initiation.  If performed more than 7 days before study 
treatment initiation, screening laboratory tests must be repeated to confirm the subject's eligibility on C1D1. 
b If LFTs are abnormal, twice weekly monitoring of LFTs are required until they return to baseline (LFTs include ALT, AST, and total bilirubin). 
c To be repeated every other cycle. 
d Serum pregnancy test required for women of child-bearing potential only and must be performed and confirmed negative within 72 hours before C1D1. 
e Urine pregnancy should be repeated on Day 1 of each cycle or as required by local regulations. 
f Hepatitis B and C serologies should be obtained for subjects without a known history of hepatitis B or C.  Those with a known history are ineligible.  See Table 26 for list of 
laboratory tests. 
 
 
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Table 23: 
Laboratory Assessments for End of Treatment Through Safety Follow-Up 
(Combination Immunotherapy Cohorts With Both Nivolumab Q2W and 
Q4W Dosing Schedules) 
Visit Day (Range) 
EOT 
Safety Follow-Up Period 
30 Days After EOT or 
Last Dose of Nivolumab 
100 Days After Last 
Dose of Nivolumab 
Evaluation/Window 
+ 5 Days 
± 7 Days 
± 7 Days 
Chemistry 
X 
X 
Liver chemistry testing 
X 
X 
Hematology 
X 
X 
Urine pregnancy test 
X 
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Table 24: 
Schedule of Assessments for Phase 1 Part 2 Subjects Treated With Epacadostat + Nivolumab (Q3W) + 
Platinum/Paclitaxel or Epacadostat + Nivolumab + Platinum/Pemetrexed or Epacadostat + Nivolumab + 
Platinum/5-FU (Combination Chemo-Immunotherapy Cohorts) 
Visit 
Screening 
Treatment Period
a 
EOT 
Follow-Up Period 
Comments 
C1 
C2 
C3+ 
Q12W 
Safety Follow-Up
b 
D1 D8 D1 D8 D1 D8 
Evaluation Window 
(Days) 
Day -28 
to -1 
±3 ±3 ±3 ±3 ±3 ±3 ±7 
+5 
30 Days 
After EOT 
±7 
100 Days 
After EOT 
± 7 
Administrative procedures 
Informed consent 
X 
Inclusion/exclusion criteria 
X 
X 
Prior medical and cancer history 
(tumor-specific) 
X 
Concomitant medication review 
X 
X (continuous) 
X 
X 
Comprehensive physical exam 
X 
Targeted physical exam 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
X 
ECG should be performed within 60 to 90 minutes after 
the first dose of epacadostat on C1D1 and C2D1 only.  In 
addition, a predose ECG will be performed on C2D1. 
After C2D1, ECG need only be performed as clinically 
indicated. 
Vital signs and weight (height at 
screening only) 
X 
X 
X 
X 
X 
Reminder card 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE assessment 
X (continuous) 
X 
X 
Subjects must be followed for AEs and SAEs throughout 
the study and for 100 days after the last dose of study 
drug. 
Laboratory assessments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory assessments will be conducted on D1 of each 
cycle starting at Cycle 4 and will be performed before the 
administration of any study drug. 
Safety laboratory assessments will be collected at EOT 
and at the 30- and 100-day safety follow-up visits.  
 
 
 
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Table 24: 
Schedule of Assessments for Phase 1 Part 2 Subjects Treated With Epacadostat + Nivolumab (Q3W) + 
Platinum/Paclitaxel or Epacadostat + Nivolumab + Platinum/Pemetrexed or Epacadostat + Nivolumab + 
Platinum/5-FU (Combination Chemo-Immunotherapy Cohorts) (Continued) 
Visit 
Screening 
Treatment Perioda 
EOT 
Follow-Up Period 
Comments 
C1 
C2 
C3+ 
Q12W 
Safety Follow-Upb 
D1 D8 D1 D8 D1 D8 
Evaluation Window 
(Days) 
Day -28 
to -1 
±3 ±3 ±3 ±3 ±3 ±3 ±7 
+5 
30 Days 
After EOT 
±7 
100 Days 
After EOT 
± 7 
Administer nivolumab 
X 
X 
X 
Nivolumab will be administered on D1 of every 3 week 
cycle (21 days). 
Administer IV chemotherapy doublet 
X 
X 
X 
Epacadostat should be administered before the start of 
nivolumab infusion. 
Nivolumab should be administered before IV 
chemotherapy (5-FU/cisplatin, platinum/ paclitaxel or 
platinum/pemetrexed). 
Platinum/paclitaxel or platinum/pemetrexed should be 
administered for a minimum of 4 cycles and up to 6 
cycles. 
Platinum/5-FU should be administered up to 6 cycles.  
5-FU will be administered as continuous infusion over 
4 days (starting on D1 and ending on D4) for up to 
6 cycles. 
Radiological tumor assessments 
X 
X 
Imaging should be performed at 8 and 16 weeks after the 
start of treatment and every 12 weeks (± 7 days) thereafter 
for up to 2 years after C1D1 regardless of any treatment 
delays. 
a Treatment cycles are every 21 days (± 3 days). 
b The mandatory safety follow-up visits should be conducted approximately 30 days and 100 days after EOT or the last dose of nivolumab or before the initiation of a new 
anticancer treatment, whichever comes first. 
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Table 25: 
Laboratory Assessments for Phase 1 Part 2 Subjects Treated With Epacadostat + Nivolumab (Q3W) + 
Platinum/Paclitaxel, Epacadostat + Nivolumab + Platinum/Pemetrexed or Epacadostat + Nivolumab + 
Platinum/5-FU (Combination Chemo-Immunotherapy Cohorts) 
Visit 
Screening
a 
Treatment Period
b 
EOT 
Safety Follow-Up
c 
Comments 
Cycle 1 
Cycle 2 
Cycle 3+ 
30 Days 
After 
EOT 
±7 
100 Days 
After 
EOT 
±7 
D1 
D8 
D15 
D1 
D8 
D15 
D1 
D8 
D15 
Evaluation Window 
(Days) 
Day -28 
to -1 
±3 ±3 
±3 
±3 
±3 
+7 
Laboratory assessments
d 
Comprehensive serum 
chemistry 
X 
X
e
X 
X 
X 
X 
X 
X 
X 
Beginning with Cycle 4, laboratory assessments 
may be performed on D1 of each subsequent 
cycle as clinically indicated (see Section 7.4.6) 
Hematology with differential 
X 
Xe
X 
X 
X 
X 
X 
X 
X 
Beginning with Cycle 4, laboratory assessments 
may be performed on D1 of each subsequent 
cycle as clinically indicated (see Section 7.4.6). 
Liver chemistry tests 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Beginning with Cycle 4, LFTs will be 
performed on D1 of every cycle, at EOT, and at 
the 30-day safety follow-up visit. 
Additional assessment of LFTs with differential 
may be conducted as clinically indicated. 
Coagulation panel 
X 
Xe
Endocrine function tests
X 
Xe
X 
X 
X 
After C3D1 every third cycle (at C6, C9, etc), 
performed every 12 weeks. 
Urinalysis 
X 
Serum pregnancy test  
(childbearing females only) 
X 
A serum pregnancy test is required for all 
women of childbearing potential during 
screening and must be within 72 hours before 
the first dose of study treatment. 
Urine pregnancy test 
(childbearing females only)
X 
X 
X 
Urine pregnancy should be repeated on D1 of 
each cycle or as required by local regulations. 
Serology for hepatitis B and 
C testing 
X 
Hepatitis B and C serologies should be obtained 
for subjects without a known history of 
hepatitis B or C.  Those with a known history 
are ineligible.  See Table 26 for list of 
laboratory tests. 
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Table 25: 
Laboratory Assessments for Phase 1 Part 2 Subjects Treated With Epacadostat + Nivolumab (Q3W) + 
Platinum/Paclitaxel, Epacadostat + Nivolumab + Platinum/Pemetrexed or Epacadostat + Nivolumab + 
Platinum/5-FU (Combination Chemo-Immunotherapy Cohorts) (Continued) 
Visit 
Screeninga 
Treatment Periodb 
EOT 
Safety Follow-Upc 
Comments 
Cycle 1 
Cycle 2 
Cycle 3+ 
30 Days 
After 
EOT 
±7 
100 Days 
After 
EOT 
±7 
D1 
D8 
D15 
D1 
D8 
D15 
D1 
D8 
D15 
Evaluation Window 
(Days) 
Day -28 
to -1 
±3 ±3 
±3 
±3 
±3 
+7 
a All safety laboratory assessments will be performed locally. 
b Treatment cycles are every 21 days (± 3 days). 
c The mandatory safety follow-up visits should be conducted approximately 30 days and 100 days after EOT, the last dose of nivolumab, or before the initiation of a new 
anticancer treatment, whichever comes first. 
d Laboratory assessments on D1 of each cycle should be performed before the administration of any study drug. 
e C1D1 laboratory tests may be omitted if the screening laboratory tests were performed within 7 days before study treatment initiation.  If performed > 7 days before C1D1, the 
tests must be repeated to confirm the subject's eligibility on C1D1. 
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Table 26: 
Laboratory Tests:  Required Analytes 
Serum Chemistry 
Hematology 
Other 
Albumin  
Amylase  
Bicarbonate 
Blood urea nitrogen or urea 
Calcium 
Chloride  
Creatinine 
Glucose 
Iron 
Lactate dehydrogenase 
Phosphorus 
Potassium 
Serum or plasma lipase 
Sodium 
Total protein 
Uric acid 
IgG 
Complete blood count, 
including:   
• Hemoglobin
• Hematocrit
• Platelet count
• Red blood cell count
• White blood cell count
Differential count
a, including: 
• Basophils
• Eosinophils
• Lymphocytes
• Monocytes
• Neutrophils
Serology: 
Hepatitis B surface antigen
b
HCV-RNA or hepatitis C virus (HCV) antibody 
where HCV RNA is not SOC 
HBV DNA  
Pregnancy test: 
Female subjects of childbearing potential only 
require a serum test at screening.  
Pregnancy tests (serum or urine) should be repeated 
if required by local regulations and at EOT. 
Urinalysis with microscopic examination: 
Color and appearance 
pH and specific gravity 
Bilirubin 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Occult blood 
Protein 
Urobilinogen 
Coagulation: 
PT 
aPTT 
INR 
Standard LFT Monitoring 
Endocrine Monitoring 
Alkaline phosphatase 
ALT 
AST 
Total bilirubin 
Direct bilirubin (only if total 
bilirubin is elevated above ULN). 
ACTH 
Serum cortisol (9 AM)
c 
LH
d 
Prolactin 
TSH 
Free thyroxine (T4) 
Total triiodothyronine (T3) 
Serum testosterone (9 AM)c,e 
ACTH = adrenocorticotropic hormone; IgG = immunoglobulin G; LH = luteinizing hormone. 
a Differential is preferred to be reported in absolutes. 
b Hepatititis B surface antigen testing will only include antigen testing. 
c Serum cortisol and testosterone ideally should be drawn close to 9 AM but can be performed anytime before noon. 
d Not needed in subjects taking thyroid hormone replacement therapy. 
e Not needed in women, surgically castrated men, or men taking LH-releasing hormone agonist therapy. 
6.1. 
Screening Period 
The screening period will be up to 28 days.  Screening is the interval between the signing of the 
ICF and the day the subject received the first dose of treatment in the study (C1D1).  Informed 
consent must be obtained before performing any study-specific procedures not considered 
standard of care.  Assessments that are required to demonstrate eligibility may be performed over 
the course of 1 or more days during this period. 
Results from the screening visit evaluations will be reviewed to confirm subject eligibility before 
enrollment or the administration of study drug.  Tests with results that fail eligibility 
requirements may be repeated once during the screening period if the investigator believes the 
results to be in error.  Additionally, a subject who fails screening may repeat the screening 
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process 1 time if the investigator believes there has been a change in eligibility status (eg, after 
recovery from an infection).  Rescreened subjects must be assigned a new subject number. 
6.2. 
Treatment Period 
The treatment period with the combination immunotherapy therapy will continue every 56 days 
(Phase 1 Part 1 and Phase 2) and with the combination chemo-immunotherapy (Phase 1 Part 2) 
will continue every 21 days and may continue for up to 2 years as long as subjects are receiving 
benefit from treatment and have not met any criteria for study withdrawal.  
6.3. 
End of Treatment 
If a decision is made that the subject will permanently discontinue study drug, the EOT visit 
should be conducted.  If the EOT visit coincides with a regular study visit, the EOT evaluations 
will supersede those of that scheduled visit, and the data should be entered in the EOT page in 
the eCRF.  The subject should be encouraged to return for the follow-up visit. 
6.4. 
Follow-Up Period 
6.4.1. 
Safety Follow-Up 
The safety follow-up period is the interval between the last dose of study treatment and the 
3 scheduled safety follow-up visits, which should occur 30 and 100 days after the EOT visit (or 
after the last dose of study drug if the EOT visit was not performed).  Adverse events and SAEs 
must be reported up until at least 100 days after the last dose of study drug, the date of the 
follow-up visit, or until study drug–related toxicities resolve, return to baseline, or are deemed 
irreversible, whichever is longer.  If a subject initiates a new anticancer therapy within 100 days 
after the last dose of study treatment, reasonable efforts should be made to conduct the next 
scheduled safety follow-up visit before the first dose of the new therapy.  Reasonable efforts 
should be made to have the subject return for the follow-up visit and report any AEs that may 
occur during this period. 
6.5. 
Unscheduled Visits 
Unscheduled study visits may occur at any time if medically warranted.  Any assessments 
performed at those visits should be recorded in the eCRF. 
6.6. 
Early Termination  
Not applicable. 
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7.
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES
7.1. 
Study Procedures
Section 6 summarizes the study procedures to be performed at each visit.  Individual study 
procedures are described in detail below.  It may be necessary to perform these procedures at 
unscheduled timepoints if deemed clinically necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the sponsor and/or 
BMS for reasons related to subject safety.  In some cases, such evaluation/testing may be 
potentially sensitive in nature (eg, hepatitis C), and thus local regulations may require that 
additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
7.2. 
Administration of Informed Consent Form 
Valid informed consent must be obtained from the study subject before conducting any 
study-specific procedures.  The granting of informed consent for study participation must be 
documented in writing, using an ICF that contains all the elements required by ICH E6 and 
describes the nature, scope, and possible consequences of the study in a form understandable to 
the study subject.  Local and institutional guidelines for ICF content and administration must be 
followed; a copy of the signed ICF must be provided to the study subject.  Subjects of 
childbearing potential must agree to take appropriate measures to avoid pregnancy in order to 
participate in the study (Appendix A). 
7.3. 
Demography and History 
7.3.1. 
Demographics and Medical History 
Demographic data and a complete medical and medication history will be collected at screening 
by the investigator or qualified designee and will include date of birth, race, ethnicity (where 
allowed by local regulations), medical and surgical history, and concurrent illnesses assessed 
using the NCI CTCAE v4.0 (NCI 2010).  Medical history should include all active conditions 
and any condition considered to be clinically significant by the investigator.  Details regarding 
the disease for which the subject has enrolled in this study (eg, date of diagnosis, primary tumor 
histology, prior systemic therapies, surgeries, radiation therapy, and stage of cancer) will be 
recorded separately and not listed in medical history. 
7.3.2. 
Prior Medications 
Prior and ongoing medications will be reviewed to determine study eligibility.  The investigator 
or qualified designee will review prior medication use, including any Protocol-specified washout 
requirement, and record prior medication taken by the subject within 28 days before starting the 
study.  Treatment for the disease for which the subject has enrolled in this study will be recorded 
separately and not listed as a prior medication. 
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7.3.3. 
Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject during 
the study.  Concomitant medications include any prescription, over-the-counter, or natural/herbal 
preparations taken or administered during the study period.  All medications related to reportable 
SAEs should be recorded as defined in Section 8.1. 
7.3.4. 
Post-Treatment Anticancer Therapy Status 
The investigator or qualified designee will review all new antineoplastic therapy initiated after 
the last dose of study treatment.  If a subject initiates a new anticancer therapy within 100 days 
after the last dose of study treatment, reasonable efforts must be made to conduct the next 
scheduled safety follow-up (30 or 100 day) visit before the first dose of the new therapy. 
7.4. 
Safety Assessments 
7.4.1. 
Adverse Events 
Adverse events will be monitored from the time the subject signs the ICF.  Subjects will be 
instructed to report all AEs during the study and will be assessed for the occurrence of AEs 
throughout the study.  In order to avoid bias in eliciting AEs, subjects will be asked general, 
nonleading questions such as "How are you feeling?"  All AEs (serious and nonserious) must be 
recorded on the source documents and eCRFs regardless of the assumption of a causal 
relationship with the study drug.  The definition, reporting, and recording requirements for AEs 
are described in Section 8. 
All AEs of unknown etiology associated with nivolumab and epacadostat exposure should be 
evaluated to determine if it is possibly an irAE.  See Section 5.7.3 regarding the identification, 
evaluation, and management of AEs of potential immunological etiology. 
7.4.2. 
Comprehensive Physical Examination 
Physical examinations must be performed by a medically qualified individual such as a licensed 
physician, physician's assistant, or an advanced registered nurse practitioner, as local law 
permits. 
The comprehensive physical examination will include the following organ or body system 
assessments:  skin; head, eyes, ears, nose, and throat; thyroid; lungs; cardiovascular system; 
abdomen (liver, spleen); extremities; lymph nodes; and a brief neurological examination.  Before 
the first dose of study treatment, clinically significant abnormal findings should be recorded as 
medical history.  After C1D1, new clinically significant abnormal findings should be recorded as 
AEs. 
7.4.3. 
Targeted Physical Examination 
For cycles that do not require a full physical examination per the schedules of assessments 
(Table 18, Table 19, and Table 24), the investigator or qualified designee will perform a directed 
physical examination as clinically indicated before study treatment administration.  A targeted 
physical examination will be a symptom-directed evaluation conducted by the investigator or 
designee.  The targeted physical examination will include assessment(s) of the body systems or 
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organs, as indicated by subject symptoms, AEs, or other findings.  New clinically significant 
abnormal findings should be recorded as AEs. 
7.4.4. 
Vital Signs 
Vital sign measurements include blood pressure, pulse, respiratory rate, body temperature, and 
weight.  Height will be measured at screening only. 
7.4.5. 
Twelve-Lead Electrocardiograms 
Baseline ECGs will be obtained at screening.  Additional ECGs will be performed on study at 
C1D1 and C1D15 for Phase 1 Part 1 and at C1D1 and C2D1 for Phase 1 Part 2; within 60 to 
90 minutes of first dose of epacadostat (unless emerging 
 data suggest alternate timing); 
predose on C1D15 for Phase 1 Part 1 and predose on C2D1 for Phase 1 Part 2.  Clinically 
significant abnormal findings at screening will be recorded as medical history.  Clinically 
significant abnormal findings after C1D1 should be recorded as an AE.  Subsequently, ECGs 
will be conducted only as clinically indicated. 
The 12-lead ECGs will be interpreted by the investigator at the site and will be used for 
immediate subject management.  The decision to include or exclude a subject or withdraw a 
subject from the study based on an ECG flagged as "Abnormal, Clinically Significant" is the 
responsibility of the investigator, in consultation with the sponsor's medical monitor, as 
appropriate.  Prolonged QTc intervals must be read by a cardiologist.  The correction method 
(Fridericia or Bazett) used for calculating QTc will need to be provided in the eCRF. 
7.4.6. 
Laboratory Assessments 
Laboratory tests for screening period should be performed within 7 days before C1D1.  After 
Cycle 1, predose laboratory procedures can be conducted up to 72 hours before study drug 
administration.  Results must be reviewed by the investigator or qualified designee and found to 
be acceptable before each dose of study treatment. 
In Part 2 of Phase 1, for the combination chemo-immunotherapy cohorts, laboratory assessments 
will be conducted on C1D1, C1D8, C2D1, C2D8, C3D1, and C3D8 and as needed as part of 
standard practice to evaluate laboratory analytes during chemotherapy regimen.  Subsequently, 
laboratory assessments will be performed on Day 1 of each cycle in the absence of clinically 
significant abnormalities, which should be monitored at a frequency sufficient to provide 
adequate surveillance.  
All safety laboratory assessments will be performed locally. 
7.4.6.1. 
Chemistry, Hematology, Coagulation Panel, Serology, and Endocrine Function 
Testing 
Chemistry, hematology, coagulation panel, and endocrine function will all be analyzed by the 
site local laboratory.  Differential counts for hematology should be provided in absolutes. 
7.4.6.2. 
Urinalysis 
Urinalysis will be analyzed by the site laboratory. 
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7.4.6.3. 
Liver Chemistry Tests 
Liver chemistry tests (ALT, AST, total bilirubin, and alkaline phosphatase) will be conducted at 
screening, on C1D1, on Day 1 of every subsequent cycle, at EOT, and at safety follow-up 
(30 days after EOT) for combination cohorts with Q2W nivolumab schedule.  LFT monitoring 
will be conducted at screening, on C1D1, C1D15, on Day 1 of every subsequent cycle, at EOT, 
and at safety follow-up (30 days after EOT) for combination cohorts with Q4W nivolumab 
schedule.  For combination chemo-immunotherapy cohorts, LFT monitoring will occur on 
C1D1, C1D8, C2D1, C2D8, C3D1, and C3D8; after Cycle 3, LFTs will be on Day 1 of each 
subsequent cycle, at EOT, at the 30-day safety follow-up visit, and as clinically indicated.  Liver 
chemistry tests will be performed by the site's local laboratory, as well as any twice-per-week 
LFT monitoring if it is required.  If LFT results (ALT, AST, or total bilirubin) are abnormal, 
twice weekly testing of these LFTs will be required until results return to baseline.  Liver 
chemistry test monitoring for persistent low-grade abnormalities does not need to be monitored 
twice a week indefinitely.  Appropriate LFT monitoring intervals should be discussed with the 
medical monitors for these circumstances.  Throughout the Protocol, LFT refers specifically to 
liver chemistry testing, and required analytes for LFTs are listed in Table 26.  
7.4.6.4. 
Pregnancy Testing 
Serum pregnancy tests will be analyzed by the site laboratory at screening.  Subsequently, urine 
pregnancy tests will be conducted on Day 1 of each cycle or as required by local regulations. 
If a subject inadvertently becomes pregnant while on study treatment, the subject will 
immediately be withdrawn from the study.  The site will contact the subject and document the 
subject's status until the pregnancy has been completed or terminated.  The outcome of the 
pregnancy will be reported to the sponsor without delay and within 24 hours if the outcome is an 
SAE (eg, death, abortion, congenital anomaly, or other disabling or life-threatening complication 
to the mother or newborn).  The study investigator will make every effort to obtain permission to 
follow the outcome of the pregnancy and report the condition of the fetus or newborn to the 
sponsor.  If a male subject impregnates his female partner, the study personnel at the site must be 
informed immediately and the pregnancy reported to the sponsor and followed as described 
above and in Section 8.5. 
7.5. 
Efficacy Assessments 
Process for image collection and transmission to the central vendor can be found in the Site 
Imaging Manual. 
7.5.1. 
Initial Tumor Imaging 
Initial tumor imaging must be performed within 28 days before C1D1.  The site study team must 
confirm the subject has measurable disease per RECIST v1.1 for solid tumors, Cheson for 
lymphomas, or RANO for glioblastoma.  The baseline imaging scan (or photographs if skin 
lesions present and assessed clinically) should also be submitted to the central imaging vendor.  
Subjects with all tumor types, except subjects with glioblastoma, are required to have a chest and 
abdominal CT scan for baseline.  Brain MRI at baseline should also be considered when disease 
burden due to any targeted tumor types is extensive (ie, when ≥ 3 metastatic disease sites are 
involved).  For subjects with MEL, baseline brain MRI is required.  In addition, subjects with 
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ovarian cancer must also have a pelvic CT scan performed.  For subjects with SCCHN a neck CT 
scan is also required.  For subjects with B-cell NHL or HL, baseline PET scans should be 
performed if standard of care.  If performed as part of standard of care at baseline, imaging 
should continue at specified intervals during study treatment.  Brain imaging for subjects whose 
primary disease is not glioblastoma should only be performed if there are signs or symptoms 
suggesting CNS disease.  For subjects with glioblastoma, tumor measurements and volumetric 
MRI of the head is also required within 14 days before the start of study drug.  Subjects with 
glioblastoma who are unable (due to existent medical condition, ie, pacemaker or implantable 
cardioverter defibrillator device) or unwilling to have a head MRI at baseline are excluded from 
the study. 
Scans performed as part of routine clinical management are acceptable for use as the screening 
scan if they are of diagnostic quality and performed within 28 days before C1D1.  The same 
imaging technique should be used in a subject throughout the study. 
For selection of target lesions, RECIST v1.1 (Appendix E), Cheson (Appendix F), or RANO 
(Appendix H) criteria should be followed.  For example, RECIST discourages selection of target 
lesions inside the field of prior irradiation.  Lesions situated in a previously irradiated area, or in 
an area subjected to other locoregional therapy, are usually not considered measurable unless it is 
the solitary site of measurable disease AND there has been demonstrated progression in the 
lesion.  Also, if a subject has only 1 measurable lesion, this lesion should not be biopsied. 
7.5.2. 
Tumor Imaging During the Study 
Tumor imaging should be continued on study treatment including photographs if skin lesion is 
present and assessed clinically, and the same imaging technique should be used in a subject 
throughout the study.  Imaging should be performed 8 and 16 weeks (± 7 days) after the start of 
treatment for subjects in the combination chemo-immunotherapy cohorts (Phase 1 Part 2) and 
then every 12 weeks thereafter.  All other subjects (Phase 1 Part 1 and Phase 2) will have 
efficacy assessments every 12 weeks.  All subjects will continue to have efficacy assessments 
until the end of treatment; no efficacy assessments are required during the safety follow-up 
period.  Imaging may be performed more frequently if clinically indicated.  Imaging should not 
be delayed for delays in cycle starts or extension of combination treatment cycle intervals. 
Per RECIST v1.1, response should be confirmed by a repeat radiographic assessment not less 
than 4 weeks from the date the response was first documented.  The scan for confirmation of 
response may be performed at the earliest 4 weeks after the first indication of response or at the 
next scheduled scan, whichever is clinically indicated. 
