Conditions: Solid Tumor
Keywords: solid tumors colorectal cancer pancreatic ductal adenocarcinoma non-small cell lung cancer PD-1 PD-L1 epacadostat IDO inhibitor
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 70
Healthy volunteers: no

Brief summary:
This was an open-label, nonrandomized, Phase 1/2 study designed to determine the safety, tolerability, and efficacy of epacadostat when given in combination with pembrolizumab and 7 different chemotherapy regimens described as Treatment Groups A through G below (see Study Drug and Background Therapies, Dose, and Mode of Administration). Phase 1 consisted of a 3 + 3 + 3 design intended to determine the MTD or PAD of epacadostat when given in combination with pembrolizumab and chemotherapy; efficacy was also explored.

Phase 2 was designed to enroll efficacy expansion cohorts to further evaluate the safety, tolerability, and efficacy of epacadostat at the MTD or PAD (as selected in Phase 1) when given in combination with pembrolizumab and chemotherapy. Each efficacy expansion cohort was to enroll participants with 1 specific type of advanced or metastatic solid tumor. Additional cohorts (ie, the mandatory biopsy cohorts) were designed to evaluate changes in the tumor microenvironment in participants with any advanced or metastatic solid tumor who had progressed on previous therapy with a PD-1 or a PD-L1 inhibitor.

No participants were enrolled in any Phase 2 efficacy expansion cohort, or in any Phase 2 mandatory biopsy cohort receiving Treatment A, B, F, or G. Phase 2 mandatory biopsy cohort participants received Treatments C, D, or E (ie, were included in Treatment Groups C, D, or E). Participants were assigned to a treatment group based on the chemotherapy regimen most appropriate for their tumor type.

Detailed description:

Arms:
arm 1: Epacadostat + pembrolizumab + mFOLFOX6 (oxaliplatin, leucovorin, 5-fluorouracil) arm 2: Epacadostat + pembrolizumab + gemcitabine and nab-paclitaxel arm 3: Epacadostat + pembrolizumab + carboplatin and paclitaxel arm 4: Epacadostat + pembrolizumab + pemetrexed and investigators choice of platinum agent arm 5: Epacadostat + pembrolizumab + cyclophosphamide arm 6: Epacadostat + pembrolizumab + gemcitabine and investigators choice of platinum agent arm 7: Epacadostat + pembrolizumab + investigators choice of platinum agent and 5-fluorouracil

Interventions: intervention 1: Epacadostat intervention 2: Pembrolizumab intervention 3: Oxaliplatin intervention 4: Leucovorin intervention 5: 5-Fluorouracil intervention 6: Gemcitabine intervention 7: nab-Paclitaxel intervention 8: Carboplatin intervention 9: Paclitaxel intervention 10: Pemetrexed intervention 11: Cyclophosphamide intervention 12: Carboplatin intervention 13: Cisplatin intervention 14: 5-Fluorouracil intervention 15: Investigator's choice of platinum agent
Intervention descriptions: intervention 1: Epacadostat oral twice-daily continuous daily dosing at the protocol-defined dose. intervention 2: Pembrolizumab intervention 3: Oxaliplatin intervention 4: Leucovorin intervention 5: 5-Fluorouracil intervention 6: Gemcitabine intervention 7: nab-Paclitaxel intervention 8: Carboplatin intervention 9: Paclitaxel intervention 10: Pemetrexed intervention 11: Cyclophosphamide intervention 12: Carboplatin intervention 13: Cisplatin intervention 14: 5-FU intervention 15: Investigator's choice of platinum agent: carboplatin or cisplatin