7.5.3. 
Assessment of Disease by Cheson Criteria for Lymphomas 
An objective assessment of disease status is required at baseline (screening) using a method that 
is appropriate for disease subtype, per established and modified guidelines (Cheson et al 2007 or 
Owen et al 2013 for Waldenström's macroglobulinemia; Appendix G), to account for the unique 
tumor response seen in this class of therapeutics. 
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7.5.3.1. 
CT Scan or MRI for Lymphoma Evaluation 
Subjects with HL will undergo CT or MRI to evaluate measurable disease during the screening 
period.  If CT/MRI assessment was performed, under standard of care, before signing of the ICF 
but within 28 days of C1D1, the result of that assessment may be recorded in the CRF in lieu of a 
study-specific assessment.  On-treatment assessments (for subjects with disease measurable by 
CT or MRI) should be performed every 8 weeks following C1D1. 
7.5.3.2. 
FDG-PET or Combined PET-CT 
If positron emission tomography (PET) using [18 F] fluorodeoxyglucose (FDG) or combined 
PET-CT is used as a functional imaging tool for staging or response assessment of lymphoma as 
a part of the standard of care, the results obtained during any study phase will be captured in the 
CRF.  
7.5.4. 
Assessment of Disease by RANO Criteria for Glioblastoma 
Investigator-assessed tumor response will be based on modified published RANO criteria 
(Appendix H) and will be adapted for defining PD to account for the unique tumor response seen 
in this class of therapeutics.  Radiologic response will be assessed by comparing the pretreatment 
baseline and on-treatment MRI scans.  Radiologic progression will be determined by using the 
smallest tumor measurement at either the pretreatment baseline or after initiation of study 
medication.  Table 27 describes the radiologic and clinical criteria that will be used for 
determining tumor response. 
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Table 27: 
RANO Criteria for Response Assessment Incorporating MRI and Clinical 
Factors 
Response 
Criteria 
Complete 
response 
Requires all of the following: 
• Complete disappearance of all enhancing measurable and nonmeasurable disease 
sustained for at least 4 weeks. 
• No new lesions. 
• Stable or improved nonenhancing (T2/FLAIR) lesions. 
• Subjects must be off corticosteroids (or on physiologic replacement doses only). 
• Stable or improved clinically. 
Note:  Subjects with nonmeasurable disease only cannot have a complete response; the best 
response possible is SD. 
Partial response 
Requires all of the following: 
• ≥ 50% decrease compared with baseline in the sum of products of perpendicular 
diameters of all measurable enhancing lesions sustained for at least 4 weeks. 
• No progression of nonmeasurable disease. 
• No new lesions. 
• Stable or improved nonenhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared with baseline scan. 
• The corticosteroid dose at the time of the scan evaluation should be no greater than the 
dose at time of baseline scan. 
• Stable or improved clinically. 
Note:  Subjects with nonmeasurable disease only cannot have a PR; the best response 
possible is SD. 
Stable disease 
Requires all of the following: 
• Does not qualify for complete response, PR, or progression. 
• Stable nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids 
compared with baseline scan.  In the event that the corticosteroid dose was increased for 
new symptoms and signs without confirmation of disease progression on neuroimaging, 
and subsequent follow-up imaging shows that this increase in corticosteroids was 
required because of disease progression, the last scan considered to show SD will be the 
scan obtained when the corticosteroid dose was equivalent to the baseline dose. 
Progression 
Defined by any of the following: 
• ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions 
compared with the smallest tumor measurement obtained either at baseline (if no 
decrease) or best response, on stable or increasing doses of corticosteroids.
a 
• Significant increase in T2/FLAIR nonenhancing lesions on stable or increasing doses of 
corticosteroids compared with baseline scan or best response after initiation of therapya 
not cause by comorbid events (eg, radiation therapy, demyelination, ischemic injury, 
infection, seizures, postoperative changes, or other treatment effects). 
• Any new lesion. 
• Clear clinical deterioration not attributable to other causes apart from the tumor 
(eg, seizures, medication adverse effects, complications of therapy, cerebrovascular 
events, infection, and so on) or changes in corticosteroid dose. 
• Failure to return for evaluation as a result of death or deteriorating condition; or clear 
progression of nonmeasurable disease. 
FLAIR = fluid-attenuated inversion recovery. 
Note:  Radiologic interpretation guidelines, definitions, and tumor measurement instructions will be provided separately.  All 
measurable and nonmeasurable lesions must be assessed using the same techniques as at baseline. 
a Stable doses of corticosteroids include subjects not on corticosteroids. 
Source:  Wen et al 2010. 
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For purposes of this study, the minimum time from baseline for determination of SD will be 
6 weeks.  
Best overall response should be determined based on response designations recorded per 
RANO-defined criteria.  The subject's BOR assignment will depend on the findings of both 
target and nontarget disease, and will also take into consideration the appearance of new lesions. 
The assessments that will contribute to the evaluation of BOR include the response assessment 
recorded between the date of randomization and the first to occur of the following: 
1. The date of objectively documented progression per RANO criteria
OR
2. The date of subsequent therapy
OR
3. The date of pathology results from diagnostic surgical resection
Among the available response assessment, the criteria listed in Table 28 will be used to 
determine BOR. 
Table 28: 
Assessment of Best Overall Response 
Best Overall Response 
Criteria 
Complete response (CR) 
CR observed in consecutive assessments ≥ 4 weeks apart per RANO. 
Partial response (PR) 
PR observed in consecutive assessments ≥ 4 weeks apart per RANO. 
Stable disease (SD)
a 
SD observed and dose not quality for CR or PR. 
Or 
Suspected PD followed with histologic results not confirming PD, and no CR, PR, or 
SD observed. 
Not evaluable (NE) 
Insufficient data to determine disease progression or response. 
Progressive disease (PD) 
No CR, PR, or SD before PD. 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD = stable disease. 
a To qualify for SD there must be a minimum on-treatment period of 6 weeks.
In order to distinguish potential treatment-associated pseudoprogression from PD and minimize 
premature discontinuation of study medication, subjects who initially meet radiologic criteria for 
disease progression but are believed to derive clinical benefit and are tolerating study medication 
should continue receiving study medication until confirmation of progression with a follow-up 
MRI.  Such patients may be allowed to continue on study therapy for up to 12 additional weeks 
as long as they are no developing significant new or worsened neurologic deficits related to 
underlying tumor. 
If the follow-up imaging after 12 weeks from initial tumor progression confirms further 
progression, the date of progression will be the date at which progression was first determined.  
For purposes of this study, the minimum duration between baseline (start of treatment) and first 
on-study scan in order to determine BOR of SD is 6 weeks.  If the minimum time is not met 
when SD is otherwise the best timepoint response, the subject's best response will depend on the 
subsequent assessments.  For example, a subject who has SD at a timepoint < 6 weeks and PD at 
a second assessment will have a best response of PD. 
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Subjects with a complete or PR must have that response sustained for 4 weeks.  Subjects who do 
not qualify for complete response, PR, or confirmed progression will be considered as SD for the 
Protocol BOR analysis. 
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7.7. 
Other Study Procedures 
7.7.1. 
Study Compliance 
Interruptions from the Protocol-specified treatment plan for > 6 weeks between nivolumab and 
epacadostat doses due to toxicity require consultation between the sponsor and investigator and 
written documentation of the collaborative decision on subject management. 
7.7.2. 
Administration of Nivolumab and Compliance 
Administration of nivolumab will be witnessed by the investigator and/or study staff.  The total 
volume of study treatment infused will be compared with the total volume prepared to determine 
compliance with each dose administered. 
The instructions for preparing and administering nivolumab will be provided in the Procedures 
Manual. 
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7.7.3. 
Administration of Epacadostat and Compliance 
Subjects will self-administer their dose of epacadostat in the morning and evening, 
approximately 12 hours apart.   
Epacadostat compliance will be calculated by the sponsor based on the drug accountability 
documented by the site staff and monitored by the sponsor/designee (tablet counts).  The 
objective is 100% compliance, and investigators and their staff should evaluate compliance at 
each visit and take appropriate steps to optimize compliance. 
7.7.4. 
Dispensing of Epacadostat 
An initial bulk supply of epacadostat will be provided to investigative sites before enrollment of 
the first subject.  Thereafter, the site staff will contact the sponsor for re-supply of epacadostat.  
When dispensing to subjects, the investigator or designee will remove the appropriate quantity of 
epacadostat from their stock, dispense the medication, and enter the amount dispensed into the 
eCRF and drug accountability log.  Full details will be provided in the Study Manual. 
7.7.5. 
Dispensing of Nivolumab 
An initial bulk supply of nivolumab will be provided to investigative sites before enrollment of 
the first subject.  Thereafter, the site will contact the sponsor for re-supply of nivolumab.  The 
investigator or designee will calculate the number of nivolumab vials needed, pull the 
appropriate number of vials to prepare the infusion solution, and enter the vials used into the 
eCRF and drug accountability log.  Full details will be provided in the Study Manual.  
7.7.6. 
Distribution of Subject Reminder Cards 
Subjects will be provided with reminder cards at each visit.  The subject reminder cards will 
indicate the date/time of the next visit and will also remind the subject when they should not take 
their morning dose of study drug and when they should arrive for the visit.  On Day 1 only 
subjects will also be given an SS information sheet for signs and symptoms of SS.  This 
information sheet also instructs subjects to seek immediate medical care if any of these 
symptoms are observed. 
7.7.7. 
Withdrawal or Discontinuation 
When a subject discontinues or withdraws before study completion, all applicable activities 
scheduled for the final study visit should be performed at the time of discontinuation.  Any AEs 
that are present at the time of discontinuation or withdrawal should be followed in accordance 
with the safety requirements outlined in Section 8.1.1.  These subjects should return to the site 
for the safety follow-up visits (described in Section 6.4.1) during the 100-day safety follow-up 
period. 
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8. 
SAFETY MONITORING AND REPORTING 
8.1. 
Adverse Events 
8.1.1. 
Definitions 
For the purposes of this Protocol, an adverse event (AE) is defined as the appearance of (or 
worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s) that 
occur after a subject provides informed consent.  Abnormal laboratory values or test results 
occurring after informed consent constitute AEs only if they induce clinical signs or symptoms, 
are considered clinically meaningful, require therapy (eg, hematologic abnormality that requires 
transfusion), or require changes in the study drug(s). 
8.1.2. 
Reporting 
Adverse events that begin or worsen after informed consent should be recorded on the Adverse 
Events page of the eCRF.  Conditions that were already present at the time of informed consent 
should be recorded on the Medical History page of the eCRF.  Adverse event monitoring should 
be continued for at least 100 days after the last dose of study drug.  Adverse events (including 
laboratory abnormalities that constitute AEs) should be described using a diagnosis whenever 
possible rather than by individual underlying signs and symptoms.  When a clear diagnosis 
cannot be identified, each sign or symptom should be reported as a separate AE. 
The term "disease progression" should be recorded as an AE/SAE only if there are no other 
identifiable AEs/SAEs associated with the disease progression at the time of reporting.  For 
events associated with disease progression, the relevant signs and symptoms should be reported 
using a diagnosis whenever possible rather than individual underlying signs and symptoms.  
When a clear diagnosis cannot be identified, each sign or symptom should be reported as a 
separate AE.  If the events resulting from disease progression meet the criteria for an SAE 
(eg, resulted in hospitalization, a life-threatening event, or death), the specific event(s) should be 
reported as an SAE(s) as described in Section 8.3.2.  In both cases (ie, AEs or SAEs related to 
disease progression), it should be indicated that each event (reported as a diagnosis or as signs 
and symptoms) is related to disease progression on the Adverse Events form of the eCRF. 
The severity of AEs will be assessed according to the CTCAE v4.0 Grades 1 through Grade 4.  
The CTCAE v4.0 severity Grade 5 (death) will not be used in this study; 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 severity:  
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2 
Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate activities of daily living. 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care activities of 
daily living. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
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The occurrence of AEs should be sought by nondirective questioning of the subject during the 
screening process after signing the ICF and at each visit during the study.  Adverse events may 
also be detected when they are volunteered by the subject during the screening process or 
between visits, or through physical examination, laboratory test, or other assessments.  As far as 
possible, each AE should be evaluated to determine: 
•
The severity grade (CTCAE Grade 1 to 4).
•
Reasonable possibility that the AE is related to the study treatment:  unrelated (no) or
related (yes).
NOTE:  Since this is a study of epacadostat combined with other study therapies, the
relationship to study drug can be assessed for epacadostat alone, nivolumab alone,
epacadostat combined with each study therapy administered, or not related to either
epacadostat or other study therapies.
•
Start and end dates, unless unresolved at final examination.
•
Action taken with respect to study drug (eg, none, dose adjusted, temporarily
interrupted, permanently discontinued, unknown, not applicable).
•
Outcome (eg, not recovered/not resolved, recovered/resolved, recovering/resolving,
recovered/resolved with sequelae, fatal, unknown).
•
Whether it is serious, as per SAE definition provided in Section 8.3.1.
Unlike routine safety assessments, SAEs are monitored continuously and have special reporting 
requirements, see Section 8.3.2. 
All AEs should be treated appropriately.  If a concomitant medication or nondrug therapy is 
given, this action should be recorded on the AE and Prior/Concomitant medications pages of the 
eCRF. 
Once an AE is detected, it should be followed until it has resolved or until it is judged to be 
permanent; assessment should be made at each visit (or more frequently if necessary) of any 
changes in severity, the suspected relationship to the study drug, the interventions required to 
treat it, and the outcome. 
When the severity of an AE changes over time for a reporting period (eg, between visits), each 
change in severity will be reported as a separate AE until the event resolves.  For example, 
2 separate AEs will be reported if a subject has Grade 1 diarrhea, meeting the definition of an 
AE, that lasts for 3 days before worsening to a Grade 3 severity.  The Grade 1 event will be 
reported as an AE with a start date equal to the day the event met the Grade 1 AE definition and 
a stop date equal to the day that the event increased in severity from Grade 1 to Grade 3.  The 
Grade 3 event will also be reported as an AE, with the start date equal to the day the event 
changed in intensity from Grade 1 to Grade 3 and a stop date equal to the day that the event 
either changed severity again or resolved. 
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8.2. 
Laboratory Test Abnormalities 
8.2.1. 
Definitions and Reporting 
Laboratory abnormalities that constitute an AE in their own right (are considered clinically 
meaningful, induce clinical signs or symptoms, require concomitant therapy, or require changes 
in study drug), should be recorded on the AE page of the eCRF.  Whenever possible, a diagnosis 
rather than a symptom should be provided (eg, anemia instead of low hemoglobin).  Laboratory 
abnormalities that meet the criteria for AEs should be followed until they have returned to 
normal or an adequate explanation of the abnormality is found.  When an abnormal laboratory 
test result corresponds to a sign or symptom of a previously reported AE, it is not necessary to 
separately record the laboratory test result as an additional event. 
Laboratory abnormalities that do not meet the definition of an AE should not be reported as AEs.  
A Grade 3 or 4 AE, as per CTCAE, does not automatically indicate an SAE unless it meets the 
definition of serious, as defined in Section 8.3.1, and/or per the investigator's discretion.  A dose 
interruption or adjustment for the laboratory abnormality may be required (see Section 5.7.2) and 
should not contribute to the designation of a laboratory test abnormality as an SAE. 
8.2.2. 
Potential Drug-Induced Liver Injury 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur before the reporting of a potential drug-induced liver injury event.  All occurrences of 
potential drug-induced liver injuries, meeting the defined criteria, must be reported as SAEs (see 
Section 8.3.2 for reporting details). 
Potential drug-induced liver injury is defined as: 
1. AT (ALT or AST) elevation > 3 times ULN
AND
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum
alkaline phosphatase),
AND
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia,
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or
the administration of other drug(s) known to be hepatotoxic.
In addition, Potential Hy's Law cases must also be reported as SAEs (Section 8.3.2).  A Potential 
Hy's Law case is defined as any situation where a study subject has an increase in AST or ALT 
≥ 3 × ULN together with total bilirubin ≥ 2 × ULN, irrespective of alkaline phosphatase, at any 
point during the study following the start of study medication. 
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8.3. 
Serious Adverse Events 
8.3.1. 
Definitions 
A SAE is defined as an event that meets 1 of the following criteria: 
•
Is fatal or life-threatening (ie, immediate risk of dying).
•
Results in persistent or significant disability or incapacity.
•
Constitutes a congenital anomaly or birth defect.
•
Is clinically meaningful (ie, defined as an event that jeopardizes the subject or
requires potential medical or surgical intervention to prevent 1 of the outcomes listed
above).  Considered meaningful by the investigator as an important medical event
that may not result in death, be life-threatening, or require hospitalization, but may be
considered a SAE when, based upon appropriate medical judgment, it may jeopardize
the subject or may require medical or surgical intervention to prevent 1 of the
outcomes listed in this definition.
•
Requires inpatient hospitalization or prolongation of existing hospitalization, unless
hospitalization is a result of:
− Routine treatment or monitoring of the studied indication not associated with any
deterioration in condition. 
− Elective or preplanned treatment for a pre-existing condition that is unrelated to 
the indication under study and has not worsened since signing the ICF. 
− Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission. 
− Social reasons and respite care, in the absence of any deterioration in the subject's 
general condition. 
− Any SAEs that are expected due to the condition being treated, including if the 
SAE is a primary outcome measure, or where there has been a clear agreement 
with regulators not to consider these as SAEs, provided the information is 
collected elsewhere. 
8.3.2. 
Reporting 
To ensure subject safety, every SAE, regardless of suspected causality, occurring after the 
subject has signed the ICF and up to the EOT visit, or up to 100 days after the subject has 
stopped study treatment, whichever is later, must be reported to the sponsor (or designee) within 
24 hours of learning of its occurrence.  Any SAEs experienced after this period should be 
reported to the sponsor (or designee) only if the investigator suspects a causal relationship to the 
study drug.  Recurrent episodes, complications, or progression of the initial SAE must be 
reported as the follow-up to the original episode within 24 hours of the investigator receiving the 
follow-up information.  An SAE occurring at a different time interval or otherwise considered 
completely unrelated to a previously reported one should be reported separately as a new event.  
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Previously planned (before providing informed consent) surgeries should not be reported as 
SAEs unless the underlying medical condition worsens over the course of the study. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form.  The investigator must assess and record the relationship of each SAE to each specific 
study drug (if there is more than 1), complete the SAE Report Form in English, and send the 
completed, signed form by fax within 24 hours to the sponsor or its designee.  The investigator 
must assess if there is a reasonable possibility that the SAE is related to the study treatment:  
unrelated (no) or related (yes). 
Serious AEs related to unblinded comparator drugs or concomitant medications/drug delivery 
systems are reported directly to the manufacturers of those drugs/devices in accordance with the 
package insert. 
The telephone and facsimile number of the sponsor's contact persons, specific to the study, are 
listed in the investigator folder provided to each site.  The original copy of the SAE Report Form 
and the fax confirmation sheet must be kept with the eCRF documentation at the study site. 
Follow-up information is sent to the same person to whom the original SAE Report Form was 
sent, using a new SAE Report Form stating that this is a follow-up to the previously reported 
SAE and giving the date of the original report.  Each recurrence, complication, or progression of 
the original event should be reported as a follow-up to that event regardless of when it occurs.  
The follow-up information should describe whether the event has resolved or continues, if and 
how it was treated, and whether the subject continued or withdrew from study participation, or if 
study drug was interrupted or discontinued. 
If the SAE is not previously documented in the IB for the study drug (new occurrence) and is 
thought to be related to the sponsor's study drug, a sponsor's associate may urgently require 
further information from the investigator for reporting to health authorities. 
The sponsor or its designee may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same drug that this SAE has been reported.  
Suspected Unexpected Serious Adverse Reactions will be collected and reported to the 
competent authorities and relevant ethics committees in accordance with Directive 2001/20/EC, 
or as per national regulatory requirements in participating countries. 
8.4. 
Emergency Unblinding of Treatment Assignment 
Not applicable. 
8.5. 
Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that study drug may 
have interfered with the effectiveness of a contraceptive medication or method.  When a 
pregnancy has been confirmed, including the pregnancy of a male subject's female partner that 
occurs during the study or within 150 days of completing the study, the following procedures 
should occur: 
• The investigator must notify the sponsor or its designee immediately.  
• The study drug must be discontinued immediately. 
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•
The subject must be withdrawn from the study.
•
The EOT visit evaluations must be performed.
•
The investigator must complete and submit the Pregnancy Initial and Follow-Up
Report forms to the sponsor or its designee.
•
A serum pregnancy test must be performed to confirm the urine pregnancy test result.
(The serum test should be performed at the investigative site to ensure the test will be
performed promptly and the result available immediately for review.)
If a negative serum test does not confirm the urine pregnancy test result, then: 
•
The investigator will use his or her expert judgment, based on an assessment of the
potential benefit/risk to the subject, to determine if it is in the subject's best interest to
resume study drug and continue participation in the study.
To ensure subject safety, each pregnancy in a subject during maternal or paternal 
exposures to study drug must be reported within 24 hours of learning of its occurrence.  
Data on fetal outcome and breastfeeding are collected for regulatory reporting and drug safety 
evaluation.  Follow-up to each pregnancy should be conducted to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence of any 
birth defects, congenital abnormalities, or maternal and/or newborn complications, by following 
until the first well-baby visit.  Pregnancy should be recorded on a Clinical Study Pregnancy 
Form and reported by the investigator to the sponsor or its designee.  Pregnancy follow-up 
should be recorded on the same form and should include an assessment of the possible 
relationship to the sponsor's study drug of any pregnancy outcome and follow-up to the first 
well-baby visit.  Any SAE experienced during pregnancy must be reported on the SAE 
Report Form and to the sponsor or its designee.  
8.6. 
Definition of an Overdose for This Protocol and Reporting of 
Overdose to the Sponsor 
For purposes of this study, an overdose is defined as the accidental or intentional administration 
of any dose of a product that is considered both excessive and medically important.  All 
occurrences of overdose must be reported as an SAE (see Section 8.3.2 for reporting details). 
8.7. 
Warnings and Precautions 
No evidence available at the time of the approval of this study Protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided IB.  Additional 
safety information collected between IB updates will be communicated in the form of 
Investigator Notifications (INs).  Any important new safety information should be discussed with 
the subject during the study as needed.  If new, significant risks are identified, they will be added 
to the ICF. 
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8.8. 
Safety Monitoring Committee 
There will be no formal external Safety Monitoring Committee (SMC) for the combination 
immunotherapy Phase 1 and Phase 2 cohorts.  For Phase 1, approximately weekly the sponsor 
will conduct telephone conferences with investigators in order to review cohort-specific data, 
overall safety data from prior cohorts (if applicable), and to agree on dose escalation, 
de-escalation, and cohort expansion decisions.  For Phase 2, safety and tolerability will be 
carefully monitored throughout the study by the sponsor in accordance with interim safety 
analyses planned procedures as described in Section 9.6. 
Due to the complexity of the study, for the combination chemo-immunotherapy cohorts in the 
Part 2 of Phase 1, an SMC will review safety data at regular intervals throughout the study.  The 
frequency of meetings will be contingent upon enrollment and availability of safety data for 
analysis and review.  Details regarding membership, roles, and responsibilities of the committee 
are specified in the SMC charter. 
8.9. 
Adverse Events of Special Interest 
Adverse events of special interest must be recorded as such in the eCRF and should be reported 
to the sponsor within 72 hours.  These events include irAEs that are seen with nivolumab and 
epacadostat therapy and any other observed autoimmune phenomenon. 
For this study they include: 
1. An elevated AST or ALT laboratory value that is ≥ 3 × ULN and an elevated total
bilirubin laboratory value that is ≥ 2 × ULN as determined by way of Protocol-specified
laboratory testing or unscheduled laboratory testing.
Note:  These criteria are based on available regulatory guidance documents.  The purpose
of the criteria is to specify a threshold of abnormal hepatic tests that may require an
additional evaluation for an underlying etiology.  The study site guidance for assessment
and follow-up of these criteria can be found in Section 8.2.2.
2. Any of the following AEs:
a.
≥ Grade 3 diarrhea
b. ≥ Grade 3 colitis
c.
≥ Grade 2 pneumonitis
d. ≥ Grade 3 hypo- or hyperthyroidism
e.
≥ Grade 3 rash or dermatitis
f.
Grade 4 laboratory abnormality
Adverse events of special interest include irAEs that are seen with immunotherapy and any other 
observed autoimmune phenomenon.  Guidance regarding identification, evaluation, and 
management of irAEs are provided in Section 5.7.3. 
The irAEs will be monitored carefully before each cycle and through post-treatment follow-up.  
Laboratory results should be evaluated and subjects should be asked for signs and symptoms 
suggestive of an immune-related event.  Subjects who develop an AE thought to be 
immune-related should have additional testing to rule out other causes.  If no other cause is 
found, then the event should be considered to be immune-related. 
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Also, as noted in Section 1.3.1, there is a possibility that epacadostat could cause an increase in 
serotonin levels in the brain that might trigger SS when administered in combination with other 
serotonergic agents (Boyer and Shannon 2005).  This syndrome has been most closely associated 
with use of MAOIs, Demerol®, linezolid, or methylene blue; all of these agents are prohibited 
during the study.  Selective serotonin reuptake inhibitors and SNRIs are permitted in the study.  
Procedures listed in Section 5.7.4 will be implemented if subjects exhibit the signs and 
symptoms of SS described in Table 16 , including tremor, hyperreflexia, and spontaneous, 
ocular, or inducible clonus together with agitation, fever, diaphoresis, or muscle rigidity. 
Adverse events of special interest that occur to any subject from the date of C1D1 through 
100 days after cessation of treatment, or the initiation of a new anticancer therapy, whichever is 
earlier, whether or not related to the sponsor's product, should be reported within 72 hours to the 
sponsor.  A detailed narrative of the event should be reported to the sponsor within 24 hours of 
the event. 
8.10. 
Product Complaints 
The sponsor collects product complaints on study drugs and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and facilitate 
process and product improvements. 
All product complaints associated with material packaged, labeled, and released by the sponsor 
or its designee will be reported. 
The investigator or his/her designee is responsible for reporting a complete description of the 
product complaint and any associated AEs via email or other written communication to the 
Incyte contact. 
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint communication with the product. 
9.
STATISTICS
9.1. 
Study Populations
•
Full analysis set (FAS):  All subjects enrolled in the study who received at least
1 dose of study drug.
•
Per protocol:  All subjects in the FAS population who are considered to be
sufficiently compliant with the Protocol.  The per protocol population will be defined
in the Statistical Analysis Plan for the study.
•
Safety evaluable:  All subjects enrolled in the study who received at least 1 dose of
study drug.
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9.2. 
Selection of Sample Size 
9.2.1. 
Cohort Size in Part 1 and Part 2 of Phase 1 Study 
The primary objective of the open-label Part 1 of Phase 1 study is to determine the RP2D of 
epacadostat in combination with nivolumab, and the primary objective of Part 2 of Phase 1 is to 
determine the safe dose of epacadostat in combination with nivolumab and chemotherapy.  The 
total number of subjects will depend on the number of dose levels tested before the MTD or 
PAD is established.  Up to approximately 63 subjects (9 subjects per dose level for 7 dose levels) 
will be enrolled in Part 1 of Phase 1 for the dose escalation of epacadostat when administered 
with nivolumab (the combination immunotherapy cohorts).  Up to 81 subjects (9 subjects per 
dose level for up to 3 dose levels in 3 combination chemo-immunotherapy cohorts) will be 
enrolled in Part 2 of Phase 1 for the dose finding of epacadostat in combination with nivolumab 
and chemotherapy (the combination chemo-immunotherapy cohorts).  Additionally, 30 subjects 
will be enrolled into each of the safety expansion of combination chemo-immunotherapy cohorts 
(epacadostat + nivolumab + chemotherapy):  Cohort A, Cohort B, and Cohort C.  Table 32 below 
tabulates the probability of observing a toxicity in a cohort of 30 subjects for various event rates.  
Overall sample size in Phase 1 (Part 1 and Part 2) will be up to approximately 234 subjects.  
Table 32: 
Probability of Observing a Toxicity for Various Safety Event Rates 
True Probability of Subjects Having an AE 
Probability of Observing an AE 
5% 
78.5% 
10% 
95.8% 
15% 
99.2% 
20% 
99.9% 
9.2.2. 
Sample Size for the Dose-Expansion Portion (Phase 2) of the Study 
The sample size of 25 subjects are expected to be enrolled in each of the 4 low historic response 
expansion cohorts (CRC, SCCHN, ovarian cancer, and DLBCL) as well as in each of 
I/O-relapsed MEL and I/O-refractory MEL cohorts and 50 subjects in each of the 2 higher 
historic ORR cohorts (NSCLC and I/O-naive MEL).  The sample size for each independent 
cohort yields a power of 80% to detect the following:  1) a target ORR of 17% to 26% increase 
(Ha) from historical response rate (H0) or 2) a PFS rate at 6 months of 14% to 22% increase (Ha) 
from historical survival probability (H0).  This assumes a 1-sided alpha of 2.5% for each of the 
endpoint within a cohort (based on Bonferroni adjustment due to dual primary endpoints), 10% 
lost to follow-up, enrollment period of 6 to 10 months (depends on cohort), and 6 to 10 months 
of follow-up (depends on cohort) after last subject enrolled.  See details in Table 33.  
Twenty-eight subjects are expected to be enrolled in the glioblastoma cohort.  This sample size 
for the glioblastoma cohort yields a power of 80% to detect an OS rate at 9 months of 25% 
increase (Ha) from historical survival probability (H0).  This assumes a 1-sided alpha of 5%, 
10% lost to follow-up, enrollment period of 4 months, and 9 months of follow-up after last 
subject enrolled.  Details are shown in Table 34. 
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Table 33: 
Sample Size Calculation for Each Cohort:  Comparing With a Known 
Proportion 
Tumor Type 
(Cohort) 
ORR 
PFS at 6 Months 
Accrual 
Time 
Minimum 
Follow-Up 
Time 
Sample 
Size 
H0 
Ha 
H0 
Ha 
NSCLC 
24% 
43% 
45% 
65% 
6 months 
6 months 
50 
I/O-naive MEL  
32% 
52% 
50% 
67% 
6 months 
10 months 
50 
I/O-relapsed MEL 
5% 
22% 
5% 
19% 
10 months 
6 months 
25 
I/O-refractory 
MEL 
5% 
22% 
5% 
19% 
10 months 
6 months 
25 
SCCHN 
19% 
44% 
15% 
37% 
10 months 
6 months 
25 
DLBCL 
5% 
22% 
15% 
37% 
10 months 
6 months 
25 
Ovarian cancer 
20% 
46% 
15% 
37% 
10 months 
6 months 
25 
CRC 
5% 
22% 
15% 
37% 
10 months 
6 months 
25 
Table 34: 
Sample Size Calculation for Glioblastoma Cohort:  Comparing With a 
Known Proportion 
Tumor Type 
(Cohort) 
OS at 9 Months 
Accrual Time 
Minimum 
Follow-Up Time 
Sample 
Size 
H0 
Ha 
Glioblastoma 
50% 
75% 
4 months 
9 months 
28 
9.3. 
Level of Significance 
The level of significance for the each of the 2 primary endpoints in Phase 2 is 1-sided 2.5% for 
the NSCLC, MEL (including I/O-naive, I/O-relapsed, and I/O-refractory cohorts), SCCHN, 
DLBCL, OC, and CRC cohorts, which is based on Bonferroni correction for Type I error 5% due 
to dual primary endpoints.  The level of significance is 1-sided 5% for the glioblastoma cohort. 
9.4. 
Statistical Analyses 
9.4.1. 
Primary Analyses 
Objective response rate and PFS are the dual primary endpoints for the solid tumor and DLBCL 
cohorts in Phase 2.  Overall survival at 9 months is the only primary endpoint in the glioblastoma 
cohort.  The Type I error will be controlled using Bonferroni method for each cohort with dual 
primary endpoints.  As a result, the overall familywise Type I error of the study (across all tumor 
types studied) is not controlled, but within each Phase 2 cohorts, the Type I error is controlled at 
1-sided 0.05.  Treatment effect will be claimed in a given tumor type if any 1 of the 2 primary 
endpoints is significant in the cohorts with dual primary endpoints.  Objective response rate is 
defined as the proportion of subjects with best response (CR or PR) by RECIST v1.1 and Cheson 
criteria for DLBCL.  The 95% exact CI for the ORR will be estimated using the Clopper-Pearson 
method for all Phase 2 cohorts except glioblastoma.  One-sample binomial test will be used to 
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test the null hypotheses.  Progression-free survival is defined as number of days from the first 
day of taking the study drug to the earlier of death or disease progression by RECIST v1.1 for 
select solid tumors and Cheson criteria for DLBCL.  Overall survival is defined as number of 
days from the first day of taking study dose to the death.  Time-to-event data will be analyzed by 
the Kaplan-Meier method, treating subjects with no observed death or progression as censored at 
their date of last valid response assessment (PFS) or last date known to be alive (OS).  The 
PFS/OS rate and the corresponding 95% CI using log-log transformation will be estimated using 
the Kaplan-Meier method and will be provided by cohort at 6 months for PFS for the respective 
cohorts and 9 months for OS for the glioblastoma cohort.  The back transformed CI for survival 
function will be used to determine whether the PFS and OS rate under the null hypothesis is 
covered. 
9.4.2. 
Secondary Analyses 
There is no hypothesis testing for secondary analyses.  For objective responders, the DOR is the 
time from the first overall response contributing to an objective response (CR or PR) to the 
earlier of the subject's death and first overall response of PD (as determined per RECIST v1.1 
and modified RECIST, Cheson and modified Cheson, or RANO and modified RANO) occurring 
after the first overall response contributing to the objective response.  Median DOR will be 
estimated using the Kaplan-Meier method for all Phase 2 cohorts.  Confidence intervals for 
median survival time will be calculated using the method of log-log transformation, which is the 
default method within SAS v9.1.  Subjects who are still responding at the time of database freeze 
or discontinuation will be right-censored at the time of last valid response assessment.  
Duration of disease control is the time from the first dose to the first objective response of PD, or 
death, whichever occurs first, for subjects who reported a BOR of SD or better.  In case of SD, 
measurements must meet the SD criteria at least once after study entry at a minimum interval of 
49 days.  For subjects who have not subsequently progressed and who remain alive, duration of 
disease control will be censored on the date of last valid tumor response assessment.  Median 
duration of disease control and CI will be estimated using Kaplan-Meier method for all Phase 2 
cohorts.   
Median OS and CIs will be estimated using the Kaplan-Meier method for all Phase 2 cohorts as 
secondary analysis except glioblastoma.  
For the Phase 2 glioblastoma cohort, ORR and 95% exact CIs will be estimated; median PFS and 
CIs will be estimated using the Kaplan Meier method.   
For subjects in Part 2 of Phase 1 treated with epacadostat in combination with nivolumab and 
chemotherapy (combination chemo-immunotherapy), ORR will be estimated with 95% exact 
binomial CI; median DOR, PFS, and CIs will be estimated using the Kaplan-Meier method.  
Overall response rate and 95% exact binomial CI will be estimated for subjects in Part 1 of 
Phase 1 treated with epacadostat in combination with nivolumab. 
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9.4.4. 
Safety Analyses 
The principal analysis will be based on the safety evaluable population, according to treatment 
assignment. 
Adverse events will be coded by the MedDRA, and incidences will be tabulated by preferred 
term and system organ class for all events, related events, and events from Grade 1 through 
Grade 4.  Severity of AEs will be based on the CTCAE scale as indicated in Section 8.1.1.  
Quantitative safety variables and their changes from baseline (laboratory, vital signs) will be 
summarized with descriptive statistics.  Clinically significant abnormal values will be flagged 
and tabulated based on predefined criteria. 
Exposure will be analyzed by describing dose intensity, which is defined as the dose received 
divided by the dose planned over a given time interval.  This will be done by cycle as well as 
overall cycles received.  For each cycle, incidences of dose reductions and cycle delays will also 
be tabulated, by reason for the reduction or delay.  The percentage of subjects with any delay 
and/or reduction will also be calculated. 
9.4.5. 
Clinical Laboratory Tests 
The clinical laboratory data will be analyzed using summary statistics (eg, means and 
frequencies), and no formal statistical comparisons among the treatments are planned.  In 
addition, distributions of key laboratory parameters (including hemoglobin, neutrophils, and 
platelets) will be plotted over time; these values will also be classified into CTCAE toxicity 
grades and tabulated.  Descriptive statistics and mean change from baseline will be determined 
for vital signs at each assessment time.  Vital sign results will be reviewed for clinically notable 
abnormalities. 
9.5. 
Analyses for the Safety Monitoring Committee 
There will be no formal SMC for the combination immunotherapy cohorts in Phase 1 Part 1 and 
Phase 2; however, ongoing safety reviews will be performed as described in Section 9.6. 
Details regarding safety data to be evaluated by the SMC in Phase 1 Part 2 will be specified in 
the SMC charter. 
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9.6. 
Interim Analysis 
No formal interim analysis for futility or efficacy is planned for this study.  An interim safety 
analysis is planned for Phase 2 after 20 subjects have been enrolled and treated for 8 weeks and 
then every 3 months thereafter.  If the following is reported during these reviews, enrollment of 
subjects will be suspended until the sponsor(s), investigators, and regulatory authorities, if 
applicable, have determined the appropriate course of action: 
•
> 40% of subjects have had DLT defined AEs that were attributable to the
investigational agents.
Based on these rules, the probabilities of stopping a treatment group for safety is provided in 
Table 35. 
Table 35: 
Probability of Early Termination for Various Safety Event Rates 
Proportion of Subjects Having an AE ≥ Grade 3 
That Was Attributable to the Investigational Agent 
Probability of Early Termination Based on an AE 
≥ Grade 3 That Was Attributable to the 
Investigational Agent
a,b 
5% 
0.0% 
10% 
0.1% 
15% 
0.6% 
20% 
3.3% 
25% 
10.2% 
30% 
23.3% 
40% 
80.7% 
a Assumes the interim safety analyses occur when enrollment is 20, 80, 160, 240, and  276, etc, subjects.  Probability estimated 
via simulation with 100,000 replications. 
b The probability of early termination = Prob (≥ 40% of subjects in the active treatment group have had an AE ≥ Grade 3 at the 
first interim safety analysis OR at the second  interim OR at the third interim OR at the fourth interim). 
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10.
STUDY DRUG MATERIALS AND MANAGEMENT
10.1. 
Investigational Products Description 
10.1.1. 
Packaging, Labeling, and Preparation of Study Drug or Placebo 
10.1.1.1. Epacadostat 
The study drug will be available as 25 mg and 100 mg tablets packaged in high-density 
polyethylene bottles.  All bottles of Incyte investigational product will be labeled to comply with 
regulatory requirements of each country.   
10.1.1.2. Nivolumab 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of 
investigational product in accordance with the Protocol and any applicable laws and regulations.  
Clinical supplies will be provided by BMS. 
Clinical supplies will be labeled in accordance with local regulatory requirements. 
The nivolumab product description is provided in Table 36. 
Table 36: 
Nivolumab Product Description 
Product Description 
and Regimen Form 
Potency 
Primary 
Packaging 
(Volume)/Label 
Type 
Secondary 
Packaging 
(Qty)/Label Type 
Appearance 
Storage 
Conditions 
Nivolumab 
(BMS-936558-01) 
solution for injection 
100 mg 
(10 mg/mL) 
10 mg/mL 
vial/open-label 
10 vials per 
carton/open-label 
Clear to opalescent 
colorless to pale 
yellow liquid.  May 
contain particles. 
2°C to 8°C. 
Protect from 
light and 
freezing. 
10.1.2. 
Storage and Stability of Study Drugs 
10.1.2.1. Epacadostat  
Clinical supplies must be stored as described in the eIB. 
10.1.2.2. Nivolumab 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label and as described in the nIB.  Receipt and dispensing of study drug must be 
recorded by an authorized person at the study site.  Clinical supplies may not be used for any 
purpose other than that stated in the Protocol. 
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10.2. 
Accountability, Handling, and Disposal of Epacadostat and 
Nivolumab 
Responsibility for drug accountability at the study site rests with the investigator; however, the 
investigator may assign some of the drug accountability duties to an appropriate pharmacist or 
other designee.  Inventory and accountability records must be maintained and readily available 
for inspection by the study monitor and are open to inspection at any time by any applicable 
regulatory authorities. 
The investigator or designee will be expected to collect and retain all used, unused, and partially 
used containers of study drug until the end of the study.  The investigator or designee must 
maintain records that document: 
•
Delivery of study drug to the study site.
•
Inventory of study drug at the site.
•
Subject use of the study drug including pill or unit counts from each supply
dispensed.
•
Return of study drug to the investigator or designee by subjects.
These records should include dates, quantities, batch or serial numbers (if available), and the 
unique code numbers (if available) assigned to the investigational product and study subjects. 
The investigational product must be used only in accordance with the Protocol.  The investigator 
will also maintain records adequately documenting that the subjects were provided the correct 
study drug specified. 
Completed accountability records will be archived by the site.  The investigator or designee will 
be expected to collect and retain all used, unused, and partially used containers of study drug 
until verified by the study monitor (unless otherwise agreed to by the sponsor).  At the 
completion of the study, the investigator or designee will oversee shipment of any remaining 
epacadostat back to the sponsor or its designee for destruction according to institutional standard 
operating procedures.  If local procedures mandate site destruction of investigational supply, the 
site should (where local procedures allow) maintain the investigational supply until the study 
monitor inspects the accountability records in order to evaluate compliance and accuracy of 
accountability by the investigative site.  At sites where the study drug is destroyed before 
monitor inspection, the monitors rely on documentation of destruction per the site SOP. 
Infusion related supplies (eg, IV bags, in-line filters, 0.9% NaCl solution) for nivolumab will not 
be supplied by the sponsor and should be purchased locally if permitted by local regulations. 
10.2.1. 
Disposal of Epacadostat and Nivolumab  
Upon completion or termination of the study, all unused and/or partially used nivolumab will be 
destroyed at the site per institutional policy.  It is the investigator's responsibility to arrange for 
disposal of all empty containers, provided that procedures for proper disposal have been 
established according to applicable federal, state, local, and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept. 
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11.
STUDY ADMINISTRATION
11.1. 
Data Management 
11.1.1. 
Data Collection 
The investigator will be provided with a eCRF for each subject.  Entries made in the eCRF must 
be verifiable against source documents; any discrepancies should be explained and documented.  
The investigator will be responsible for reviewing all data and eCRF entries and will sign and 
date the designated pages in each subject's eCRF, verifying that the information is true and 
correct.  The investigator is responsible for the review and approval of all responses. 
11.1.2. 
Data Management 
Data management will be performed from eCRFs.  All eCRF data will be entered into a validated 
database.  All data entry, verification, and validation will be performed in accordance with the 
current standard operating procedures of the Data Management Department at the sponsor or its 
designee.  The database will be authorized for lock once all defined procedures are completed. 
11.2. 
Study Monitoring 
Qualified representatives of the sponsor or its designee, "study monitors," will monitor the study 
according to a predetermined monitoring plan.  Monitoring visits provide the sponsor with the 
opportunity to: 
•
Evaluate the progress of the study.
•
Verify the accuracy and completeness of eCRFs.
•
Assure that all Protocol requirements, applicable laws and/or regulations, and
investigator's obligations are being fulfilled.
•
Resolve any inconsistencies in the study records.
The investigator must allow the study monitors to periodically review, at mutually convenient 
times during the study and after the study has been completed, all CRFs and office, hospital, and 
laboratory records supporting the participation of each subject in the study.  The eCRFs and 
other documentation supporting the study must be kept up-to-date by the investigator and the 
research staff at the investigative site.  These study materials must be available for review by the 
study monitor, and/or other qualified representatives of the sponsor or its designee, at each 
monitoring visit. 
The study monitor will review the various records of the study (eCRFs, subject medical and 
laboratory records, and other pertinent data).  The study monitor will verify the eCRF data 
against original source documentation for accuracy and completeness.  The study monitor will 
identify data discrepancies and collaborate with the investigator and research staff to resolve the 
discrepancies in a timely manner.  Protocol deviations will also be identified and recorded on a 
"Protocol Deviation Log."  The study monitor will follow an "Issue Escalation" plan in order to 
ensure that each issue identified during a monitoring visit is appropriately documented, reported, 
and resolved in a timely manner in accordance with the plan's requirements. 
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11.3. 
Protocol Adherence 
The principal investigator must obtain IRB or IEC approval for the investigation.  Initial IRB or 
IEC approval and all materials approved by the IRB or IEC for this study including the subject 
ICF and recruitment materials must be maintained by the investigator and made available for 
inspection. 
Each investigator must adhere to the Protocol as described in this document and agree that 
changes to the Protocol, with the exception of medical emergencies, must be discussed and 
approved, firstly, by the sponsor or its designee and, secondly, by the IRB or IEC.  Each 
investigator is responsible for enrolling subjects who have met the Protocol inclusion and 
exclusion criteria.  The IRB or IEC that granted original approval, or the IRB or IEC currently 
responsible for overseeing the conduct of the study, must be notified of all changes in and 
deviations from the Protocol that may increase risk to the subject, and/or that may adversely 
affect the rights of the subject or validity of the investigation.  The investigator must send a copy 
of the approval letter from the IRB or IEC to the sponsor or its designee and retain the original in 
the site study regulatory file. 
Major eligibility deviations must be reported to the IRB or IEC in accordance with the IRB or 
IEC requirements.  During the course of the study, the monitor must notify the sponsor or its 
designee of subjects found not to have met eligibility criteria.  The medical monitor, in 
collaboration with the investigator, will determine if the subject should be withdrawn from the 
study. 
11.4. 
Financial Disclosure 
All clinical investigators participating in clinical studies subject to FDA Regulation Title 21 
Code of Federal Regulations (CFR) Part 54 – Financial Disclosure by Clinical Investigators, are 
required before study initiation to submit a completed Clinical Investigator Financial Disclosure 
Request Form that sufficiently details any financial interests and arrangements that apply.  For 
the purpose of this regulation, clinical investigator is defined as any investigator or 
subinvestigator who is directly involved in the treatment or evaluation of research subjects, 
including the spouse and each dependent child of the clinical investigator.  These requirements 
apply to both US and foreign clinical investigators conducting covered clinical studies. 
Any new investigators or subinvestigators added to the covered clinical study during its conduct 
must also submit a completed Clinical Investigator Financial Disclosure Request Form.  During a 
covered clinical study, any changes to the financial information previously reported by a clinical 
investigator must be reported to the sponsor or its designee.  At the conclusion of the covered 
clinical study, the clinical investigators will be reminded of their obligation to report to the 
sponsor or its designee any changes to the financial information previously reported.  The 
clinical investigators will also be reminded that they must report any changes in their financial 
information for a period of 1 year after completion of the covered clinical study. 
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11.5. 
Compliance With Study Registration and Results Posting 
Requirements 
Under the terms of the Food and Drug Administration Modernization Act and the Food and Drug 
Administration Amendments Act, the sponsor of the study is solely responsible for determining 
whether the study and its results are subject to the requirements for submission to the Clinical 
Trials Data Bank, www.clinicaltrials.gov.  Information posted will allow individuals to identify 
potentially appropriate studies for their disease conditions and pursue participation by calling a 
central contact number for further information on appropriate study locations and study site 
contact information. 
12.
QUALITY CONTROL AND QUALITY ASSURANCE
12.1. 
Sponsor Audits 
At some point during the study, individuals from the sponsor's Quality Assurance department 
and/or their authorized representative may visit the investigator's site to conduct an audit of the 
study.  The purpose of this visit will be to determine the investigator's adherence to the Protocol, 
applicable regulations, and the sponsor's procedures, in addition to assessing the accuracy of the 
study data.  Before initiating this audit, the investigator will be contacted by the sponsor to 
arrange a convenient time for this visit.  The investigator and staff are expected to cooperate with 
the auditors and allow access to all subject records supporting the eCRFs and other study-related 
documents. 
12.2. 
Inspection by Regulatory Authorities 
At some point during the investigational product's development program, a regulatory authority 
may visit the investigator to conduct an inspection of the study and the site.  The investigator and 
staff are expected to cooperate with the inspectors and allow access to all source documents 
supporting the eCRFs and other study-related documents.  The investigator must immediately 
notify the sponsor when contacted by any regulatory authority for purposes of conducting an 
inspection. 
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13.
ETHICS
13.1. 
Ethical Conduct of the Study 
This study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and conducted in adherence to the study Protocol, GCPs as defined in 
Title 21 of the US CFR Parts 50, 54 56, 312, and Part 11, as well as ICH GCP consolidated 
guidelines (E6) and applicable regulatory requirements. 
13.2. 
Written Informed Consent 
Informed consent documentation that includes both information about the study and the ICF will 
be prepared and given to the subject.  This document will contain all elements required by the 
ICH E6 Guideline for GCP and any additional elements required by local regulations.  The 
document must be in a language understandable to the subject and must specify who informed 
the subject.  Where required by local law, the person who informs the subject must be a 
physician. 
The principal investigator at each center will ensure that the subject is given full and adequate 
verbal and written information about the nature, purpose, and the possible risk and benefit of the 
study.  Subjects must also be notified that they are free to discontinue study drug and withdraw 
from the study at any time.  The subject should be given the opportunity to ask questions and 
allowed time to consider the information provided. 
The subject's signed and dated ICF must be obtained before conducting any study procedures.  
The principal investigator must maintain the original, signed ICF.  A copy of the signed ICF 
must be given to the subject.  The investigator should inform the subject's primary physician 
about the subject's participation in the study if the subject has a primary physician and if the 
subject agrees to the primary physician being informed. 
Preparation of the ICF is the responsibility of the investigator and must include all elements 
required by the ICH GCP, and applicable regulatory requirements, and must adhere to the ethical 
principles that have their origin in the Declaration of Helsinki.  A template will be provided by 
the sponsor or its designee.  The sponsor or its designee must review and approve all changes to 
site-specific ICFs.  The ICF must include a statement that the sponsor or its designee and 
regulatory authorities have direct access to subject records.  Before the beginning of the study, 
the IRB or IEC must provide the investigator with written approval/favorable opinion of the 
written ICF and any other information to be provided to the subjects. 
13.3. 
Ethics Review 
It is the responsibility of the investigator to assure that all aspects of the ethics review are 
conducted in accordance with the Declaration of Helsinki as described in the ICH E6:  Guideline 
for GCP, and/or local laws, whichever provides the greatest level of protection for the study 
participants.  The Protocol and any information supplied to the subject to obtain informed 
consent, including written ICFs, subject recruitment procedures (eg, advertisements), and written 
information to be provided to subjects (information leaflets), must be reviewed and approved by 
a qualified IRB/IEC before enrollment of participants in the study.  Before initiation of the study, 
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the sponsor or its designee must receive documentation of the IRB or IEC approval, which 
specifically identifies the study/Protocol, and a list of the committee members. 
The principal investigator is responsible for informing the IRB or IEC of any amendment to the 
Protocol in accordance with local requirements.  Protocol amendments and revisions to the ICF 
must be submitted to and approved by the IRB or IEC. 
Investigators must submit progress reports to the IRB or IEC in accordance with the IRB or IEC 
requirements and local regulations.  Annual re-approval of the study must be obtained.  Copies 
of progress reports and annual re-approvals must be sent to the sponsor or its designee. 
The principal investigator is also responsible for providing the IRB or IEC with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product.  The sponsor or its designee will provide this information to the principal investigator. 
When the sponsor or its designee provides the investigator with a safety report, the investigator is 
responsible for ensuring that the safety report is reviewed and processed in accordance with 
regulatory requirements and with the policies and procedures established by their respective 
IRBs or IECs. 
After completion or termination of the study, the investigator must submit a final report to the 
IRB or IEC and to the sponsor or its designee. 
The investigator, as part of the records retention requirements for the study, must maintain 
documentation of all submissions, correspondence, and approvals to and from the IRB or IEC. 
Each clinical investigator is responsible to conduct the study in accordance with the Protocol, all 
applicable laws, regulations, and GCP according to ICH guidelines. 
13.4. 
Data Privacy 
The investigator and the sponsor or its designee must adhere to applicable data privacy laws and 
regulations.  The investigator and the sponsor (or its designee) are responsible for ensuring that 
sensitive information is handled in accordance with local requirements (eg, HIPAA).  