Protocol document:
Prot_000.pdf: 
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Protocol INCB 24360-207 Am 7 
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Clinical Study Protocol 
INCB 24360-207 / NCT03085914
A Phase 1/2, Open-Label, Safety, Tolerability, and Efficacy Study of 
Epacadostat in Combination With Pembrolizumab and Chemotherapy in 
Subjects With Advanced or Metastatic Solid Tumors 
(ECHO-207/KEYNOTE-723)
Product: 
Epacadostat (INCB024360) 
IND Number: 
132,309 
EudraCT Number: 
2016-004678-16 
Phase of Study: 
1/2 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
Original Protocol (Version 0): 
16 NOV 2016 
Amendment (Version) 1: 
10 JAN 2017 
Amendment (Version) 2: 
28 MAR 2017 
Amendment (Version) 3: 
18 MAY 2017 
Amendment (Version) 4: 
31 JUL 2017 
Amendment (Version) 5: 
02 FEB 2018 
Amendment (Version) 6: 
31 AUG 2018 
Amendment (Version) 7: 
14 FEB 2019 
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 24360-207 Am 7 
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INVESTIGATOR'S AGREEMENT 
I have read the INCB 24360-207 Protocol Amendment 7 (Version 7 dated 14 FEB 2019) 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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SYNOPSIS 
Name of Investigational Product:  Epacadostat (INCB024360) 
Title of Study:  A Phase 1/2, Open-Label, Safety, Tolerability, and Efficacy Study of Epacadostat in 
Combination With Pembrolizumab and Chemotherapy in Subjects With Advanced or Metastatic Solid 
Tumors (ECHO-207/KEYNOTE-723) 
Protocol Number:  INCB 24360-207 
Study Phase:  1/2 
Indication:  Advanced or metastatic solid tumors (Phase 1); advanced or metastatic colorectal cancer 
(CRC), pancreatic ductal adenocarcinoma (PDAC), non–small cell lung cancer (NSCLC), urothelial 
carcinoma (UC), squamous cell carcinoma of the head and neck (SCCHN), or any advanced or metastatic 
solid tumor that progressed on previous therapy with a programmed cell death protein 1 (PD-1) or 
programmed cell death ligand 1 (PD-L1) inhibitor (Phase 2)  
Primary Objectives: 
• Phase 1:  To evaluate the safety, tolerability, and dose-limiting toxicities (DLTs) and to define a 
maximum tolerated dose (MTD) and/or pharmacologically active dose (PAD) of epacadostat in 
combination with pembrolizumab and chemotherapy in subjects with advanced or metastatic solid 
tumors. 
• Phase 2:  To evaluate the efficacy of epacadostat in combination with pembrolizumab and 
chemotherapy in subjects with advanced or metastatic CRC, PDAC, NSCLC, UC, SCCHN, or any 
advanced or metastatic solid tumor who progressed on previous therapy with a PD-1 or PD-L1 inhibitor 
by assessing objective response rate (ORR) per RECIST v1.1. 
Secondary Objectives: 
• Phase 1:  To explore the efficacy of epacadostat in combination with pembrolizumab and chemotherapy 
in subjects with advanced or metastatic solid tumors by assessing ORR per RECIST v1.1. 
• Phase 2:  To further evaluate the safety and tolerability of epacadostat at the MTD and/or PAD in 
combination with pembrolizumab and chemotherapy in subjects with selected advanced or metastatic 
solid tumors. 
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Primary Endpoints: 
• Phase 1:  Safety and tolerability will be assessed by monitoring frequency, duration, and severity of 
adverse events (AEs) through physical examinations, by evaluating changes in vital signs and 
electrocardiograms (ECGs), and through clinical laboratory blood and urine sample evaluations. 
• Phase 2:  ORR, defined as the percentage of subjects having a complete response (CR) or partial 
response (PR), will be determined by investigator assessment of radiographic disease per RECIST v1.1. 
Secondary Endpoints: 
• Phase 1:  ORR, defined as the percentage of subjects having a CR or PR, will be determined by 
investigator assessment of radiographic disease per RECIST v1.1. 
• Phase 2:  Safety and tolerability will be assessed by monitoring frequency, duration, and severity of 
AEs through physical examinations, by evaluating changes in vital signs and ECGs, and through 
clinical laboratory blood and urine sample evaluations. 
Overall Study Design: 
Note:  As of 25 OCT 2018, this study is closed to enrollment.  As of this date, no subjects were 
enrolled in Phase 2 efficacy expansion (all treatment groups) or Phase 2 mandatory biopsy 
Treatment Groups A, B, F, and G.  Any text included in this Protocol synopsis that references these 
treatment groups and cohorts has not been deleted but should be disregarded. 
This is an open-label, nonrandomized, Phase 1/2 study to determine the safety, tolerability, and efficacy 
of epacadostat when given in combination with pembrolizumab and 7 chemotherapy regimens.  Phase 1 
will consist of a 3 + 3 + 3 design and will determine the MTD or PAD of epacadostat when given in 
combination with pembrolizumab and chemotherapy; efficacy will also be explored.  Subjects with 
advanced or metastatic solid tumors who have progressed after receiving at least 1 previous standard 
therapy for advanced or metastatic disease (or who are intolerant to or refuse standard of care) and for 
whom treatment with 1 of the chemotherapy regimens is appropriate will be enrolled in Phase 1.  Phase 2 
will further evaluate the safety, tolerability, and efficacy of the MTD or PAD of epacadostat selected in 
Phase 1 when given in combination with pembrolizumab and chemotherapy.  Subjects with advanced or 
metastatic CRC, PDAC, NSCLC (squamous or nonsquamous), UC, or SCCHN who have not previously 
received chemotherapy as first-line therapy for advanced or metastatic disease and have not previously 
received immune checkpoint inhibitors nor an indoleamine 2,3-dioxygenase (IDO) inhibitor will be 
enrolled in Phase 2.  A separate cohort of subjects with any advanced or metastatic solid tumor who 
progressed on previous therapy with a PD-1 or PD-L1 inhibitor will also be enrolled in Phase 2. 
Phase 1: 
A 3 + 3 + 3 design will be used in which 7 treatment groups will be explored in parallel.  A minimum of 
3 evaluable subjects will be enrolled in each treatment group beginning with Cohort 1 (epacadostat 
100 mg twice daily [BID]; starting dose), and the first 3 evaluable subjects will be observed for a 
minimum of 28 days in the cohorts where mFOLFOX6 or nab-paclitaxel/gemcitabine are administered or 
21 days for all other chemotherapy regimens.  To be considered evaluable for dose tolerability, subjects 
should meet 1 of the following criteria:  1) received the cohort-specified dose of epacadostat, 
pembrolizumab, and chemotherapy for at least 80% of planned doses in the DLT observation period 
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(45 doses epacadostat/2 doses pembrolizumab for subjects who received mFOLFOX6 or 
nab-paclitaxel/gemcitabine; 34 doses epacadostat/1 dose pembrolizumab for subjects who received any 
other chemotherapy regimens) and completed the DLT observation period or 2) had a DLT during the 
DLT observation period.  It is recognized that certain toxicities due to chemotherapy (eg, including but 
not limited to gastrointestinal toxicity, including diarrhea; renal insufficiency; high-grade laboratory 
abnormalities; hypersensitivity/rash) may initially be clinically indistinguishable from toxicities due to 
immunotherapy.  Epacadostat will be held for these toxicities, and as a result, subjects may not receive at 
least 80% of the prescribed dose during Cycle 1.  In these cases, the Safety Monitoring Committee (SMC) 
may assess subjects who receive dose intensities somewhat below 80% for the determination of DLTs, 
and consider in the adjudication process the specific toxicities encountered, likely cause of toxicities, and 
dose intensity and tolerability beyond Cycle 1.  Additional subjects will be enrolled in a cohort to achieve 
the minimum of 3 evaluable subjects.  Subjects who discontinue for reasons other than a DLT (eg, events 
clearly associated with the underlying disease, disease progression, concomitant medication, comorbidity, 
or an AE clearly unrelated to treatment) during the DLT observation period will be considered 
nonevaluable for DLTs and will be replaced. 
The scenarios for expansion and de-escalation and the doses of epacadostat to be evaluated are 
summarized below: 
1. If 0 DLTs occur in 3 subjects in Cohort 1, 3 additional subjects will be treated in Cohort 1.  If there is 
≤ 1 DLT in these 6 subjects, enrollment in Phase 2 for that treatment group may proceed.  
2. If 1 of 3 subjects in Cohort 1 has a DLT, 3 additional subjects will be enrolled in Cohort 1.  If there 
are no additional DLTs (≤ 1 DLT in 6 subjects), enrollment in Phase 2 for that treatment group may 
proceed. 
3. If 2 of 6 subjects in Cohort 1 have a DLT, 3 additional subjects will be enrolled in Cohort 1.  If there 
are no additional DLTs (≤ 2 DLTs in 9 subjects), enrollment in Phase 2 for that treatment group may 
proceed. 
4. If ≥ 2 of 3, 3 of 6, or 3 of 9 subjects have DLTs within a cohort, de-escalation of epacadostat to 
50 mg BID (Cohort ‒1) will be evaluated using the same criteria. 
If Cohort ‒1 is not tolerated within a given treatment group, that treatment group will not be pursued 
further.  The study will be terminated if Cohort ‒1 is not tolerated in all treatment groups.  
Epacadostat Dose Cohort 
Epacadostat Dose 
–1 
50 mg BID 
1 (starting dose) 
100 mg BIDa 
a If epacadostat 100 mg BID is not tolerated within a treatment group, epacadostat 50 mg BID will be evaluated. 
Dose interruptions and/or modifications may be implemented based on toxicity.  Dose modifications 
should not be made during the DLT observation period without discussion with the medical monitor.  
Intrasubject dose escalation is not permitted. 
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Subjects will be assigned to a treatment group based on the chemotherapy regimen most appropriate for 
their tumor type as summarized below: 
Treatment 
Group A 
Epacadostat 
Pembrolizumab 
mFOLFOX6 
BID PO continuous daily 
dosing (see epacadostat dose 
cohort table) 
200 mg IV Q3W 
• Oxaliplatin 85 mg/m² IV on Day 1 and 
Day 15 
• Leucovorin 400 mg/m² IV on Day 1 and 
Day 15 
• 5-Fluorouracil 400 mg/m² IV bolus, then 
1200 mg/m² per day IV infusion over 
46 hours for a total dose of 2400 mg/m2, on 
Day 1 and Day 15 
Treatment 
Group B 
Epacadostat 
Pembrolizumab 
nab-Paclitaxel and Gemcitabine 
BID PO continuous daily 
dosing (see epacadostat dose 
cohort table) 
200 mg IV Q3W 
• nab-Paclitaxel 125 mg/m2 IV on Days 1, 8, 
and 15 
• Gemcitabine 1000 mg/m2 IV on Days 1, 8, 
and 15 
Treatment 
Group C 
Epacadostat 
Pembrolizumab 
Paclitaxel and Carboplatin 
BID PO continuous daily 
dosing (see epacadostat dose 
cohort table) 
200 mg IV Q3W 
• Paclitaxel 200 mg/m2 IV on Day 1 Q3W 
• Carboplatin AUC 6 IV on Day 1 Q3W 
Treatment 
Group D 
Epacadostat 
Pembrolizumab 
Pemetrexed and Platinum Agent 
BID PO continuous daily 
dosing (see epacadostat dose 
cohort table) 
200 mg IV Q3W 
• Pemetrexed 500 mg/m2 IV on Day 1 Q3W 
• Investigators choice of platinum agent: 
Carboplatin AUC 5 IV on Day 1 Q3W or 
Cisplatin 75 mg/m2 on Day 1 Q3W 
Treatment 
Group E 
Epacadostat 
Pembrolizumab 
Cyclophosphamide 
BID PO continuous daily 
dosing (see epacadostat dose 
cohort table) 
200 mg IV Q3W 
50 mg PO once daily 
Treatment 
Group F 
Epacadostat 
Pembrolizumab 
Gemcitabine and Platinum Agent 
BID PO continuous daily 
dosing (see epacadostat dose 
cohort table) 
200 mg IV Q3W 
• Gemcitabine 1000 mg/m2 IV on Day 1 and 
Day  8 Q3W 
• Investigators choice of platinum agent: 
Carboplatin AUC 5 IV on Day 1 Q3W or 
Cisplatin 70 mg/m2 on Day 1 Q3W 
Treatment 
Group G 
Epacadostat 
Pembrolizumab 
Platinum Agent and 5-Fluorouracil 
BID PO continuous daily 
dosing (see epacadostat dose 
cohort table) 
200 mg IV Q3W 
Investigator's choice of platinum agent: 
• Carboplatin AUC 5 IV on Day 1 Q3W or 
Cisplatin 100 mg/m2 IV 
• 5-Fluorouracil 1000 mg/m2 per day IV 
infusion on Days 1-4  (for a total dose of 
4000 mg/m2 over 96 hours) Q3W 
IV = intravenous; PO = orally; Q3W = every 3 weeks. 
Phase 2:  Efficacy Expansion and Mandatory Biopsy Cohorts 
Phase 2 efficacy expansion cohorts will evaluate the efficacy of the MTD or PAD of epacadostat 
determined in Phase 1 in combination with pembrolizumab and chemotherapy and further evaluate the 
safety and tolerability of the combination.  The efficacy expansion cohorts will be limited to the following 
advanced or metastatic tumor types:  
1. CRC (Treatment Group A:  epacadostat + pembrolizumab + mFOLFOX6):  Simon 2-Stage design 
2. PDAC (Treatment Group B:  epacadostat + pembrolizumab + nab-paclitaxel/gemcitabine):  Simon 
2-Stage design 
3. Squamous NSCLC (Treatment Group C:  epacadostat + pembrolizumab + paclitaxel/carboplatin) 
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4. Nonsquamous NSCLC (Treatment Group D:  epacadostat + pembrolizumab + pemetrexed/platinum 
agent) 
5. Any solid tumor that progressed on previous therapy with a PD-1 or PD-L1 inhibitor (Treatment Group 
E:  epacadostat + pembrolizumab + cyclophosphamide) 
6. UC (Treatment Group F:  epacadostat + pembrolizumab+ gemcitabine/platinum agent) 
7. SCCHN (Treatment Group G:  epacadostat + pembrolizumab+ platinum agent/5-fluorouracil) 
Enrollment in a specific efficacy expansion cohort in Phase 2 may begin after a minimum of 6 subjects 
have been treated with epacadostat 100 mg BID in the corresponding treatment group in Phase 1 and 
there is ≤ 1 DLT in these 6 subjects. 
Continuous evaluation of toxicity events will be performed in the efficacy expansion cohorts.  If the 
cumulative incidence of treatment-related serious AEs (SAEs) is > 40% and/or the cumulative incidence 
of ≥ Grade 3 immune-related AEs is > 40% after 10 subjects are enrolled in a specific Phase 2 efficacy 
expansion cohort, further enrollment in that cohort will be interrupted until the sponsor, investigators, and 
health authorities (if applicable) determine an appropriate course of action.  If an efficacy expansion 
cohort is discontinued due to toxicity, a new cohort may be initiated at a lower dose of epacadostat. 
In addition to the efficacy expansion cohorts listed above, separate mandatory biopsy cohorts will be 
enrolled to evaluate changes in the tumor microenvironment.  For the cohorts where IV chemotherapy is 
administered, subjects will receive IV chemotherapy only during Cycle 1 followed by epacadostat + 
pembrolizumab + IV chemotherapy starting with Cycle 2 Day 1.  For the CRC and PDAC cohorts, a 
minimum of 10 subjects with evaluable paired biopsy specimens will be enrolled.  A fresh tumor biopsy 
will be collected during screening.  On-treatment biopsies are mandatory and will be collected between 
Days 21 and 27 of Cycle 1 (IV chemotherapy only) and Cycle 2 (epacadostat + pembrolizumab + IV 
chemotherapy).  For subjects with squamous NSCLC, nonsquamous NSCLC, UC, or SCCHN, a 
minimum of 10 subjects with evaluable paired biopsy specimens will be enrolled.  A fresh tumor biopsy 
will be collected during screening.  On-treatment biopsies are mandatory and will be collected between 
Days 14 and 20 of Cycle 1 (IV chemotherapy only) and Days 7 and 13 of Cycle 3 (epacadostat + 
pembrolizumab + IV chemotherapy).  For subjects with any advanced or metastatic solid tumor that 
progressed on previous therapy with a PD-1 or PD-L1 inhibitor, a minimum of 5 subjects with evaluable 
paired biopsy specimens will be enrolled in the mandatory biopsy cohort; however, this cohort will be 
administered epacadostat, cyclophosphamide, and pembrolizumab starting on Cycle 1 Day 1.  A fresh 
tumor biopsy will be collected during screening, and an on-treatment biopsy is mandatory and will be 
collected between Days 7 and 13 of Cycle 3. 
If a subject is selected for inclusion in the mandatory biopsy cohort, and it is subsequently determined that 
tumor tissue cannot safely be obtained, or the biopsy does not meet the minimum standards for evaluation 
(as outlined in the Laboratory Manual), the subject may still enroll in the mandatory biopsy cohort and 
will be followed for efficacy and safety.  The subject may be replaced in order to enroll sufficient 
numbers of subjects with paired biopsies.  
Note:  As of 25 OCT 2018, on-treatment tumor biopsies are no longer required for subjects who are 
already enrolled in the mandatory biopsy cohorts. 
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Study Population: 
Phase 1:  Subjects with histologically or cytologically confirmed advanced or metastatic solid tumors 
who have failed previous standard therapy (or who refuse or are intolerant to standard-of-care therapy). 
Phase 2:  Subjects with histologically or cytologically confirmed advanced or metastatic CRC, PDAC, 
squamous NSCLC, nonsquamous NSCLC, UC, SCCHN who have not received first-line therapy for 
advanced or metastatic disease; subjects with any advanced or metastatic solid tumor with confirmed 
progression on previous therapy with a PD-1 or PD-L1 inhibitor. 
Key Inclusion Criteria:   
• Men or women aged 18 years or older. 
• Presence of measurable disease per RECIST v1.1.  Tumor lesions located in a previously irradiated 
area, or in an area subjected to other loco-regional therapy, are considered measureable if progression 
has been demonstrated in the lesion. 
• ECOG performance status of 0 or 1. 
• Willing to avoid pregnancy or fathering children from screening through 120 days after the last dose of 
epacadostat and pembrolizumab based on criteria defined in the body of the Protocol. 
Phase 1 subjects only: 
• Subjects with locally advanced or metastatic solid tumors who have disease progression after treatment 
with available therapies that are known to confer clinical benefit, or who are intolerant to treatment, or 
subjects who refuse standard treatment.  Locally advanced disease must not be amenable to resection 
with curative intent. 
Note:  Subjects should not have received more than 2 previous therapies for advanced or metastatic 
disease.  Subjects who received more than 2 previous therapies for advanced or metastatic disease must 
be discussed with medical monitor to confirm eligibility. 
• Subjects must not have received therapy with an IDO inhibitor. 
Phase 2 CRC subjects only: 
• Histologically or cytologically confirmed advanced or metastatic adenocarcinoma of the colon or 
rectum. 
• Subjects must not have received previous chemotherapy as first-line therapy for advanced or metastatic 
disease. 
Note:  Subjects who completed a chemotherapy regimen 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 therapy, the subject will not be eligible. 
• Subjects must not have received previous immune checkpoint inhibitors (eg, cytotoxic T-lymphocyte–
associated protein 4 [CTLA-4] inhibitor, PD-1 inhibitor, PD-L1 inhibitor, or any other antibody or drug 
specifically targeting T-cell costimulation), and/or an IDO inhibitor.  Subjects who received other 
immunotherapies must be discussed with medical monitor to confirm eligibility. 
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Phase 2 PDAC subjects only: 
• Histologically or cytologically confirmed advanced or metastatic PDAC. 
• Subjects must not have received previous chemotherapy as first-line therapy for advanced or metastatic 
disease. 
Note:  Subjects who completed a chemotherapy regimen 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 therapy, the subject will not be eligible. 
• Subjects must not have received previous immune checkpoint inhibitors (eg, CTLA-4 inhibitor, PD-1 
inhibitor, PD-L1 inhibitor, or any other antibody or drug specifically targeting T-cell costimulation), 
and/or an IDO inhibitor.  Subjects who received other immunotherapies must be discussed with medical 
monitor to confirm eligibility. 
Phase 2 squamous or nonsquamous NSCLC subjects only: 
• Histologically or cytologically confirmed Stage IIIB, Stage IV, or recurrent squamous or nonsquamous 
NSCLC. 
• Subjects without driver mutations (eg, BRAF or epidermal growth factor receptor [EGFR] mutations, 
anaplastic lymphoma kinase (ALK) fusion oncogene or ROS1 rearrangements) must not have received 
previous chemotherapy as first-line therapy for Stage IIIB, Stage IV, or recurrent NSCLC. 
Note:  Subjects who completed a chemotherapy regimen 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 therapy, the subject will not be eligible. 
• Subjects with driver mutations (eg, BRAF or EGFR mutations, ALK fusion oncogene or ROS1 
rearrangements) must have received prior treatment only with an approved kinase inhibitor with 
subsequent disease progression. 
• Subjects must not have received previous immune checkpoint inhibitors (eg, CTLA-4 inhibitor, PD-1 
inhibitor, PD-L1 inhibitor, or any other antibody or drug specifically targeting T-cell costimulation), 
and/or an IDO inhibitor.  Subjects who received other immunotherapies must be discussed with medical 
monitor to confirm eligibility. 
Phase 2 subjects in the cohort of subjects with any solid tumor that progressed on previous therapy with a 
PD-1 or PD-L1 inhibitor only: 
• Histologically or cytologically confirmed advanced or metastatic solid tumors that progressed (primary 
refractory or secondary relapsed) on previous monotherapy with a PD-1 or PD-L1 inhibitor or previous 
combination therapy that included a PD-1 or PD-L1 inhibitor in the advanced or metastatic setting. 
Note:  Primary refractory subjects must have received at least 2 doses of PD-1 or PD-L1 inhibitor and 
have disease progression at least 8 weeks from the first dose of the PD-1 or PD-L1 inhibitor that is 
confirmed at least 4 weeks (no less than 28 days) later (confirmatory imaging may be performed during 
the screening period with medical monitor approval).  The PD-1 or PD-L1 inhibitor does not need to be 
the last treatment received before signing informed consent.  Subjects who received only 1 dose of the 
PD-1 or PD-L1 inhibitor or discontinued for toxicity without disease progression within 8 weeks of the 
first dose of the PD-1 or PD-L1 inhibitor are not eligible. 
Note:  Secondary relapsed subjects must have had a PR or CR while on treatment with a PD-1 or 
PD-L1 inhibitor but later had disease progression that is confirmed at least 4 weeks (no less than 
28 days) later.  The PD-1 or PD-L1 inhibitor does not need to have been the last treatment received 
before signing informed consent.   
• Subjects must not have received previous therapy with an IDO inhibitor. 
• Subjects who received immunotherapies other than a PD-1 or PD-L1 inhibitor must be discussed with 
medical monitor to confirm eligibility. 
• Subjects may have received previous chemotherapy for advanced or metastatic disease. 
Note:  There is no limit to the number of previous chemotherapy regimens. 
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Phase 2 subjects in the mandatory biopsy cohort only: 
• Willing to undergo pretreatment and on-treatment core or excisional tumor biopsies. 
Note:  Fresh baseline tumor biopsies (defined as a biopsy specimen taken since completion of the most 
recent prior systemic regimen) are required for all Phase 2 mandatory biopsy subjects. 
Phase 2 efficacy expansion subjects only: 
• Willing to undergo pretreatment core or excisional tumor biopsies. 
Note:  Fresh baseline tumor biopsies (defined as a biopsy specimen taken since completion of the most 
recent prior systemic regimen) are preferred.  If a subject has inaccessible lesions, subject may be 
enrolled with medical monitor approval.  In this case submission of archived tumor tissue may be 
acceptable.  In all cases, biopsies will be confirmed to contain adequate tumor tissue by a local 
pathology review. 
Phase 2 UC subjects only:  
• Have histologically or cytologically confirmed advanced/unresectable (inoperable) or metastatic 
urothelial cancer of the renal pelvis, ureter, bladder, or urethra.  Both transitional cell and mixed 
transitional/non-transitional (predominantly transitional) cell histologies are allowed. 
• Subjects must not have received previous chemotherapy as first-line therapy for advanced or metastatic 
disease. 
Note:  Adjuvant platinum-based chemotherapy, following radical cystectomy, with recurrence 
> 12 months from completion of therapy is permitted.  Neoadjuvant platinum-based chemotherapy, 
with recurrence > 12 months since completion of therapy is permitted. 
• Subjects must not have received previous immune checkpoint inhibitors (eg, CTLA-4 inhibitor, PD-1 
inhibitor, PD-L1 inhibitor, or any other antibody or drug specifically targeting T-cell costimulation), 
and/or an IDO inhibitor.  Subjects who received other immunotherapies must be discussed with medical 
monitor to confirm eligibility. 
Phase 2 SCCHN subjects only:  
• Histologically or cytologically-confirmed recurrent or metastatic SCCHN of the oral cavity, 
oropharynx, hypopharynx, and larynx that is considered incurable by local therapies. 
Note:  Subjects with primary tumors of the nasopharynx, salivary gland, unknown primary origin, or 
nonsquamous histologies are not eligible.  
• Documentation of results from testing of human papilloma virus (HPV) status for oropharyngeal cancer 
using p16 IHC testing. 
Note:  Subjects with primary tumor site of the oral cavity, hypopharynx, and larynx are not required to 
undergo HPV testing by p16 IHC as these tumor locations are assumed to be HPV negative.  
• Subjects must not have received previous chemotherapy as first-line therapy for recurrent or metastatic 
disease. 
Note:  Systemic therapy completed > 6 months before signing consent if given as part of multimodal 
treatment for locally advanced disease is allowed. 
• Subjects must not have received previous immune checkpoint inhibitors (eg, CTLA-4 inhibitor, PD-1 
inhibitor, PD-L1 inhibitor, or any other antibody or drug specifically targeting T-cell costimulation), 
and/or an IDO inhibitor.  Subjects who received other immunotherapies must be discussed with medical 
monitor to confirm eligibility. 
Key Exclusion Criteria:   
• Laboratory and medical history parameters not within the Protocol-defined range.  If the screening 
laboratory tests below were conducted > 7 days before treatment initiation, they will need to be 
repeated on Cycle 1 Day 1 before initiation of treatment. 
- Absolute neutrophil count < 1.5 × 109/L. 
- Platelet count < 100 × 109/L. 
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- Hemoglobin < 9 g/dL or < 5.6 mmol/L. 
- Serum creatinine > 1.5 × institutional upper limit of normal (ULN), OR measured or calculated 
creatinine clearance (glomerular filtration rate can also be used in place of creatinine or creatinine 
clearance) < 50 mL/min for subjects with creatinine levels > 1.5 × institutional ULN. 
- Aspartate aminotransferase, alanine aminotransferase (ALT), and alkaline phosphatase ≥ 2.5 × ULN. 
Note:  Subjects with 1) bone metastases and 2) no hepatic parenchymal metastases on screening 
radiographic examinations may enroll if the alkaline phosphatase is ≤ 5 × ULN.  Subjects with 
1) bone metastases and 2) hepatic parenchymal metastases on screening radiographic examinations 
may enroll if the alkaline phosphatase is ≤ 5 × ULN only with medical monitor approval. 
- Total bilirubin ≥ 1.2 × ULN. 
Note:  If total bilirubin is ≥ 1.2 × ULN, conjugated (direct) bilirubin must be tested, and subjects will 
be excluded if the value is ≥ 2.0 × ULN or ≥ 40% of total bilirubin, if there is no institutional ULN. 
- International normalized ratio (INR), prothrombin time, and activated partial thromboplastin time 
(aPTT) > 1.5 × ULN (unless the subject is receiving anticoagulant therapy, in which case the subject 
may be included as long as the INR, prothrombin time, and aPTT are within therapeutic range of 
intended use of anticoagulants). 
Note:  Partial thromboplastin time may be used in place of aPTT per institutional standards. 
• Receipt of anticancer medications or investigational drugs within the following intervals before Cycle 1 
Day 1: 
- ≤ 14 days for chemotherapy or targeted small molecule therapy. 
Note:  Bisphosphonates are permitted concomitant medications. 
- ≤ 28 days for previous monoclonal antibody used for anticancer therapy. 
Note:  Use of denosumab is permitted. 
- ≤ 7 days for immune-suppressive–based treatment for any reason. 
Note:  Use of inhaled or topical steroids, prophylactic corticosteroids for radiographic procedures, or 
systemic corticosteroid at doses of prednisone ≤10 mg/day or equivalent is permitted. 
- ≤ 28 days or 5 half-lives (whichever is longer) before Cycle 1 Day 1 for all other investigational 
agents or devices.  For investigational agents with long half-lives (eg, > 5 days), enrollment before 
the fifth half-life requires medical monitor approval. 
• Previous radiotherapy within 14 days of Cycle 1 Day 1 (except for radiation to the central nervous 
system [CNS], which requires a ≥ 28-day washout as described below).  Subjects must also not require 
chronic use of corticosteroids and must not have had radiation pneumonitis as a result of treatment.  A 
1-week washout is permitted for palliative radiation to non–CNS disease with sponsor approval. 
• Known active CNS metastases and/or carcinomatous meningitis. 
Note:  Participants with previously-treated brain metastases may participate provided they are 
1) radiologically stable (ie, without evidence of progression for at least 28 days by repeat imaging prior 
to the first dose of study treatment [repeat imaging may be performed during the screening period with 
medical monitor approval]), and 2) without requirement of steroid treatment for at least 14 days prior to 
first dose of study treatment, and 3) clinically stable, with any neurological signs or symptoms having 
returned to baseline. This exception does not include carcinomatous meningitis, which is excluded 
regardless of clinical stability. 
Note:  Subjects with evidence of cerebral edema or those with < 28 days since radiation therapy to the 
CNS will be excluded from study. 
• Has not recovered to ≤ Grade 1 from toxic effects of previous therapy and/or complications from 
previous surgical intervention before starting study therapy. 
Note:  Subjects with stable chronic AEs (≤ Grade 2) not expected to resolve (eg, alopecia) are 
exceptions and may enroll. 
Note:  Subjects with a history of peripheral neuropathy ≥ Grade 2 will be excluded. 
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• Receipt of a live vaccine within 30 days of planned start of study therapy. 
Note:  Examples of live vaccines include, but are not limited to, the following:  measles, mumps, 
rubella, chicken pox/zoster, yellow fever, rabies, Bacillus Calmette-Guérin, and typhoid vaccine.  
Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, 
intranasal influenza vaccines are live attenuated vaccines and are not allowed. 
• Active infection requiring systemic therapy. 
• Subjects who have any active or inactive autoimmune disease or syndrome (ie, rheumatoid arthritis, 
moderate or severe psoriasis, multiple sclerosis, inflammatory bowel disease) that has required systemic 
treatment in the past 2 years or who are receiving systemic therapy for an autoimmune or inflammatory 
disease (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). 
Note:  Exceptions include subjects with vitiligo or resolved childhood asthma/atopy, hypothyroidism 
stable on hormone replacement, controlled asthma, Type I diabetes, Graves' disease, or Hashimoto's 
disease, or with medical monitor approval. 
• History of (noninfectious) pneumonitis that required steroids or current pneumonitis or interstitial lung 
disease. 
• History of 1) allogeneic stem cell or solid organ transplant that requires use of immunosuppressive 
therapy, 2) has a diagnosis of immunodeficiency, or 3) is receiving chronic systemic steroid therapy (in 
doses exceeding 10 mg daily of prednisone or its equivalent) or any other form of immunosuppressive 
therapy within 7 days before Cycle 1 Day 1. 
Note:  The use of physiologic doses of corticosteroids may be approved after consultation with the 
sponsor. 
• Known history of or screening test is positive for hepatitis B virus (HBV; eg, HBsAg reactive or HBV 
DNA detected) or hepatitis C virus (HCV; HCV antibody positive and/or HCV RNA qualitative is 
detected). 
Note:  Hepatitis C antibody–positive subjects who received and completed treatment for hepatitis C that 
was intended to eradicate the virus may participate if hepatitis C RNA levels are undetectable. 
Note:  For Phase 2, treated hepatitis B subjects are eligible if there is no evidence of active infection 
(HBV DNA–negative and HBV DNA surface antigen–negative). 
• Known history of human immunodeficiency virus (HIV; HIV 1/2 antibodies). 
• History or presence of an ECG that, in the investigator's opinion, is clinically meaningful.  Screening 
QTc interval > 480 milliseconds is excluded (corrected by Fridericia method).  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. 
Note:  QTc prolongation due to pacemaker may enroll if the JTc is normal or with medical monitor 
approval. 
• Clinically significant cardiac disease, including unstable angina, acute myocardial infarction within 
6 months of Cycle 1 Day 1, New York Heart Association Class III or IV congestive heart failure, and 
arrhythmia requiring therapy. 
Note:  A subject with an arrhythmia may enroll if the subject is on antiarrhythmic medication and is in 
sinus rhythm on the screening ECG. 
• Subjects with a history of bleeding related to cancer under study requiring a medical intervention 
(eg, embolization procedure, RBC transfusion, or hospitalization) within 30 days of study enrollment. 
• Known allergy or severe hypersensitivity (≥ Grade 3) reaction to any component of epacadostat, 
pembrolizumab, or chemotherapy regimen components and/or their formulation excipients. 
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• Presence of a gastrointestinal condition (eg, inflammatory bowel disease, Crohn's disease, ulcerative 
colitis) that may affect drug absorption.   
Note:  Subjects with feeding tubes are eligible. 
• Receiving monoamine oxidase inhibitors (MAOIs) or drug that has significant MAOI activity 
(eg, meperidine, linezolid, methylene blue) within the 21 days before screening. 
• Women who are pregnant or breastfeeding.  
Phase 1 and 2 subjects in Treatment Group A and Treatment Group G only: 
• Known dihydropyrimidine dehydrogenase deficiency (heterozygous or homozygous mutations). 
Phase 2 subjects in the cohort of subjects with any solid tumor that progressed on previous therapy with a 
PD-1 or PD-L1 inhibitor only: 
• History of any grade immune-related ocular AEs. 
• History of a ≥ Grade 3 immune-related AE from previous immunotherapies. 
Note:  Subjects with immune-related adrenal insufficiency because of previous immunotherapy who are 
medically stable and adequately managed on a stable dose of replacement therapy may be enrolled. 
• Current urinary outflow obstruction. 
Epacadostat, Dosage, and Mode of Administration: 
In Phase 1, the dose of epacadostat will be dependent upon cohort assignment.  In Phase 2, the dose of 
epacadostat will be dependent upon the MTD or PAD determined in Phase 1.  Intrasubject dose-escalation 
is not permitted. 
Epacadostat will be self-administered orally BID in 28- or 21-day cycles depending on the chemotherapy 
administered and will continue through the end of the cycle in which the 35th infusion of pembrolizumab 
is administered if, in the investigator's judgment, the subject is receiving benefit from therapy and has not 
met any criteria for treatment discontinuation.  For Phase 1 and Phase 2 efficacy expansion subjects 
enrolled in Treatment Groups A, B, C, D, E, F, and G, and for Phase 2 mandatory biopsy subjects 
enrolled in Treatment Group E, epacadostat will be administered beginning on Cycle 1 Day 1 and 
continuously thereafter.  For Phase 2 subjects enrolled in the mandatory biopsy cohorts where IV 
chemotherapy is administered (Treatment Groups A, B, C, D, F, and G), epacadostat will be administered 
beginning on Cycle 2 Day 1 and continuously thereafter.  All BID doses will be taken in the morning and 
evening, approximately 12 hours apart without regard to food.  If a dose is missed by more than 4 hours, 
then that dose should be skipped, and the next dose should be taken at the next scheduled timepoint. 
Background Therapy, Dosage, and Mode of Administration: 
Subjects will receive pembrolizumab and the assigned chemotherapy regimen as noted below.  
Intrasubject dose escalation of pembrolizumab or chemotherapy is not allowed. 
Pembrolizumab will be administered as a 200 mg IV infusion over 30 minutes (-5 min/+10 min) every 
3 weeks for a total of 35 infusions if, in the investigator's judgment, the subject is receiving benefit from 
therapy and has not met any criteria for treatment  discontinuation.  For Phase 1 and Phase 2 efficacy 
expansion subjects enrolled in Treatment Groups A, B, C, D, E, F, and G, and for Phase 2 mandatory 
biopsy subjects enrolled in Treatment Group E, pembrolizumab will be administered starting on Cycle 1 
Day 1.  For Phase 2 subjects enrolled in the mandatory biopsy cohorts where IV chemotherapy is 
administered (Treatment Groups A, B, C, D, F, and G), pembrolizumab will be administered starting on 
Cycle 2 Day 1. 
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Oxaliplatin, leucovorin, and 5-fluorouracil (mFOLFOX6) will be administered on Days 1 and 15 of 
each 28-day cycle.  Subjects will receive oxaliplatin 85 mg/m² IV given concurrently with leucovorin 
400 mg/m² IV over 2 hours (± 15 min; or equivalent dose and schedule based on institutional practice), 
followed by 5-fluorouracil 400 mg/m² IV bolus (administration time per institutional practice), then a 
5-fluorouracil 1200 mg/m² per day IV infusion over 46 hours (for a total dose of 2400 mg/m²).  There is 
no limit to the number of cycles of mFOLFOX6.  Investigators may reduce or discontinue oxaliplatin for 
peripheral neuropathy; if discontinued, investigators have the option to discontinue 5-fluorouracil and 
leucovorin.  Subjects may receive prophylactic granulocyte colony stimulating factor (G-CSF) support 
with filgrastim per institutional guidelines.  Prophylactic G-CSF should not be given in the first cycle 
unless discussed with the medical monitor. 
nab-Paclitaxel and Gemcitabine will be administered on Days 1, 8, and 15 of each 28-day cycle.  
nab-Paclitaxel will be administered at 125 mg/m² IV over 30 minutes (± 5 min).  Gemcitabine will be 
administered at 1000 mg/m² IV over 30 minutes (± 5 min).  There is no limit to the number of cycles of 
nab-paclitaxel/gemcitabine.  Subjects may receive prophylactic G-CSF support with filgrastim per 
institutional guidelines.  Prophylactic G-CSF should not be given in the first cycle unless discussed with 
the medical monitor. 
Paclitaxel and Carboplatin will be administered on Day 1 of each 21-day cycle for a minimum of 
4 cycles and a maximum of 6 cycles.  Paclitaxel will be administered at 200 mg/m² IV over 3 hours 
(± 15 min).  Carboplatin will be administered at AUC 6 IV over 30 minutes (± 5 min).  Subjects must 
receive premedications (IV or PO) with corticosteroids, H1- and H2-antagonists, and antiemetics based 
on institutional guidelines, investigator practice, or local prescribing information or standards of care.  
Subjects may receive prophylactic G-CSF support with filgrastim per institutional guidelines.  
Prophylactic G-CSF should not be given in the first cycle unless discussed with the medical monitor.  
Pemetrexed and platinum agent will be administered on Day 1 of each 21-day cycle for a minimum of 
4 cycles and a maximum of 6 cycles.  Pemetrexed will be administered at 500 mg/m² IV over 10 minutes 
(± 5 min).  Pemetrexed may continue as maintenance therapy after the 6 cycles.  Investigators will have a 
choice of platinum agent:  carboplatin, which will be administered at AUC 5 IV over 30 minutes 
(± 5 min), or cisplatin, which will be administered at 75 mg/m2 over 2 hours (± 5 min).  Subjects must 
receive premedications (IV or PO) with corticosteroids, antiemetics, and vitamin B12 and folic acid 
supplementation based on institutional guidelines, investigator practice, or local prescribing information 
or standards of care.  Subjects receiving cisplatin must also receive hydration as per institutional 
guidelines.  Subjects may receive prophylactic G-CSF support with filgrastim per institutional guidelines.  
Prophylactic G-CSF should not be given in the first cycle unless discussed with the medical monitor. 
Cyclophosphamide will be self-administered 50 mg PO once daily beginning on Cycle 1 Day 1 and 
continuously thereafter in 21-day cycles.  There is no limit to the number of cycles of cyclophosphamide.  
Subjects may receive prophylactic G-CSF support with filgrastim per institutional guidelines.  
Prophylactic G-CSF should not be given in the first cycle unless discussed with the medical monitor.  
Gemcitabine and platinum agent will be administered in a 21-day cycle for a maximum of 6 cycles.  
Gemcitabine will be administered at 1000 mg/m² IV over 30 minutes (± 5 min) on Days 1 and 8.  
Investigators will have a choice of platinum agent to follow the gemcitabine infusion on 
Day 1:  carboplatin, which will be administered at AUC 5 IV over 30 minutes (± 5 min), or cisplatin, 
which will be administered at 70 mg/m2 over 2 hours (± 5 min).  Subjects must receive premedications 
(IV or PO) with corticosteroids and antiemetics based on institutional guidelines, investigator practice, or 
local prescribing information or standards of care.  Subjects receiving cisplatin must also receive 
hydration as per institutional guidelines.  Subjects may receive prophylactic G-CSF support with 
filgrastim per institutional guidelines.  Prophylactic G-CSF should not be given in the first cycle unless 
discussed with the medical monitor. 
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Platinum agent and 5-fluorouracil will be administered in a 21-day cycle for a maximum of 6 cycles.  
Investigators will have a choice of platinum agent:  carboplatin, which will be administered at AUC 5 IV 
over 30 minutes (± 5 min), or cisplatin, which will be administered at 100 mg/m2 over 60 minutes 
(± 5 min) on Day 1.  The platinum agent will be followed by 5-fluorouracil 1000 mg/m2 per day IV 
infusion over Days 1 through 4 (for a total dose of 4000 mg/m2 over 96 hours).  Subjects must receive 
premedications (IV or PO) with corticosteroids and antiemetics based on institutional guidelines, 
investigator practice, or local prescribing information or standards of care.  Subjects receiving cisplatin 
must also receive hydration as per institutional guidelines.  Subjects may receive prophylactic G-CSF 
support with filgrastim per institutional guidelines.  Prophylactic G-CSF should not be given in the first 
cycle unless discussed with the medical monitor. 
Study Schedule/Procedures: 
The study comprises the following parts: 
• Screening:  Up to 28 days before enrollment.  Screening will begin at the time that the subject signs the 
informed consent and will continue until the date the subject is enrolled in the study received the first 
dose of treatment in the study (Cycle 1 Day 1). 
• Treatment:  Begins on the day that the subject receives the first dose of treatment in the study on 
Cycle 1 Day 1 and may continue in 28-day cycles (mFOLFOX6 or nab-paclitaxel/gemcitabine) or 
21-day cycles (all other chemotherapy regimens); additional site visits will occur during each cycle.  
Subjects will have regularly scheduled study visits on Day 1 (± 3 days) of each cycle.  Additional study 
visits may be required during some cycles for safety, efficacy, 
 assessments as 
described below. 
• End of treatment:  Occurs when the subject permanently discontinues epacadostat and pembrolizumab 
(+ 7 days). 
• Safety follow-up:  30 days (± 7 days) and 90 days (± 7 days) after the EOT visit. 
Note:  As of Amendment 7, disease status (if applicable) and survival follow-up visits are no longer 
required.  The last study visit will be the 90-day safety follow-up visit. 
Safety Assessments 
NOTE:  As of Amendment 7, the only safety data that will be collected will be related to SAEs and 
AEs leading to discontinuation of treatment.  All safety procedures should be per standard of care 
for pembrolizumab and will not be collected in the database.  Therefore, only safety labs required 
for pembrolizumab should be conducted at each cycle.  No other assessments outside of standard of 
care are required. 
Regular telephone conferences with study investigators will be scheduled by the sponsor in order to 
review cohort-specific data and overall safety data, agree on dose de-escalation, adjudicate individual 
high-grade AEs as potentially dose-limiting, and guide other major study decisions during Phase 1 and 
until the last subject has been treated for 3 months. 
Efficacy Assessments 
NOTE:  As of Amendment 7, no further efficacy assessment will be required beyond Week 18.  
Imaging for the study will only be required at Week 9 and Week 18 per RECIST v1.1.  Imaging should 
continue per standard of care for pembrolizumab after Week 18.  If the subject has radiographic 
progression, they may have the option to continue treatment until confirmation of progression at least 
4 weeks later (but no later than 6 weeks) where feasible, provided that the subject meets the definition of 
clinical stability defined as follows: 
• Absence of clinically significant signs and symptoms (including worsening of laboratory values) 
indicating disease progression. 
• No decline in ECOG performance status. 
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• Absence of rapid progression of disease. 
• Absence of progressive tumors at critical anatomical sites (eg, spinal cord compression) requiring 
urgent alternative medical intervention. 
Estimated Duration of Participation: 
Up to 28 days for screening, continuous treatment in consecutive 28-day (mFOLFOX6 and 
nab-paclitaxel/gemcitabine) or 21-day cycles (all other chemotherapy regimens) as long as subjects are 
receiving benefit and do not met any criteria for discontinuation of epacadostat and pembrolizumab, and 
30 and 90 days for safety follow-up.  Study participation, including post-treatment follow-up, is expected 
to average 16 months for an individual subject. 
Estimated Number of Subjects:  Up to 421 subjects may be enrolled in the study. 
Phase 1 – Approximately 42 to 126 evaluable subjects 
Phase 2 (Efficacy Expansion + Mandatory Biopsy) – Approximately 237 to 295 evaluable subjects. 
As of 25 OCT 2018, this study is closed to enrollment. 
A total of 70 subjects have been enrolled.  No subjects were enrolled in Phase 2 efficacy expansion 
(all treatment groups) or Phase 2 mandatory biopsy Treatment Groups A, B, F, and G. 
Estimated Number of Study Sites:  Approximately 25 sites 
Principal Coordinating Investigator:  
, MD, 
 
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Statistical Methods: 
As of 25 OCT 2018, no subjects were enrolled in Phase 2 efficacy expansion (all treatment groups) 
or Phase 2 mandatory biopsy Treatment Groups A, B, F, and G.  Any text included in this Protocol 
synopsis that references these treatment groups and cohorts has not been deleted but should be 
disregarded. 
This is an open-label, nonrandomized, 7-parallel treatment group, Phase 1/2 study.  Phase 1 consists of a 
3 + 3 + 3 design for each of the 7 treatment groups.  A minimum of 6 and up to 9 subjects will be enrolled 
in each dose level.  The total number of subjects for Phase 1 will depend on the frequency of DLTs and 
the number of dose levels tested before the MTD or PAD is reached.  
Phase 2 consists of expansion cohorts (efficacy and mandatory biopsy) in specific tumor types (advanced 
or metastatic CRC, PDAC, squamous or nonsquamous NSCLC, UC, SCCHN, or any advanced or 
metastatic solid tumor that progressed on previous therapy with a PD-1 or PD-L1 inhibitor).  A Simon 
2-stage design will be used for the CRC and PDAC efficacy expansion cohorts.  A single-stage design 
will be used for all other efficacy expansion cohorts.  The response rates for the historical control (p0), 
desired response rates for the combination (p1), number of subjects needed in Stage 1 (n1) and Stage 2 
(n2), total number of subjects (n), first-stage threshold declaring cohort undesirable (r1), and the 
upper-limit of the number of responses in n subjects such that futility of the drug is concluded (r) are 
provided for each expansion cohort in the table below. 
Values for the CRC, PDAC, squamous NSCLC, and nonsquamous NSCLC, UC, and SCCHN efficacy 
expansion cohorts are calculated based on a 1-sided Type I error of 0.1 and power of 80%; values for the 
cohort enrolling solid tumors that progressed on prior PD-1/PD-L1 therapy are based on a 1-sided Type I 
error of 0.1 and power of approximately 98%. 
Tumor Type 
p0 
p1 
n1 
n2 
n 
r1 
r 
CRC 
40% 
60% 
12 
26 
38 
5 
18 
PDAC 
25% 
45% 
15 
12 
27 
4 
9 
Squamous NSCLC 
30% 
50% 
- 
- 
33 
- 
13 
Nonsquamous NSCLC 
50% 
70% 
- 
- 
33 
- 
20 
Solid tumors that progressed on previous 
therapy with a PD-1 or PD-L1 inhibitor 
5% 
25% 
- 
- 
33 
- 
3 
UC 
60% 
80% 
- 
- 
33 
- 
23 
SCCHN 
50% 
70% 
- 
- 
33 
- 
20 
In addition to the efficacy expansion cohorts listed above, separate mandatory biopsy cohorts will be 
enrolled to evaluate changes in the tumor microenvironment.  Assuming the true rate of subjects positive 
for the biomarker is 50%, the probability of observing ≥ 4 subjects out of 10 with the biomarker is 83% 
for CRC, PDAC, squamous NSCLC, nonsquamous NSCLC, UC, and SCCHN cohorts, and the 
probability of observing ≥ 2 subjects out of 5 with the biomarker is 81% for previous PD-1 or PD-L1 
inhibitor therapy cohort. 
All statistical analyses are exploratory in nature.  Descriptive statistics will be derived where appropriate.  
Continuous endpoints will be summarized with number of subjects, mean, standard deviation, minimum, 
median, and maximum for each cohort.  Categorical endpoints will be summarized with frequency and 
percentage for each cohort.  If data warrants, ORR will be estimated with 95% exact confidence interval. 
Safety Monitoring Committee: 
Due to the complexity of the study, an SMC will review safety data at regular intervals throughout the 
study.  Details regarding membership, roles, and responsibilities of the committee are specified in the 
SMC charter. 
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TABLE OF CONTENTS 
SYNOPSIS ......................................................................................................................................3 
LIST OF ABBREVIATIONS ........................................................................................................27 
1. 
INTRODUCTION ......................................................................................................30 
1.1. 
Role of the Immune System in Cancer .......................................................................30 
1.1.1. 
Inhibition of Indoleamine 2,3-Dioxygenase 1 as a Target for Cancer .......................30 
1.2. 
Overview of Epacadostat ............................................................................................31 
1.3. 
Overview of Pembrolizumab ......................................................................................33 
1.4. 
Overview of 5-Fluorouracil, Leucovorin, and Oxaliplatin in Colorectal 
Cancer .........................................................................................................................34 
1.5. 
Overview of nab-Paclitaxel/Gemcitabine in Pancreatic Cancer ................................35 
1.6. 
Overview of Platinum-Based Doublet Chemotherapy in Non–Small Cell 
Lung Cancer ................................................................................................................35 
1.7. 
Overview of Low-Dose Cyclophosphamide ..............................................................36 
1.8. 
Overview of Gemcitabine/Platinum Agent in Urothelial Carcinoma .........................36 
1.9. 
Overview of Platinum Agent/5-Fluorouracil in Squamous Cell Carcinoma of 
the Head and Neck ......................................................................................................37 
1.10. 
Study Rationale ...........................................................................................................37 
1.10.1. 
Justification for Treatment Regimen ..........................................................................38 
1.10.2. 
Rationale for Efficacy Endpoints................................................................................40 
1.11. 
Potential Risks of the Treatment Regimen .................................................................41 
 
41 
1.11.2. 
Risks From Pembrolizumab .......................................................................................41 
1.11.3. 
Risks From mFOLFOX6 ............................................................................................42 
1.11.4. 
Risks From nab-Paclitaxel/Gemcitabine ....................................................................42 
1.11.5. 
Risks From Paclitaxel/Carboplatin .............................................................................42 
1.11.6. 
Risks From Pemetrexed/Platinum Agent....................................................................43 
1.11.7. 
Risks From Cyclophosphamide ..................................................................................43 
1.11.8. 
Risks From Gemcitabine/Platinum Agent ..................................................................43 
1.11.9. 
Risks From Platinum Agent/5-Fluorouracil ...............................................................44 
1.11.10. 
Risks From Combining an IDO Inhibitor With Chemotherapy .................................44 
1.11.11. 
Risks From Combining a PD-1 Inhibitor With Chemotherapy ..................................44 
1.11.12. 
Risks From Combining Epacadostat and Pembrolizumab .........................................45 
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2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................46 
2.1. 
Study Objectives .........................................................................................................46 
2.1.1. 
Primary Objectives .....................................................................................................46 
2.1.2. 
Secondary Objectives .................................................................................................46 
 
46 
2.2. 
Study Endpoints ..........................................................................................................47 
2.2.1. 
Primary Endpoints ......................................................................................................47 
2.2.2. 
Secondary Endpoints ..................................................................................................47 
 
47 
3. 
SUBJECT ELIGIBILITY ...........................................................................................48 
3.1. 
Subject Inclusion Criteria ...........................................................................................48 
3.2. 
Subject Exclusion Criteria ..........................................................................................53 
4. 
INVESTIGATIONAL PLAN .....................................................................................57 
4.1. 
Overall Study Design ..................................................................................................57 
4.1.1. 
Phase 1 ........................................................................................................................57 
4.1.2. 
Phase 2:  Efficacy Expansion and Mandatory Biopsy Cohorts ..................................60 
4.2. 
Measures Taken to Avoid Bias ...................................................................................63 
4.3. 
Number of Subjects ....................................................................................................63 
4.3.1. 
Planned Number of Subjects ......................................................................................63 
4.3.2. 
Replacement of Subjects .............................................................................................63 
4.4. 
Duration of Treatment and Subject Participation .......................................................63 
4.5. 
Overall Study Duration ...............................................................................................64 
4.6. 
Study Termination ......................................................................................................64 
5. 
TREATMENT ............................................................................................................65 
5.1. 
Treatment Assignment ................................................................................................65 
5.1.1. 
Subject Numbering and Treatment Assignment .........................................................65 
5.1.2. 
Randomization and Blinding ......................................................................................65 
5.2. 
Study Drug ..................................................................................................................65 
5.2.1. 
Epacadostat .................................................................................................................65 
5.2.1.1. 
Description and Administration ..................................................................................65 
5.2.1.2. 
Supply, Packaging, and Labeling ...............................................................................66 
5.2.1.3. 
Storage ........................................................................................................................66 
5.3. 
Background Therapies ................................................................................................66 
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5.3.1. 
Pembrolizumab ...........................................................................................................66 
5.3.1.1. 
Description and Administration ..................................................................................66 
5.3.1.2. 
Supply, Packaging, and Labeling ...............................................................................67 
5.3.1.3. 
Storage ........................................................................................................................67 
5.3.2. 
Oxaliplatin, Leucovorin, 5-Fluorouracil .....................................................................67 
5.3.2.1. 
Description and Administration ..................................................................................67 
5.3.2.2. 
Supply, Packaging, and Labeling ...............................................................................68 
5.3.3. 
nab-Paclitaxel and Gemcitabine .................................................................................68 
5.3.3.1. 
Description and Administration ..................................................................................68 
5.3.3.2. 
Supply, Packaging, and Labeling ...............................................................................69 
5.3.4. 
Paclitaxel and Carboplatin ..........................................................................................69 
5.3.4.1. 
Description and Administration ..................................................................................69 
5.3.4.2. 
Supply, Packaging, and Labeling ...............................................................................70 
5.3.5. 
Pemetrexed and Platinum Agent ................................................................................70 
5.3.5.1. 
Description and Administration ..................................................................................70 
5.3.5.2. 
Supply, Packaging, and Labeling ...............................................................................71 
5.3.6. 
Cyclophosphamide .....................................................................................................71 
5.3.6.1. 
Description and Administration ..................................................................................71 
5.3.6.2. 
Supply, Packaging, and Labeling ...............................................................................71 
5.3.7. 
Gemcitabine and Platinum Agent ...............................................................................72 
5.3.7.1. 
Description and Administration ..................................................................................72 
5.3.7.2. 
Supply, Packaging, and Labeling ...............................................................................72 
5.3.8. 
Platinum Agent and 5-Fluorouracil ............................................................................73 
5.3.8.1. 
Description and Administration ..................................................................................73 
5.3.8.2. 
Supply, Packaging, and Labeling ...............................................................................73 
5.4. 
Treatment Compliance ................................................................................................74 
5.5. 
Treatment Interruptions and Adjustments ..................................................................74 
5.5.1. 
Dose Modifications .....................................................................................................74 
5.5.1.1. 
Dose-Limiting Toxicity and Determination of Maximum Tolerated Dose ................74 
5.5.1.2. 
Procedures for Cohort Review and Dose De-Escalation ............................................76 
5.5.2. 
Criteria and Procedures for Dose Reductions or Interruptions of Epacadostat 
and/or Pembrolizumab ................................................................................................76 
5.5.3. 
Management of Immune-Related Adverse Events .....................................................77 
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5.5.4. 
Management of Chemotherapy-Related Adverse Events ...........................................77 
5.5.5. 
Treatment After Initial Radiologic Evidence of Disease Progression ........................78 
5.5.6. 
Procedure for Subjects Exhibiting Serotonin Syndrome ............................................79 
5.6. 
Discontinuation of Subjects From Study Treatment ..................................................81 
5.6.1. 
Discontinuation Criteria ..............................................................................................81 
5.6.2. 
Discontinuation Procedures ........................................................................................82 
5.7. 
Procedures for Withdrawal From Study .....................................................................82 
5.8. 
Concomitant Medications ...........................................................................................82 
5.8.1. 
Permitted (Acceptable) Medications ..........................................................................83 
5.9. 
Restricted Medications ...............................................................................................83 
5.10. 
Prohibited Medications/Treatment .............................................................................83 
5.10.1. 
Supportive Care Guidelines ........................................................................................84 
6. 
STUDY ASSESSMENTS ..........................................................................................85 
6.1. 
Screening ..................................................................................................................108 
6.2. 
Treatment ..................................................................................................................109 
6.3. 
End of Treatment ......................................................................................................109 
6.4. 
Follow-Up .................................................................................................................109 
6.4.1. 
Safety Follow-Up ......................................................................................................109 
6.4.2. 
Disease Status Follow-Up .........................................................................................110 
6.4.3. 
Survival Follow-Up ..................................................................................................110 
6.5. 
End of Study .............................................................................................................110 
6.6. 
Unscheduled Visits ...................................................................................................110 
7. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES .........................111 
7.1. 
Administration of Informed Consent Form ..............................................................111 
7.2. 
Interactive Response Technology Procedure ............................................................111 
7.3. 
Demography and Medical History ............................................................................111 
7.3.1. 
Demographics and General Medical History ...........................................................111 
7.3.2. 
Disease Characteristics and Treatment History ........................................................111 
7.4. 
Prior and Concomitant Medications and Procedures ................................................112 
7.5. 
Safety Assessments ...................................................................................................112 
7.5.1. 
Adverse Events .........................................................................................................112 
7.5.2. 
Physical Examinations ..............................................................................................112 
7.5.2.1. 
Comprehensive Physical Examination .....................................................................112 
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7.5.2.2. 
Targeted Physical Examination ................................................................................113 
7.5.3. 
Vital Signs ................................................................................................................113 
7.5.4. 
Electrocardiograms ...................................................................................................113 
7.5.5. 
Laboratory Assessments ...........................................................................................113 
7.5.5.1. 
Serum Chemistry ......................................................................................................113 
7.5.5.2. 
Hematology ...............................................................................................................114 
7.5.5.3. 
Liver Chemistry ........................................................................................................114 
7.5.5.4. 
Coagulation Panel .....................................................................................................114 
7.5.5.5. 
Endocrine Function ...................................................................................................114 
7.5.5.6. 
Urinalysis ..................................................................................................................114 
7.5.5.7. 
Pregnancy Testing ....................................................................................................114 
7.5.5.8. 
Serology ....................................................................................................................114 
 