Appropriate consent and authorizations for use and disclosure and/or transfer (if applicable) of 
protected information must be obtained. 
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14.
DATA HANDLING AND RECORDKEEPING
14.1. 
Inspection of Records 
The sponsor or its designee will be allowed to conduct site visits to the investigation facilities for 
the purpose of monitoring any aspect of the study.  The investigator agrees to allow the monitor 
to inspect the drug storage area, study drug stocks, drug accountability records, subject charts 
and study source documents, and other records relative to study conduct. 
The investigator must ensure that all records pertaining to the conduct of the clinical study (as 
listed above) are adequately maintained for a period of 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region, or at least 2 years have elapsed since the formal termination of 
clinical development of the investigational product. 
14.2. 
Retention of Records 
The principal investigator must maintain all documentation relating to the study for a period of 
2 years after the last marketing application approval, or if not approved, 2 years following the 
termination of the test article for investigation.  If it becomes necessary for the sponsor or the 
regulatory authority to review any documentation relating to the study, the investigator must 
permit access to such records. 
The investigator must not destroy any records associated with the study without receiving 
approval from Incyte.  The investigator must notify the sponsor or its designee in the event of 
accidental loss or destruction of any study records.  If the investigator leaves the institution 
where the study was conducted, the sponsor or its designee must be contacted to arrange 
alternative record storage options. 
Whenever possible, an original recording of an observation must be retained as the source 
document.  However, a photocopy of a record is acceptable, provided it is legible and is a 
verified copy of the original document. 
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. 
14.3. 
Confidentiality 
Subject names will not be supplied to the sponsor or its designee if applicable.  Only the subject 
number and subject's initials will be recorded in the eCRF, where permitted; if the subject's name 
appears on any other document (eg, laboratory report), it must be obliterated on the copy of the 
document to be supplied to the sponsor or its designee.  Study findings stored on a computer will 
be stored in accordance with local data protection laws.  The subjects will be informed that 
representatives of the sponsor or its designee, IRB or IEC, or regulatory authorities may inspect 
their medical records to verify the information collected, and that all personal information made 
available for inspection will be handled in strictest confidence and in accordance with local data 
protection laws. 
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15.
PUBLICATION POLICY
By signing the study Protocol, the investigator and his or her institution agree that the results of 
the study may be used by the sponsor, Incyte Corporation (Incyte), for the purposes of national 
and international registration, publication, and information for medical and pharmaceutical 
professionals.  If necessary, the authorities will be notified of the investigator's name, address, 
qualifications, and extent of involvement.  The terms regarding the publication of study results 
are contained in the agreement signed with the sponsor or its designee.  The signed agreement is 
retained by the sponsor or its designee. 
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16.
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APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS 
For Subjects Participating in the Study: 
The following methods that can achieve a failure rate of less than 1% per year when used 
consistently and correctly are considered as highly effective birth control methods.  
Such methods include: 
•
Combined (estrogen and progestogen containing) hormonal contraception associated
with inhibition of ovulation1
− oral
− intravaginal
− transdermal
•
Progestogen-only hormonal contraception associated with inhibition of ovulation1
− oral
− injectable
− implantable2
•
Intrauterine device (IUD)2
•
Intrauterine hormone-releasing system (IUS)2
•
Bilateral tubal ligation or occlusion2
•
Vasectomised partner2,3
•
Sexual abstinence4
1  Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the 
contraception method. 
2  Contraception methods that in the context of this guidance are considered to have low user dependency. 
3  Vasectomised partner is a highly effective method provided of avoiding pregnancy that partner is the sole sexual 
partner of the WOCBP trial participant and that the vasectomised partner has received medical assessment of the 
surgical success.  
4  In the context of this guidance, sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments.  The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the subject. 
Source:  CTFG 2014. 
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APPENDIX C. MANAGEMENT ALGORITHMS 
These general guidelines constitute guidance to the investigator and may be supplemented by 
discussions with the medical monitor representing the sponsor.  The guidance applies to all 
immuno-oncology (I-O) agents and regimens.  
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice.  Noninflammatory etiologies should be considered and appropriately 
treated.  
Corticosteroids are a primary therapy for I-O drug-related adverse events.  The oral equivalent of 
the recommended IV doses may be considered for ambulatory patients with low-grade toxicity.  
The lower bioavailability of oral corticosteroids should be taken into account when switching to 
the equivalent dose of oral corticosteroids.  
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended.  
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the I-O agent or regimen being used. 
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GI Adverse Event Management Algorithm
Grade of Diarrhea/
Colitis
(NCI CTCAE v4)
Management
Follow-up
Grade 1
Diarrhea:< 4 stools/day over baseline;
Colitis:asymptomatic
Grade 3-4
Diarrhea (G3): ≥7 stools per day over 
baseline; incontinence; IV fluids ≥24 
hrs; interfering with  activities of daily 
living (ADL)
Colitis (G3): severe abdominal pain, 
medical intervention indicated, 
peritoneal signs
G4: life-threatening, perforation
• Continue  I-O therapy per 
protocol
• Symptomatic treatment
• Discontinue I-O therapy per 
protocol
• 1.0 to 2.0 mg/kg/day 
methylprednisolone  IV or  IV
equivalent
• Add prophylactic antibiotics for 
opportunistic infections
• Consider lower endoscopy
• Close monitoring for worsening symptoms. 
• Educate patient to report worsening immediately
If worsens: 
• Treat as Grade (G) 2 or 3/4
If improves: 
• Continue steroids until grade 1, then taper over at 
least 1 month
If persists > 3-5 days, or recurs after improvement:
• Add infliximab 5 mg/kg (if no contraindication).
Note: Infliximab should not be used in cases of 
perforation or sepsis
Grade 2
Diarrhea: 4-6 stools per day over 
baseline; IV fluids indicated <24 hours 
(hrs); not interfering with ADL
Colitis:abdominal pain; blood in stool
• Delay I-O therapy per protocol
• Symptomatic treatment
If improves to grade 1: 
• Resume I-O therapy per protocol
If persists > 5-7 days or recur:
• 0.5-1.0 mg/kg/day methylprednisolone or oral equivalent
• When symptoms improve to grade 1, taper steroids over
at least 1 month, consider prophylactic antibiotics for
opportunistic infections, and resume I-O therapy per 
protocol.
If worsens or persists > 3-5 days with oral steroids: 
• Treat as grade 3/4
Rule out non-inflammatory causes. If non-inflammatory cause is identified, treat accordingly and continue I-O therapy. Opiates/narcotics 
may mask symptoms of perforation. Infliximab should not be used in cases of perforation or sepsis.
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed.  Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids.
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Renal Adverse Event Management Algorithm
Grade of Creatinine  
Elevation    
(NCI CTCAE v4)
Management
Follow-up
Grade 1
Creatinine > upper limit 
of normal (ULN) and  > 
than baseline but  ≤ 1.5x 
baseline
Grade 4
Creatinine > 6x ULN
• Continue I-O therapy per protocol
• Monitor creatinine weekly
• Discontinue I-O therapy per 
protocol
• Monitor creatinine daily
• 1.0-2.0 mg/kg/day
methylprednisolone IV or IV
equivalent
• Consult nephrologist
• Consider renal biopsy
If returns to baseline: 
•Resume routine creatinine monitoring per protocol
If worsens:
•Treat as Grade 2 or 3/4
If returns to Grade 1 :  Taper steroids over at least 1 month and
add prophylactic antibiotics for opportunistic infections
Grade 2-3
Creatinine > 1.5x baseline 
to ≤ 6x ULN
• Delay I-O therapy per protocol
• Monitor creatinine every 2-3 days
• 0.5 to 1.0 mg/kg/day 
methylprednisolone  IV or oral
equivalent
• Consider renal biopsy
If returns to Grade 1:
•Taper steroids over at least 1 month, consider prophylactic 
antibiotics for opportunistic infections, and resume I-O therapy 
and routine creatinine monitoring per protocol
If elevations persist > 7 days or worsen:
•Treat as Grade 4
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed.  Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids.
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Pulmonary Adverse Event Management Algorithm
Grade of 
Pneumonitis
(NCI CTCAE v4)
Management
Follow-up
Grade 1
Radiographic changes only 
Grade 3-4
Severe new symptoms;
New/worsening hypoxia;
Life-threatening
• Consider delay of I-O therapy
• Monitor for symptoms every 2-3 
days
• ConsiderPulmonary and 
Infectious Disease (ID) consults
• Discontinue  I-O therapy per 
protocol
• Hospitalize
• Pulmonary and ID consults
• 2-4  mg/kg/day
methylprednisolone IV or IV
equivalent
• Add prophylactic antibiotics for 
opportunistic infections
• Consider bronchoscopy, lung 
biopsy
• Re-image at least every 3 weeks
If worsens: 
• Treat as Grade 2 or 3-4
If improves to baseline:
• Taper steroids over at least 6 weeks
If not improving after 48 hours or worsening:
• Add additional immunosuppression (e.g. infliximab,
cyclophosphamide, intravenous immunoglobulin (IVIG), or 
mycophenolate mofetil)
Grade 2
Mild to moderate  new 
symptoms
• Delay I-O therapy per protocol
• Pulmonary and ID consults
• Monitor symptoms daily, consider 
hospitalization
• 1.0 mg/kg/day methyl-
prednisolone IV or oral equivalent
• Consider  bronchoscopy , lung 
biopsy
• Re-image every 1-3 days
If improves:  
• When symptoms return to nearbaseline, taper steroids over 
at least 1 month and then resume I-O therapy per protocol 
and consider prophylactic antibiotics
If not improving after 2 weeks  or worsening:
• Treat as Grade 3-4
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. Evaluate with imaging 
and pulmonary consultation.
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed.  Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids.
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Hepatic Adverse Event Management Algorithm
Grade of Liver 
Test  Elevation 
        
(NCI CTCAE v4)
Management
Follow-up
Grade 1
AST or ALT > ULN  to 3.0 x 
ULN and/or Total 
bilirubin (T. bili) > ULN  -
1.5 x ULN
Grade 3-4
AST or ALT > 5 x ULN   
and /or T.bili >3 x ULN
• Continue I-O therapy per protocol
• Discontinue  I-O therapy*
• Increase frequency of monitoring 
to every 1-2 days
• 1.0 to 2.0 mg/kg/day 
methylprednisolone IV or IV
equivalent**
• Add prophylactic antibiotics for 
opportunistic infections
• Consult gastroenterologist
• Continue liver function tests (LFT) monitoring per protocol
If worsens:
• Treat as Grade 2 or 3-4
If returns to grade 2:
•Taper steroids over at least 1 month
If does not improve in >3-5 days, worsens or rebounds:
• Add  mycophenolate mofetil 1 gram (g) twice daily (BID)
• If no response within an additional 3-5 days, consider other 
immunosuppressants per local guidelines
Grade 2
AST or ALT > 3.0 to ≤ 5 x 
ULN and/or T. bili > 1.5 
to ≤ 3 x ULN
• Delay I-O therapy per protocol
• Increase frequency of monitoring 
to every 3 days
If returns to baseline: 
•Resume routine monitoring, resume I-O therapy per protocol
If elevations persist > 5-7 days or worsen :
• 0.5-1 mg/kg/day methylprednisolone or oral equivalent and
when LFT returns to grade 1 or baseline, taper steroids over at 
least 1 month, consider prophylactic antibiotics for 
opportunistic infections, and resume I-O therapy per protocol
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed.  Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids.
*I-O therapy may be delayed rather than discontinued if AST/ALT ≤ 8 x ULN and T.bili ≤ 5 x ULN.
**The recommended starting dose for grade 4 hepatitis is 2 mg/kg/day methylprednisolone IV.
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. Consider imaging for 
obstruction. 
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Endocrinopathy Management Algorithm
Asymptomatic 
thyroid 
stimulating 
hormone (TSH) 
elevation
Suspicion of adrenal 
crisis (e.g. severe 
dehydration, 
hypotension, shock 
out of proportion to 
current illness
• Continue I-O therapy per protocol
• If TSH < 0.5 x lower limit of normal (LLN), or TSH > 2 x ULN, or consistently out of range in 2 subsequent 
measurements: include free thyroxine (fT4) at subsequent cycles as clinically indicated; consider 
endocrinology consult
• Delay or discontinue I-O therapy per protocol
• Rule out sepsis
• Stress dose of IV steroids with mineralocorticoid activity
• IV fluids
• Consult endocrinologist
• If adrenal crisis ruled out,  then treat as above for symptomatic 
endocrinopathy
Symptomatic 
endocrinopathy
• Evaluate endocrine function
• Consider pituitary scan
Symptomatic with abnormal lab/pituitary scan:
• Delay I-O therapy per protocol
• 1-2 mg/kg/day methylprednisolone IV or by mouth (PO)
equivalent
• Initiate appropriate hormone therapy
No abnormal lab/pituitary MRI scan but symptoms persist:
• Repeat labs in 1-3 weeks /MRI in 1 month
If improves  (with or without 
hormone replacement):
• Taper steroids over at least 1 
month and consider prophylactic 
antibiotics for opportunistic 
infections
• Resume I-O therapy per protocol
• Patients with adrenal
insufficiency may need to 
continue steroids with 
mineralocorticoid component
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. Consider visual field testing, 
endocrinology consultation, and imaging.
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, 
once sustained clinical improvement is observed.  Lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids.
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Skin Adverse Event Management Algorithm
Grade of 
Rash 
(NCI CTCAE v4)
Management
Follow-up
Grade 1-2
Covering  ≤ 30% 
body surface area 
(BSA)*
Grade 3-4
Covering >30% BSA; 
Life threatening 
consequences*
• Symptomatic therapy (e.g. antihistamines,
topical steroids)
• Continue I-O therapy per protocol
• Delay or discontinue I-O therapy per 
protocol
• Consider skin biopsy
• Dermatology consult
• 1.0-2.0 mg/kg/day IV methylprednisolone
IV or IV equivalent
If persists > 1-2 weeks or recurs:
• Consider skin biopsy
• Delay I-O therapy per protocol
• Consider 0.5-1.0 mg/kg/day methylprednisolone IV or
oral  equivalent. Once improving , taper steroids over 
at least 1 month, consider prophylactic antibiotics for 
opportunistic infections, and resume I-O therapy per 
protocol
If worsens:
• Treat as Grade 3-4
If improves to Grade 1:
• Taper steroids over at least 1 month and add
prophylactic antibiotics for opportunistic infections
• Resume I-O therapy per protocol
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed.  Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids.
*Refer to NCI CTCAE v4 for term-specific grading criteria.
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. 
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Neurological Adverse Event Management Algorithm
Grade of 
Neurological 
Toxicity 
(NCI CTCAE v4)
Management
Follow-up
Grade 1
Asymptomatic or 
mild symptoms; 
Intervention not 
indicated
Grade 3-4
Severe symptoms; 
Limiting self-care  
ADL;        
Life-threatening
• Continue I-O therapy per protocol
• Discontinue I-O therapy per protocol
• Obtain neurology consult
• Treat symptoms per local guidelines
• 1.0-2.0 mg/kg/day IV
methylprednisolone  IV or IV equivalent
• Add prophylactic antibiotics for 
opportunistic infections
Continue to monitor the patient. 
If worsens:
• Treat as Grade 2 or 3-4
If improves to Grade 2: 
• Taper steroids over at least 1 month
If worsens or atypical presentation:
• Consider IVIG or other immunosuppressive therapies per 
local guidelines
Grade 2
Moderate symptoms; 
Limiting instrumental 
ADL
• Delay I-O therapy per protocol
• Treat symptoms per local guidelines
• Consider  0.5 to 1.0 mg/kg/day 
methylprednisolone  IV or  PO 
equivalent
C
If improves to baseline: 
•Resume I-O therapy per protocol when improved to baseline
If worsens:
•Treat as Grade 3-4
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy.
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, 
once sustained clinical improvement is observed.  Lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids.
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APPENDIX D. PROHIBITED MONOAMINE OXIDASE INHIBITORS 
AND DRUGS ASSOCIATED WITH SIGNIFICANT 
MONOAMINE OXIDASE INHIBITORY ACTIVITY 
Monoamine Oxidase Inhibitors 
Drugs Associated With Significant Monoamine 
Oxidase Inhibitory Activity 
Hydrazines (example phenelzine) 
Meperidine 
Isocarboxazid 
Linezolid 
Tranylcypromine 
Methylene blue 
Brofaromine 
Rasagiline 
Selegiline 
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APPENDIX E. RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS (RECIST) VERSION 1.1 
RECIST v1.1* will be used in this study for assessment of tumor response.  While either CT or 
MRI may be used, as per RECIST v1.1, CT is the preferred imaging technique in this study. 
* As published in the European Journal of Cancer:
Source:  Eisenhauer et al 2009. 
In addition, volumetric analysis will be explored by central review for response assessment. 
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APPENDIX F. RESPONSE CRITERIA FOR LYMPHOMA 
LYMPHOMA COMPLETE RESPONSE, PARTIAL RESPONSE, STABLE DISEASE, 
RELAPSED/PROGRESSIVE DISEASE RESPONSE CRITERIA (Cheson et al 2007) 
Complete Response (CR) 
The designation of CR requires the following: 
1. Complete disappearance of all detectable clinical evidence of disease and disease-related
symptoms such as 'B symptom' if present before therapy.
2. a. Typically FDG-avid lymphoma:  in patients with no pretreatment PET scan or when 
the PET scan was positive before therapy, a post-treatment residual mass of any size 
is permitted as long as it is PET negative.  
b. Variably FDG-avid lymphomas/FDG avidity unknown:  in patients without a
pretreatment PET scan, or if a pretreatment PET scan was negative, all lymph nodes
and nodal masses must have regressed on CT to normal size (≤ 1.5 cm in their
greatest transverse diameter for nodes > 1.5 cm before therapy).  Previously involved
nodes that were 1.1 to 1.5 cm in their long axis and more than 1.0 cm in their short
axis before treatment must have decreased to ≤ 1.0 cm in their short axis after
treatment.
3. The spleen and/or liver, if considered enlarged before therapy on the basis of a physical
examination or CT scan, should not be palpable on physical examination and should be
considered normal size by imaging studies, and nodules related to lymphoma should
disappear.
4. If the bone marrow was involved by lymphoma before treatment, the infiltrate must have
cleared on repeat bone marrow biopsy.  The biopsy sample on which this determination is
made must be adequate (with a goal of > 20 mm unilateral core).  If the sample is
indeterminate by morphology, it should be negative by immunohistochemistry.  A sample
that is negative by immunohistochemistry but that demonstrates a small population of
clonal lymphocytes by flow cytometry will be considered a CR until data become
available demonstrating a clear difference in patient outcome.
Partial Response (PR) 
The designation of PR requires all of the following: 
1. At least a 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the
largest dominant nodes or nodal masses.  These nodes or masses should be selected
according to all of the following:  they should be clearly measurable in at least
2 perpendicular dimensions; if possible they should be from disparate regions of the
body; and they should include mediastinal and retroperitoneal areas of disease whenever
these sites are involved.
2. No increase should be observed in the size of other nodes, liver, or spleen.
3. Splenic and hepatic nodules must regress by ≥ 50% in their SPD or, for single nodules, in
the greatest transverse diameter.
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4. With the exception of splenic and hepatic nodules, involvement of other organs is usually
assessable and no measurable disease should be present.
5. Bone marrow assessment is irrelevant for determination of a PR if the sample was
positive before treatment.  However, if positive, the cell type should be specified
(eg, large-cell lymphoma or small neoplastic B-cells).  Patients who achieve a CR by the
above criteria, but who have persistent morphologic bone marrow involvement will be
considered partial responders.  When the bone marrow was involved before therapy and a
clinical CR was achieved, but with no bone marrow assessment after treatment, patients
should be considered partial responders.
6. No new sites of disease should be observed.
7. Typically FDG-avid lymphoma:  for patients with no pretreatment PET scan or if the
PET scan was positive before therapy, the post-treatment PET should be positive in at
least 1 previously involved site.
8. Variably FDG-avid lymphomas/FDG-avidity unknown:  for patients without a
pretreatment PET scan, or if a pr-treatment PET scan was negative, CT criteria should be
used.
Stable Disease (SD) 
Stable disease (SD) is defined as the following: 
1. A patient is considered to have SD when he or she fails to attain the criteria needed for a
CR or PR, but does not fulfill those for progressive disease (see Relapsed Disease [after
CR]/Progressive Disease [after PR, SD]).
2. Typically FGD-avid lymphomas:  the PET should be positive at prior sites of disease
with no new areas of involvement on the post-treatment CT or PET.
3. Variably FDG-avid lymphomas/FDG-avidity unknown:  for patients without a
pretreatment PET scan or if the pretreatment PET was negative, there must be no change
in the size of the previous lesions on the post-treatment CT scan.
Relapsed Disease (After CR)/Progressive Disease (After PR, SD) 
Lymph nodes should be considered abnormal if the long axis is more than 1.5 cm regardless of 
the short axis.  If a lymph node has a long axis of 1.1 to 1.5 cm, it should only be considered 
abnormal if its short axis is more than 1.0.  Lymph nodes ≤ 1.0 × ≤ 1.0 cm will not be considered 
as abnormal for relapse or progressive disease. 
1. Appearance of any new lesion more than 1.5 cm in any axis during or at the end of
therapy, even if other lesions are decreasing in size.  Increased FDG uptake in a
previously unaffected site should only be considered relapsed or progressive disease after
confirmation with other modalities.  In patients with no prior history of pulmonary
lymphoma, new lung nodules identified by CT are mostly benign.  Thus, a therapeutic
decision should not be made solely on the basis of the PET without histologic
confirmation.
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2. At least a 50% increase from nadir in the sum of the product diameters of any previously
involved nodes, or in a single involved node, or the size of other lesions (eg, splenic or
hepatic nodules).  To be considered progressive disease, a lymph node with a diameter of
the short axis of less than 1.0 cm must increase by ≥ 50% and to a size of 1.5 × 1.5 cm or
more than 1.5 cm in the long axis.
3. At least a 50% increase in the longest diameter of any single previously identified node
more than 1 cm in its short axis.
4. Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the
lesion was PET positive before therapy unless the lesion is too small to be detected with
current PET systems (< 1.5 cm in its long axis by CT).
Measurable extranodal disease should be assessed in a manner similar to that for nodal disease.  
For these recommendations, the spleen is considered nodal disease.  Disease that is only 
assessable (eg, pleural effusions, bone lesions) will be recorded as present or absent only, unless, 
while an abnormality is still noted by imaging studies or physical examination, it is found to be 
histologically negative. 
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APPENDIX G. RESPONSE ASSESSMENT FOR WALDENSTRÖM'S 
MACROGLOBULEMIA 
Categorical Response Definitions in Waldenström's Macroglobulinemia 
Response Category 
Response Definition 
Complete Response 
• Absence of serum monoclonal IgM protein by immunofixation
• Normal serum IgM level
• Complete resolution of extramedullary disease, ie, lymphadenopathy
and splenomegaly if present at baseline
• Morphologically normal bone marrow aspirate and trephine biopsy
Very Good Partial Response 
• Monoclonal IgM protein is detectable ≥ 90% reduction in serum IgM
level from baseline*
• Complete resolution of extramedullary disease, ie,
lymphadenopathy/splenomegaly if present at baseline
• No new signs or symptoms of active disease
Partial Response 
• Monoclonal IgM protein is detectable ≥ 50% but < 90% reduction in
serum IgM level from baseline*
• Reduction in extramedullary disease, ie,
lymphadenopathy/splenomegaly if present at baseline
• No new signs or symptoms of active disease
Minor Response 
• Monoclonal IgM protein is detectable ≥ 25% but < 50% reduction in
serum IgM level from baseline*
• No new signs or symptoms of active disease
Stable Disease 
• Monoclonal IgM protein is detectable < 25% reduction and < 25%
increase in serum IgM level from baseline*
• No progression in extramedullary disease, ie,
lymphadenopathy/splenomegaly
• No new signs or symptoms of active disease
Progressive Disease 
• ≥ 25% increase in serum IgM level* from lowest nadir (requires
confirmation) and/or
• progression in clinical features attributable the disease
NOTE:  Very good partial response will still be categorized as partial response (PR) and minor response should still 
be categorized as stable disease (SD) in the CRF. 
*Sequential changes in IgM levels may be determined either by M protein quantification by densitometry or total
serum IgM quantitation by nephelometry. 
Source:  Owen et al 2013. 
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APPENDIX H. RESPONSE CRITERIA FOR GLIOBLASTOMA 
RANO Criteria for Response Assessment Incorporating MRI and Clinical Factors 
Response 
Criteria 
Complete response 
Requires all of the following:  complete disappearance of all enhancing measurable and 
nonmeasurable disease sustained for at least 4 weeks; no new lesions; stable or improved 
non-enhancing (T2/FLAIR) lesions; subjects must be off corticosteroids (or on 
physiologic replacement doses only); and stable or improved clinically.  Note:  Subjects 
with nonmeasurable disease only cannot have a complete response; the best response 
possible is stable disease. 
Partial response 
Requires all of the following:  ≥ 50% decrease compared with baseline in the sum of 
products of perpendicular diameters of all measurable enhancing lesions sustained for at 
least 4 weeks; no progression of nonmeasurable disease; no new lesions; stable or 
improved nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids 
compared with baseline scan; the corticosteroid dose at the time of the scan evaluation 
should be no greater than the dose at time of baseline scan; and stable or improved 
clinically.  Note:  Subjects with nonmeasurable disease only cannot have a partial 
response; the best response possible is stable disease. 
Stable disease 
Requires all of the following:  does not qualify for complete response, partial response, or 
progression; stable non-enhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared with baseline scan.  In the event that the corticosteroid dose was 
increased for new symptoms and signs without confirmation of disease progression on 
neuroimaging, and subsequent follow-up imaging shows that this increase in 
corticosteroids was required because of disease progression, the last scan considered to 
show stable disease will be the scan obtained when the corticosteroid dose was equivalent 
to the baseline dose. 