115 
7.6. 
Efficacy Assessments ...............................................................................................115 
7.6.1. 
Initial Tumor Imaging ...............................................................................................115 
7.6.2. 
Tumor Imaging During the Study.............................................................................115 
7.6.2.1. 
Assessment of Progressive Disease According to Immune-Related RECIST 
Criteria ......................................................................................................................116 
7.7. 
Performance and Quality-of-Life Assessments ........................................................117 
7.7.1. 
Eastern Cooperative Oncology Group Performance Status ......................................117 
 
118 
 
118 
 
 
118 
 
118 
 
119 
 
121 
 
121 
7.9. 
Translational Assessments ........................................................................................122 
7.9.1. 
Correlative Assessments and Specimen Requirements ............................................122 
7.9.2. 
Whole Blood for Correlative Assessment ................................................................122 
7.9.3. 
Plasma for Correlative Assessment ..........................................................................122 
7.9.4. 
Tumor Biopsy ...........................................................................................................122 
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7.9.4.1. 
Tumor Biopsy in the Phase 2 Mandatory Biopsy Subjects ......................................123 
7.9.4.2. 
Tumor Biopsy in the Phase 2 Efficacy Expansion Subjects .....................................124 
 
124 
7.10. 
Other Study Procedures ............................................................................................125 
7.10.1. 
Distribution of Subject Reminder Cards and Subject Diaries ..................................125 
7.10.2. 
Post-Treatment Anticancer Therapy Status ..............................................................125 
7.10.3. 
Data Collection for Survival Follow-Up ..................................................................125 
8. 
SAFETY MONITORING AND REPORTING .......................................................126 
8.1. 
Adverse Events .........................................................................................................126 
8.1.1. 
Definitions ................................................................................................................126 
8.1.2. 
Reporting ..................................................................................................................126 
8.2. 
Laboratory Test Abnormalities .................................................................................128 
8.2.1. 
Potential Drug-Induced Liver Injury (Hy's Law) .....................................................128 
8.3. 
Serious Adverse Events ............................................................................................129 
8.3.1. 
Definitions ................................................................................................................129 
8.3.2. 
Reporting ..................................................................................................................129 
8.4. 
Emergency Unblinding of Treatment Assignment ...................................................130 
8.5. 
Pregnancy .................................................................................................................131 
8.6. 
Events of Clinical Interest ........................................................................................131 
8.7. 
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor ...............................................................................................................132 
8.8. 
Warnings and Precautions ........................................................................................132 
8.9. 
Safety Monitoring Committee ..................................................................................132 
8.10. 
Product Complaints ..................................................................................................133 
9. 
STATISTICS ............................................................................................................134 
9.1. 
Study Populations .....................................................................................................134 
9.2. 
Selection of Sample Size ..........................................................................................134 
9.2.1. 
Sample Size in Phase 1 .............................................................................................134 
9.2.2. 
Sample Size in Phase 2 .............................................................................................134 
9.2.2.1. 
Efficacy Expansion ...................................................................................................134 
9.2.2.2. 
Phase 2 Mandatory Biopsy Cohorts .........................................................................135 
9.3. 
Level of Significance ................................................................................................135 
9.4. 
Statistical Analyses ...................................................................................................136 
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9.4.1. 
Primary Analyses ......................................................................................................136 
9.4.2. 
Secondary Analyses ..................................................................................................136 
 
136 
9.4.4. 
Safety Analyses ........................................................................................................136 
9.4.4.1. 
Adverse Events .........................................................................................................136 
9.4.4.2. 
Clinical Laboratory Tests .........................................................................................137 
9.4.4.3. 
Vital Signs ................................................................................................................137 
9.4.4.4. 
Electrocardiograms ...................................................................................................137 
9.4.4.5. 
Events of Clinical Interest ........................................................................................138 
 
138 
 
138 
9.5. 
Analyses for the Safety Monitoring Committee .......................................................138 
9.6. 
Interim Analysis ........................................................................................................138 
10. 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES ........................................................................................................140 
10.1. 
Investigator Responsibilities .....................................................................................140 
10.2. 
Accountability, Handling, and Disposal of Study Drug ...........................................141 
10.3. 
Data Management .....................................................................................................142 
10.4. 
Data Privacy and Confidentiality of Study Records .................................................142 
10.5. 
Financial Disclosure .................................................................................................143 
10.6. 
Publication Policy .....................................................................................................143 
11. 
REFERENCES .........................................................................................................144 
APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS .............................................................................152 
153 
APPENDIX C. EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS .....................................................................................154 
APPENDIX D. PROHIBITED MONOAMINE OXIDASE INHIBITORS AND 
DRUGS ASSOCIATED WITH SIGNIFICANT MONOAMINE OXIDASE 
INHIBITORY ACTIVITY .......................................................................................155 
APPENDIX E. COMMON TERMINOLOGY CRITERIA FOR ADVERSE 
EVENTS V4.0 ..........................................................................................................156 
APPENDIX F. RESPONSE EVALUATION CRITERIA IN SOLID TUMORS V1.1 ...........157 
APPENDIX G. DOSE MODIFICATIONS FOR EPACADOSTAT AND 
PEMBROLIZUMAB ................................................................................................158 
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APPENDIX H. DOSE MODIFICATIONS FOR MFOLFOX6 ...............................................167 
APPENDIX I. DOSE MODIFICATIONS FOR GEMCITABINE/NAB-PACLITAXEL ........170 
APPENDIX J. DOSE MODIFICATIONS FOR PACLITAXEL/CARBOPLATIN ................173 
APPENDIX K. DOSE MODIFICATIONS FOR PEMETREXED/PLATINUM 
AGENT .....................................................................................................................176 
APPENDIX L. DOSE MODIFICATIONS FOR CYCLOPHOSPHAMIDE ...........................178 
APPENDIX M. DOSE MODIFICATIONS FOR GEMCITABINE/PLATINUM 
AGENT .....................................................................................................................180 
APPENDIX N. DOSE MODIFICATIONS FOR PLATINUM 
AGENT/5-FLUOROURACIL .................................................................................183 
APPENDIX O. PROTOCOL AMENDMENT SUMMARY OF CHANGES .........................186 
 
LIST OF TABLES 
Table 1: 
Epacadostat Dose Cohorts ..........................................................................................58 
Table 2: 
Treatment Groups .......................................................................................................59 
Table 3: 
Definition of Dose-Limiting Toxicity ........................................................................75 
Table 4: 
Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease ........................................................................................................................79 
Table 5: 
Sign and Symptoms of Serotonin Syndrome ..............................................................80 
Table 6: 
Schedule of Assessments for ALL Ongoing Subjects After Amendment 7 
Approval .....................................................................................................................86 
Table 7: 
Schedule of Assessments for Phase 1 or Phase 2 Efficacy Expansion 
Subjects in Treatment Group A or Treatment Group B .............................................87 
Table 8: 
Laboratory Assessments for Phase 1 or Phase 2 Efficacy Expansion Subjects 
in Treatment Group A or Treatment Group B ............................................................89 
Table 9: 
Schedule of Assessments for Phase 2 Mandatory Biopsy Subjects in 
Treatment Group A or Treatment Group B ................................................................91 
Table 10: Laboratory Assessments for Phase 2 Mandatory Biopsy Subjects in 
Treatment Group A or Treatment Group B ................................................................95 
Table 11: Schedule of Assessments for Phase 1 or Phase 2 Efficacy Expansion 
Subjects in Treatment Group C, Treatment Group D, Treatment Group F, 
and Treatment Group G ..............................................................................................97 
Table 12: Schedule of Assessments for Phase 1, Phase 2 Efficacy Expansion, or 
Phase 2 Mandatory Biopsy Subjects in Treatment Group E ......................................99 
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Table 13: Laboratory Assessments for Phase 1 or Phase 2 Efficacy Expansion Subjects 
in Treatment Group C, Treatment Group D, Treatment Group E, Treatment 
Group F, and Treatment Group G .............................................................................101 
Table 14: Schedule of Assessments for Phase 2 Mandatory Biopsy Subjects in 
Treatment Group C, Treatment Group D, Treatment Group F, and Treatment 
Group G ....................................................................................................................103 
Table 15: Laboratory Assessments for Phase 2 Mandatory Biopsy Subjects in 
Treatment Group C, Treatment Group D, Treatment Group E, Treatment 
Group F, and Treatment Group G .............................................................................106 
Table 16: Clinical Laboratory Analytes ....................................................................................108 
Table 17: Sample Collection Time Windows for Pharmacokinetic Assessments for 
Epacadostat ...............................................................................................................118 
Table 18: Schedule of Dose Administrations and Pharmacokinetic Samples on Cycle 1 
Day 1 and Cycle 2 Day 1 for Phase 2 Efficacy Expansion Subjects in 
Treatment Group C ...................................................................................................119 
Table 19: Schedule of Dose Administrations and Pharmacokinetic Samples on Cycle 1 
Day 1 and Cycle 2 Day 1 for Phase 2 Efficacy Expansion Subjects in 
Treatment Group D Treated With Carboplatin .........................................................120 
Table 20: Schedule of Dose Administrations and Pharmacokinetic Samples on Cycle 1 
Day 1 and Cycle 2 Day 1 for Treatment Group D Phase 2 Efficacy 
Expansion Subjects in Treatment Group D Treated With Cisplatin .........................121 
Table 21: Sample Size and Decision Rule for Simon 2-Stage Design Phase 2 Efficacy 
Expansion Cohorts ....................................................................................................135 
Table 22: Sample Size and Decision Rule for Single-Stage Design Phase 2 Efficacy 
Expansion Cohorts ....................................................................................................135 
Table 23: Criteria for Clinically Notable Vital Sign Abnormalities .........................................137 
Table 24: Criteria for Clinically Notable Electrocardiogram Abnormalities ...........................138 
Table 25: Probabilities of Early Termination for Simon 2-Stage Design .................................139 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................62 
 
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LIST OF ABBREVIATIONS 
The following abbreviations and special terms are used in this clinical study Protocol. 
Abbreviation 
Definition 
AE 
adverse event 
ALK 
anaplastic lymphoma kinase 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
 
 
BCG 
Bacillus Calmette-Guérin 
BID 
twice daily 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
 
 
 