Progression 
Defined by any of the following:  ≥ 25% increase in sum of the products of perpendicular 
diameters of enhancing lesions compared with the smallest tumor measurement obtained 
either at baseline (if no decrease) or best response, on stable or increasing doses of 
corticosteroids
a; significant increase in T2/FLAIR non-enhancing lesions on stable or
increasing doses of corticosteroids compared with baseline scan or best response after 
initiation of therapya not cause by comorbid events (eg, radiation therapy, demyelination, 
ischemic injury, infection, seizures, postoperative changes, or other treatment effects); any 
new lesion; clear clinical deterioration not attributable to other causes apart from the 
tumor (eg, seizures, medication adverse effects, complications of therapy, cerebrovascular 
events, infection, and so on) or changes in corticosteroid dose; failure to return for 
evaluation as a result of death or deteriorating condition; or clear progression of 
non-measurable disease. 
FLAIR = fluid-attenuated inversion recovery. 
Note:  Radiologic interpretation guidelines, definitions and tumor measurement instructions will be provided separately.  All 
measurable and nonmeasurable lesions must be assessed using the same techniques as at baseline. 
a Stable doses of corticosteroids include subjects not on corticosteroids. 
Source:  Wen et al 2010. 
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Summary of the RANO Response Criteria 
Criterion 
CR 
PR 
SD 
PD 
T1 gadolinium 
disease 
None 
≥ 50% decrease 
< 50% decrease but , 
25% increase 
≥ 25% increase
a
T2/FLAIR 
Stable or decrease 
Stable or decrease 
Stable or decrease 
Increasea 
New lesion 
None 
None 
None 
Presenta 
Corticosteroids 
None 
Stable or decrease 
Stable or decrease 
NA
b 
Clinical status 
Stable or increase 
Stable or increase 
Stable or increase 
Decreasea 
Requirement for 
response 
All 
All 
All 
Anya 
RANO = Response Assessment in Neuro-Oncology; CR = complete response; PR = partial response; SD = stable disease; 
PD = progressive disease; FLAIR = fluid-attenuated inversion recovery; NA = not applicable. 
a Progression occurs when this criterion is present. 
b Increase in corticosteroids alone will not be taken into account in determining progression in the absence of persistent clinical 
deterioration. 
For purposes of this study, the minimum time from baseline for determination of SD will be 
6 weeks. 
Best overall response should be determined based on response designations recorded per RANO 
defined criteria.  The subject's BOR assignment will depend on the findings of both target and 
non-target disease, and will also take into consideration the appearance of new lesions.  
The assessments that will contribute to the evaluation of BOR include the response assessment 
recorded between the date of randomization and the first to occur of the following: 
1. The date of objectively documented progression per RANO criteria
OR
2. The date of subsequent therapy
OR
3. The date of pathology results from diagnostic surgical resection
Among the available response assessment, the criteria listed in the table below will be used to 
determine BOR.  
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Assessment of Best Overall Response 
Best Overall Response 
Criteria 
Complete Response (CR) 
CR observed in consecutive assessments≥ 4 weeks apart per RANO 
Partial Response (PR) 
PR observed in consecutive assessments≥ 4 weeks apart per RANO 
Stable Disease (SD)
a
SD observed and dose not quality for CR or PR  
Or 
Suspected PD followed with histologic results not confirming PD, and no CR, PR 
or SD observed 
Not Evaluable (NE) 
Insufficient data to determine disease progression or response 
Progressive Disease (PD) 
No CR, PR, or SD prior to PD 
a  To qualify for SD there must be a minimum on-treatment period of 6 weeks. 
In order to distinguish potential treatment-associated pseudoprogression from progressive 
disease and minimize premature discontinuation of study medication, subjects who initially meet 
radiologic criteria for disease progression but are believed to derive clinical benefit and are 
tolerating study medication should continue receiving study medication until confirmation of 
progression with a follow up MRI.  Such subjects may be allowed to continue on study therapy 
for up to 12 additional weeks as long as they are no developing significant new or worsened 
neurologic deficits related to underlying tumor. 
If the follow-up imaging after 12 weeks from initial tumor progression confirms further 
progression, the date of progression will be the date at which progression was first determined.  
For purposes of this study, the minimum duration between baseline (start of treatment) and first 
on-study scan in order to determine BOR of SD is 6 weeks.  If the minimum time is not met 
when SD is otherwise the best timepoint response, the subject's best response will depend on the 
subsequent assessments.  For example, a subject who has SD at a timepoint < 6 weeks and PD at 
a second assessment will have a best response of PD. 
Subjects with a complete or partial response must have that response sustained for 4 weeks.  
Subjects who do not qualify for complete response, partial response, or confirmed progression 
will be considered as stable disease for the protocol BOR analysis. 
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APPENDIX I. DOSE MODIFICATIONS FOR PACLITAXEL/PLATINUM 
(CARBOPLATIN OR CISPLATIN) 
I.1. 
Criteria for Start of Cycle (Criteria for Administration on Day 1 of Each Cycle) 
After confirmation that each subject satisfies criteria for the start of each cycle described in 
Table I-1, paclitaxel will be administered first, followed by platinum (carboplatin or cisplatin).  
If any criteria are not met, administration of therapy will be postponed.  From the second cycle 
onwards, study treatment will be discontinued if administration of therapy has not been initiated 
by 14 days after the estimated Day 1. 
Table I-1: 
Criteria for Administration of Carboplatin and Paclitaxel on Day 1 of Each 
Cycle 
Parameter 
Criterion for Start 
WBC 
≥ 2.5 × 109/L 
Neutrophil count 
≥ 1.0 × 109/L 
Platelet count 
≥ 100 × 109/L 
Renal function 
≥ 50 ml/min for cisplatin or ≥ 20 mL/min for 
carboplatin  
AND  
< 10% change in GFR from previous cycle 
Nonhematologic 
toxicities 
Bilirubin 
≤ ULN 
AST/ALT 
< 2.5 × ULN 
If platinum (carboplatin or cisplatin) and/or paclitaxel are held for any of the reasons noted in 
Table I-1 above, both epacadostat and nivolumab should be held as well, and the subject will be 
evaluated at least weekly until the toxicity has resolved.  The dose of each agent selected for use 
in the new cycle will follow the guidelines shown in Table I-2, Table I-3, and Table I-4, taking 
tolerability of the most recent dose into account. 
I.2. 
Platinum (Carboplatin or Cisplatin) and Paclitaxel Dose Modifications 
Table I-2 and Table I-3 provide guidance for dose reductions for the first appearance of the 
specified toxicities for cisplatin/paclitaxel or carboplatin/paclitaxel, respectively. 
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Table I-2: 
Criteria for Carboplatin and Paclitaxel Dose Reductions for Specified Toxicities 
Hematologic 
toxicity 
ANC 
Platelet 
Count 
Action 
Dose Modification Following Recovery 
Paclitaxel 
Cisplatin 
≥ 1.0 × 109/L 
AND 
≥ 100 × 109/L 
Dose as scheduled 
Full dose 
Full dose 
< 1.0 × 109/L 
OR 
≤ 100 × 109/L 
Delay 1 week until recovery 
75%-100% dose 
75% dose 
< 1.0 × 109/L 
AND 
≤ 100 × 109/L 
Delay 1 week until recovery 
75% dose reduction 
75% dose 
Renal impairment 
If the calculated GFR falls by more than 10% from the previous cycle, then consider a dose modification. 
GFR 
Cisplatin Dose 
≥ 50 mL/min 
Full dose per Protocol. 
≥ 30 to < 50 
mL/min 
Reduce cisplatin dose 50% or switch to carboplatin AUC 6. 
< 30 mL/min 
Discontinue cisplatin, continue paclitaxel. 
Additional toxicities 
Toxicity 
Definition 
Dose Modification 
Febrile neutropenia 
ANC < 0.5 × 109/L plus fever requiring IV antibiotics 
± hospitalization 
Dose cisplatin at 75% and dose paclitaxel at 
135 mg/m2. 
Fatigue 
Grade 3 
At first occurrence, 25% dose reduction for paclitaxel; 
if persistent, 50% reduction or omit paclitaxel only. 
Neuropathy 
Grade 2 
Reduce paclitaxel to 135 mg/m2 in all subsequent 
cycles.  If persistent, 90 mg/m2 or omit. 
Grade 3 
Withhold paclitaxel until < Grade 1; restart at 
90 mg/m2.  Discontinue if no recovery. 
Arthralgia and/or 
myalgia 
Grade ≥ 2 toxicity 
Dose cisplatin at 75% and dose paclitaxel at 
135 mg/m2. 
Other toxicities 
Grade 3 toxicity  
(except alopecia, nausea, and vomiting) 
Continue with 75% dose of cisplatin and/or paclitaxel 
at 135 mg/m2 provided toxicity has resolved to 
Grade 1 or less.  If further toxicity occurs, an 
additional reduction may be made after discussion 
with medical monitor. 
Grade 4 toxicity  
(except alopecia, nausea, and vomiting) 
Withhold treatment and discuss with medical monitor. 
Note:  Dose adjustments are based on nadir blood counts since the preceding chemotherapy administration.  All dose modifications should be made based on the worst grade 
toxicity per CTCAE v4.0. 
Note:  If considered in the best interest of the participant, and consistent with local practice, investigators may decide to use supportive measures/treatment and/or secondary 
prophylaxis instead of dose reductions for the next cycle.  Also, if toxicity can clearly be attributed to one of the drugs, the investigator may choose to only dose reduce one of 
the cytotoxics. 
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Table I-3: 
Criteria for Carboplatin and Paclitaxel Dose Reductions for Specified Toxicities
Hematologic 
toxicity 
ANC 
Platelet 
Count 
Action 
Dose Modification Following Recovery 
Paclitaxel 
Carboplatin 
≥ 1.0 × 109/L 
AND 
≥ 100 × 109/L 
Dose as scheduled 
Full dose 
Full dose 
< 1.0 × 109/L 
OR 
≤ 100 × 109/L 
Delay 1 week until recovery 
75%-100% dose 
Reduce by 1 AUC 
< 1.0 × 109/L 
AND 
≤ 100 × 109/L 
Delay 1 week until recovery 
75% dose 
Reduce by 1 AUC 
Renal impairment 
If the calculated GFR falls by more than10% from the previous cycle, then consider a dose modification. 
GFR 
Carboplatin Dose 
≥ 30 mL/min 
Use AUC as per Protocol. 
20-30 mL/min 
EDTA then use AUC as per protocol, or consider discontinuing carboplatin. 
< 20 mL/min 
Discontinue carboplatin, continue paclitaxel. 
Additional toxicities 
Toxicity 
Definition 
Dose Modification 
Febrile neutropenia 
ANC < 0.5 × 109/L plus fever requiring IV antibiotics 
± hospitalization 
Dose reduction of carboplatin 20% and dose paclitaxel 
at 135 mg/m2. 
Fatigue 
Grade 3 
At first occurrence, 25% dose reduction for paclitaxel; 
if persistent, 50% reduction or omit paclitaxel only. 
Neuropathy 
Grade 2 
Reduce paclitaxel to 135 mg/m2 in all subsequent 
cycles.  If persistent, 90 mg/m2 or omit. 
Grade 3 
Withhold paclitaxel until < Grade 1; restart at 
90 mg/m2.  Discontinue if no recovery. 
Arthralgia and/or 
myalgia 
Grade ≥ 2 toxicity 
Consider prednisolone 10 mg BID for 5 days starting 
24 hours after paclitaxel.  If arthralgia and/or myalgia 
persists, reduce subsequent paclitaxel dose to 135 
mg/m2. 
Other toxicities 
Grade 3 toxicity 
(except alopecia, nausea, and vomiting) 
Continue with 20% dose reduction of carboplatin 
and/or paclitaxel at 135 mg/m2 provided toxicity has 
resolved to Grade 1 or less.  If further toxicity occurs, 
an additional reduction may be made after discussion 
with medical monitor. 
Grade 4 toxicity 
(except alopecia, nausea, and vomiting) 
Withhold treatment and discuss with medical monitor. 
Note:  Dose adjustments are based on nadir blood counts since the preceding chemotherapy administration.  All dose modifications should be made based on the worst grade 
toxicity per CTCAE v4.0. 
Note:  If considered in the best interest of the participant, and consistent with local practice, investigators may decide to use supportive measures/treatment and/or secondary 
prophylaxis instead of dose reductions for the next cycle.  Also, if toxicity can clearly be attributed to one of the drugs, the investigator may choose to only dose reduce one of 
the cytotoxics. 
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Table I-4 provides guidance for dose reductions for elevations of AST, ALT, and/or bilirubin. 
Table I-4: 
Management Guidelines for Hepatic Toxicity 
AST/ALT 
Bilirubin
Epacadostat and Nivolumab 
Platinum 
Paclitaxel 
Grade 1 
(< 3 × ULN) 
≤ 1.5 × ULN 
Continue epacadostat and nivolumab and monitor LFTs twice 
weekly until resolves to ≤ Grade 1 or baseline. 
Continue same 
dose 
Continue 
same dose 
Grade 2 
(3 × to < 5 × ULN) 
≤ 1.5 × ULN 
Hold epacadostat and nivolumab and monitor LFTs twice weekly 
until resolves to ≤ Grade 1 or baseline.  Consider steroids if 
AST/ALT do not resolve within 2 weeks of dose.  Resume at 
previous dose if recovers within 12 weeks.  If AE does not 
resolve within 12 weeks or if unable to reduce corticosteroids to 
≤ 10 mg prednisone or equivalent within 12 weeks, study 
treatment with both study drugs should be discontinued. 
Continue same 
dose 
Continue 
same dose 
Grade 2 
(3 × to < 5 × ULN) 
Grade 1 
(ULN to 
1.5 × ULN) 
Hold epacadostat and nivolumab and monitor LFTs twice weekly 
until resolves to ≤ Grade 1 or baseline.  Consider steroids if 
AST/ALT do not resolve within 2 weeks of dose.  Resume at 
previous dose if recovers within 12 weeks.  If AE does not 
resolve within 12 weeks or if unable to reduce corticosteroids to 
≤ 10 mg prednisone or equivalent within 12 weeks, study 
treatment with both study drugs should be discontinued. 
Continue same 
dose 
Reduce dose 
to 135 mg/m2 
Grade 2 
(3 × to < 5 × ULN) 
Grade 2 
(1.5 × to 3 × ULN) 
*Note:  If
> 2 × ULN, meets 
Hy's Law
a 
Hold epacadostat and nivolumab and monitor LFTs twice weekly 
until resolves to ≤ Grade 1 or baseline.  Consider steroids if 
AST/ALT and/or bilirubin do not resolve within 2 weeks of dose.  
Resume at previous dose if recovers within 12 weeks.  If AE does 
not resolve within 12 weeks or if unable to reduce corticosteroids 
to ≤ 10 mg prednisone or equivalent within 12 weeks, study 
treatment with both study drugs should be discontinued. 
Continue same 
dose 
Reduce dose 
to 75 mg/m2 
ANY Grade 3 or Grade 4 
Permanently discontinue study treatment. 
Hy's Lawa 
Permanently discontinue study treatment. 
LFT = liver chemistry test. 
a Hy's law is defined as follows:  1) Aminotransferase elevation (ALT or AST) > 3 × ULN; 2) Total bilirubin > 2 × ULN, without initial findings of cholestasis 
(elevated serum ALP); 3) No other immediately apparent possible cause of aminotransferase elevation and hyperbilirubinemia, including, but not limited to, 
viral hepatitis, liver metastases, pre-existing chronic or acute liver disease, or the administration of other drug(s) known to be hepatotoxic.  Permanently 
discontinue study therapy at the first occurrence of liver enzyme elevations meeting the criteria for Hy's law. 
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APPENDIX J. DOSE MODIFICATIONS FOR 
PEMETREXED/PLATINUM (CARBOPLATIN OR 
CISPLATIN) 
J.1. 
Criteria for Start of Cycle (Criteria for Administration on Day 1 of Each Cycle) 
After confirmation that each subject satisfies criteria for the start of each cycle described in 
Table J-1, pemetrexed and carboplatin or pemetrexed and cisplatin may be administered.  If any 
criteria are not met, administration of therapy will be postponed.  From the second cycle 
onwards, the study treatment will be discontinued if administration of therapy has not been 
initiated by 14 days after the estimated Day 1. 
Table J-1: 
Criteria for Administration of Platinum (Carboplatin or Cisplatin) and 
Pemetrexed on Day 1 of Each Cycle 
Parameter 
Criteria for Start 
WBC 
≥ 2.5 × 109/L 
Neutrophil count 
≥ 1.0 × 109/L 
Platelet count 
≥ 100 × 109/L 
Renal function 
> 50 ml/min for cisplatin or > 20 mL/min for carboplatin 
AND  
< 10% change in GFR from previous cycle 
Nonhematologic toxicities 
Bilirubin 
≤ ULN 
AST/ALT 
< 2.5 × ULN 
If pemetrexed and/or platinum (carboplatin or cisplatin) are held for any of the reasons noted in 
Table J-1 above, both epacadostat and nivolumab should be held as well, and the subject will be 
evaluated at least weekly until the toxicity has resolved.  The dose of each agent selected for use 
in the new cycle will follow the guidelines shown in Table J-2, taking tolerability of the most 
recent dose into account. 
J.2. 
Pemetrexed and Platinum (Carboplatin or Cisplatin) Dose Modifications 
Table J-2 provides guidance for dose reductions for hematologic toxicities, and Table J-3 
provides guidance for nonhematologic toxicities.   
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Table J-2: 
Criteria for Dose Reductions for Hematologic Toxicities
Hematologic 
toxicity 
Nadir ANC 
Nadir Platelet Count 
Dose Modification Following Recovery 
Pemetrexed 
Platinum 
≥ 0.5 
AND 
≥ 50 
Full dose 
Full dose 
Any 
AND 
≤ 50  
without bleeding 
75% of previous dose 
75% of previous dose 
Any 
AND 
≤ 50 
with bleeding 
50% of previous dose 
50% of previous dose 
Febrile neutropenia 
75% of previous dose 
75% of previous dose 
Note:  Dose adjustments are based on nadir blood counts since the preceding chemotherapy administration.  All dose 
modifications should be made based on the worst grade toxicity per CTCAE v4.0. 
Note:  If considered in the best interest of the participant, and consistent with local practice, investigators may decide to use 
supportive measures/treatment and/or secondary prophylaxis instead of dose reductions for the next cycle.  Also, if toxicity can 
clearly be attributed to one of the drugs, the investigator may choose to only dose reduce one of the cytotoxics. 
Table J-3: 
Criteria for Dose Reductions for Nonhematologic Toxicities
Criteria 
Epacadostat and pembrolizumab 
Pemetrexed 
Platinum 
Diarrhea 
*See also irAE of
Colitis/enteritis 
(See 
Section 5.7.3.2, 
Table 11) 
Grade 1 
Continue epacadostat and nivolumab, initiate 
supportive care. 
No dose 
reduction 
No dose 
reduction 
Grade 2 
Hold epacadostat and nivolumab and initiate 
supportive care.  Resume at previous dose if 
recovers to ≤ Grade 1 within 2 weeks.  If 
diarrhea does not resolve within 2 weeks, 
consider steroids.  When resolved to ≤ Grade 1 
and steroids tapered, epacadostat should be 
reduced 1 dose level, but nivolumab 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. 
No dose 
reduction 
No dose 
reduction 
Grade 3 or 4 
Hold epacadostat and nivolumab, and initiate 
supportive care and steroids.  When resolved 
to ≤ Grade 1 and steroids tapered, epacadostat 
should be reduced 1 dose level, but nivolumab 
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. 
25% dose 
reduction 
25% dose 
reduction 
Mucositis 
Grade 3 
Reduce epacadostat 1 dose level and resume 
nivolumab at the same dose. 
50% dose 
reduction 
No dose 
reduction 
Neurotoxicity 
Grade 2 
Resume epacadostat and nivolumab at the 
same dose. 
25% dose 
reduction 
25% dose 
reduction 
Grade 3 or 4 
Reduce epacadostat 1 dose level and resume 
nivolumab at the same dose. 
Discontinue 
study 
treatment 
Discontinue 
study treatment 
Other 
nonhematologic 
toxicity 
Grade 3 
Reduce epacadostat 1 dose level and resume 
nivolumab at the same dose. 
25% dose 
reduction 
25% dose 
reduction 
Grade 4 
Permanently discontinue epacadostat and 
nivolumab unless discussed with medical 
monitor. 
25% dose 
reduction 
25% dose 
reduction 
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Table J-3: 
Criteria for Dose Reductions for Nonhematologic Toxicities (Continued) 
Renal impairment 
If the calculated GFR falls by more than10% from the previous cycle, consider dose reduction. 
GFR 
Cisplatin dose 
GFR 
Carboplatin dose 
≥ 50 mL/min 
Full dose per Protocol. 
≥ 30 mL/min 
Use AUC as per Protocol. 
≥ 30 to 
< 50 mL/min 
Reduce cisplatin dose 50% or 
switch to carboplatin AUC 6. 
20-30 mL/min 
EDTA then use AUC as per 
Protocol, or consider to 
discontinue carboplatin. 
< 30 mL/min 
Discontinue cisplatin, continue 
paclitaxel. 
< 20 mL/min 
Discontinue carboplatin, 
continue paclitaxel. 
Note:  If considered in the best interest of the participant, and consistent with local practice, investigators may decide to use 
supportive measures/treatment and/or secondary prophylaxis instead of dose reductions for the next cycle.  Also, if toxicity can 
clearly be attributed to one of the drugs, the investigator may choose to only dose reduce one of the cytotoxics. 
Table J-4 provides guidance for dose reductions for elevations of AST, ALT, and/or bilirubin. 
Table J-4: 
Criteria for Dose Reductions for Hepatic Toxicity 
AST/ALT 
Bilirubin 
Epacadostat and Nivolumab 
Platinum 
Pemetrexed 
Grade 1 
(< 3 × ULN) 
≤ 1.5 × ULN 
Continue epacadostat and nivolumab and monitor 
LFTs twice weekly until resolves to ≤ Grade 1 or 
baseline. 
Continue 
same dose 
Continue 
same dose 
Grade 2 
(3 × to 
< 5 × ULN) 
≤ 1.5 × ULN 
Hold epacadostat and nivolumab and monitor LFTs 
twice weekly until resolves to ≤ Grade 1 or baseline.  
Consider steroids if AST/ALT do not resolve within 
2 weeks of dose.  Resume at previous dose if 
recovers within 12 weeks.  If AE does not resolve 
within 12 weeks or if unable to reduce corticosteroids 
to ≤ 10 mg prednisone or equivalent within 12 weeks, 
study treatment with both study drugs should be 
discontinued. 
Continue 
same dose 
Continue 
same dose 
Grade 2 
(3 × to 
< 5 × ULN) 
Grade 1 
(ULN to 
1.5 × ULN) 
Hold epacadostat and nivolumab and monitor LFTs 
twice weekly until resolves to ≤ Grade 1 or baseline.  
Consider steroids if AST/ALT do not resolve within 
2 weeks of dose.  Resume at previous dose if 
recovers within 12 weeks.  If AE does not resolve 
within 12 weeks or if unable to reduce corticosteroids 
to ≤ 10 mg prednisone or equivalent within 12 weeks, 
study treatment with both study drugs should be 
discontinued. 
Continue 
same dose 
Continue 
same dose 
Grade 2 
(3 × to 
< 5 × ULN) 
Grade 2 
(1.5 × to 
3 × ULN) 
*Note:  If
> 2 × ULN, 
meets Hy's Law
a
Hold epacadostat and nivolumab and monitor LFTs 
twice weekly until resolves to ≤ Grade 1 or baseline.  
Consider steroids if AST/ALT and/or bilirubin do not 
resolve within 2 weeks of dose.  Resume at previous 
dose if recovers within 12 weeks.  If AE does not 
resolve within 12 weeks or if unable to reduce 
corticosteroids to ≤ 10 mg prednisone or equivalent 
within 12 weeks, study treatment with both study 
drugs should be discontinued. 
Continue 
same dose 
Continue 
same dose 
ANY Grade 3 or Grade 4 
Permanently discontinue study treatment. 
Hy's Lawa 
Permanently discontinue study treatment. 
LFT = liver chemistry test. 
a Hy's law is defined as follows:  1) Aminotransferase elevation (ALT or AST) > 3 × ULN; 2) Total bilirubin > 2 × ULN, 
without initial findings of cholestasis (elevated serum ALP); 3) No other immediately apparent possible cause of 
aminotransferase elevation and hyperbilirubinemia, including, but not limited to, viral hepatitis, liver metastases, pre-existing 
chronic or acute liver disease, or the administration of other drug(s) known to be hepatotoxic.  Permanently discontinue study 
therapy at the first occurrence of liver enzyme elevations meeting the criteria for Hy's law. 
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APPENDIX K. DOSE MODIFICATIONS FOR PLATINUM 
(CARBOPLATIN OR CISPLATIN)/5-FLUOROURACIL 
K.1. 
Criteria for Start of Cycle (Criteria for Administration on Day 1 of Each Cycle) 
After confirmation that each subject satisfies criteria for the start of each cycle described in 
Table K-1, 5-FU and platinum may be administered.  If any criteria are not met, administration 
of therapy will be postponed.  From the second cycle onwards, the study treatment will be 
discontinued if administration of therapy has not been initiated by 14 days after the estimated 
Day 1. 
Table K-1: 
Criteria for Administration of 5-FU/Platinum on Day 1 of Each Cycle 
Parameter 
Criterion for Start 
WBC 
≥ 3.0 × 109/L 
Neutrophil count 
≥ 1.5 × 109/L 
Platelet count 
≥ 100 × 109/L 
Infection 
No fever (> 38.0°C or 100.4°F) suspect for infection 
Nonhematologic 
toxicities 
Diarrhea 
No watery diarrhea 
Renal function 
> 50 ml/min for cisplatin or > 20 mL/min for carboplatin 
AND  
< 10% change in GFR from previous cycle 
Others 
< Grade 2 (except for nausea, vomiting, anorexia, and fatigue) 
If 5-FU/platinum is held for any of the reasons noted in Table K-1 above, both epacadostat and 
nivolumab should be held as well, and the subject will be evaluated at least weekly until the 
toxicity has resolved.  The dose of each agent selected for use in the new cycle will follow the 
guidelines shown in Table K-2 and Table K-3 for hematologic toxicities, taking tolerability of 
the most recent dose into account. 
K.2. 
Dose Modifications for Hematologic Toxicities 
Table K-2 provides guidance for dose reductions for hematologic toxicities. 
Table K-2: 
Dose Reductions Criteria for Hematologic Toxicities 
Hematologic 
toxicity 
Dose modifications based on neutrophil and/or platelet count on day of treatment (Day 1) 
ANC 
Platelet 
Count 
Action 
Dose Modification Following 
Recovery 
5-FU 
Platinum 
≥ 1.0 × 109/L 
AND 
≥ 
100 × 109/L 
Dose as 
scheduled 
Full dose 
Full dose 
< 1.0 × 109/L 
OR 
≤ 
100 × 109/L 
Delay 1 week 
until recovery 
75%-100% dose 
75% dose 
< 1.0 × 109/L 
AND 
≤ 
100 × 109/L 
Delay 1 week 
until recovery 
75% dose 
75% dose 
Table K-3 provides guidance for dose reductions for the second appearance of the specified 
hematologic toxicities.  Based on the most severe toxicity experienced since the last treatment, 
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the dose modifications included in Table K-4 below will also be used for nonhematologic 
toxicities.  When the dose of 5-FU is reduced, the dose of leucovorin will remain the same.  If 
oxaliplatin is discontinued for peripheral neuropathy, 5-FU, leucovorin, nivolumab, and 
epacadostat may be continued until additional discontinuation criteria are met. 
Table K-3: 
Dose Reductions Criteria for Recurrent Hematologic Toxicities
Hematologic 
toxicity 
ANC 
Platelet 
Count 
Action 
Dose Modification Following 
Recovery 
5-FU 
Platinum 
≥ 1.0 × 109/L 
AND 
≥ 
100 × 109/L 
Dose as 
scheduled 
Full dose 
Full dose 
< 1.0 × 109/L 
OR 
≤ 
100 × 109/L 
Delay 1 week 
until recovery 
75%-100% dose 
75% dose 
< 1.0 × 109/L 
AND 
≤ 
100 × 109/L 
Delay 1 week 
until recovery 
75% dose 
75% dose 
After a second dose reduction, if any hematologic toxicities reoccur (third occurrence) and are 
clearly associated with chemotherapy regimen, chemotherapy regimen may be discontinued.  
However, epacadostat and nivolumab may be continued at the same dose at the discretion of the 
investigator and with the approval of the medical monitor. 
K.3. 
Management Guidelines for Nonhematologic Toxicities 
Table K-4 provides guidance for dose reductions for the appearance of nonhematologic 
toxicities.  Toxicities must be resolved to ≤ Grade 1 before resuming study treatment.  Some AEs 
may overlap with the occurrence of some potential irAEs (eg, diarrhea and colitis/enteritis).  In 
these cases, both the AE and irAE guidances should be reviewed to determine the most 
appropriate management of dose interruptions and dose reductions for any study medications. 
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Table K-4: 
Dose Reductions Criteria for Nonhematologic Toxicities
Criteria 
Epacadostat and Nivolumab 
5-FU 
Platinum 
Diarrhea 
*See also irAE of
Colitis/enteritis 
(see Section 5.7.3.2, 
Table 11) 
Grade 1 
Continue epacadostat and nivolumab, 
initiate supportive care. 
No dose reduction 
No dose reduction 
Grade 2 
Hold epacadostat and nivolumab, and 
initiate supportive care.  Resume at 
previous dose if recovers to ≤ Grade 1 
within 2 weeks.  If diarrhea does not 
resolve within 2 weeks, consider steroids. 
When resolved to ≤ Grade 1 and steroids 
tapered, epacadostat should be reduced 
1 dose level, but nivolumab may be 
restarted at the same dose and schedule.  
If AE does not resolve within 6 weeks, 
treatment with epacadostat and 
nivolumab should be discontinued or 
discussed with medical monitor. 
No dose reduction 
No dose reduction 
Grade 3 or 4 
Hold epacadostat and nivolumab, and 
initiate supportive care and steroids.  
When resolved to ≤ Grade 1 and steroids 
tapered, epacadostat should be reduced 
1 dose level, but nivolumab may be 
restarted at the same dose and schedule.  
If AE does not resolve within 6 weeks, 
treatment with epacadostat and 
nivolumab should be discontinued or 
discussed with medical monitor. 
75% dose 
75% dose 
Mucositis 
Grade 3 
Hold epacadostat and nivolumab, and 
initiate supportive care.  Resume at 
previous dose if recovers to ≤ Grade 1 
within 2 weeks.  If mucositis does not 
resolve within 2 weeks, epacadostat 
should be reduced 1 dose level, but 
nivolumab may be restarted at the same 
dose and schedule after resolution to 
≤ Grade 1 and steroids tapered.  If the 
mucositis is clearly attributed to 5-FU, 
epacadostat and nivolumab does not need 
to be held or dose reduced. 
75% dose 
No dose reduction 
Mucositis 
Grade 4 
Permanently discontinue epacadostat and 
nivolumab unless discussed with medical 
monitor.  If the mucositis is clearly 
attributed to 5-FU, no action is required 
with regard to nivolumab and 
epacadostat. 
Discontinue 
Discontinue 
Neurologic 
toxicities 
Grade 2 
Resume epacadostat and nivolumab at 
same dose. 
No dose reduction. 
Stop treatment for 
hyperammonemic 
encephalopathy, 
acute cerebellar 
syndrome, 
confusion, 
disorientation, 
ataxia or visual 
disturbances. 
75% dose 
Grade 3 
Reduce epacadostat 1 dose level and 
resume nivolumab at same dose. 
Stop treatment 
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Table K-3: 
Dose Reductions Criteria for Nonhematologic Toxicities (Continued) 
Criteria 
Epacadostat and Nivolumab 
5-FU 
Platinum 
Other 
nonhematologic 
toxicity 
Grade 3 
Reduce epacadostat 1 dose level and 
resume nivolumab at same dose. 
75% dose 
75% dose 
Grade 4 
Permanently discontinue epacadostat and 
nivolumab unless discussed with medical 
monitor. 
Stop treatment 
Note:  If considered in the best interest of the participant, and consistent with local practice, investigators may decide to use 
supportive measures/treatment, and/or secondary prophylaxis instead of dose reductions for the next cycle.  Also, if toxicity can 
clearly be attributed to one of the drugs, the investigator may choose to only dose reduce one of the cytotoxics. 
Table K-5 provides guidance for dose reductions for elevations of AST, ALT, and/or bilirubin. 
Table K-5: 
Dose Reductions Criteria for Hepatic Toxicity 
AST/ALT 
Bilirubin 
Epacadostat and Nivolumab 
5-FU 
Platinum 
Grade 1 
(< 3 × ULN) 
≤ 1.5 × 
ULN 
Continue epacadostat and nivolumab and monitor 
LFTs twice weekly until resolves to ≤ Grade 1 or 
baseline. 
Continue 
same dose 
Continue 
same dose 
Grade 2 
(3 × to 
< 5 × ULN) 
≤ 1.5 × 
ULN 
Hold epacadostat and nivolumab and monitor 
LFTs twice weekly until resolves to ≤ Grade 1 or 
baseline.  Consider steroids if AST/ALT do not 
resolve within 2 weeks of dose.  Resume at 
previous dose if recovers within 12 weeks.  If AE 
does not resolve within 12 weeks or if unable to 
reduce corticosteroids to ≤ 10 mg prednisone or 
equivalent within 12 weeks, study treatment with 
both study drugs should be discontinued. 
Continue 
same dose 
Continue 
same dose 
Grade 2 
(3 × to 
< 5 × ULN) 
Grade 1 
(ULN to 
1.5 × ULN) 
Hold epacadostat and nivolumab and monitor 
LFTs twice weekly until resolves to ≤ Grade 1 or 
baseline.  Consider steroids if AST/ALT do not 
resolve within 2 weeks of dose.  Resume at 
previous dose if recovers within 12 weeks.  If AE 
does not resolve within 12 weeks or if unable to 
reduce corticosteroids to ≤ 10 mg prednisone or 
equivalent within 12 weeks, study treatment with 
both study drugs should be discontinued. 
Continue 
same dose 
Continue 
same dose 
Grade 2 
(3 × to 
< 5 × ULN) 
Grade 2 
(1.5 × to 
3 × ULN) 
*Note:  If
> 2 × ULN, 
meets Hy's 
Law
a 
Hold epacadostat and nivolumab and monitor 
LFTs twice weekly until resolves to ≤ Grade 1 or 
baseline.  Consider steroids if AST/ALT and/or 
bilirubin do not resolve within 2 weeks of dose.  
Resume at previous dose if recovers within 
12 weeks.  If AE does not resolve within 12 weeks 
or if unable to reduce corticosteroids to ≤ 10 mg 
prednisone or equivalent within 12 weeks, study 
treatment with both study drugs should be 
discontinued. 
Continue 
same dose 
Continue 
same dose 
ANY Grade 3 or Grade 4 
Permanently discontinue study treatment. 
Hy's Lawa 
Permanently discontinue study treatment. 
LFT = liver chemistry test. 
a Hy's law is defined as follows:  1) Aminotransferase elevation (ALT or AST) > 3 × ULN; 2) Total bilirubin > 2 × ULN, 
without initial findings of cholestasis (elevated serum ALP); 3) No other immediately apparent possible cause of 
aminotransferase elevation and hyperbilirubinemia, including, but not limited to, viral hepatitis, liver metastases, pre-existing 
chronic or acute liver disease, or the administration of other drug(s) known to be hepatotoxic.  Permanently discontinue study 
therapy at the first occurrence of liver enzyme elevations meeting the criteria for Hy's law. 
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APPENDIX L. PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document 
Date 
Date of Protocol: 
15 AUG 2014 
Date of Amendment (Version) 1: 
01 OCT 2014 
Date of Amendment (Version) 2: 
03 APR 2015 
Date of Amendment (Version) 3: 
16 JUL 2015 
Date of Amendment (Version) 4: 
12 FEB 2016 
Date of Amendment (Version) 5: 
13 JUL 2016 
Date of Amendment (Version) 6: 
05 JUL 2017 
Date of Amendment (Version) 7: 
29 SEP 2017 
Date of Amendment (Version) 8: 
31 MAY 2018 
Amendment (Version) 8 
The primary purpose of this amendment is to update the Introduction and investigational agent 
background, to revise the Schedule of Assessments, to remove the post-treatment disease status 
and survival follow-up periods, to clarify the maximum duration of nivolumab and epacadostat 
treatment, to update the subject management guidelines for disease status, to revise the 
chemotherapy pre-medication guidelines and to update the toxicity management guidelines for 
subjects in the chemo-immunotherapy cohorts. 
1. Synopsis; Section 5.8, Criteria for Permanent Discontinuation of Study Drug(s);
Section 5.9.1, Study Completion Criteria; Section 6, Study Assessments;
Section 7.3.4, Post-Treatment Anticancer Therapy Status; Section 7.5.2, Tumor
Imaging During the Study; Section 7.5.3, Assessment of Disease According to
Modified RECIST for Solid Tumors; Section 7.8.7, Withdrawal or Discontinuation
Description of change:  The post-treatment disease status and survival follow-up periods
have been removed from the Protocol.
Rationale for change:  The sponsor has determined that post-treatment disease status
and survival follow-up data are no longer needed.
2. Synopsis; Section 1.4.1, Rationale for 2-Year Duration of Treatment, Section 5.5,
Duration of Treatment and Subject Participation; Section 5.8, Criteria for
Permanent Discontinuation of Study Drug(s); Section 6.2, Treatment Period
Description of change:  A maximum treatment duration for nivolumab and epacadostat
was updated to 2 years.
Rationale for change:  Accumulating data suggest that treatment beyond 2 years is
unlikely to confer additional clinically meaningful benefit and that the risk of progression
after discontinuing treatment at 2 years is low.
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3. Synopsis; Section 5.2.1, Paclitaxel/Platinum (Carboplatin or Cisplatin);
Section 5.2.2, Pemetrexed/Platinum (Carboplatin or Cisplatin); Section 5.2.3,
Platinum (Carboplatin or Cisplatin)/5-Fluorouracil
Description of change:  The Protocol was updated to clarify that premedications,
including corticosteroids, may be given based on institutional guidelines and study
investigator practice.
Rationale for change:  To allow for greater flexibility and Investigator discretion in
prechemotherapy prophylaxis.
4. Synopsis; Section 6, Study Assessments; Section 6.4.2, Disease Status Follow-Up;
Section 7.5.2, Tumor Imaging During the Study
Description of change:  Imaging schedule was updated to specify that subjects in the
combination chemo-immunotherapy cohorts (Phase 1 Part 2) should be assessed at 8 and
16 weeks after the start of treatment and then every 12 weeks thereafter.  The imaging
schedule for all other subjects (Phase 1 Part 1 and Phase 2) was updated to every
12 weeks.  The imaging schedule for all subjects was also updated to indicate that no
additional imaging is required after end of treatment.
Rationale for change:  To perform fewer, less frequent imaging assessments for subject
convenience and to relieve site staff burden while still evaluating disease status at
clinically appropriate intervals.
5. Synopsis; Section 6, Study Assessments; Section 7.4.6, Laboratory Assessments;
Section 7.4.6.3, Liver Chemistry Tests
Description of change:  The requirements for liver chemistry testing for subjects in the
combination chemo-immunotherapy cohorts was updated to Day 1 of each cycle, starting
with Cycle 4.
Rationale for change:  To clarify the requirement and to implement clinically acceptable
monitoring of liver function.
6. Section 1.2.1, Rationale for Combining PD-1 Inhibitor and IDO1 Inhibito
Description of change:  Additional background was added pertaining to the results of a
Phase 3 randomized study of pembrolizumab plus epacadostat versus pembrolizumab
versus placebo in unresectable or metastatic melanoma.
Rationale for change:  To provide relevant background information pertaining to
epacadostat.
7. Synopsis; Section 6, Study Assessments; Section 7.8, Tumor Biopsy Collection and
Analysis
Description of change:  The requirement for tumor biopsy (screening or on-treatment)
has been removed from the Protocol.
Rationale for change:  Biopsy tissue is no longer needed for translational or correlative
analysis, and thus the biopsy requirement was removed.
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8. Appendix I, Dose Modifications for Paclitaxel/Platinum (Carboplatin or Cisplatin);
Appendix J, Dose Modifications for Pemetrexed/Platinum (Carboplatin or
Cisplatin); Appendix K, Dose Modifications for Platinum (Carboplatin or
Cisplatin)/5-Fluorouracil
Description of change:  Updated the dose hold and dose reduction criteria for specified
toxicities.
Rationale for change:  To clarify the dose hold and dose reduction criteria for each of
the chemoimmunotherapy combinations.
9. Synopsis; Section 5.8, Criteria for Permanent Discontinuation of Study Drug(s);
Section 6, Study Assessments; Section 7.3.4, Post-Treatment Anticancer Therapy
Status
Description of change:  Removed the 60-day post-treatment safety follow-up visit.
Rationale for change:  Standard follow-up timepoints for nivolumab combinations has
changed to 30- and 100-day post-treatment only; 60-day follow-up was removed to
relieve subject burden.
10. Synopsis; Section 5.7.4, Treatment After Initial Evidence of Radiologic Disease
Progression; Section 5.8, Criteria for Permanent Discontinuation of Study Drug(s);
Section 6, Study Assessments; Section 7.5.3, Assessment of Disease According to
Modified RECIST for Solid Tumors
Description of change:  The option to treat clinically stable subjects beyond initial
disease progression using modified assessment criteria (RECIST, Cheson, RANO) was
removed from the Protocol.
Rationale for change:  Given the lack of evidence that epacadostat augments the activity
of nivolumab (as described in Section 1.2.1), it is unnecessary to evaluate subjects for
pseudoprogression.
11. Section 1.1.1, Inhibition of PD-1 as a Target for Cancer; Section 1.1.6, Overview of
Platinum-Based Doublet Chemotherapy Compared With Immunotherapy in
Squamous and Nonsquamous Non–Small Cell Lung Cancer; Section 1.3.10, Risks
From Combining a PD-1 Inhibitor With Chemotherapy; Section 1.4, Justification of
Treatment Regimens
Description of change:  The background information for nivolumab was updated;
current safety and efficacy data for recent studies evaluating chemo-immunotherapy
combinations was added.
Rationale for change: To reflect the current approval status in nivolumab and recently
updated data regarding anti-PD-1/chemotherapy combinations.
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12. Section 1.3.1, Risks From Epacadostat; Section 5.7.4, Procedures for Subjects
Exhibiting Serotonin Syndrome
Description of change:  The epacadostat risk language and serotonin syndrome
management guidelines were updated to reflect current language.
Rationale for change:  To incorporate updated information regarding the risk and
management of serotonin syndrome.
13. Section 6, Study Assessments (Table 20, Schedule of Assessments End of Treatment
Through Safety Follow-Up [Combination Immunotherapy Cohorts With Both Q2W
and Q4W Nivolumab Dosing Schedules]; Table 24, Schedule of Assessments for
Phase 1 Part 2 Subjects Treated With Epacadostat + Nivolumab [Q3W] +
Platinum/Paclitaxel or Epacadostat + Nivolumab + Platinum/Pemetrexed or
Epacadostat + Nivolumab + Platinum/5-FU [Combination Chemo Immunotherapy
Cohorts])
Description of change:  The physical exam requirement at EOT was updated from a
complete physical exam to a targeted physical exam.
Rationale for change:  Targeted physical exam at the EOT is sufficient to monitor
subject safety.
15. Section 6, Study Assessments (Table 26, Laboratory Tests:  Required Analytes)
Description of change:  Urea was added as an acceptable alternative to blood urea
nitrogen, plasma lipase was added as an acceptable alternative to serum lipase, and
reticulocyte count was deleted.
Rationale for change:  To clarify the required laboratory analytes.
16. Section 6, Study Assessments; Section 7.5.2, Tumor Imaging During the Study
Description of change:  Deleted text regarding collection of radiographic tumor
assessments for independent review.
Rationale for change:  Independent review is no longer planned.
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17. 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 (Version) 7 
This amendment has 2 main purposes: 
•
To provide separate schedule of assessment tables for the Q2W and Q4W nivolumab
dosing schedules in order to clarify the clinical visit schedules for study and
laboratory assessments.
This amendment includes the changes to Protocol INCB 24360-204 Amendment 6 
(05 JUL 2017) summarized below.  A redline version of the amendment depicting the updated 
and previous text is also provided. 
1. Synopsis; Section 4.1.2, Phase 2 Combination Immunotherapy Cohort Expansions
Description of change:  The I/O relapsed MEL cohort definition was deleted as the
definitions for both I/O relapsed and refractory melanoma cohorts are included in the
eligibility section.
Rationale for change:  To remove redundant information.
2. Synopsis
Description of change:  In the Combination Immunotherapy and Chemo-
Immunotherapy, Regimen and Mode of Administration section, the last paragraph of the
Nivolumab subsection was removed as it was repeating the same information it was
included in the previous paragraph.
Rationale for change:  To remove the redundant information.
3. Synopsis; Section 3.2, Subject Inclusion Criteria (Criterion 4b)
Description of change:  Added the requirement that subjects must not have ocular
melanoma.
Rationale for change:  This requirement was inadvertently removed in Amendment 6
and has been added back.
4. Synopsis; Section 3.2, Subject Inclusion Criteria (Criterion 4b)
Description of change:  A new criterion was added to indicate that subjects with
immunotherapy (I/O) refractory melanoma (MEL) must have no more than 2 prior lines
of therapy for advanced/metastatic disease, only 1 of which can be a prior anti–PD-1/PD-
L1 therapy, with or without anti–CTLA-4 therapy.  Prior anti–CTLA-4 monotherapy is
not permitted.
Rationale for change:  To clarify prior therapy requirements for subjects with
I/O-refractory MEL.
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5. Synopsis; Section 3.2, Subject Inclusion Criteria (Criterion 4d) 
Description of change:  The prior systemic therapy requirement for subjects with 
squamous cell carcinoma of the head and neck (SCCHN) was separated into 2 criteria, 
one for Phase 1 Part 1 and Phase 2 cohorts, and one for Phase 1 Part 2 cohorts. 
Rationale for change:  To clarify the prior systemic therapy requirement for 
combination immunotherapy and combination chemo-immunotherapy SCCHN cohorts. 
6. Synopsis 
Description of change:  The estimated study duration section, which included study 
timelines, was removed. 
Rationale for change:  This section is no longer required as the information is included 
in the ClinicalTrials.gov posting for the study. 
8. Section 6, Study Assessments (Table 24); Section 7.4.5, Twelve-Lead 
Electrocardiogram  
Description of change:  Revised to indicate 1) continuous concomitant medication 
review and adverse events assessment, 2) 12-lead ECG during the treatment period on 
C1D1 and C2D1 only; 3) administration of IV chemotherapy doublet (platinum/paclitaxel 
or platinum/pemetrexed) will be minimum 4 cycles and up to 6 cycles (to align with the 
dosing schedule in Table 3), and 4) epacadostat will be administered before the start of 
nivolumab infusion. 
Rationale for change:  To clarify that concomitant medication review and adverse 
events review will occur throughout the study up to 100 days safety follow-up visit, and 
to clarify the chemotherapy regimen duration in the study as well as the epacadostat 
administration order on the days when chemotherapy is being administered. 
9. Section 6, Study Assessments (Table 25) 
Description of change:  Coagulation panel and endocrine function tests should be 
performed at the same clinic visit; the table was updated to adjust the test schedules and 
to state that both tests will take place every third cycle after the first 3 cycles. 
Rationale for change:  To clarify assessment schedules for coagulation panel and 
endocrine function tests. 
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10. Section 6, Study Assessments (Tables 25 and Table 26)
Description of change:  Clarification regarding hepatitis B surface antigen testing was
removed from the table body and added as a footnote to Table 26, stating that  hepatitis B
surface antigen testing will only include antigen testing (not antibody testing).
Rationale for change:  To clarify the serological marker for hepatitis B testing.
11. Section 5.13, Prohibited Medications and Measures
Description of change:  UGT1A9 list of medications was updated.
Rationale for change:  To align with compound level revised list.
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 (Version) 6 
This amendment has 2 purposes: 
•
Addition of new immunotherapy/chemotherapy combination cohorts in Phase 1 to
evaluate the safety and tolerability of and to determine the recommended Phase 2
dose for epacadostat (INCB24360) and nivolumab in combination with standard-of-
care (SOC) chemotherapy regimens in subjects with advanced or metastatic
squamous cell carcinoma of the head and neck (SCCHN) and non−small lung cancer
(NSCLC).  Phase 1 is now divided into 2 parts:  Part 1 is the original combination
immunotherapy regimen, and Part 2 describes the new combination immunotherapy
and chemotherapy regimens.
•
Addition of 2 new melanoma (MEL) cohorts in Phase 2 to evaluate the safety and
efficacy of epacadostat in combination with nivolumab in subjects who relapsed or
are refractory to programmed death receptor-1 (PD-1)/programmed death ligand-1
(PD-L1) therapy.
This amendment includes the following additional changes to Protocol INCB 24360-204 
Amendment 5 (13 JUL 2016) 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 Purpose;
Section 3, Subject Eligibility; Section 4, Investigational Plan; Section 5, Treatment
of Subjects; Section 6, Study Assessments; Section 7, Conduct of Study Assessments
and Procedures; Section 8.8, Safety Monitoring Committee; Section 9, Statistics;
Section 16, References; Appendices J, K, and L (Dose Modifications for
Paclitaxel/Platinum, Pemetrexed/Platinum, and Platinum/5-Fluourouracil,
respectively)
Description of change:  Three new cohorts have been added to the study as Phase 1
Part 2, in which subjects will receive the following regimens:
•
5-Flurouracil + carboplatin or cisplatin in combination with nivolumab and
epacadostat in subjects with SCCHN as first-line therapy.
•
Pemetrexed + cisplatin or carboplatin with nivolumab and epacadostat in subjects
with nonsquamous NSCLC as first-line therapy.
•
Paclitaxel + cisplatin or carboplatin with nivolumab and epacadostat in subjects with
NSCLC as first-line therapy.
Safety and tolerability have been added as primary objectives, with efficacy was added as 
secondary objective.  The study design has been revised to include 
chemo-immunotherapy combination dose-finding and safety expansion cohorts.  All 
relevant Protocol sections, including tables and figures, have been revised and updated 
accordingly. 
Rationale for change:  To provide background, study and dose rationale, study design, 
study objectives and endpoints, inclusion and exclusion criteria, study treatment details, 
study schedule and assessments, and statistical considerations to evaluate epacadostat and 
nivolumab (immunotherapy combinations) in combination with SOC chemotherapy 
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regimens for advanced cancers.  Emerging data from other clinical studies indicate that 
immunotherapy combinations with chemotherapy may increase response rates and 
survival in certain tumor types.  Further, safety will be monitored with the study team, 
site investigators, and a safety monitoring committee. 
2. Synopsis; Section 1, Introduction; Section 2, Study Objectives and Purpose;
Section 3, Subject Eligibility; Section 4, Investigational Plan; Section 5, Treatment
of Subjects; Section 6, Study Assessments; Section 7, Conduct of Study Assessments
and Procedures; Section 8.8, Safety Monitoring Committee; Section 9, Statistics;
Section 16, References
Description of change:  Two new MEL cohorts have been added in Phase 2 to evaluate
subjects with disease that has relapsed after or is refractory to anti−PD-1/PD-L1 therapy.
Subjects will receive epacadostat 100 mg twice daily (BID) in combination with 480 mg
nivolumab intravenously (IV) every 4 weeks (q4w).  Objectives for the safety and
tolerability as well as efficacy of the combination immunotherapy for these cohorts have
been added.  Applicable information regarding the role and rationale for use of
immunotherapy combinations in relapsed and refractory solid tumors has also been
added.  All relevant Protocol sections, including tables and figures, have been updated
accordingly.
Rationale for change:  Patients with MEL who have failed prior PD-1 or PD-L1
immunotherapies have high unmet need.  Preliminary objective responses were observed
in subjects who had prior anti−PD-1/PD-L1 therapies in this study.  The safety data to
date (Perez et al 2017) demonstrated that there were fewer dose holds and dose
reductions in patients treated with epacadostat 100 mg BID compared to 300 mg BID in
combination with nivolumab; therefore, the epacadostat dose will initially be 100 mg
BID in these new cohorts.