 
CNS 
central nervous system 
CR 
complete response 
CRC 
colorectal cancer 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T-lymphocyte–associated protein 4 
DC 
dendritic cells 
DCR 
disease control rate 
DLT 
dose-limiting toxicities 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
ECG 
electrocardiogram 
ECI 
event of clinical interest 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EGFR 
epidermal growth factor receptor 
eIB 
epacadostat Investigator's Brochure 
EOS 
end of study 
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Abbreviation 
Definition 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin embedded 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
human immunodeficiency virus 
HPV 
human papilloma virus 
HR 
hazard ratio 
ICD 
immunogenic cell death 
ICF 
informed consent form  
ICH 
International Council on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IDO 
indoleamine 2,3-dioxygenase 
IDO1 
indoleamine 2,3-dioxygenase 1 
IEC 
independent ethics committee 
IN 
Investigator Notification 
INR 
international normalized ratio 
irAE 
immune-related adverse event 
IRB 
institutional review board 
irRC 
immune-related response criteria 
irRECIST 
immune-related Response Evaluation Criteria in Solid Tumors 
IV 
intravenous 
IRT 
interactive response technology  
LFT 
liver chemistry test 
mAb 
monoclonal antibody 
MAOI 
monoamine oxidase inhibitors 
M-CAVI 
methotrexate, carboplatin, vinblastine 
MedDRA 
Medical Dictionary for Regulatory Activities 
mFOLFOX6 
5-fluorouracil, leucovorin, and oxaliplatin 
MRI 
magnetic resonance imaging 
MSI 
microsatellite-instability 
MTD 
maximum tolerated dose 
MVAC 
methotrexate, vinblastine, doxorubicin, and cisplatin 
NSCLC 
non–small cell lung cancer 
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Abbreviation 
Definition 
ORR 
objective response rate 
OS 
overall survival 
PAD 
pharmacologically active dose 
PD 
progressive disease 
PD-1 
programmed cell death protein 1 
PDAC 
pancreatic ductal adenocarcinoma 
PD-L1 
programmed cell death ligand 1 
PFS 
progression-free survival 
PI 
prescribing information 
pIB 
pembrolizumab Investigator's Brochure 
PK 
pharmacokinetic 
PO 
orally 
PR 
partial response 
PT-DC 
platinum-based doublet chemotherapy 
Q3W 
every 3 weeks 
RBC 
red blood cell 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SCCHN 
squamous cell carcinoma of the head and neck 
SD 
stable disease 
SMC 
Safety Monitoring Committee 
SmPC 
summary of product characteristics 
SNRI 
serotonin/norepinephrine reuptake inhibitor 
SS 
serotonin syndrome 
SSRI 
selective serotonin reuptake inhibitor 
T1DM 
Type 1 diabetes mellitus 
TKI 
tyrosine kinase inhibitor 
TNBC 
triple-negative breast cancer 
Treg 
regulatory T cells 
UC 
urothelial carcinoma 
ULN 
upper limit of normal  
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1. 
INTRODUCTION 
1.1. 
Role of the Immune System in Cancer 
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 coinhibitory receptors such as cytotoxic T-lymphocyte–associated protein 4 
(CTLA-4) by ipilimumab, programmed cell death protein 1 (PD-1) by pembrolizumab or 
nivolumab, and programmed cell death ligand 1 (PD-L1) by atezolizumab, avelumab, or 
durvalumab provide a critical mechanism for redirecting the host immune response against the 
tumor (Chen and Mellman 2013).  Although these agents have antitumor activity when 
administered as monotherapy, 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). 
1.1.1. 
Inhibition of Indoleamine 2,3-Dioxygenase 1 as a Target for Cancer 
Recent interest has focused on the role of indoleamine 2,3-dioxygenase 1 (IDO1) as a 
mechanism of induction of tolerance to malignancy (Godin-Ethier et al 2011).  IDO1 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.  IDO1 is the first 
rate-limiting enzyme in one of the catabolic pathways of tryptophan. 
The expression and activity profiles of IDO1 are distinct from those of tryptophan dioxygenase, 
an enzyme predominantly expressed in 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 dendritic cells (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) such as dendritic cell maturation and T-cell 
growth arrest and cell death (Mellor and Munn 1999).  IDO1 activity also promotes the 
differentiation of naive T cells to cells with a regulatory phenotype (Treg; Fallarino et al 2006).  
Because 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 Treg may provide an additional mechanism whereby IDO1 
could promote an immunosuppressive environment. 
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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 
compounds, taxane derivatives, 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 melanoma, ovarian, colorectal, and pancreatic cancers 
(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 malignancies in combination with 
chemotherapeutics and/or immunotherapy-based strategies. 
1.2. 
Overview of Epacadostat 
Epacadostat is a novel, potent, and selective inhibitor of the IDO1 enzyme in both human tumor 
cells and human DCs.  A Phase 1 monotherapy study in subjects with advanced solid tumors is 
complete and showed epacadostat monotherapy was generally well-tolerated at doses of up to 
700 mg twice daily (BID).  The most common adverse events (AEs) were Grade 1 or 2 fatigue 
and gastrointestinal disturbances.  No responses were observed; however, 7 out of 52 subjects 
had stable disease (SD) for at least 16 weeks (Beatty et al 2017).  With the recent emergence of 
immune-targeted agents (eg, PD-1, PD-L1, and CTLA-4 inhibitors), being investigated in several 
solid tumors and hematologic malignancies the combination of epacadostat with these agents 
was explored and several Phase 1 and Phase 2 studies are ongoing. 
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In a Phase 1 open-label, dose-escalation study (INCB 24360-201), epacadostat in combination 
with ipilimumab (3 mg/kg intravenous [IV]), was evaluated in 21-day cycles.  The initial 
evaluation of epacadostat 300 mg BID in combination with ipilimumab was terminated due to 
the occurrence of clinically significant alanine aminotransferase (ALT)/aspartate 
aminotransferase (AST) elevations in 5 of 7 subjects treated at this dose level.  These AEs were 
reversible in all subjects upon discontinuation of study therapy and administration of 
corticosteroids.  Enrollment was restarted at lower doses, and 40 subjects were enrolled:  25 mg 
BID (n = 8), 50 mg BID continuous (n = 16), 50 mg BID intermittent dosing (2 weeks on and 
1 week off; n = 9), and 75 mg total daily dose (50 mg q AM and 25 mg q PM; n = 7).  The most 
common all grade immune-related AEs (irAEs) were rash (50%), pruritus (35%), diarrhea 
(28%), increased ALT/AST (23%), and hypothyroidism (10%).  Immune-related AEs ≥ Grade 3 
occurred in 23% of subjects.  The most common ≥ Grade 3 irAEs were increased AST/ALT 
(10%) and colitis (5%).  Among 30 immunotherapy-naive subjects, objective response rate 
(ORR) was 30% (9/30) per immune-related response criteria (irRC) and 27% (8/30) per 
RECIST.  The disease control rate (DCR; complete response (CR) + partial response [PR] + SD) 
was 60% per irRC and 57% per RECIST.  Median progression-free survival (PFS) was 
8.3 months by irRC and 6.7 months by RECIST.  Among 10 points previously treated with 
immunotherapy, the DCR by both criteria was 30% (all SDs; Gibney et al 2015). 
A Phase 1/2 study is currently evaluating epacadostat in combination with pembrolizumab 
(INCB 24360-202).  Epacadostat 25 mg BID, 50 mg BID, and 100 mg BID with pembrolizumab 
2 mg/kg IV every 3 weeks and epacadostat 300 mg BID with pembrolizumab 200 mg IV every 
3 weeks was evaluated in Phase 1 dose-escalation; epacadostat 50 mg BID, 100 mg BID, and 
300 mg BID with pembrolizumab 200 mg IV every 3 weeks was evaluated in Phase 1 
dose-expansion.  The most common (≥ 15%) all-grade treatment-related AEs were fatigue, rash, 
arthralgia, pruritus, diarrhea, and nausea.  Grade ≥ 3 treatment-related AEs were observed in 
19% (most common:  rash [8%] and increased lipase [3%]).  There were no treatment-related 
deaths.  Among 19 subjects who were treatment-naive for advanced melanoma (M1c 53%), 
5 CRs, 6 PRs, and 3 SDs were observed.  All responses are confirmed and ongoing (median 
follow-up in responders [minimum, maximum]: 56+ [46, 90+ weeks]).  Median PFS has not 
been reached; the PFS rate was 74% at 6 months and 57% at 12 months.  Responses were also 
observed in subjects previously treated for advanced melanoma (n = 3; 1 CR, 1 SD) and subjects 
with non–small cell lung cancer (NSCLC; n = 12; 5 PRs, 2 SDs), renal cell carcinoma (RCC; 
n = 11; 2 PRs, 5 SDs), endometrial adenocarcinoma (n = 7; 1 CR, 1 PR), urothelial carcinoma 
(UC; n = 5; 3 PRs), triple-negative breast cancer (TNBC; n = 3; 2 SDs), and squamous cell 
carcinoma of the head and neck (SCCHN; n = 2; 1 PR, 1 SD).  Based on the overall safety and 
efficacy profile, epacadostat 100 mg BID was selected as the recommended dose for Phase 2 
(Gangadhar et al 2016), and efficacy and safety of the combination is being investigated in 
tumor-specific cohorts of diffuse large B-cell lymphoma, melanoma, NSCLC, UC, TNBC, 
SCCHN, ovarian cancer, RCC, and microsatellite-instability (MSI) high colorectal cancer 
(CRC), gastric cancer, and hepatocellular carcinoma.  Recently presented data from Phase 1 and 
Phase 2 subjects showed ORRs and DCRs, respectively, of 35% and 63% in 40 NSCLC subjects 
(Gangadhar et al 2017); 33% and 50% in 30 RCC subjects (Lara et al 2017); 35% and 53% in 
40 UC subjects (Smith et al 2017); and 34% and 61% in 38 SCCHN subjects 
(Hamid et al 2017a). 
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A randomized, double-blind, Phase 3 study (INCB 24360-301) of pembrolizumab in 
combination with epacadostat or placebo in treatment-naive subjects with unresectable or 
metastatic melanoma was initiated based on results observed in the Phase 1 study.  The dual 
primary endpoints of the study are PFS per RECIST v1.1 and OS.  During an interim analysis, 
the external Data Monitoring Committee concluded that the study did not meet the primary 
endpoint of improving PFS in the combination compared to pembrolizumab monotherapy.  
Additionally, the external Data Monitoring Committee further determined that the OS endpoint 
was not expected to reach statistical significance.  Of note, there were no new safety concerns.  
This study remains open so that subjects who are still on treatment will have continued access to 
open-label pembrolizumab monotherapy.  
While the results from Study INCB 24360-301 are specific to melanoma and cannot be 
extrapolated to other tumor types, the sponsor, in collaboration with Merck, halted further 
enrollment in Phase 3 studies investigating epacadostat in combination with pembrolizumab in 
subjects with SCCHN, UC, and RCC.  The remaining Phase 3 studies investigating epacadostat 
in combination with pembrolizumab in subjects with NSCLC were amended to become 
randomized Phase 2 studies. 
For a thorough overview of the pharmacology of epacadostat and ongoing clinical studies, refer 
to the epacadostat Investigator's Brochure (eIB). 
1.3. 
Overview of Pembrolizumab 
Pembrolizumab is a potent humanized immunoglobulin G4 monoclonal antibody (mAb) with 
high specificity of binding to the PD-1 receptor, thus inhibiting its interaction with PD-L1 and 
programmed cell death ligand 2 (PD-L2).  Based on preclinical in vitro data, pembrolizumab has 
high affinity and potent receptor blocking activity for PD-1.  Pembrolizumab has an acceptable 
preclinical safety profile and is in clinical development as an IV immunotherapy for advanced 
malignancies.  Pembrolizumab is indicated for the treatment of patients across a number of 
indications.  For more details on specific indications, refer to the pembrolizumab Investigator's 
Brochure (pIB). 
Activity of pembrolizumab monotherapy over platinum-based doublet chemotherapy (PT-DC) in 
subjects with previously untreated advanced NSCLC subjects who were PD-L1+ (≥ 50% 
expression on tumor cells) was demonstrated in a Phase 3 study (Reck et al 2016).  Median PFS 
was 10.3 months with pembrolizumab and 6.0 months with chemotherapy (hazard ratio 
[HR] = 0.50, 95% confidence interval [CI], 0.37 to 0.68; p < 0.001).  Overall survival was 
significantly longer with pembrolizumab versus chemotherapy (HR = 0.60, 95% CI, 0.41 to 
0.89; p = 0.005).  Objective response rate was greater in subjects treated with pembrolizumab 
versus investigator's choice chemotherapy (45% vs 28%).   
Activity of pembrolizumab monotherapy over chemotherapy in subjects with advanced UC that 
progressed during or after the receipt of platinum-based chemotherapy was investigated in the 
Phase 3 KEYNOTE-045 study (Bellmunt et al 2017).  A statistically significant advantage in OS 
of pembrolizumab over chemotherapy was demonstrated (HR 0.73, 95% CI, 0.59 to 0.91; 
p = 0.0022).  The median OS was 10.3 months with pembrolizumab and 7.4 months with 
chemotherapy.  Notably, PFS for the 2 groups was similar (HR 0.98, 95% CI, 0.81 to 1.19) 
despite an ORR for pembrolizumab of 21.1% versus 11.4% for chemotherapy.  The median time 
to response was 2.1 months with both pembrolizumab and chemotherapy.  The median duration 
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response was not reached with pembrolizumab (range, 1.6+ to 15.6+ months) and was 
4.3 months (range, 1.4+ to 15.4+) with chemotherapy.  Interim analysis of the Phase 2 
KEYNOTE-052 study demonstrated the activity of pembrolizumab monotherapy in 
cisplatin-ineligible subjects with unresectable or metastatic UC (Balar et al 2016).  ORR was 
24% (CR 6%) in all subjects, and favorable response rates were observed in subjects with high 
PD-L1 expression,  defined as combined positive score of ≥ 10% (ORR 37%; CR 13%). 
Activity of pembrolizumab monotherapy in subjects with recurrent or metastatic 
non-nasopharyngeal SCCHN was demonstrated in 2 cohorts of the Phase 1/2 KEYNOTE-012 
study (Seiwert et al 2016, Chow et al 2016) and in the Phase 2 KEYNOTE-055 study 
(Bauml et al 2017).  In the expansion cohort of KEYNOTE-012, 132 subjects with recurrent 
and/or metastatic SCCHN regardless of PD-L1 expression received pembrolizumab 200 mg 
every 3 weeks.  ORR was 18% by central review (Chow et al 2016).  Median duration of 
response (DOR) was not reached (range:  ≥ 2 months to ≥ 11 months) as of the data cutoff.  
Median PFS was 2 months, and the 6-month rates for PFS were 23%.  Median OS was 8 months, 
and the 6-month OS rate was 59%.  Responses were observed regardless of PD-L1 expression 
and association with human papilloma virus (HPV) status (Chow et al 2016).  
In the KEYNOTE-055 study, 171 subjects with recurrent or metastatic SCCHN who were 
resistant to platinum agent and cetuximab received pembrolizumab 200 mg every 3 weeks.  
Objective response rate was 16% by central review with a median DOR of 8 months 
(range, 2+ to 12+ months).  Median PFS was 2.1 months, and median OS was 8 months.  
Responses were observed regardless of PD-L1 expression and HPV status (Bauml et al 2017). 
1.4. 
Overview of 5-Fluorouracil, Leucovorin, and Oxaliplatin in 
Colorectal Cancer 
The mFOLFOX6 regimen is composed of 5-fluorouracil, leucovorin, and oxaliplatin.  
5-Fluorouracil is a nucleoside metabolic inhibitor that interferes with the synthesis of DNA, and 
to a lesser extent RNA, leading to cell death in rapidly growing cells.  When used in combination 
with leucovorin, the effect of FdUMP, an active metabolite of 5-fluorouracil, on inhibiting 
thymidylate synthase is enhanced.  Oxaliplatin is a platinum agent that binds to DNA to form 
crosslinks that inhibit DNA replication and transcription.  Of the 3 commercially available 
platinum agents, oxaliplatin is the preferred agent for the treatment of subjects with colorectal 
tumors. 
In addition to mFOLFOX6, other common first-line oxaliplatin-based approaches in subjects 
with advanced CRC include CapeOX (capecitabine and oxaliplatin) or FOLFOXIRI with or 
without targeted agents (NCCN 2017a, Van Cutsem et al 2016).  Historical data show that ORRs 
ranging from 35% to 55% with oxaliplatin-based regimens were observed in the first line-setting 
in subjects with metastatic CRC (Tournigand et al 2004, Saltz et al 2008, Bokemeyer et al 2009, 
Van Cutsem et al 2009, Douillard et al 2010). 
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1.5. 
Overview of nab-Paclitaxel/Gemcitabine in Pancreatic Cancer 
Gemcitabine is a nucleoside metabolic inhibitor that kills cells undergoing DNA synthesis and 
blocks the progression of cells through the G1/S-phase boundary.  nab-Paclitaxel is an 
albumin-bound formulation of paclitaxel, an antimicrotubule agent that promotes the assembly of 
microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization.  
This stability results in the inhibition of the normal dynamic reorganization of the microtubule 
network that is essential for vital interphase and mitotic cellular functions.  
Activity for gemcitabine in combination with nab-paclitaxel in subjects with advanced 
pancreatic cancer was demonstrated in a Phase 1/2 study (Von Hoff et al 2011) and in a Phase 3 
study (Von Hoff et al 2013).  In the Phase 1/2 study, among the 44 subjects treated at the 
maximum tolerated dose (MTD; gemcitabine 1000 mg/m2 followed by nab-paclitaxel 125 mg/m2 
on Days 1, 8, and 15 of every 28-day cycle), the response rate was 48%, and median survival 
was 12.2 months.  At this dose, Grade 3 or 4 toxicities included fatigue in 27%, neuropathy in 
20%, and neutropenia in 49%.  In the Phase 3 study, subjects treated with this combination 
showed a 31% reduction in the risk of progression or death with a median PFS of 5.5 versus 
3.7 months and an ORR of 23% compared with 7% with gemcitabine alone.  The most common 
Grade 3 or greater treatment-related AEs were neutropenia (38% vs 27%), fatigue (17% vs 7%), 
and neuropathy (17% vs 1%) in the combination treatment group versus the gemcitabine-only 
treatment group.  There was no difference in serious life-threatening toxicity (4% in each 
treatment group).  Based on results from this Phase 3 study, combination of nab-paclitaxel and 
gemcitabine is now accepted standard of care as first-line treatment for subjects with 
advanced/metastatic pancreatic cancer. 
1.6. 
Overview of Platinum-Based Doublet Chemotherapy in Non–Small 
Cell Lung Cancer 
Cisplatin and carboplatin binds to DNA to form crosslinks that inhibit DNA replication and 
transcription and are the more commonly used commercially available platinum agents for the 
treatment of subjects with non-colorectal tumors.  Paclitaxel is an antimicrotubule agent that 
promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by 
preventing depolymerization, resulting in the inhibition of the normal dynamic reorganization of 
the microtubule network that is essential for vital interphase and mitotic cellular functions.  
Pemetrexed is a folate analog metabolic inhibitor that disrupts folate-dependent metabolic 
processes essential for cell replication.  In combination with a platinum agent, paclitaxel and 
pemetrexed represent standard-of-care first-line therapy for NSCLC subjects (without sensitizing 
epidermal growth factor receptor [EGFR] mutations or anaplastic lymphoma kinase [ALK] 
translocation) with squamous and nonsquamous histologies, respectively (NCCN 2017c, 
Novello et al 2016). 
Randomized studies comparing various PT-DC regimens in NSCLC have shown similar efficacy 
results, with ORRs ranging from 15% to 32%, median PFS of 4.0 to 5.1 months, and median OS 
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). 
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1.7. 
Overview of Low-Dose Cyclophosphamide 
Cyclophosphamide is an alkylating agent that is thought to exert its effect by cross-linking tumor 
cell DNA.  Cyclophosphamide is primarily used at high doses for the treatment of hematologic 
malignancies (lymphomas, multiple myeloma, leukemias) but can be used for the treatment of 
ovarian and breast cancers.  Additionally, cyclophosphamide can be used as an 
immunosuppressive agent for the treatment of autoimmune and immune-mediated diseases.  
Preclinical and clinical findings have demonstrated that cyclophosphamide is a potent immune 
modulator that targets suppressive regulatory immune cells within the tumor microenvironment 
while enhancing effector cells.  Low doses of cyclophosphamide have been used to selectively 
deplete Tregs while enhancing effector and memory cytotoxic T cells within the tumor 
microenvironment, which resulted in suppressed tumor growth and enhanced survival 
(Abu Eid et al 2016, Ahlmann and Hempel 2016). 
1.8. 
Overview of Gemcitabine/Platinum Agent in Urothelial Carcinoma 
Activity of gemcitabine/cisplatin combination chemotherapy compared with methotrexate, 
vinblastine, doxorubicin, and cisplatin (MVAC) as first-line treatment for metastatic UC was 
investigated in a Phase 3 study in 405 subjects (von der Maase et al 2000).  Overall survival was 
similar on both arms (HR = 1.04, 95% CI, 0.82 to 1.32; p = 0.75), as were time to progressive 
disease, time to treatment failure, and response rate (gemcitabine/cisplatin, 49%; MVAC, 46%); 
however, gemcitabine/cisplatin provided a better safety profile and tolerability.  Unfortunately, 
cisplatin ineligibility is common in subjects with UC because of renal dysfunction (creatinine 
clearance < 60 mL/min) or performance status of 2, both, or additional comorbidity.  Carboplatin 
provides an alternative for cisplatin in these subjects.  Results from a Phase 3 study comparing 
gemcitabine/carboplatin with methotrexate/carboplatin/vinblastine (M-CAVI) in 
238 cisplatin-ineligible subjects showed ORRs of 41.2% (36.1% confirmed response) with 
gemcitabine/carboplatin and 30.3% (21.0% confirmed response) with M-CAVI (p = 0.08 
unconfirmed response; p = 0.01 confirmed response) and similar OS (HR = 0.94, 95% CI, 
0.72 to 1.2; p = 0.64) and PFS (HR = 1.04; 95% CI, 0.80, 1.35).  However, more subjects have 
severe acute toxicity (death resulting from toxicity, Grade 4 thrombocytopenia with bleeding, 
Grade 3 to 4 renal toxicity, neutropenic fever, or Grade 3 to 4 mucositis) with M-CAVI 
compared with gemcitabine-carboplatin (21.2% vs 9.3%; De Santis et al 2012).  Results from 
these Phase 3 studies form the basis of combination therapy with gemcitabine and a platinum 
agent as first-line standard-of-care treatment for subjects with advanced/metastatic UC 
(NCCN 2017d, Bellmunt et al 2014). 
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1.9. 
Overview of Platinum Agent/5-Fluorouracil in Squamous Cell 
Carcinoma of the Head and Neck 
Initial treatment options for patients with recurrent or metastatic SCCHN include various 
chemotherapy agents (platinum agent [cisplatin or carboplatin], 5-fluorouracil, or taxanes), either 
alone or in combination, and the biologic agent cetuximab (NCCN 2017b, Gregoire et al 2010).  
In Phase 3 studies cisplatin/5-fluourouracil, ORRs were 30% (Forastiere et al 1992, Jacobs 
et al 1992, Clavel et al 1994, Gibson et al 2005) while ORR with carboplatin/5-fluorouracil was 
21% (Forastiere et al 1992).  While these ORRs are considered significant improvements relative 
to single-agent platinum therapy, improvements in OS have not been observed.  The addition of 
the EGFR-targeted monoclonal antibody cetuximab to platinum agent (cisplatin or carboplatin) 
and 5-fluorouracil (EXTREME regimen) prolonged median OS from 7.4 months to 10.1 months 
(HR = 0.80; p = 0.04) and median PFS from 3.3 months to 5.6 months (HR = 0.54; p < 0.001) 
compared with a platinum agent and 5-fluorouracil doublet.  Additionally, ORR increased from 
20% with platinum/5-fluorouracil to 36% with the EXTREME regimen (p < 0.001; 
Vermorken et al 2008).  Based on these results, the EXTREME regimen is now the standard of 
care for patients with non-nasopharyngeal SCCHN in the recurrent and metastatic setting 
(NCCN 2017b, Gregoire et al 2010). 
1.10. 
Study Rationale 
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).  FOLFOX-bevacizumab may induce a decrease in granulocytic 
myeloid-derived suppressor cells, high levels of which are associated with a poor prognosis 
(Limagne et al 2016).  Gemcitabine and cyclophosphamide have been shown to improve 
antitumor immunity by depleting immunosuppressive Tregs (Ghiringhelli et al 2007, Le and 
Jaffee 2012, Shevchenko et al 2013).  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-fluorouracil 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 subjects for whom these 
chemotherapies are the accepted standard of care. 
Programmed cell death 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 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%, PFS 13 vs 8.9 months, ≥ Grade 3 treatment-related AEs 39% vs 26%; 
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; 
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Giaccone et al 2015). Confirmatory Phase 3 clinical studies in advanced/metastatic NSCLC are 
ongoing for these 3 therapies. 
In addition to NSCLC, preliminary data of PD-1 or PD-L1 inhibitors in combination with 
chemotherapy in metastatic CRC and pancreatic cancer have been reported.  In a Phase 1 study 
in subjects with previously untreated metastatic CRC (n = 23), atezolizumab in combination with 
FOLFOX and bevacizumab showed an ORR of 52% with a median PFS of 14.1 months.  The 
regimen was well-tolerated, and no unexpected toxicities observed (Wallin et al 2016).  In a 
Phase 1 investigator-initiated study of pembrolizumab in combination with mFOLFOX6 in 
subjects with advanced gastric malignancies (n = 10), the combination of pembrolizumab at 
doses of up to 200 mg given every 2 weeks with mFOLFOX6 was well-tolerated.  Common 
≥ Grade 3 AEs were neutropenia (40%) and hyponatremia (30%).  Stable disease was observed 
in 4 of 7 CRC subjects (Stenehjem et al 2016).  Preliminary data from a Phase 1/2 study of 
nab-paclitaxel ± gemcitabine with nivolumab in subjects with locally advanced or metastatic 
pancreatic cancer showed the addition of nivolumab to nab-paclitaxel or 
nab-paclitaxel/gemcitabine was tolerable.  No dose-limiting toxicities (DLTs) were observed in 
the 11 subjects treated with nivolumab plus nab-paclitaxel, and the most common AEs were 
anemia, neutropenia, and pulmonary embolism (18% each).  One DLT was observed in the 
6 subjects treated with nab-paclitaxel/gemcitabine plus nivolumab, and the most common AE 
was anemia (33%).  Two of 6 subjects treated with nab-paclitaxel and nivolumab had a PR and 
4 had SD.  Of the 11 subjects treated with nab-paclitaxel/gemcitabine and nivolumab, 3 subjects 
had a PR and 3 subjects had SD (George et al 2016). 
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 
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 2016).  
Indoximod in combination with nab-paclitaxel and gemcitabine in subjects with metastatic 
pancreatic cancer was also well-tolerated in a Phase 1/2 study, and preliminary efficacy showed 
durable responses in 42% of subjects (Bahary et al 2016). 
Combining the IDO1 inhibitor epacadostat, pembrolizumab, and chemotherapy may result in 
greater immunomodulatory effects in the tumor microenvironment, resulting in enhanced clinical 
benefit in subjects with advanced or metastatic solid tumors. 
1.10.1. 
Justification for Treatment Regimen 
The initial epacadostat dose selected for this study in combination with pembrolizumab and 
chemotherapy is 100 mg BID, with the option to de-escalate to 50 mg BID based on DLTs 
observed in the safety run-in.  The initial dose selected is based on the preliminary observation 
that the average kynurenine inhibition at 6 hours after administration of epacadostat using a 
standardized whole blood assay is 89%, and the safety profile of this dose level has been 
well-tolerated.  Pharmacokinetic (PK) and pharmacodynamic observations from studies 
INCB 24360-101 and INCB 24360-201 in subjects with cancer support the 25 mg BID to 
300 mg BID dose levels, which provide a differential pharmacologic effect.  Based on a 6-hour 
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observation period at steady state on Day 15 after administration of epacadostat and using a 
standardized whole blood assay, kynurenine levels are incompletely inhibited (66%), compared 
with baseline levels in subjects treated with 25 mg BID, but are nearly maximally inhibited 
(89%) in subjects treated with 100 mg BID.  Complete inhibition of IDO1 is not required for 
maximally effective activity in preclinical models; however, maximally effective doses in 
nonclinical models result in exposures that are comparable to monotherapy doses of 50 mg BID 
to 300 mg BID in humans.  Additionally, a detailed interrogation of the effect of dose and 
exposure on the pharmacodynamic effect of epacadostat on the tryptophan pathway was 
performed in Study INCB 24360-101.  Using an ex vivo assay optimized for determining the 
inhibition of the metabolism of tryptophan to kynurenine by IDO1, epacadostat treatment 
produced significant dose-dependent reductions in plasma kynurenine levels and in the plasma 
kynurenine/tryptophan ratio at all doses and in all subjects.  Near maximal changes were 
observed at doses of ≥ 100 mg BID with > 80% to 90% inhibition of IDO1 achieved throughout 
the dosing period (Beatty et al 2017). 
Epacadostat doses of up to 700 mg BID as monotherapy have been well-tolerated.  In the 
INCB 24360-202 study, epacadostat doses of up to 300 mg BID were evaluated in combination 
with pembrolizumab.  The MTD was not exceeded in this study.  While there was a higher 
incidence of Grade 3 rash in the 300 mg BID cohort than in the 100 mg BID cohort, these did not 
qualify as protocol-specified DLTs.  The dose of epacadostat 300 mg BID is currently being 
investigated in other studies of epacadostat in combination with other checkpoint inhibitors. 
In the Phase 3 INCB 24360-301 study, the combination of epacadostat 100 mg BID plus 
pembrolizumab 200 mg every 3 weeks (Q3W) was chosen based upon a benefit/risk assessment 
made specifically in melanoma in collaboration with Merck.  In INCB 24360-202, there was 
evidence of improved efficacy in melanoma subjects at all doses of epacadostat from 50 mg to 
300 mg BID.  Given that melanoma is an immunotherapy responsive tumor, and lower doses of 
epacadostat appeared to have similar activity, epacadostat 100 mg BID dose was selected for 
evaluation in the INCB 24360-301 study because of the lower incidence of dose interruptions 
and dose reductions compared with the 300 mg BID dose observed in the INCB 24360-202 
study. 
The starting dose selected for the current study was formed on the basis of having a 
well-tolerated safety profile as monotherapy and in combination with other immunotherapy 
agents, as well as providing nearly maximum target inhibition of IDO1.  Given that epacadostat 
was determined to be safe as monotherapy at doses up to 700 mg BID, the choice of the 
pharmacologically active dose (PAD) of 100 mg BID is justified as the starting dose in this 
combination study, and the dose range of 50 mg BID to 100 mg BID is justified as the dose 
range to potentially evaluate in this study. 
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1.10.2. 
Rationale for Efficacy Endpoints 
RECIST v1.1 (Eisenhauer et al 2009) will be used by the local site to determine eligibility and 
evaluate disease status.  However, because immunotherapeutic agents may produce antitumor 
effects by potentiating endogenous cancer-specific immune responses that may take weeks to 
emerge, the response patterns seen with immunotherapeutic agents may extend beyond the 
typical time course of responses seen with cytotoxic agents and can manifest a clinical response 
after an initial increase in tumor burden or appearance of new lesions.  As a result, RECIST v1.1 
may not provide a comprehensive response assessment of immunotherapeutic agents; therefore, 
RECIST v1.1 will be used with the following adaptation: 
If radiologic imaging shows initial PD, tumor assessment should be repeated ≥ 4 weeks later 
(but no later than 6 weeks) to confirm PD with the option of continuing assigned treatment 
while awaiting radiologic confirmation of progression.  If repeat imaging shows stability or 
reduction in tumor burden compared with the initial scan demonstrating PD, treatment may 
be continued or resumed.  If repeat imaging confirms progressive PD, subjects will be 
discontinued from treatment.  In determining whether or not the tumor burden has increased 
or decreased, investigators should consider all target lesions as well as nontarget lesions. 
In subjects who have initial radiologic evidence of PD, it is at the discretion of the investigator to 
continue a subject on treatment until repeat imaging is obtained.  This decision should be based 
on the subject's overall clinical condition, including performance status, clinical symptoms, and 
laboratory data.  Subjects may receive treatment while waiting for confirmation of PD if they are 
clinically stable, as defined by the following criteria: 
• Absence of clinically significant signs and symptoms (including worsening of 
laboratory values) indicating disease progression. 
• No decline in ECOG performance status. 
• Absence of rapid progression of disease. 
• Absence of progressive tumor at critical anatomical sites (eg, spinal cord 
compression) requiring urgent alternative medical intervention. 
When feasible, subjects should not be discontinued until progression is confirmed.  Subjects who 
are deemed clinically unstable are not required to have repeat imaging for confirmation of PD. 
In all other instances, treatment decisions will be made based on investigator review of the 
clinical and radiographic data. 
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1.11. 
Potential Risks of the Treatment Regimen 
1.11.2. 
Risks From Pembrolizumab 
The most frequently reported adverse events (≥ 10%) in 2799 subjects treated with 
pembrolizumab were fatigue, nausea, decreased appetite, diarrhea, cough, pruritus, dyspnea, 
arthralgia, rash, constipation, headache, vomiting, asthenia, pyrexia, back pain, anemia, and 
peripheral edema.  The 5 most frequently reported SAEs were pneumonia (3.0%), pleural 
effusion (1.7%), pneumonitis (1.6%), dyspnea (1.6%), and pulmonary embolism (1.5%).  For full 
details and recommended management guidelines, refer to the pembrolizumab Investigator's 
Brochure (pIB). 
It is unknown whether pembrolizumab is excreted in human milk.  Pembrolizumab may have 
adverse effects on a fetus in utero.  Furthermore, it is not known if pembrolizumab has transient 
adverse effects on the composition of sperm. 
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1.11.3. 
Risks From mFOLFOX6 
The most common adverse reactions (incidence ≥ 40%) of oxaliplatin were peripheral sensory 
neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in transaminases and 
alkaline phosphatase (ALP), diarrhea, emesis, fatigue, and stomatitis.  Serious adverse reactions 
including anaphylaxis and allergic reactions, neuropathy, pulmonary toxicities, and 
hepatotoxicity can occur.  Anaphylactic reactions to oxaliplatin may occur within minutes of 
administration. 
In clinical studies of oxaliplatin, the most common adverse reactions in previously untreated and 
treated subjects with advanced CRC were peripheral sensory neuropathies, fatigue, neutropenia, 
nausea, emesis, and diarrhea.  Both 5-fluorouracil and oxaliplatin are associated with 
gastrointestinal and hematologic adverse reactions.  When oxaliplatin is administered in 
combination with 5-fluorouracil, the incidence of these events is increased.  Allergic 
sensitization, including anaphylactoid reactions and urticaria, has been reported after the 
administration of both oral and parenteral leucovorin. 
1.11.4. 
Risks From nab-Paclitaxel/Gemcitabine 
The most common (≥ 20%) adverse reactions of nab-paclitaxel in pancreatic ductal 
adenocarcinoma (PDAC) are neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, 
peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration.  
Additionally, nab-paclitaxel causes myelosuppression.  Sensory neuropathy occurs frequently 
and may require dose reduction or treatment interruption.  Sepsis occurred in subjects with or 
without neutropenia who received nab-paclitaxel in combination with gemcitabine.  Pneumonitis 
occurred with the use of nab-paclitaxel in combination with gemcitabine.  Severe 
hypersensitivity reactions with fatal outcome have been reported.  nab-Paclitaxel contains 
albumin derived from human blood, which has a theoretical risk of viral transmission.  Refer to 
the US prescribing information (Abraxane PI 2015) or EU SmPC (Abraxane SmPC 2015) for 
nab-paclitaxel for full details. 
1.11.5. 
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 subjects 
previously receiving emetogenic therapy.  Although peripheral neurotoxicity is infrequent, its 
incidence is increased in subjects older than 65 years and in subjects 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 studies.  Fatal reactions have occurred in subjects 
despite premedication. 
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1.11.6. 
Risks From Pemetrexed/Platinum Agent 
The most common adverse reactions (incidence ≥ 20% with single-agent use) with pemetrexed 
are fatigue, nausea, and anorexia.  When pemetrexed is used in combination with a platinum 
agent, common adverse reactions 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 PI 2013) or EU SmPC (Alimta SmPC 2016) for pemetrexed for full details. 
1.11.7. 
Risks From Cyclophosphamide 
The most often reported adverse reactions with cyclophosphamide are neutropenia, febrile 
neutropenia, fever, alopecia, nausea, vomiting, and diarrhea.  Cyclophosphamide can cause 
myelosuppression (leukopenia, neutropenia, thrombocytopenia, and anemia), bone marrow 
failure, and severe immunosuppression, which may lead to serious and sometimes fatal 
infections, including sepsis and septic shock.  Hemorrhagic cystitis, pyelitis, ureteritis, 
hematuria, and secondary malignancies (urinary tract cancer, myelodysplasia, acute leukemias, 
lymphomas, thyroid cancer, and sarcomas) have been reported.  Myocarditis, myopericarditis, 
pericardial effusion including cardiac tamponade, and congestive heart failure, which may be 
fatal, have been reported.  Pneumonitis, pulmonary fibrosis, pulmonary veno-occlusive disease, 
and other forms of pulmonary toxicity leading to respiratory failure have been reported during 
and after treatment with cyclophosphamide.  Veno-occlusive liver disease including fatal 
outcome has been reported. 
1.11.8. 
Risks From Gemcitabine/Platinum Agent 
In the Phase 3 study of gemcitabine/cisplatin versus MVAC, ≥ Grade 3 anemia was more 
common with gemcitabine/cisplatin (27%) versus MVAC (18%); however, this did not result in 
an increase in RBC transfusion rates.  Subjects treated with gemcitabine/cisplatin had more 
≥ Grade 3 thrombocytopenia compared with MVAC (57% vs 21%, respectively); but there was 
no Grade 4 bleeding on either arm, and ≥ Grade 3 thrombocytopenia was infrequently associated 
with Grade 3 bleeding (2% for both treatment groups; von der Maase et al 2000).  In the Phase 3 
study in UC, severe acute toxicity (death, Grade 4 thrombocytopenia with bleeding, ≥ Grade 3 
renal toxicity, neutropenic fever, or mucositis) was observed in 9.3% of subjects receiving 
gemcitabine-carboplatin and 21.2% of subjects receiving M-CAVI.  The most common 
≥ Grade 3 AEs were leukopenia (44.9%, 46.6%), neutropenia (52.5%, 63.5%), febrile 
neutropenia (4.2%, 14.4%), thrombocytopenia (48.3%, 19.4%), and infection (11.8%, 12.7%) in 
subjects treated with gemcitabine/carboplatin versus M-CAVI, respectively 
(De Santis et al 2012). 
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1.11.9. 
Risks From Platinum Agent/5-Fluorouracil 
In a Phase 3 study of cisplatin/5-fluorouracil and carboplatin/5-fluorouracil versus single-agent 
methotrexate as first-line treatment for metastatic SCCHN, 33% of subjects treated with 
cisplatin/5-fluorouracil and 26% of subjects treated with carboplatin/5-fluorouracil had 
≥ Grade 3 AEs.  Compared with single-agent methotrexate, leukopenia was more frequent in 
cisplatin-treated subjects, and thrombocytopenia was more frequent in carboplatin-treated 
subjects.  Stomatitis, nausea, and vomiting were common nonhematologic events with the 
platinum agent/5-fluorouracil regimens, and renal toxicity was more frequent in cisplatin-treated 
subjects (Forastiere et al 1992). 
1.11.10. 
Risks From Combining an IDO Inhibitor With Chemotherapy 
In a Phase 1 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 
plus docetaxel in subjects with metastatic breast cancer, the most common indoximod-related 
AEs of any grade occurring in ≥ 10% of subjects were fatigue (20%), nausea (20%), diarrhea 
(13%), and headache (12%; Tang et al 2016). 
Recently presented safety data from a Phase 1/2 study evaluating the combination of indoximod 
with nab-paclitaxel/gemcitabine in subjects with metastatic pancreatic cancer showed the most 
frequently reported AEs (regardless of attribution) occurring in ≥ 10% of subjects were anemia, 
constipation, diarrhea, nausea, vomiting, fatigue, peripheral edema, abdominal pain, decreased 
appetite, weight loss, dizziness, fever, peripheral neuropathy, alopecia, rash, hypotension, 
hypokalemia, hyponatremia, ALT increased, AST increased, ALP increased, platelet count 
decreased, white blood cell count decreased, and neutrophil count decreased (Bahary et al 2016). 
1.11.11. 
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 AEs in 11 subjects with metastatic pancreatic 
cancer treated with nab-paclitaxel/gemcitabine plus nivolumab was anemia (33%; 
George et al 2016). 
Recently presented safety data from a randomized cohort of the KEYNOTE-021 study where 
subjects with nonsquamous NSCLC were treated with pemetrexed/carboplatin plus 
pembrolizumab showed the most common ≥ Grade 3 treatment-related AEs were anemia (12%), 
decreased neutrophil count (5%), and acute kidney injury, decreased lymphocyte count, fatigue, 
neutropenia, sepsis, and thrombocytopenia (3% each; Langer et al 2016).  In an open-label 
cohort from the same study, NSCLC subjects treated with paclitaxel/carboplatin plus 
pembrolizumab, treatment-related AEs ≥ Grade 3 occurred in 36% subjects; the most common 
events were anemia, neutropenia, and febrile neutropenia (n = 2 each; Gadgeel et al 2016). 
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1.11.12. 
Risks From Combining Epacadostat and Pembrolizumab 
In the Phase 1 portion of the INCB 24360-202 study of epacadostat in combination with 
pembrolizumab, the most common all-grade treatment-related AEs were fatigue (29%), rash 
(29%), pruritus (23%), arthralgia (19%), diarrhea (18%), and nausea (16%).  Treatment-related 
AEs ≥ Grade 3 were observed in 19% (most common:  rash [8%] and increased lipase [3%]).  
Five subjects (8%) experienced treatment-related AEs that led to discontinuation, including 
Grade 3 arthralgia, Grade 3 AST increased/Grade 2 ALT increased, Grade 3 lipase increased, 
Grade 3 aseptic meningitis, and Grade 2 nervous system disorder.  There were no treatment-
related deaths (Gangadhar et al 2016). 
Data from 294 subjects in the Phase 2 portion of the study (epacadostat 100 mg PO BID + 
pembrolizumab 200 mg IV Q3W) further support the acceptable safety and tolerability profile of 
this combination.  The most common all-grade treatment-related AEs were fatigue (29%), rash 
(17%), nausea (11%), and pruritus (10%).  Treatment-related AEs ≥ Grade 3 were observed in 
18%.  Treatment-related AEs leading to treatment discontinuations occurred in 11 subjects (4%); 
the most common were arthralgia and rash (n = 2 subjects each) and there was only 
1 treatment-related AE that led to death (respiratory failure, secondary to aspiration pneumonia; 
pneumonitis could not be ruled out; Hamid et al 2017b). 
In Study INCB 24360-301, the external Data Monitoring Committee found no new safety 
concerns with pembrolizumab plus epacadostat compared with pembrolizumab monotherapy.  
Treatment-related AEs ≥ Grade 3 occurred in 22% of subjects receiving epacadostat plus 
pembrolizumab and in 17% of subjects receiving placebo plus pembrolizumab.  Treatment-
related AEs leading to treatment discontinuations occurred in 11% and 10% of subjects treated 
with epacadostat plus pembrolizumab and placebo plus pembrolizumab, respectively 
(Long et al 2018). 
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2. 
STUDY OBJECTIVES AND ENDPOINTS  
2.1. 
Study Objectives 
2.1.1. 
Primary Objectives 
• Phase 1:  To evaluate the safety, tolerability, and DLTs and to define an MTD and/or 
PAD of epacadostat in combination with pembrolizumab and chemotherapy in 
subjects with advanced or metastatic solid tumors. 
• Phase 2:  To evaluate the efficacy of epacadostat in combination with pembrolizumab 
and chemotherapy in subjects with advanced or metastatic CRC, PDAC, NSCLC, 
UC, SCCHN, or any advanced or metastatic solid tumor who progressed on previous 
therapy with a PD-1 or PD-L1 inhibitor by assessing ORR per RECIST v1.1. 
2.1.2. 
Secondary Objectives 
• Phase 1:  To explore the efficacy of epacadostat in combination with pembrolizumab 
and chemotherapy in subjects with advanced or metastatic solid tumors by assessing 
ORR per RECIST v1.1. 
• Phase 2:  To further evaluate the safety and tolerability of epacadostat at the MTD 
and/or PAD in combination with pembrolizumab and chemotherapy in subjects with 
selected advanced or metastatic solid tumors. 
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2.2. 
Study Endpoints 
2.2.1. 
Primary Endpoints 
• Phase 1:  Safety and tolerability will be assessed by monitoring frequency, duration, 
and severity of AEs through physical examinations, by evaluating changes in vital 
signs and electrocardiograms (ECGs), and through clinical laboratory blood and urine 
sample evaluations. 
• Phase 2:  ORR, defined as the percentage of subjects having a CR or PR, will be 
determined by investigator assessment of radiographic disease per RECIST v1.1. 
2.2.2. 
Secondary Endpoints 
• Phase 1:  ORR, defined as the percentage of subjects having a CR or PR, will be 
determined by investigator assessment of radiographic disease per RECIST v1.1. 
• Phase 2:  Safety and tolerability will be assessed by monitoring frequency, duration, 
and severity of AEs through physical examinations, by evaluating changes in vital 
signs and ECGs, and through clinical laboratory blood and urine sample evaluations. 
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3. 
SUBJECT ELIGIBILITY 
Phase 1:  Subjects with histologically or cytologically confirmed advanced or metastatic solid 
tumors who have failed previous standard therapy (or who refuse or are intolerant to 
standard-of-care therapy). 
Phase 2:  Subjects with histologically or cytologically confirmed advanced or metastatic CRC, 
PDAC, squamous NSCLC, nonsquamous NSCLC, UC, SCCHN who have not received first-line 
therapy for advanced or metastatic disease; subjects with any advanced or metastatic solid tumor 
with confirmed progression on previous therapy with a PD-1 or PD-L1 inhibitor. 
Deviations from eligibility criteria are not allowed, because they can potentially jeopardize the 
scientific integrity of the study, regulatory acceptability, and/or subject safety.  Therefore, 
adherence to the criteria as specified in the Protocol is essential. 
3.1. 
Subject Inclusion Criteria 
A subject who meets all of the following criteria may be included in the study: 
Phase 1 and Phase 2: 
1. Ability to comprehend and willing to sign an informed consent form (ICF). 
2. Men or women aged 18 years or older. 
3. Presence of measurable disease per RECIST v1.1 (Appendix F).  Tumor lesions located 
in a previously irradiated area, or in an area subjected to other loco-regional therapy, are 
considered measureable if progression has been demonstrated in the lesion. 
4. ECOG performance status of 0 or 1 (Appendix C). 
5. Willing to avoid pregnancy or fathering children based on the criteria below: 
a. Woman of nonchildbearing potential (ie, surgically sterile with a hysterectomy and/or 
bilateral oophorectomy OR ≥ 12 months of amenorrhea and at least 51 years of age.) 
b. Woman of childbearing potential who has a negative serum pregnancy test at 
screening and before the first dose on Day 1 and who agrees to take appropriate 
precautions to avoid pregnancy (with at least 99% certainty) from screening through 
120 days after the last dose of epacadostat and pembrolizumab.  Permitted methods 
that are at least 99% effective in preventing pregnancy (see Appendix A) should be 
communicated to the subject and their understanding confirmed. 
Note:  If a subject continues on chemotherapy after discontinuing epacadostat and 
pembrolizumab, contraception methods should continue for 180 days after the last 
dose of chemotherapy. 
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c. Man who agrees to take appropriate precautions to avoid fathering children (with at 
least 99% certainty) from screening through 120 days after the last dose of 
epacadostat and pembrolizumab.  Permitted methods that are at least 99% effective in 
preventing pregnancy (see Appendix A) should be communicated to the subject and 
their understanding confirmed. 
Note:  If a subject continues on chemotherapy after discontinuing epacadostat and 
pembrolizumab, contraception methods should continue for 180 days after the last 
dose of chemotherapy. 
6. Willing and able to comply with scheduled visits, the treatment plan, and laboratory tests. 
Phase 1 subjects only: 
7. Subjects with locally advanced or metastatic solid tumors who have disease progression 
after treatment with available therapies that are known to confer clinical benefit, who are 
intolerant to treatment, or who refuse standard treatment.  Locally advanced disease must 
not be amenable to resection with curative intent. 
Note:  Subjects should not have received more than 2 previous therapies for advanced or 
metastatic disease.  Subjects who received more than 2 previous therapies for advanced 
or metastatic disease must be discussed with medical monitor to confirm eligibility. 
8. Subjects must not have received therapy with an IDO inhibitor. 
Phase 2 CRC subjects only: 
9. Histologically or cytologically confirmed advanced or metastatic adenocarcinoma of the 
colon or rectum. 
10. Subjects must not have received previous chemotherapy as first-line therapy for advanced 
or metastatic disease. 
Note:  Subjects who completed a chemotherapy regimen 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 therapy, the 
subject will not be eligible. 
11. Subjects must not have received previous immune checkpoint inhibitors (eg, CTLA-4 
inhibitor, PD-1 inhibitor, PD-L1 inhibitor, or any other antibody or drug specifically 
targeting T-cell costimulation) and/or an IDO inhibitor.  Subjects who received other 
immunotherapies must be discussed with medical monitor to confirm eligibility. 
Phase 2 PDAC subjects only: 
12. Histologically or cytologically confirmed advanced or metastatic PDAC. 
13. Subjects must not have received previous chemotherapy as first-line therapy for advanced 
or metastatic disease. 
Note:  Subjects who completed a chemotherapy regimen 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 therapy, the 
subject will not be eligible. 
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14. Subjects must not have received previous immune checkpoint inhibitors (eg, CTLA-4 
inhibitor, PD-1 inhibitor, PD-L1 inhibitor, or any other antibody or drug specifically 
targeting T-cell costimulation) and/or an IDO inhibitor.  Subjects who received other 
immunotherapies must be discussed with medical monitor to confirm eligibility. 
15. Does not require recurrent paracentesis for management of ascites or thoracentesis for 
management of pleural effusion. 
16. Albumin > 3.0 g/dL. 
17. Absence of erosion into the stomach or other viscera by computed tomography scan. 
Phase 2 squamous or nonsquamous NSCLC subjects only: 
18. Histologically or cytologically confirmed Stage IIIB, Stage IV, or recurrent squamous or 
nonsquamous NSCLC. 
19. Subjects without driver mutations (eg, BRAF or EGFR mutations, ALK fusion oncogene 
or ROS1 rearrangements) must not have received previous chemotherapy as first-line 
therapy for Stage IIIB, Stage IV, or recurrent NSCLC. 
Note:  Subjects who completed a chemotherapy regimen 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 therapy, the 
subject will not be eligible. 
20. Subjects with driver mutations (eg, BRAF or EGFR mutations, ALK fusion oncogene or 
ROS1 rearrangements) must have received prior treatment only with an approved TKI 
with subsequent disease progression. 
21. Subjects must not have received previous immune checkpoint inhibitors (eg, CTLA-4 
inhibitor, PD-1 inhibitor, PD-L1 inhibitor, or any other antibody or drug specifically 
targeting T-cell costimulation) and/or an IDO inhibitor.  Subjects who received other 
immunotherapies must be discussed with medical monitor to confirm eligibility. 
22. For subjects with squamous histology, willing and able to take premedications to prevent 
hypersensitivity reactions. 
23. For subjects with nonsquamous histology, willing and able to take vitamin B12 and folic 
acid supplements. 
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Phase 2 subjects in the cohort of subjects with any solid tumor that progressed on previous 
therapy with a PD-1 or PD-L1 inhibitor only: 
24. Histologically or cytologically confirmed advanced or metastatic solid tumors that 
progressed (primary refractory or secondary relapsed) on previous monotherapy with a 
PD-1 or PD-L1 inhibitor or previous combination therapy that included a PD-1 or PD-L1 
inhibitor in the advanced or metastatic setting. 
Note:  Primary refractory subjects must have received at least 2 doses of PD-1 or PD-L1 
inhibitor and have had disease progression at least 8 weeks from the first dose of the 
PD-1 or PD-L1 inhibitor that is confirmed at least 4 weeks (no less than 28 days) later 
(confirmatory imaging may be performed during the screening period with medical 
monitor approval).  The PD-1 or PD-L1 inhibitor does not need to have been the last 
treatment received before signing informed consent.  Subjects who received only 1 dose 
of the PD-1 or PD-L1 inhibitor or discontinued for toxicity without disease progression 
within 8 weeks of the first dose of the PD-1 or PD-L1 inhibitor are not eligible.  
Note:  Secondary relapsed subjects must have had a PR or CR while on treatment with a 
PD-1 or PD-L1 inhibitor but later had disease progression that is confirmed at least 
4 weeks (no less than 28 days) later.  The PD-1 or PD-L1 inhibitor does not need to have 
been the last treatment received before signing informed consent.  Subjects must not have 
received previous therapy with an IDO inhibitor. 
25. Subjects who received immunotherapies other than a PD-1 or PD-L1 inhibitor must be 
discussed with medical monitor to confirm eligibility. 
26. Subjects may have received previous chemotherapy for advanced or metastatic disease. 
Note:  There is no limit to the number of previous chemotherapy regimens. 
Phase 2 subjects in the mandatory biopsy cohort only: 
27. Willing to undergo pretreatment and on-treatment core or excisional tumor biopsies. 
Note:  Fresh baseline tumor biopsies (defined as a biopsy specimen taken since 
completion of the most recent prior systemic regimen) are required for all Phase 2 
mandatory biopsy subjects. 
Phase 2 efficacy expansion subjects only: 
28. Willing to undergo pretreatment core or excisional tumor biopsies. 
Note:  Fresh baseline tumor biopsies (defined as a biopsy specimen taken since 
completion of the most recent prior systemic regimen) are preferred.  If a subject has 
inaccessible lesions, the subject may be enrolled with medical monitor approval.  In this 
case, submission of archived tumor tissue may be acceptable.  In all cases, biopsies will 
be confirmed to contain adequate tumor tissue by a local pathology review. 
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Phase 2 UC subjects only: 
29. Have histologically or cytologically confirmed advanced/unresectable (inoperable) or 
metastatic urothelial cancer of the renal pelvis, ureter, bladder, or urethra.  Both 
transitional cell and mixed transitional/nontransitional (predominantly transitional) cell 
histologies are allowed. 
30. Subjects must not have received previous chemotherapy as first-line therapy for advanced 
or metastatic disease. 
Note:  Adjuvant platinum-based chemotherapy, following radical cystectomy, with 
recurrence > 12 months from completion of therapy is permitted.  Neoadjuvant 
platinum-based chemotherapy with recurrence > 12 months since completion of therapy 
is permitted. 
31. Subjects must not have received previous immune checkpoint inhibitors (eg, CTLA-4 
inhibitor, PD-1 inhibitor, PD-L1 inhibitor, or any other antibody or drug specifically 
targeting T-cell costimulation) and/or an IDO inhibitor.  Subjects who received other 
immunotherapies must be discussed with medical monitor to confirm eligibility. 
Phase 2 SCCHN subjects only: 
32. Histologically or cytologically confirmed recurrent or metastatic SCCHN of the oral 
cavity, oropharynx, hypopharynx, and larynx that is considered incurable by local 
therapies. 
Note:  Subjects with primary tumors of the nasopharynx, the salivary gland, unknown 
primary origin, or nonsquamous histologies are not eligible.  
33. Documentation of results from testing of HPV status for oropharyngeal cancer using p16 
IHC testing. 
Note:  Subjects with primary tumor site of the oral cavity, hypopharynx, and larynx are 
not required to undergo HPV testing by p16 IHC, as these tumor locations are assumed to 
be HPV negative.  
34. Subjects must not have received previous chemotherapy as first-line therapy for recurrent 
or metastatic disease. 
Note:  Systemic therapy completed > 6 months before signing consent if given as part of 
multimodal treatment for locally advanced disease is allowed. 
35. Subjects must not have received previous immune checkpoint inhibitors (eg, CTLA-4 
inhibitor, PD-1 inhibitor, PD-L1 inhibitor, or any other antibody or drug specifically 
targeting T-cell costimulation) and/or an IDO inhibitor.  Subjects who received other 
immunotherapies must be discussed with medical monitor to confirm eligibility. 
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3.2. 
Subject Exclusion Criteria 
A subject who meets any of the following criteria will be excluded from the study: 
Phase 1 and Phase 2 
1. Laboratory and medical history parameters not within the Protocol-defined range.  If the 
screening laboratory tests below were conducted > 7 days before treatment initiation, 
they will need to be repeated on Cycle 1 Day 1 before initiation of treatment. 
a. Absolute neutrophil count (ANC) < 1.5 × 109/L. 
b. Platelet count < 100 × 109/L. 
c. Hemoglobin < 9 g/dL or < 5.6 mmol/L. 
d. Serum creatinine > 1.5 × institutional upper limit of normal (ULN), OR measured or 
calculated creatinine clearance (glomerular filtration rate can also be used in place of 
creatinine or creatinine clearance) < 50 mL/min for subjects with creatinine levels 
> 1.5 × institutional ULN. 
e. AST, ALT, and ALP ≥ 2.5 × ULN. 
Note:  Subjects with 1) bone metastases and 2) no hepatic parenchymal metastases on 
screening radiographic examinations may enroll if the ALP is ≤ 5 × ULN.  Subjects 
with 1) bone metastases and 2) hepatic parenchymal metastases on screening 
radiographic examinations may enroll if the ALP is ≤ 5 × ULN only with medical 
monitor approval. 
f. Total bilirubin ≥ 1.2 × ULN. 
Note:  If total bilirubin is ≥ 1.2 × ULN, conjugated (direct) bilirubin must be tested, 
and subjects will be excluded if the value is ≥ 2.0 × ULN or ≥ 40% of total bilirubin, 
if there is no institutional ULN. 
g. International normalized ratio (INR), prothrombin time, and activated partial 
thromboplastin time (aPTT) > 1.5 × ULN (unless the subject is receiving 
anticoagulant therapy, in which case the subject may be included as long as the INR, 
prothrombin time, and aPTT are within the therapeutic range of intended use of 
anticoagulants). 
Note:  Partial thromboplastin time may be used in place of aPTT per institutional 
standards. 
2. Receipt of anticancer medications or investigational drugs within the following intervals 
before Cycle 1 Day 1: 
a. ≤ 14 days for chemotherapy or targeted small molecule therapy. 
Note:  Bisphosphonates are permitted concomitant medications. 
b. ≤ 28 days for previous monoclonal antibody used for anticancer therapy. 
Note:  Use of denosumab is permitted. 
c. ≤ 7 days for immune-suppressive–based treatment for any reason. 
Note:  Use of inhaled or topical steroids, prophylactic corticosteroids for radiographic 
procedures, or systemic corticosteroid at doses of prednisone ≤ 10 mg/day or 
equivalent is permitted. 
d. ≤ 28 days or 5 half-lives (whichever is longer) before Cycle 1 Day 1 for all other 
investigational agents or devices.  For investigational agents with long half-lives 
(eg, > 5 days), enrollment before the fifth half-life requires medical monitor approval. 
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3. Previous radiotherapy within 14 days of Cycle 1 Day 1 (except for radiation to central 
nervous system (CNS), which requires a ≥ 28-day washout as described below).  Subjects 
must also not require chronic use of corticosteroids and must not have had radiation 
pneumonitis as a result of treatment.  A 1-week washout is permitted for palliative 
radiation to non-CNS disease with sponsor approval. 
4. Known active CNS metastases and/or carcinomatous meningitis. 
Note:  Participants with previously-treated brain metastases may participate provided 
they are 1) radiologically stable (ie, without evidence of progression for at least 28 days 
by repeat imaging prior to the first dose of study treatment [repeat imaging may be 
performed during the screening period with medical monitor approval]), and 2) without 
requirement of steroid treatment for at least 14 days prior to first dose of study treatment, 
and 3) clinically stable, with any neurological signs or symptoms having returned to 
baseline. This exception does not include carcinomatous meningitis, which is excluded 
regardless of clinical stability. 
Note:  Subjects with evidence of cerebral edema or those with < 28 days since radiation 
therapy to the CNS will be excluded from study. 
5. Has not recovered to ≤ Grade 1 from toxic effects of previous therapy and/or 
complications from previous surgical intervention before starting study therapy. 
Note:  Subjects with stable chronic AEs (≤ Grade 2) not expected to resolve 
(eg, alopecia) are exceptions and may enroll. 
Note:  Subjects with a history of peripheral neuropathy ≥ Grade 2 will be excluded. 
6. Receipt of a live vaccine within 30 days of planned start of study therapy. 
Note:  Examples of live vaccines include, but are not limited to, the following:  measles, 
mumps, rubella, chicken pox/zoster, yellow fever, rabies, Bacillus Calmette-Guérin 
(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. 
7. Active infection requiring systemic therapy. 
8. Subjects who have any active or inactive autoimmune disease or syndrome 
(ie, rheumatoid arthritis, moderate or severe psoriasis, multiple sclerosis, inflammatory 
bowel disease) that has required systemic treatment in the past 2 years or who are 
receiving systemic therapy for an autoimmune or inflammatory disease (ie, with use of 
disease-modifying agents, corticosteroids, or immunosuppressive drugs). 
Note:  Exceptions include subjects with vitiligo or resolved childhood asthma/atopy, 
hypothyroidism stable on hormone replacement, controlled asthma, Type I diabetes, 
Graves' disease, or Hashimoto's disease, or with medical monitor approval. 
9. History of (noninfectious) pneumonitis that required steroids or current pneumonitis or 
interstitial lung disease. 
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10. History of 1) allogeneic stem cell or solid organ transplant that requires use of 
immunosuppressive therapy, 2) has a diagnosis of immunodeficiency, or 3) is receiving 
chronic systemic steroid therapy (in doses exceeding 10 mg daily of prednisone or its 
equivalent) or any other form of immunosuppressive therapy within 7 days before 
Cycle 1 Day 1. 
Note:  The use of physiologic doses of corticosteroids may be approved after 
consultation with the sponsor. 
11. Known history of or screening test that is positive for hepatitis B virus (HBV; eg, HBsAg 
reactive or HBV DNA detected) or hepatitis C virus (HCV; HCV antibody positive 
and/or HCV RNA qualitative is detected). 
Note:  Hepatitis C antibody–positive subjects who received and completed treatment for 
hepatitis C that was intended to eradicate the virus may participate if hepatitis C RNA 
levels are undetectable. 
Note:  For Phase 2, treated hepatitis B subjects are eligible if there is no evidence of 
active infection (HBV DNA–negative and HBV DNA surface antigen–negative). 
12. Known history of human immunodeficiency virus (HIV; HIV 1/2 antibodies). 
13. Known secondary malignancy that is progressing or requires active treatment.  
Exceptions include early stage cancers treated with curative intent, basal cell carcinoma 
of the skin, squamous cell carcinoma of the skin, in situ cervical cancer, or in situ breast 
cancer that has undergone potentially curative therapy. 
14. History or presence of an abnormal ECG that, in the investigator's opinion, is clinically 
meaningful.  Screening QTc interval > 480 milliseconds is excluded (corrected by 
Fridericia method).  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. 
Note:  QTc prolongation due to pacemaker may enroll if the JTc is normal or with 
medical monitor approval. 
15. Clinically significant cardiac disease, including unstable angina, acute myocardial 
infarction within 6 months of Cycle 1 Day 1, New York Heart Association Class III or IV 
congestive heart failure, and arrhythmia requiring therapy.   
Note:  A subject with an arrhythmia may enroll if the subject is on antiarrhythmic 
medication and is in sinus rhythm on the screening ECG. 
16. Subjects with a history of bleeding related to cancer under study requiring a medical 
intervention (eg, embolization procedure, RBC transfusion, or hospitalization) within 
30 days of study enrollment. 
17. Known allergy or severe hypersensitivity (≥ Grade 3) reaction to any component of 
epacadostat, pembrolizumab, or chemotherapy regimen components and/or their 
formulation excipients. 
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18. Presence of a gastrointestinal condition (eg, inflammatory bowel disease, Crohn's disease, 
ulcerative colitis) that may affect drug absorption. 
Note:  Subjects with feeding tubes are eligible. 
19. Receiving MAOIs or drug that has significant MAOI activity (eg, meperidine, linezolid, 
methylene blue) within the 21 days before screening.  See Appendix D for prohibited 
medications associated with MAO inhibition. 
20. Use of any UGT1A9 inhibitor from screening through safety follow-up period.  See 
Section 5.10 for more details. 
21. Any history of SS after receiving serotonergic drugs. 
22. Women who are pregnant or breastfeeding.  
23. Any condition that would jeopardize the safety of the subject or compliance with the 
Protocol. 
Phase 1 and 2 subjects in Treatment Group A and Treatment Group G only: 
24. Known dihydropyrimidine dehydrogenase deficiency (heterozygous or homozygous 
mutations). 
Phase 2 subjects in the cohort of subjects with any solid tumor that progressed on previous 
therapy with a PD-1 or PD-L1 inhibitor only: 
25. History of any grade immune-related ocular AEs. 
26. History of a ≥ Grade 3 immune-related AEs from previous immunotherapies. 
Note:  Subjects with immune-related adrenal insufficiency because of previous 
immunotherapy who are medically stable and adequately managed on a stable dose of 
replacement therapy may be enrolled. 
27. Current urinary outflow obstruction. 
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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
Note:  As of 25 OCT 2018, this study is closed to enrollment.  As of this date, no subjects 
were enrolled in Phase 2 efficacy expansion (all treatment groups) or Phase 2 mandatory 
biopsy Treatment Groups A, B, F, and G.  Any text included in the body of this Protocol 
that references these treatment groups and cohorts has not been deleted but should be 
disregarded. 
This is an open-label, nonrandomized, Phase 1/2 study to determine the safety, tolerability, and 
efficacy of epacadostat when given in combination with pembrolizumab and 7 chemotherapy 
regimens (Figure 1).  Phase 1 will consist of a 3 + 3 + 3 design and will determine the MTD or 
PAD of epacadostat when given in combination with pembrolizumab and chemotherapy; 
efficacy will also be explored.  Subjects with advanced or metastatic solid tumors who have 
progressed after receiving at least 1 previous standard therapy for advanced or metastatic disease 
(or who are intolerant to or refuse standard of care) and for whom treatment with 1 of the 
chemotherapy regimens is appropriate will be enrolled in Phase 1.  Phase 2 will further evaluate 
the safety, tolerability, and efficacy of the MTD or PAD of epacadostat selected in Phase 1 when 
given in combination with pembrolizumab and chemotherapy.  Subjects with advanced or 
metastatic CRC, PDAC, NSCLC (squamous or nonsquamous), UC, or SCCHN who have not 
previously received chemotherapy as first-line therapy for advanced or metastatic disease and 
have not previously received immune checkpoint inhibitors nor an IDO inhibitor will be enrolled 
in Phase 2.  A separate cohort of subjects with any advanced or metastatic solid tumor who 
progressed on previous therapy with a PD-1 or PD-L1 inhibitor will also be enrolled in Phase 2. 
4.1.1. 
Phase 1 
A 3 + 3 + 3 design will be used in which 7 treatment groups will be explored in parallel.  A 
minimum of 3 evaluable subjects will be enrolled in each treatment group beginning with 
Cohort 1 (epacadostat 100 mg BID; starting dose), and the first 3 evaluable subjects will be 
observed for a minimum of 28 days in the cohorts where mFOLFOX6 or 
nab-paclitaxel/gemcitabine are administered or 21 days for all other chemotherapy regimens.  To 
be considered evaluable for dose tolerability, subjects should meet 1 of the following 
criteria:  1) received the cohort-specified dose of epacadostat, pembrolizumab, and 
chemotherapy for at least 80% of planned doses in the DLT observation period (45 doses 
epacadostat/2 doses pembrolizumab for subjects who received mFOLFOX6 or 
nab-paclitaxel/gemcitabine; 34 doses epacadostat/1 dose pembrolizumab for subjects who 
received any other chemotherapy regimens) and completed the DLT observation period or 
2) had a DLT during the DLT observation period.  It is recognized that certain toxicities due to 
chemotherapy (eg, including but not limited to gastrointestinal toxicity, including diarrhea; renal 
insufficiency; high-grade laboratory abnormalities; hypersensitivity/rash) may initially be 
clinically indistinguishable from toxicities due to immunotherapy.  Epacadostat will be held for 
these toxicities, and as a result, subjects may not receive at least 80% of the prescribed dose 
during Cycle 1.  In these cases, the Safety Monitoring Committee (SMC) may assess subjects 
who receive dose intensities somewhat below 80% for determining DLTs and consider in the 
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adjudication process the specific toxicities encountered, likely cause of toxicities, and dose 
intensity and tolerability beyond Cycle 1.  Additional subjects will be enrolled in a cohort to 
achieve the minimum of 3 evaluable subjects.  Subjects who discontinue for reasons other than a 
DLT (eg, events clearly associated with the underlying disease, disease progression, concomitant 
medication, comorbidity, or an AE clearly unrelated to treatment) during the DLT observation 
period will be considered nonevaluable for DLTs and will be replaced. 
The scenarios for expansion and de-escalation are summarized below, and the doses of 
epacadostat to be evaluated are summarized in Table 1: 
1. If 0 DLTs occur in 3 subjects in Cohort 1, 3 additional subjects will be treated in 
Cohort 1.  If there is ≤ 1 DLT in these 6 subjects, enrollment in Phase 2 for that treatment 
group may proceed. 
2. If 1 of 3 subjects in Cohort 1 has a DLT, 3 additional subjects will be enrolled in 
Cohort 1.  If there are no additional DLTs (≤ 1 DLT in 6 subjects), enrollment in Phase 2 
for that treatment group may proceed. 
3. If 2 of 6 subjects in Cohort 1 have a DLT, 3 additional subjects will be enrolled in 
Cohort 1.  If there are no additional DLTs (≤ 2 DLTs in 9 subjects), enrollment in Phase 2 
for that treatment group may proceed. 
4. If ≥ 2 of 3, 3 of 6, or 3 of 9 subjects have DLTs within a cohort, de-escalation of 
epacadostat to 50 mg BID (Cohort ‒1) will be evaluated using the same criteria. 
If Cohort ‒1 is not tolerated within a given treatment group, that treatment group will not be 
pursued further.  The study will be terminated if Cohort ‒1 is not tolerated in all treatment 
groups. 
Table 1: 
Epacadostat Dose Cohorts 
Epacadostat Dose Cohort 
Epacadostat Dose 
–1 
50 mg BID 
1 (starting dose) 
100 mg BID
a
 
a If epacadostat 100 mg BID is not tolerated within a treatment group, epacadostat 50 mg BID will be evaluated. 
Dose interruptions and/or modifications may be implemented based on toxicity as described in 
Section 5.5.1.1.  Dose modifications should not be made during the DLT observation period 
without discussion with the medical monitor.  Intrasubject dose escalation is not permitted. 
Subjects will be assigned to a treatment group (Table 2) based on the chemotherapy regimen 
most appropriate for their tumor type. 
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Table 2: 
Treatment Groups 
Treatment 
Group A 
Epacadostat 
Pembrolizumab  
mFOLFOX6 
BID PO continuous 
daily dosing 
(see Table 1) 
200 mg IV Q3W 
• Oxaliplatin 85 mg/m2 IV on Day 1 and 
Day 15 
• Leucovorin 400 mg/m2 IV on Day 1 and 
Day 15 
• 5-Fluorouracil 400 mg/m2 IV bolus, then 
1200 mg/m2 per day IV infusion over 
46 hours for a total dose of 2400 mg/m2, on 
Day 1 and Day 15 
Treatment 
Group B 
Epacadostat 
Pembrolizumab  
nab-paclitaxel and Gemcitabine 
BID PO continuous 
daily dosing 
(see Table 1) 
200 mg IV Q3W 
• nab-Paclitaxel 125 mg/m2 IV on Days 1, 8, 
and 15 
• Gemcitabine 1000 mg/m2 IV on Days 1, 8, 
and 15 
Treatment 
Group C 
Epacadostat 
Pembrolizumab 
Paclitaxel and Carboplatin 
BID PO continuous 
daily dosing 
(see Table 1) 
200 mg IV Q3W 
• Paclitaxel 200 mg/m2 IV on Day 1 Q3W 
• Carboplatin AUC 6 IV on Day 1 Q3W 
Treatment 
Group D 
Epacadostat 
Pembrolizumab 
Pemetrexed and Platinum Agent 
BID PO continuous 
daily dosing 
(see Table 1) 
200 mg IV Q3W 
• Pemetrexed 500 mg/m2 IV on Day 1 Q3W  
• Investigators choice of platinum agent: 
Carboplatin AUC 5 IV on Day 1 Q3W or 
Cisplatin 75 mg/m2 on Day 1 Q3W 
Treatment 
Group E 
Epacadostat 
Pembrolizumab 
Cyclophosphamide 
BID PO continuous 
daily dosing 
(see Table 1) 
200 mg IV Q3W 
50 mg PO once daily 
Treatment 
Group F 
Epacadostat 
Pembrolizumab 
Gemcitabine and Platinum Agent 
BID PO continuous 
daily dosing 
(see Table 1) 
200 mg IV Q3W 
• Gemcitabine 1000 mg/m2 IV on Day 1 and 
Day 8 Q3W 
• Investigators choice of platinum agent: 
Carboplatin AUC 5 IV on Day 1 Q3W or 
Cisplatin 70 mg/m2 on Day 1 Q3W 
Treatment 
Group G 
Epacadostat 
Pembrolizumab 
Platinum Agent and 5-Fluorouracil 
BID PO continuous 
daily dosing 
(see Table 1) 
200 mg IV Q3W 
Investigator's choice of platinum agent:  
• Carboplatin AUC 5 IV on Day 1 Q3W or 
Cisplatin 100 mg/m2 IV  
• 5-Fluorouracil 1000 mg/m2 per day IV 
infusion on Days 1-4 (for a total dose of 
4000 mg/m2 over 96 hours) Q3W 
IV = intravenous; PO = orally. 
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4.1.2. 
Phase 2:  Efficacy Expansion and Mandatory Biopsy Cohorts 
Phase 2 efficacy expansion cohorts will evaluate the efficacy of the MTD or PAD of epacadostat 
determined in Phase 1 in combination with pembrolizumab and chemotherapy and to further 
evaluate the safety and tolerability of the combination.  The efficacy expansion cohorts will be 
limited to the following advanced or metastatic tumor types: 
1. CRC (Treatment Group A:  epacadostat + pembrolizumab + mFOLFOX6):  Simon 
2-Stage design 
2. PDAC (Treatment Group B:  epacadostat + pembrolizumab + 
nab-paclitaxel/gemcitabine):  Simon 2-Stage design 
3. Squamous NSCLC (Treatment Group C:  epacadostat + pembrolizumab + 
paclitaxel/carboplatin) 
4. Nonsquamous NSCLC (Treatment Group D:  epacadostat + pembrolizumab + 
pemetrexed/platinum agent) 
5. Any solid tumor that progressed on previous therapy with a PD-1 or PD-L1 inhibitor 
(Treatment Group E:  epacadostat + pembrolizumab + cyclophosphamide) 
6. UC (Treatment Group F:  epacadostat + pembrolizumab + gemcitabine/platinum agent) 
7. SCCHN (Treatment Group G:  epacadostat + pembrolizumab + platinum 
agent/5-fluorouracil) 
Enrollment in a specific efficacy expansion cohort in Phase 2 may begin after a minimum of 
6 subjects have been treated with epacadostat 100 mg BID in the corresponding treatment group 
in Phase 1 and there is ≤ 1 DLT in these 6 subjects. 
Continuous evaluation of toxicity events will be performed in the efficacy expansion cohorts.  If 
the cumulative incidence of treatment-related SAEs is > 40% and/or the cumulative incidence of 
≥ Grade 3 irAEs  is > 40% after 10 subjects are enrolled in a specific Phase 2 efficacy expansion 
cohort, further enrollment in that cohort will be interrupted until the sponsor, investigators, and 
health authorities (if applicable) determine an appropriate course of action.  If an efficacy 
expansion cohort is discontinued due to toxicity, a new cohort may be initiated at a lower dose of 
epacadostat. 
In addition to the efficacy expansion cohorts listed above, separate mandatory biopsy cohorts 
will be enrolled to evaluate changes in the tumor microenvironment.  For the cohorts where IV 
chemotherapy is administered, subjects will receive IV chemotherapy only during Cycle 1 
followed by epacadostat + pembrolizumab + IV chemotherapy starting with Cycle 2 Day 1.  For 
the CRC and PDAC cohorts, a minimum of 10 subjects with evaluable paired biopsy specimens 
will be enrolled.  A fresh tumor biopsy will be collected during screening.  On-treatment biopsies 
are mandatory and will be collected between Days 21 and 27 of Cycle 1 (IV chemotherapy only) 
and Cycle 2 (epacadostat + pembrolizumab + IV chemotherapy).  For the squamous NSCLC, 
nonsquamous NSCLC, UC, or SCCHN cohorts, a minimum of 10 subjects with evaluable paired 
biopsy specimens will be enrolled.  A fresh tumor biopsy will be collected during screening.  
On-treatment biopsies are mandatory and will be collected between Days 14 and 20 of Cycle 1 
(IV chemotherapy only) and Days 7 and 13 of Cycle 3 (epacadostat + pembrolizumab + IV 
chemotherapy).  For subjects with any advanced or metastatic solid tumor that progressed on 
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previous therapy with a PD-1 or PD-L1 inhibitor, a minimum of 5 subjects with evaluable paired 
biopsy specimens will be enrolled in the mandatory biopsy cohort; however, this cohort will be 
administered epacadostat, pembrolizumab, and cyclophosphamide starting on Cycle 1 Day 1.  A 
fresh tumor biopsy will be collected during screening, and an on-treatment biopsy is mandatory 
and will be collected between Days 7 and 13 of Cycle 3. 
If a subject is selected for inclusion in the mandatory biopsy cohort, and it is subsequently 
determined that tumor tissue cannot safely be obtained, or if the biopsy does not meet minimum 
standards for evaluation (as outlined in the Laboratory Manual), the subject may still enroll in the 
mandatory biopsy cohort and will be followed for efficacy and safety.  The subject may be 
replaced in order to enroll sufficient numbers of evaluable subjects with paired biopsies. 
Note:  As of 25 OCT 2018, on-treatment tumor biopsies are no longer required for subjects 
who are already enrolled in the mandatory biopsy cohorts. 
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Figure 1: 
Study Design 
 