3. Synopsis; Section 1.4, Justification for Treatment Regimen; Section 4.1, Overall
Study Design; Section 4.2, Study Endpoints; Section 5.1.2, Nivolumab
Description of change:  The dose of nivolumab for the relapsed/refractory MEL cohorts
will be 480 mg via 30-minute IV infusion q4w.  The dose of nivolumab for Phase 1 Part
2 (new chemo-immunotherapy cohorts) will be 360 mg via 30-minute IV infusion every
3 weeks (q3w).  Corresponding pharmacokinetic (PK) justification for these 2 new
dosing schedules as well as supportive safety data have been added to Section 1.4.  All
relevant Protocol sections, including tables and figures, have been updated accordingly.
Rationale for change:  A pooled analysis derived from a comprehensive population
pharmacokinetics (PPK) analysis for nivolumab demonstrated that nivolumab PK was
linear, with dose-proportional exposures over a dose range of 0.1 to 10 mg/kg and similar
across tumor types.  Using the PPK model, the exposures following the administration of
nivolumab 360 mg q3w and 480 mg q4w were simulated.  Based on this analysis, it is
predicted that both 360 mg q3w and 480 mg q4w doses are similar to 240 mg every
2 weeks (q2w) or 3 mg/kg q2w following the administration in subjects who have an
approximately median weight of 80 kg.  Thus, the 360 mg q3w and 480 mg q4w doses
and schedules are supported by exposure-response analyses and will be used in this study
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in the chemo-immunotherapy combination cohorts and in the new relapsed and refractory 
MEL cohorts, respectively. 
4. Synopsis; Section 3.1, Study Population; Section 3.2, Subject Inclusion Criteria
(Criteria 4 and 4g)
Description of change:  The definition of glioblastoma has been revised as relapsed or
refractory.
Rationale for change:  To provide a clarification for the definition of eligible
glioblastoma subjects in the study.
5. Synopsis, Section 3.2, Subject Inclusion Criteria (Criterion 7); Section 7.8, Tumor
Biopsy Collection and Analysis
Description of change:  For the new cohorts in Phase 1 Part 2 (chemo-immunotherapy
cohorts) and Phase 2 (immuno-oncology relapsed and refractory MEL cohorts), it is
required that biopsies must be confirmed to contain adequate tumor tissue by local
pathology review.  Inclusion criterion 7 was also revised to emphasize that the collection
of archived tumor tissue is an alternative to fresh baseline tumor biopsies with medical
monitor approval.  A minimum required number of blocks for archived biopsies will be
20 slides (instead of 20-25 slides).
Rationale for change:   To clarify the Protocol text and to ensure that it is clear that
confirmation of tumor tissue presence in biopsy samples is a requirement.
6. Synopsis; Section 3.3, Subject Exclusion Criteria
a.
Description of change:  Exclusion criteria 1, 1d, 1e, and 1.f have been revised.  The
greater than symbol was updated to greater than or equal to for serum creatinine in
1d; also, the option for glomerular filtration rate in place of creatinine was removed.
Alkaline phosphatase was removed from criterion 1e, and criterion 1f was revised for
bilirubin restriction based on the updated safety information at the program level.
Rationale for change:  Accumulating data from the epacadostat program and lower
risks for the development of liver events, alkaline phosphatase will no longer be
evaluated as an eligibility criterion in conjunction with ALT/AST.  Exclusion
criterion 1d has been updated to allow subjects with serum creatinine < 1.5 × ULN or
measured or calculated creatinine clearance ≥ 50 mL/min to be enrolled in the study.
Exclusion criterion 1f has been revised to allow subjects with total bilirubin
< 1.5 × ULN or conjugated (direct) bilirubin < 40% of total bilirubin to be enrolled in
the study.
b. Description of change:  Exclusion criterion 5 has been revised to specify that any
prior immune-related adverse events (irAEs) must be resolved to ≤ Grade 1 before the
first dose of epacadostat and nivolumab.  Subjects with any ≥ Grade 3 irAEs (except
lymphopenia or asymptomatic amylase/lipase elevations) from prior
immunotherapies, including cytotoxic T-lymphocyte-associated antigen-4 treatment,
are excluded.  Subjects with history of ≥ Grade 3 endocrinopathies must be discussed
with the medical monitor to determine eligibility.
Rationale for change:  To provide clarification about pre-existing irAEs that
subjects may have had due to prior treatment before starting to this study and to
provide guidance to the investigators in evaluation of these subjects during screening.
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c. Description of change:  Exclusion criterion 6 was revised to specify that steroid use 
as a concomitant medication for glioblastoma subjects will be permitted when applied 
for systemic use or for physiological replacement doses of steroids. 
Rationale for change:  To provide clarification that there is an exception for 
glioblastoma subjects in steroid use due to its permitted use as a part of the SOC. 
d. Description of change:  Exclusion criterion 17 has been revised to specify that 
hepatitis C virus (HCV) Ab testing is required for screening purposes in countries 
where HCV RNA is not part of the SOC.  In these cases, HCV antibody−positive 
subjects will be excluded.  Subjects who have had definitive treatment for HCV are 
permitted if HCV RNA is undetectable at screening visit.  Table 24 has been revised 
accordingly. 
Rationale for change:  To clarify the exclusion of subjects identified as at risk for 
viral reactivation and to add country-specific hepatitis screening information. 
e. Description of change:  Exclusion criterion 22 has been updated to specify the 
acceptable QTc interval calculation formulas. 
Rationale for change:  To provide clarification and flexibility in calculation of QTc 
interval. 
f. Description of change:  Exclusion criterion 29 has been added to exclude subjects 
with bleeding associated with tumors that invade or are adjacent to major blood 
vessels, as shown unequivocally by imaging studies, or history of bleeding related to 
disease under study within 3 months of Cycle 1 Day 1. 
Rationale for change:  Although there is no evidence that epacadostat and/or other 
immunotherapies may pose an increased risk for bleeding in subjects whose tumor 
adjacent to major blood vessels, this exclusion criterion was added for the subject 
safety. 
7. Synopsis; Section 4.2.1.2, Phase 2; Section 4.2.2, Secondary Endpoints; Section 4.3, 
Measures Taken to Avoid Bias; Section 9.4, Statistical Analyses 
Description of change:  The primary response criteria for the efficacy evaluation of solid 
tumors, lymphoma, and glioblastoma have been corrected, as they were included 
"modified" prefixes.  The sections were revised to indicate that secondary endpoint 
efficacy analysis will be performed based on the traditional response criteria (Response 
Evaluation Criteria In Solid Tumors Version 1.1 [RECIST v1.1], Cheson, and Response 
Assessment in Neuro-Oncology [RANO]) as well as modified versions as described in 
the protocol (modified RECIST, modified Cheson, and modified RANO). 
Rationale for change:  To clarify the primary and secondary endpoint analysis response 
criteria for solid tumors, lymphoma, and glioblastoma. 
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8. Synopsis; Section 4.4, Number of Subjects; Section 9, Statistics 
Description of change:  The anticipated number of subjects participating in the study 
and selection of sample sizes/statistical methods have been updated.  Per this amendment, 
there will be approximately 207 subjects enrolled in Phase 1 of the study (instead of 
approximately up to 63) and approximately 278 subjects enrolled in Phase 2 (instead of 
approximately up to 228), for a total of approximately 485 subjects enrolled (instead of 
approximately up to 291). 
Rationale for change:  To account for changes in study design due to the new cohorts 
added as Part 2 of Phase 1 and Phase 2 of the study. 
9. Synopsis; Section 5.1, Administration of Study Drugs; Section 5.2, Background 
Therapies 
Description of change:  Information has been added regarding epacadostat 
administration and nivolumab administration in Phase 1 and Phase 2; for combination 
chemo-immunotherapy cohorts, timing after epacadostat and before premedications or 
chemotherapy and the timing of administration of new chemotherapy regimens has been 
included. 
Rationale for change:  To clarify timing and administration of study drugs and 
premedications in Phase 1 and Phase 2. 
10. Synopsis; Section 6, Study Assessments (Tables 18-20); Section 6.4.2, Disease Status 
Follow-Up 
Description of change:  Disease status follow-up window in Phase 1 Part 1 and Phase 2 
(combination immunotherapy cohorts) has been revised from every 8 weeks ± 5 days to 
every 8 weeks ± 7 days. 
Rationale for change:  To define the follow-up period for disease status and make it 
consistent throughout the Protocol. 
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12. Synopsis; Section 8.8, Safety Monitoring Committee; Section 9.5, Analyses for the 
Safety Monitoring Committee 
Description of change:  New section and text added for the establishment of a sponsor-
led Safety Monitoring Committee (SMC) for the new cohorts in Phase 1 Part 2 
(combination chemo-immunotherapy cohorts) and Phase 2 (immuno-oncology relapsed 
and refractory MEL cohorts). 
Rationale for change:  To describe the SMC and its function to closely monitor the 
safety of subjects enrolled in the new cohorts added to Phase 1 Part 2 (chemo-
immunotherapy cohorts) and Phase 2 (immuno-oncology relapsed and refractory MEL 
cohorts). 
13. Section 1.3.1, Risks from Epacadostat; Section 5.7.5, Procedures for Subjects 
Exhibiting Serotonin Syndrome (Table 16) 
Description of change:  Added data on serotonin syndrome across the epacadostat 
program and revised the serotonin syndrome monitoring instructions. 
Rationale for change:  There have been 2 separate events in 2 ongoing clinical studies 
(not in this study to date) reported across the epacadostat program as serotonin syndrome 
(each event was Grade 1).  Although serotonin syndrome is uncommon, the monitoring 
of this event will continue in this program.  The related Protocol sections have been 
updated accordingly. 
14. Section 1.3.1, Risks From Epacadostat; Section 5.7.5, Procedures for Subjects 
Exhibiting Serotonin Syndrome; Section 8.9, Adverse Events of Special Interest; 
Section 16, References; Appendix K, Publication on Serotonin Syndrome 
Description of change:  The Boyer and Shannon 2005 publication was removed from 
Appendix K.  This was an administrative update. 
Rationale for change:  To cite the published article as a reference rather than including 
it in full as an appendix. 
15. Section 5.7.2, Criteria and Procedures for Interruption (Table 8); Section 5.7.3.1, 
Procedures and Guidelines for Pneumonitis (Table 10) 
Description of change:  The following note has been added to the relevant sections of 
Table 8 and Table 10 based on the severity of events:  "In case nivolumab is discontinued 
permanently, epacadostat should be discontinued as well." 
Rationale for change:  To provide guidance and clarification for restarting study 
treatment or permanent discontinuation. 
16. Section 5.8, Criteria for Permanent Discontinuation of Study Drug(s) 
Description of change:  Additional criteria have been added to determine possible 
subject discontinuation from study treatment. 
Rationale for change:  To provide investigators with additional options for decision-
making for the enrolled subjects found ineligible during the study and for the subjects 
noncompliant with study drug administration and/or assessments. 
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17. Section 5.11.3, Management of Infusion Reactions From Nivolumab
Description of change:  Added the management guidance for severe hypersensitivity
reactions caused by infusions under Grade 3 and Grade 4 symptoms.
Rationale for change:  To provide more guidance about how to manage Grade 3 and
Grade 4 hypersensitivity events that may develop after the infusion.
18. Section 6, Study Assessments (Tables 18-21)
Description of change:  Revised the table titles and reordered the laboratory
assessments.  Table 20 has been revised to include whole blood and plasma sample
collection timings.
Rationale for change:  To provide clarity due to the addition of new cohorts and timings
for whole blood and plasma sample collections.
19. Section 6, Study Assessments (Tables 18 and 19); Section 7.4.6.4, Pulse Oximetry
(O2 Saturation)
Description of change:  Section 7.4.6.4 has been removed, and Tables 18 and 19 have
been revised, as pulse oximetry is no longer a required assessment in this study.
Rationale for change:  Pulse oximetry changes are not sensitive or specific for the
diagnosis of pneumonitis that is suspected based on clinical signs and symptoms and
confirmed with radiographic evaluations.  Treatment decisions do not depend on changes
in pulse oximetry parameters.
20. Section 8.1.2, Reporting; Appendix F, Common Terminology Criteria For Adverse
Events v4.0
Description of change:  Revised adverse event reporting requirements.  Additionally,
Appendix F has been removed.
Rationale for change:  To align with the updated Protocol template language and to add
adverse event grading definitions per National Cancer Institute Common Terminology
Criteria for Adverse Events v4.0.
21. Section 8.9, Adverse Events of Special Interest
Description of change:  Revised the definition for adverse events of special interest
further based on emerging data at the program level.  The first definition now specifies
that an elevated AST or ALT laboratory value that is ≥ 3 × ULN and an elevated total
bilirubin laboratory value that is ≥ 2 × ULN as determined by way of Protocol-specified
laboratory testing or unscheduled laboratory testing is considered an adverse event of
special interest.  The second definition now has 2 additional criteria:  ≥ Grade 3 rash or
dermatitis and Grade 4 laboratory abnormality.  Some paragraphs were reordered.
Rationale for change:  To provide clarification about the adverse events of special
interest to guide investigators to identify and to report these types of events.
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22. Section 10.2, Accountability, Handling, and Disposal of Study Drug
Description of change:  Updated study drug compliance, accountability, and destruction
requirements at the investigational sites.
Rationale for change:  To align with the revised compound-level updates and
requirements.
23. 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 (Version) 5 
The primary purpose of this amendment is to modify the Protocol to enable European (EU) sites 
to participate in this study. 
This amendment includes the changes to the Protocol INCB 24360-204 Amendment 4 
(12 FEB 2016) summarized below.  A redline version of the amendment depicting the updated 
and previous text is also provided. 
1. Title Page 
Description of change:  EudraCT number was included on the title page. 
Rationale for change:  EudraCT Number was obtained. 
2. Section 1, Introduction; Section 1.2.2, Preclinical and Clinical Study Data for 
Epacadostat and Nivolumab; Section 1.3.2, Risks for Nivolumab; Section 10.1.2.2, 
Nivolumab; Section 16, References 
Description of change:  The reference for the nivolumab Investigator's Brochure was 
replaced with references to the nivolumab Summary of Product Characteristics (SmPC) 
and United States Package Insert (USPI).  In Section 1.3.2, cross-references to 
Section 5.6.3, Table 7, and Appendix C were added for details regarding immune-related 
toxicities, and the paragraph regarding the overall safety experience with nivolumab was 
deleted. 
Rationale for change:  References to the SmPC and USPI added to provide nivolumab 
approved product information and background for nonclinical and clinical data in the EU 
and US, respectively.  Cross-references to Section 5.6.3, Table 7, and Appendix C were 
added to provide adequate details for immune-related toxicities. 
3. Section 1.1.1, Inhibition of PD-1 as a Target for Cancer 
Description of change:  Information about nivolumab marketing approval in the US and 
EU was updated. 
Rationale for change:  To include up-to-date US and EU marketing approval 
information for nivolumab. 
4. Synopsis; Section 3.2, Subject Inclusion Criteria; Section 8.5, Pregnancy  
Description of change:  Duration of contraception requirement in inclusion criterion #8 
was increased from 125 days to 150 days after the last dose of study treatment.  In 
Section 8.5, the window for pregnancy was also updated to pregnancy occurring during 
the study or within 150 days (instead of 125 days) of completing the study. 
Rationale for change:  To comply with the SmPC recommendations. 
5. Synopsis; Section 3.2, Subject Inclusion Criteria 
Description of change:  A note was added to inclusion criterion 4a for subjects with 
Stage IIIB, Stage IV, or recurrent NSCLC who have tumors with driver mutations treated 
with a tyrosine kinase inhibitor therapy. 
Rationale for change:  To clarify that tyrosine kinase inhibitor therapy alone is not 
considered a second systemic chemotherapy regimen. 
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6. Section 5.9, Beginning and End of the Study 
Description of change:  "Any remaining subjects may continue to receive study 
medication and be seen by the investigator per usual standard of care for this subject 
population.  In addition, the investigator will be expected to monitor for and report any 
SAEs and pregnancies, as detailed in Section 8.3 (Serious Adverse Events)." was revised 
as "Any remaining subjects may continue to receive study medication per Protocol."   
Rationale for change:  Subjects continuing to receive study medication will remain on 
study and be followed per Protocol. 
7. Section 1.1.1. Inhibition of PD-1 as a Target for Cancer; Section 3.3, Subject 
Exclusion Criteria; Section 5.11, Restricted Medications and Measures; Section 
5.12, Prohibited Medications and Measures; Section 5.6.5, Procedures for Subjects 
Exhibiting Serotonin Syndrome; Section 8.9, Adverse Events of Special Interest 
Description of change:  In Section 1.1.1, the brand name Opdivo was deleted.  In 
Section 5.11 the brand name "Coumadin" was deleted and replaced with the generic drug 
name "warfarin."  In Sections 3.3 and 5.12, the brand name "FluMist" was deleted.  In 
Sections 5.6.5 and 8.9, the brand name Demerol was deleted and replaced with the 
generic drug names meperidine/pethidine. 
Rationale for change:  To provide generic drug names only. 
8. Synopsis; Section 6, Study Assessments (Tables 15 and Table 17) 
Description of change:  Table 15 notes that there will be laboratory assessments and 
reminder card distribution on Cycle 1 Day 8, and laboratory assessments on Cycle 1 
Days 22, 36, and 50. 
Per Protocol Amendment 4 (dated 12 FEB 2016), 
 
 
.  In addition, in Section 7.4.6.3 (Liver Chemistry Tests), the frequency of 
liver chemistry tests was changed to every cycle rather than every week.  Therefore, there 
will be no laboratory assessments on Cycle 1 Day 8 or Cycle 1 Days 22, 36, and 50. 
Since there will be no scheduled clinical visit on Cycle 1 Day 8, the reminder card 
distribution will not occur as marked in Table 15.  Adverse events and concomitant 
medication assessments for Cycle 1 Day 8 will be collected by phone call (new footnote 
"a" has been added to Table 15). 
Rationale for change:  To align Tables 15 and 17 with changes made in Protocol 
Amendment 4 to Sections 7.7.1 and 7.4.6.3. 
9. Section 7.5.1, Initial Tumor Imaging 
Description of change:  Subjects with glioblastoma are no longer required to have a 
chest and abdominal CT scan. 
Rationale for change:  To exempt subjects with glioblastoma from the baseline chest 
and abdominal CT scan because extracranial metastases are rare in these subjects. 
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10. Section 10.1.1.1, Epacadostat; Section 10.1.1.2, Nivolumab
Description of change:  Epacadostat packaging and labeling statement was revised as
"All bottles of Incyte investigational product will be labeled to comply with regulatory
requirements of each country."  Nivolumab labeling statement was revised as "Clinical
supplies will be labeled in accordance with local regulatory requirements."
Rationale for change:  To acknowledge compliance with labeling requirements in all
countries.
11. Section 13.3, Ethics Review
Description of change:  The word "IEC" (independent ethics committee) was added to
the fifth paragraph.
Rationale for change:  To include EU terminology.
12. Appendix A, Information Regarding Effectiveness of Contraceptive Methods
Description of change:  Appendix A was updated with Clinical Trial Facilitation Group
recommendations related to contraception in clinical trials being conducted in European
countries.
Rationale for change:  The clinical study will be conducted in ex-US centers; therefore,
the contraception language was updated for EU compliance.
13. 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 (Version) 4 
The primary purpose of this amendment is to include epacadostat updates at the program level as 
well as clarify Phase 1 and Phase 2 cohort enrollments. 
This amendment includes the changes to the Protocol INCB 24360-204 Amendment 3 
(16 JUL 2015) summarized below.  A redline version of the amendment depicting the updated 
and previous text is also provided. 
1. Section 1.3.1, Risks From Epacadostat
Description of change:  Updated to report that 253 unique subjects have been exposed to
epacadostat as monotherapy and/or in combination with checkpoint inhibitors as of
29 OCT 2015.
Rationale for change:  Updated with information contained in the recently revised
epacadostat Investigator Brochure.
2. Section 1.4, Justification for Treatment Regimen
Description of change:  Updated the dose justification paragraph, which included
INCB 24360-201 data supporting the doses of epacadostat used in this study.
Rationale for change:  The section was updated with the most recent data included in
the epacadostat Investigator's Brochure.
3. Synopsis; Section 2.1, Primary Objectives
Description of change:  Clarification was included to state that "objective" response rate
is going to be used as one of the criteria for response measurement analysis, not "overall"
response rate.
Rationale for change:  To be consistent with the statistical analysis section of the
Protocol (Section 9).
4. Synopsis; Section 2.2, Secondary Objectives; Section 3.2, Subject Inclusion Criteria
(Inclusion Criterion 5); Section 4.1, Overall Study Design; 4.2.2, Secondary
Endpoints
Description of change:  Clarification to specify that diffuse large B-cell lymphoma
(DLBCL) is included as NHL not HL.
Rationale for change:  To correct the category of DLBCL as it belongs to NHL type not
HL type of lymphoma.
5. Synopsis; Section 3.2, Subject Inclusion Criteria
Description of change:  Inclusion criterion 4g note was updated to indicate that relapse
is defined as progression following initial line of therapy and if the participant had a
surgical resection for relapsed disease and no antitumor therapy was instituted for up to
12 weeks, this is considered 1 relapse or recurrence.
Rationale for change:  Revised for clarity.
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6. Synopsis; Section 3.3, Subject Exclusion Criteria 
Description of change:  Exclusion criterion 1f was updated to indicate that total bilirubin 
above the institutional upper limit of normal or conjugated bilirubin ≥ 1.2 × upper limit of 
normal (ULN) is excluded.  If no institutional ULN for conjugated bilirubin is provided, 
conjugated bilirubin > 40% of total bilirubin is excluded. 
Rationale for change:  Revised to be consistent with other epacadostat Protocols.  In 
cases where a benign cause of elevated bilirubin may be present (eg, Gilbert's syndrome), 
an exception is clarified to indicate that conjugated (direct) bilirubin > 40% of total 
bilirubin is excluded.  Conjugated bilirubin need only be tested if total bilirubin is 
elevated. 
7. Synopsis; Section 3.3, Subject Exclusion Criteria; Section 6, Study Assessments 
(Table 17, Laboratory Assessments for Screening Through Treatment Phase; 
Table 19, Laboratory Tests:  Required Analytes) 
Description of change:  Exclusion criterion 17 was updated to specify that subjects with 
a known history of or who are positive for hepatitis B (HBsAg reactive) or hepatitis C 
(HCV RNA [qualitative] is detected) will be excluded.  Hepatitis B surface antigen 
antibody, hepatitis B virus DNA, and hepatitis C virus antibody will not be tested in the 
study.  Table 17 and Table 19 were revised accordingly. 
Rationale for change:  The purpose of this change is to clarify the exclusion of patients 
who are identified as at risk for viral reactivation.  The previous criteria excluded patients 
who were vaccinated for hepatitis B and could not provide documentation of prior 
vaccination;  such patients are not at risk for viral reactivation. 
8. Synopsis; Section 3.3, Subject Exclusion Criteria; Section 5.11, Restricted 
Medications and Measures; Section 5.12, Prohibited Medications and Measures 
Description of change:  Exclusion criterion 6 was revised to specify subjects who use 
the systemic steroid or prednisone in doses that are equivalent to ≥ 10 mg/day within 
7 days (instead of ≥ 7.5 mg within 14 days) prior to the first dose of treatment will not be 
eligible.  The threshold for systemic steroids was also changed to 10 mg/day in 
Sections 5.11 and 5.12. 
Rationale for change:  Updated to be consistent with other immunotherapy agents that 
use 10 mg as a cutoff since it is considered the physiologic replacement dose. 
9. Section 3.3, Subject Exclusion Criteria 
Description of change:  Exclusion criterion 9 was revised to clarify if a subject with 
glioblastoma had a major surgery; it must be ≥ 21 days since the surgery performed prior 
to enrollment. 
Rationale for change:  This criterion was aligned with inclusion criterion 4g.  
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10. Synopsis; Section 3.3, Subject Exclusion Criteria
Description of change:  Exclusion criterion 22 was updated to indicate that subjects with
a screening QTc interval > 480 milliseconds (instead of 470 milliseconds) will be
excluded.
Rationale for change:  Based on the QTc interval analysis conducted in Phase 1 and
Phase 2 epacadostat studies, no clinically meaningful changes or trends were observed in
QTc interval prolongation and the relationship between epacadostat plasma concentration
and QTc intervals.
11. Synopsis; Section 3.3, Subject Exclusion Criteria
Description of change:  Exclusion criterion 27b was removed as it was indicating that if
subjects with unresectable or Stage IV melanoma received prior anti-CTLA-4 treatment,
they will not be eligible for the study.
Rationale for change:  This criterion was inconsistent with exclusion criterion 4a,
indicating that anti-CTLA-4 therapy is permitted for subjects with metastatic melanoma
as first-line treatment.
12. Synopsis; Section 4.1 Overall Study Design
Description of change:  The text was revised to allow subjects with colorectal cancer
(CRC) to be enrolled in 300 mg cohort in Phase 1.
Rationale for change:  This change will allow CRC subjects to be enrolled in Phase 1
300 mg cohort as it was initially planned and approved in the original study design.
There was no safety concern when the previous Protocol was amended to exclude CRC
subjects from the 300 mg Phase 1 cohort.
13. Synopsis; Section 4.1.1, Phase 1 Dose-Escalation Design
Description of change:  The text was revised to specify that additional Phase 2 cohorts
in the other tumor types may be opened to test 100 mg epacadostat BID.  In addition, if
additional cohorts are opened for other tumor types to test 100 mg BID, and 300 mg is
elected as RP2D, then the remaining subjects enrolled in these cohorts may be treated
with epacadostat 300 mg BID.  The study design schematic (Figure 1) was updated
accordingly.
Rationale for change:  The additional tumor types may be added in the Phase 2 100 mg
BID cohorts, which will be conducted in parallel to the Phase 1 300 mg BID cohort.  This
will allow further safety and efficacy data to be obtained in other tumor types before
determining the recommended dose for Phase 2 expansion.
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14. Synopsis; Section 4.1.1, Phase 1 Dose-Escalation Design
Description of change:  The text was revised to specify if MTD is not determined based
on the Phase 1 and ongoing Phase 2 data, then the remaining Phase 2 cohorts may be
opened at the pharmacologically active dose (eg, 100 mg BID).
Rationale for change:  Revised to specify what action will be taken for Phase 2 dosing if
MTD cannot be determined.