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4.2. 
Measures Taken to Avoid Bias 
This is an open-label study.  Assessment of safety using CTCAE v4.0 and efficacy using 
RECIST v1.1 are objective measurements, and only comparisons to pretreatment conditions will 
be made. 
4.3. 
Number of Subjects 
4.3.1. 
Planned Number of Subjects 
Up to 421 subjects from up to 25 sites may be enrolled in the study: 
• Phase 1 – Approximately 42 to 126 evaluable subjects. 
• Phase 2 (Efficacy Expansion + Mandatory Biopsy) – Approximately 237 to 
295 evaluable subjects. 
As of 25 OCT 2018, this study is closed to enrollment.  A total of 70 subjects were enrolled.  
No subjects were enrolled in Phase 2 efficacy expansion (all treatment groups) or Phase 2 
mandatory biopsy Treatment Groups A, B, F, and G. 
4.3.2. 
Replacement of Subjects 
Subjects may be replaced for any of the following reasons: 
• Subject is not evaluable for DLTs (see Section 5.5.1.1). 
• In the Phase 2 mandatory biopsy cohorts, subject has not met the biopsy requirements 
for the study (ie, pre- and on-treatment samples). 
• Subject does not meet the eligibility requirements of the study (eg, accidental 
enrollment). 
4.4. 
Duration of Treatment and Subject Participation 
After signing the ICF, screening assessments may be completed over a period of up to 28 days.  
Each subject enrolled in the study may receive treatment in continuous 28-day (mFOLFOX6 or 
nab-paclitaxel/gemcitabine) or 21-day cycles (all other chemotherapy regimens) if, in the 
judgment of the investigator, the subject is receiving benefit from treatment and has not met any 
criteria for treatment discontinuation.   
Subjects who complete a standard duration of chemotherapy, or who must stop chemotherapy 
due to cumulative chemotherapy-related toxicities, may continue on pembrolizumab for a total of 
35 pembrolizumab infusions and epacadostat through the end of the cycle in which the 35th 
pembrolizumab infusion is administered.  Subjects may not start a new or different 
chemotherapy regimen during this period.  Unless a maximum number of chemotherapy cycles 
are noted in the Protocol (see Section 5.3), subjects may continue chemotherapy beyond the 
maximum administration of epacadostat or pembrolizumab at the discretion of the treating 
physician in line with local prescribing labels, treatment guidelines, and/or standards of care.  If 
subjects are continued on chemotherapy, contraception methods should continue for 180 days 
after the last dose of chemotherapy. 
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Subjects who must discontinue epacadostat due to epacadostat-related toxicities may continue 
pembrolizumab for a total of 35 pembrolizumab infusions.  Unless a maximum number of 
chemotherapy cycles are noted in the Protocol (see Section 5.3), subjects may continue 
chemotherapy beyond the maximum administration of pembrolizumab at the discretion of the 
treating physician in line with local prescribing labels, treatment guidelines, and/or standards of 
care.  If subjects are continued on chemotherapy, contraception methods should continue for 
180 days after the last dose of chemotherapy. 
Once a subject discontinues epacadostat and pembrolizumab, the subject will enter the follow-up 
period (see Section 6.4). 
Study participation, including post-treatment follow-up, is expected to average 16 months for an 
individual subject (mFOLFOX6:  18-24 months, nab-paclitaxel/gemcitabine:  8-12 months; 
paclitaxel/carboplatin:  12-18 months; pemetrexed/platinum agent:  12-18 months; 
cyclophosphamide:  4-6 months; gemcitabine/platinum agent:  8-12 months; platinum 
agent/5-fluorouracil:  8-12 months). 
4.5. 
Overall Study Duration 
The study begins when the first subject signs the ICF.  The end of the study will occur when all 
subjects have discontinued epacadostat and pembrolizumab and have completed the 30- and 
90-day safety follow-up assessments or a minimum of 18 weeks 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 18 weeks, 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 medications 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, AEs of special interest, and pregnancies, as detailed in 
Section 8.  The remaining subjects are considered to be on study until a discontinuation criterion 
is met and written notification is provided to the sponsor. 
4.6. 
Study Termination 
The investigator retains the right to terminate study participation at any time, according to the 
terms specified in the study contract.  The investigator is to notify the institutional review board 
(IRB)/independent ethics committee (IEC) in writing of the study's completion or early 
termination, 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, if required by regulatory decision, or upon 
review of emerging data.  If the study is terminated prematurely, the sponsor will notify the 
investigators, the IRBs and IECs, and regulatory bodies of the decision and reason for 
termination of the study. 
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5. 
TREATMENT 
5.1. 
Treatment Assignment 
5.1.1. 
Subject Numbering and Treatment Assignment 
Each subject will be identified in the study by a subject ID number, which is a combination of 
the site ID and subject number.  Site staff should contact the interactive response technology 
(IRT) to obtain the subject ID number during screening.  This subject ID number will be 
maintained throughout the study and will not be reassigned.  Subjects who fail screening and are 
repeating the screening process due to a change in eligibility status will be assigned a new 
subject ID number.  For subjects who signed an ICF but are not treated, refer to the electronic 
case report form (eCRF) Completion Guidelines for instructions on which eCRFs to complete. 
Site staff will contact the IRT to enroll the subject and obtain the initial assignment for the 
relevant treatments.  The investigator or designee will select the assigned treatments from the 
stock that correspond to the number provided by the IRT, record the unique identifiers in the 
eCRF, and dispense the treatment to the subject.  All subsequent dispensing of relevant 
treatments should follow this process.  Full details will be provided in the IRT manual. 
If a subject is mistakenly given treatment that is not assigned by the IRT, the IRT help desk must 
be notified immediately.  The reason for the misallocation of the treatment must be documented 
by the study site. 
5.1.2. 
Randomization and Blinding 
Not applicable. 
5.2. 
Study Drug 
5.2.1. 
Epacadostat 
5.2.1.1. 
Description and Administration 
Epacadostat will be self-administered orally BID without regard to food.  Doses will be taken in 
the morning and evening, approximately 12 hours apart.  If a dose is missed by more than 
4 hours, then that dose should be skipped, and the next dose should be taken at the next 
scheduled timepoint. 
For Phase 1 and Phase 2 efficacy expansion subjects enrolled in Treatment Groups A, B, C, D, E, 
F, and G, and the Phase 2 mandatory biopsy subjects enrolled in Treatment Group E, epacadostat 
will be administered beginning on Cycle 1 Day 1 and continuously thereafter.  For Phase 2 
subjects enrolled in the mandatory biopsy cohorts where IV chemotherapy is administered 
(Treatment Groups A, B, C, D, F, and G), epacadostat will be administered beginning on Cycle 2 
Day 1 and continuously thereafter.  Treatment will continue through the end of the cycle in 
which the 35th pembrolizumab infusion is administered if, in the investigator's judgment, the 
subject is receiving benefit from therapy and has not met any criteria for treatment 
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discontinuation (see Section 5.6.1).  Treatment will end the evening before the scheduled date of 
the subject's end-of-treatment (EOT) visit. 
Phase 1 subjects enrolled in Treatment Groups A, B, C, D, E, F, and G and Phase 2 efficacy 
expansion subjects enrolled in Treatment Groups A, B, E, F, and G will self-administer 
epacadostat except for the morning dose on Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 2 Day 1, 
where epacadostat will be given at the study site, 
 