15. Synopsis; Section 4.2.1. Primary Endpoint, Section 4.2.2. Secondary Endpoints
Description of change:  First primary endpoint for Phase 1 and secondary endpoint
safety for Phase 2 texts were revised to specify that safety will be assessed by monitoring
the frequency and severity of AEs, SAEs, and deaths.
Rationale for change:  Revised for clarity.
16. Synopsis; Section 4.2.2. Secondary Endpoints
Description of change:  Efficacy endpoint was revised to clarify that progression-free
survival (PFS) will be assessed at 6 months. Also, the last sentence has been removed.
Rationale for change:  Revised for clarity and to specify the timepoints for PFS
assessment.
18. Synopsis; Section 4.4 Number of Subjects
Description of change:  Total number of subjects to be enrolled in the entire study was
updated as approximately 291 (previously 303).
Rationale for change:  Updated for clarity.
19. Synopsis; Section 5.11, Restricted Medications and Measures
Description of change:  Guidelines for coumarin-based anticoagulants were updated and
a table recommending a warfarin dose adjustment based on various epacadostat doses
was included.
Rationale for change:  Based on the observed magnitude of epacadostat/warfarin PK
interaction and PK/PD modeling results from a completed drug-drug interaction study,
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 in S- and R- warfarin oral clearance values.  Close
INR monitoring is recommended for subjects on a stable dose of warfarin who are
starting treatment with epacadostat.  Based on this PK/PD modeling, a table of
recommendations for warfarin dose modifications for subjects was added.
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20. Section 1.3.1, Risks from Epacadostat; Section 6, Study Assessments; Section 7.4.4,
Assessment of Serotonin Syndrome Symptoms
Description of change:  Serotonin syndrome assessment was removed from the schedule
of assessments (Table 15 and Table 16) and corresponding sections.
Rationale for change:  Of the 253 subjects administered epacadostat to date, none have
exhibited serotonin syndrome.  Subjects and sites are being informed of the signs and
symptoms associated with serotonin syndrome; however, the scheduled serotonin
syndrome assessment was removed from the Protocol.
21. Section 6, Study Assessments; Section 7.9.3, Administration of Epacadostat and
Compliance
Description of change:  Epacadostat administration at the clinic on Cycle 1 Day 8 was
removed from Table 15.
Rationale for change:  To remove the inconsistency between footnote and the schedule
on the table as well as with the other relevant sections in the Protocol.
22. Section 6, Study Assessments; Section 7.4.6.3 Liver Function Tests
Description of change:  The test name was revised to liver chemistry test to be
consistent with the program level wording.  In addition, the frequency of liver chemistry
test monitoring was changed to every 8 weeks rather than weekly monitoring.
Rationale for change:  Because of the low occurrences of Grade 3 or greater ALT and
AST elevations seen on the study, weekly monitoring of liver chemistry test is not
required.
24. Section 8.9, Adverse Events of Special Interest
Description of change:  Electronic media and paper as reporting devices were removed.
Rationale for change:  Either electronic media or paper will not be used as a reporting
devices to report both adverse events of special interest and immune-related adverse
events.
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25. Synopsis; Section 9.2.2, Sample Size for the Dose-Expansion Portion (Phase 2) of the 
Study; Section 9.4.1, Primary Analyses  
Description of change:  The durations entered as weeks were converted to months.  In 
addition, the text related to time-to-event data analysis was revised to clarify when the 
data are censored. 
Rationale for change: Updates done for further clarification. 
26. Section 9.1, Study Populations 
Description of change:  Definition for safety evaluable subjects was revised.  Definition 
for Phase 1 population was removed as it was not applicable for this study. 
Rationale for change:  Updated for clarity. 
27. Section 9.4.2, Secondary Analyses 
Description of change:  Definition and the method of analysis for duration of disease 
control was revised. 
Rationale for change:  Revised for clarity. 
28. Incorporation of administrative changes.  INCB024360 was replaced with the generic 
name epacadostat throughout the Protocol, and 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 (Version) 3 
The primary purpose of this amendment is to change the dose for nivolumab for Phase 2 to a flat 
dose (240 mg) and to update the study design to allow the Phase 2 NSCLC and melanoma 
expansion cohorts to open with the 100 mg BID dose of INCB024360 once 100 mg BID is 
determined to be safe in Phase 1. 
This amendment includes the changes to the Protocol INCB 24360-204 Amendment 2 (03 APR 
2015) summarized below.  A red-line version of the amendment depicting the updated and 
previous text is also provided. 
1. Synopsis; Section 1.4, Justification for Treatment Regimen; Section 2.2, Secondary 
Objectives; Section 4.1.2, Overall Study Design; Section 5.1.2, Nivolumab 
Description of change:  The dose of nivolumab for the Phase 2 expansion cohorts was 
changed to from 3 mg/kg via 60-minute IV infusion to 240 mg via 30-minute IV infusion.  
 safety data have been added to Section 4.1 to support this dose 
change. 
Rationale for change:  Nivolumab PK was determined to be linear, with dose 
proportional exposures over a dose range of 0.1 to 10 mg/kg and similar across tumor 
types.  Further preliminary data indicate that nivolumab PK are similar in nonsolid and 
solid tumors.  Nivolumab clearance and volume of distribution were found to increase 
with increasing body weight, but the increase was less than proportional, indicating that a 
milligram per kilogram dose represents an overadjustment for the effect of body weight 
on nivolumab PK.  Conversely, given the relationship between nivolumab PK and body 
weight, a flat dose is expected to lead to lower exposures in heavier subjects, relative to 
the exposures in lighter subjects.  It should be noted that a dose of 240 mg nivolumab is 
identical to a dose of 3 mg/kg for subjects weighing 80 kg, which is the approximate 
median body weight of subjects in the 3 Phase 2 and 3 clinical studies of nivolumab 
monotherapy.  Nivolumab has been shown to be safe and well tolerated up to a dose level 
of 10 mg/kg, and the relationship between nivolumab exposure produced by 3 mg/kg and 
efficacy has been found to be relatively flat.  Thus, the 240 mg every-2-weeks dose and 
schedule is supported by safety, efficacy, and exposure-response analyses results. 
2. Synopsis; Section 4.1.1, Phase 1 Dose-Escalation Design 
Description of change:  For the dose-escalation portion of the study (Phase 1), the 
number of subjects was reduced from 15 to 9 subjects per cohort (total N = 63), and no 
subjects with colorectal cancer (CRC) will be enrolled in the 300 mg cohort.  The design 
has been revised so that if INCB024360 100 mg BID in combination with nivolumab is 
deemed tolerable in Phase 1, the Phase 2 melanoma and NSCLC expansion cohorts will 
open with INCB024360 100 mg BID in combination with nivolumab. The 300 mg BID 
dose will be tested in parallel to the Phase 2 melanoma and NSCLC cohorts, and if it is 
deemed tolerable, the remaining Phase 2 cohorts may be opened with 300 mg BID as the 
recommended Phase 2 dose (RP2D).  In Phase 2, if either melanoma or NSCLC cohorts 
at 100 mg BID enroll < 50% (≤ 25 subjects), the remaining enrollment in either of these 
cohorts may be treated with INCB024360 300 mg BID at the sponsor's discretion, in lieu 
of opening cohorts of melanoma and NSCLC with 300 mg BID.  If 300 mg BID is not 
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tolerated, an intermediate dose of 200 mg BID may be tested or 100 mg BID may be 
selected as the RP2D.  A new figure depicting the revised study design has been added. 
Rationale for change:  The Phase 1 safety expansion cohort size has been reduced since 
the emerging safety profile of the combination is well tolerated.  The exposure for 
INCB024360 100 mg BID based on PK measurements is in the range of active levels in 
nonclinical models; therefore, expansion cohorts may be further evaluated at this dose 
while a final dose escalation is completed.  Depending on the enrollment rates, these 
cohorts may complete enrollment at the initial dose or proceed with the higher dose if 
that is determined to be safe. 
3. Synopsis; Section 3.2, Subject Inclusion Criteria
a.
Description of change:  The inclusion criterion #4a for subjects with non–small cell
lung cancer (NSCLC) has been revised to specify Stage IIIB (vs Stage III) and that
subjects must have received only 1 prior systemic regimen for Stage IIIB, Stage IV,
or recurrent NSCLC.
Rationale for change:  Subjects with Stage IIIA disease may be candidates for
surgery and therefore not candidates for this study.  The number of prior regimens for
subjects with NSCLC has been revised to be consistent with current practice for use
of nivolumab in this setting.
b. Description of change:  The inclusion criterion #4b for subjects with melanoma has
been revised to indicate that subjects may be treatment-naïve or have received only
1 prior treatment for advanced or metastatic disease.
Rationale for change:  Based on recent NCCN guidelines, this criteria was revised to
be consistent with current practice for use of nivolumab in this setting.
c.
Description of change:  The inclusion criterion #7 for baseline tumor biopsy has
been updated to indicate that for archived tumor tissue, unstained slides must have
been prepared from a formalin fixed paraffin-embedded block obtained within
6 months before screening.
Rationale for change:  Additional clarification regarding acceptable archived tissue
specimens permitted for inclusion in this study.
4. Synopsis; Section 3.3, Subject Exclusion Criteria
a.
Description of change:  The exclusion criterion #22 for abnormal electrocardiogram
(ECG) has been revised to indicate that in the event that a single QTc is > 470
milliseconds, a subject may be enrolled if the average QTc for the 3 ECGs is < 470
milliseconds.  In addition, the JTc must be < 340 milliseconds if JTc is used in place
of the QTc, and subjects with left bundle branch block are excluded.
Rationale for change:  These criteria have been updated to be consistent with
Incyte's current standard language across clinical programs for ECG requirements.
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b. Description of change:  Use of any prohibited medication listed in Section 5.12 was 
added to the list of exclusion criteria as #28. 
Rationale for change:  Prohibited medications are now included in the exclusion 
criteria so that these are considered and assessed during the subject screening process 
for enrollment to the study. 
c. Description of change:  Two exclusion criteria for subjects with unresectable or 
Stage IV melanoma that were previously included in the inclusion criteria section 
were moved to the exclusion criteria section (subjects with ocular melanoma and 
subjects treated with prior anti–CTLA-4).  
Rationale for change:  Given these 2 criteria are exclusions they were moved to 
appropriate section of the Protocol for ease of reference. 
5. Section 5.6.3.1, Procedures and Guidelines for Pneumonitis; Section 6, Study 
Assessments (Tables 14, 15, and 18); Section 7.4.7, Pulmonary Function Tests 
Description of change:  Pulmonary function testing was removed from the screening 
assessments and from the subject evaluation recommended for symptomatic pneumonitis. 
Rationale for change:  All subjects are required to have baseline CT scans of the chest at 
baseline, which provides reasonable baseline assessment for a subject's pulmonary status.  
Oxygen saturation is also assessed at baseline as well as on-study treatment in order to 
continually assess the subject's pulmonary status. 
6. Section 6, Study Assessments (Tables 14 and 18) 
Description of change:  In Table 14, targeted physical examination was added to 
Cycle 2, Days 15, 29, and 43.  In Table 18, HPV (for subjects with SCCHN only) and 
MSI (for subjects with CRC only) were added to the table of required analytes for 
laboratory tests. 
Rationale for change:  Targeted physical examination was omitted from table for these 
visits.  HPV and MSI were added for consistency to match table with text in other 
relevant sections. 
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8. Section 6, Study Assessments (Table 16); Section 7.4.7, Laboratory Assessments 
Description of change:  Revised to indicate that screening laboratory tests should be 
performed within 7 days before the first dose of treatment instead of within 10 days.  If 
the screening laboratory tests were performed more than 7 days before treatment 
initiation, they must be repeated before study treatment initiation (Cycle 1 Day 1).  
Rationale for change:  Guidance for timing of screening laboratory tests has been 
updated for consistency with exclusion criteria, which notes that laboratory assessments 
performed within 7 days do not need to be repeated on Cycle 1  Day 1 before dosing. 
9. Section 7.4.7.5, Pregnancy Testing 
Description of change:  Updated to indicate that urine pregnancy tests will be conducted 
on Day 1 of each cycle or as required by local regulations. 
Rationale for change:  Text has been updated to match Table 16, Laboratory 
Assessments for Screening Through Treatment Phase. 
10. Section 7.5, Efficacy Assessments 
Description of change:  Section 7.5.1 was updated to indicate that brain MRI at baseline 
should also be considered when disease burden due to any targeted tumor types is 
extensive (ie, when ≥ 3 metastatic disease sites are involved), and that for selection of 
target lesions, RECIST v1.1, Cheson, or RANO criteria should be followed.  In 
Section 7.5.3, a table of guidelines for imaging and treatment after first radiographic 
evidence of disease progression was added. 
Rationale for change:  Guidance for consideration of baseline brain MRIs has been 
added, and guidance for imaging and treatment after first evidence of progressive disease 
has been added. 
11. Section 7.8, Tumor Biopsy Collection and Analysis 
Description of change:  The number of required archival unstained slides has been 
updated to 20 to 25 slides (instead of 15 to 25). 
Rationale for change:  Based on current sample analyses plan, 20 to 25 slides would be 
needed to complete all planned testing. 
12. Section 8.8, Data Monitoring Committee; Section 9.5, Data Monitoring Committee; 
Section 9.6, Interim Analysis 
Description of change:  Details have been added regarding data monitoring specific to 
Phase 1 and Phase 2 of the study and regarding an interim safety analysis for Phase 2. 
Rationale for change:  Details for safety oversight for Phase 1 and Phase 2 have been 
included. 
13. Appendix E, Prohibited Monoamine Oxidase Inhibitors and Drugs Associated With 
Significant Monoamine Oxidase Inhibitory Activity 
Description of change:  List of prohibited MAOIs has been updated.  
Rationale for change: The list has been updated after review of current literature. 
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14. Incorporation of administrative changes.  Other minor, administrative changes have
been incorporated throughout the protocol and are noted in the red-line/strike-out version
of the amendment.
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Amendment (Version) 2 
The primary purpose of Amendment 2 is to include an additional expansion cohort in subjects 
with glioblastoma. 
1. Synopsis, Primary Objectives/Endpoints (also Sections 2.1 and 4.2.1), Secondary
Objectives/Endpoints (also Sections 2.2 and 4.2.2), Overall Study Design (Section
4.1, 4.3), Statistical Methods (Sections  9.2.2,  9.3, 9.4.1, and 9.4.2);  Study
Population (Section 3), Study Schedule/Procedures (Section 7.5 and 7.5.5); Section
5.12, Prohibited Medications and Measures; Appendix K, Response Criteria for
Glioblastoma
Description:  An additional expansion cohort has been added for subjects with
glioblastoma.
Rationale:  This cohort has been added to obtain further safety and efficacy data,
particularly in the subset of subjects with glioblastoma.
2. Synopsis, Planned Number of Subjects; Section 4.4, Number of Subjects
Description:  The planned number of subjects has been updated to reflect the addition of
the glioblastoma expansion cohort of 28 subjects.
Rationale:  An additional cohort has been added to further explore the safety and
efficacy of this combination in subjects with glioblastoma.
3. Section 1.1.1, Inhibition of PD-1 as a Target for Cancer; Section 1.1.4 Rationale for
Studying Immunotherapy in Advanced or Metastatic Cancers; Section 1.2.1,
Rationale for Combining PD-1 and IDO1 inhibitor in Advanced or Metastatic
Cancers, Including Melanoma, NSCLC, SCCHN, Ovarian Cancer, Colorectal
Cancer, DLBCL, and Glioblastoma
Description:  Information regarding the approval of nivolumab by the FDA has been
added to the background and rationale.  In addition, background data to support the
combination of a PD-1 and IDO1 inhibitor in glioblastoma has been added.
Rationale:  Nivolumab has been approved for treatment of subjects with unresectable or
metastatic melanoma and disease progression following ipilimumab and, if BRAF V600
mutation positive, a BRAF inhibitor.  This indication is approved under accelerated
approval based on tumor response rate and durability of response. Continued approval for
this indication may be contingent upon verification and description of clinical benefit in
the confirmatory trials.  Nivolumab was also approved on 04 MAR 2015 to treat patients
with advanced (metastatic) squamous NSCLC with progression on or after platinum-
based chemotherapy.
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4. Synopsis, Key Inclusion Criteria; Section 3.2, Subject Inclusion Criteria #4a, b, c, d, 
and f 
Description:  The inclusion criteria for subjects with NSCLC, melanoma, CRC, SCCHN, 
and B cell NHL or HL have been updated. 
Rationale:  The inclusion criteria for subjects with NSCLC, melanoma, CRC, SCCHN, 
and B cell NHL or HL have been updated to clarify patient population and prior therapy 
requirements. 
5. Synopsis, Key Exclusion Criteria; Section 3.3, Subject Exclusion Criteria #1e and 22 
Description:  Exclusions for alkaline phosphatase values and QTc requirements for 
subjects with pacemakers have been updated. 
Rationale:  These exclusion criteria have been updated to clarify requirements for  
alkaline phosphatase in the context of bone metastases and QTc requirements for subjects 
with pacemakers. 
6. Synopsis, Phase 1 Dose Escalation; Section 4.1.1, Phase 1 Dose Escalation 
Description:  The 300 mg BID dose cohort was clarified as an optional dose level that 
may be tested in parallel to opening the expansion cohorts.   
Rationale:  To provide to option to further escalate INCB024360 if a lower dose is 
selected as the PAD. 
7. Section 5.5.1, Definition of Dose-Limiting Toxicities (Table 3, Criteria for Defining 
Dose-Limiting Toxicities); Section 5.6.2, Criteria and Procedures Interruption 
(Table 4, Dose Modification Guidelines for Drug-Related Adverse Events)  
Description:  Clarification has been added to the DLT criteria for the Grade 3 rash to 
specify steroid use means systemic steroids. 
Rationale:  Use of topical steroids only would not warrant an event to be considered a 
DLT. 
8. Section 5.11, Restricted Medications and Measures 
Description:  Updated guidance was added for use of coumarin-based anticoagulants. 
Rationale:  A study was conducted (Study INCB 24360-102) that investigated the 
potential drug-drug interaction between INCB024360 and warfarin.  Results from the 
preliminary PK and PD analyses concluded that multiple dosing of INCB024360 300 mg 
BID increased S-warfarin and R warfarin geomean plasma AUCs by 43% and 68%, 
respectively, accompanied by mild but statistically significant INR and PT increases.  
Modeling showed that, with the same degree of warfarin PK interaction, the magnitude of 
INR increase may be significantly greater in patients on stable warfarin regimen targeting 
a typical INR range of 2 to 3 (which is higher than the INR observed in this study 
following a single warfarin dose).  Therefore, we recommend an approximate one-third 
reduction of warfarin dose for subjects who also receive INCB024360, along with close 
INR monitoring.  No clinically relevant interaction was observed on INCB024360 PK 
with concomitant warfarin. 
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9. Section 5.11, Restricted Medications and Measures 
Description:  Restrictions for the use of the anticonvulsant carbamazepine has been 
added to the list of restricted study medications. 
Rationale:  Restrictions for the use of the anticonvulsant carbamazepine has been added 
to the list of restricted study medications with the addition of the glioblastoma cohort. 
10. Section 5.12, Prohibited Medications and Measures 
Description:  The following has been added or clarified in the prohibited medications 
section:  administration of an injectable flu vaccine is prohibited during the DLT 
observation period, clarification has been added that live attenuated vaccines are 
prohibited, the list of prohibited UGT1A9 inhibitors has been updated, and guidance 
regarding corticosteroid use for subjects with glioblastoma has been added.   
Rationale:  Updates have been made to address questions related to vaccine use and 
UGT1A9 inhibitors, and to address corticosteroid use in the new expansion cohort of 
subjects with glioblastoma. 
11. Section 6.0 , Study Assessments (Table 12, Schedule of Assessments – Screening 
Through Treatment Phase; Table 13, Schedule of Assessments End of Treatment 
through Survival Follow-Up); Section 7.4.7, Chest Radiograph 
Description of change:  Chest radiograph has been removed from the required screening 
assessments 
Rationale for change:  All subjects will have a CT of the chest performed during 
screening; therefore, no additional chest radiograph needs to be performed. 
12. Section 6.0, Study Assessments (Table 12, Schedule of Assessments for Screening 
Through Treatment Phase); Section 7.4.7, Pulmonary Function Tests 
Description:  Pulmonary function testing may be omitted for subjects with stomas due to 
laryngectomies. 
Rationale:  Subjects with stomas are unable to perform pulmonary function testing and 
are therefore permitted to omit this testing at screening. 
13. Section 7.4.8.3, Liver Function Tests 
Description:  Text has been added to clarify LFT monitoring requirements for subjects 
with persistent low-grade abnormalities. 
Rationale:  Liver function test monitoring for persistent low-grade abnormalities does 
not need to be monitored twice a week indefinitely.  Appropriate LFT monitoring 
intervals should be discussed with the medical monitor for these circumstances. 
14. Section 8.1.1, Adverse Events, Definitions and Reporting 
Description of change:  Guidance has been added for reporting of adverse events due to 
disease progression. 
Rationale for change:  Additional guidance has been added to assist sites in determining 
when it is and is not appropriate to report adverse events related to disease progression. 
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15. Incorporation of administrative changes.  Other minor, administrative changes have
been incorporated throughout the Protocol and are noted in the red-line/strike-out version
of the amendment.
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Protocol INCB 24360-204 Amendment 8 
Version 8 
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Amendment (Version) 1 
The primary purpose of the amendment is to address FDA queries, including clarifications and 
requested changes to the inclusion criteria, updates to the definition of dose-limiting toxicities, 
ECG monitoring and to add regularly scheduled urine pregnancy testing for females of 
childbearing potential. 
This amendment includes the changes to Protocol INCB 24360-204 (dated 15 AUG 2014) 
summarized below.  A red-line version of the amendment depicting the updated and previous 
text is also provided. 
1. Synopsis, Phase 1 Dose Escalation; Section 4.1.1 Phase 1 Dose-Escalation Design; 
Section 5.5.1, Definition of Dose-Limiting Toxicities 
Description of change:  A dose-limiting toxicity (DLT) reporting period of 6 weeks has 
been added to the Phase 1 dose-escalation portion of the study. 
Rationale for change:  This revision to increase the DLT reporting period to at least 
6 weeks was requested by FDA. 
2. Synopsis, Study Population; Section 3.1, Study Population, Section 3.2, Subject 
Inclusion Criteria (Criterion #4) 
Description of change:  Inclusion criteria for selected cancers for this study have been 
revised to allow only subjects with refractory or relapsed disease after standard of care 
therapy. 
Rationale for change:  FDA requested that the Protocol be revised to only include 
subjects who have refractory or relapsed disease after standard of care therapy. 
3. Synopsis, Key Inclusion Criteria; Section 3.2, Subject Inclusion Criteria 
(Criterion #4a, NSCLC) 
Description of change:  An inclusion criterion for subjects with NSCLC has been 
revised to require EFGR and ALK mutation status testing as well as treatment with TKI 
if mutation status is mutant. 
Rationale for change:  FDA requested that the Protocol be revised to state that all 
subjects must be screened for EGFR and ALK mutations.  Also, FDA agrees that if the 
subject has a driver mutation such as EGFR or ALK, he/she must have received a 
tyrosine-kinase inhibitor (TKI). 
4. Synopsis, Key Inclusion Criteria; Section 3.2, Subject Inclusion Criteria 
(Criterion #4b, Melanoma) 
Description of change:  The text has been revised to provide clarity for required 
documentation of BRAF mutation status for subject with metastatic melanoma. 
Rationale for change:  The text has been revised to provide clarity that only V600E 
BRAF mutation testing is required.  It is not required for subjects to have the BRAF 
activating mutation. 
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5. Section 5.5.1, Definition of Dose-Limiting Toxicities (Table 3, Criteria for Defining
Dose-Limiting Toxicities)
Description of change:  The following has been added to the criteria for defining a DLT:
Febrile neutropenia ≥ Grade 3 for 72 hours, ≥ Grade 3 hemolysis, Grade 4 anemia not
explained by underlying disease, ≥ Grade 3 thrombocytopenia with clinically significant
bleeding or requirement for transfusion, Grade 2 AST or ALT with symptomatic liver
inflammation, AST or ALT > 3 × ULN and concurrent total bilirubin > 2 × ULN without
initial findings of cholestasis.
Rationale for change:  The FDA has requested the above criteria be added to the criteria
for defining DLTs.
6. Section 6, Study Assessments for Screening through Treatment Phase (Table 12);
Section 7.4.6, Twelve-Lead Electrocardiograms
Description of change:  A predose ECG assessment has been added to Cycle 1 Day 15.
Rationale for change:  FDA suggested ECG monitoring be performed at expected
steady state for INCB024360.
7. Section 6, Study Assessments (Tables 14 and Table 16); Section 7.4.9.5, Pregnancy
Testing
Description of change:  Urine pregnancy tests have been added to Day 1 of each
treatment cycle for women of childbearing potential.
Rationale for change:  The FDA has requested the Protocol be revised to include a urine
pregnancy test at the start of each cycle for women of childbearing potential.
Description of change:  Serum IgM assessments have been added for subjects with
Waldenström's macroglobulinemia
Rationale for change:  These laboratory assessments had been omitted from the
schedule of assessments.
8. Section 6, Study Assessments (Tables 12-15); Section 7.8, Tumor Biopsy Collection
and Analysis
Description of change:  Administrative clarifications have been made to the schedules of
assessments and laboratory assessments to be consistent with other sections of the
Protocol, including but not limited to:  adding bone marrow examination for subjects with
disease subtypes that utilize bone marrow histology as part of objective criteria for
disease staging and response as noted in Appendix H (Cheson criteria), 
 with optional tumor biopsy that is described in the Synopsis and
Section 7.8.
Rationale for change:  Inconsistencies or omissions between Protocol text and schedule
of assessment tables have been corrected.
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Protocol INCB 24360-204 Amendment 8 
Version 8 
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11. Incorporation of administrative changes.  Other minor, administrative changes have
been incorporated throughout the Protocol including updating the abbreviations table and
are noted in the attached red-line/strike-out version of the amendment.
CONFIDENTIAL 
Incyte Document Number IC-DEV-PROT-AMEND-0350.
Printed on: , ; Printed by: .