.  On days when epacadostat is administered in the clinic, 
epacadostat should be taken before beginning the infusion of pembrolizumab. 
Phase 2 efficacy expansion subjects enrolled in Treatment Groups C and D will self-administer 
epacadostat except for the morning dose on Cycle 1 Day 1 and Cycle 2 Day 1, 
 
.  Subjects will skip 
their morning dose on Cycle 1 Day 1 dose and initiate epacadostat with the evening dose on 
Cycle 1 Day 1.  For Cycle 2 Day 1, epacadostat will be administered in the clinic before infusion 
of the chemotherapy regimens and pembrolizumab. 
5.2.1.2. 
Supply, Packaging, and Labeling 
Epacadostat will be available as 100-mg tablets packaged in high-density polyethylene bottles.  
All tablet excipients comply with the requirements of the applicable compendial monographs 
(Ph. Eur., USP/NF; refer to the eIB). 
All Incyte investigational product labels will be in the local language and will comply with the 
legal requirements of each country. 
5.2.1.3. 
Storage 
Bottles should be stored at room temperature (15°C to 30°C [59°F to 86°F]) and closed tightly to 
protect the tablets from humidity. 
5.3. 
Background Therapies 
5.3.1. 
Pembrolizumab 
5.3.1.1. 
Description and Administration 
Subjects will receive pembrolizumab 200 mg as a 30-minute IV infusion every 3 weeks.  Sites 
should make every effort to target infusion timing to be as close as possible to 30 minutes 
(-5 min/+10 min). 
For Phase 1 and Phase 2 efficacy expansion subjects enrolled in Treatment Groups A, B, C, D, E, 
F, and G, and for Phase 2 mandatory biopsy subjects enrolled in Treatment Group E, 
pembrolizumab will be administered starting on Cycle 1 Day 1.  For subjects enrolled in the 
Phase 2 mandatory biopsy cohorts where IV chemotherapy is administered (Treatment 
Groups A, B, C, D, F, and G), pembrolizumab will be administered starting on Cycle 2 Day 1. 
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Treatment will continue for a total of 35 pembrolizumab infusions if, in the investigator's 
judgment, the subject is receiving benefit from therapy and has not met any criteria for treatment 
discontinuation (see Section 5.6.1).  Dosing interruptions are permitted in the case of 
medical/surgical events or logistical reasons (ie, elective surgery, unrelated medical events, 
subject vacation, holidays) not related to study therapy.  Subjects should resume pembrolizumab 
within 3 weeks of the scheduled interruption.  The reason for interruption should be documented 
in the eCRF. 
Sites are instructed to consult the Pharmacy Manual for additional information and instructions 
for preparation and infusion of pembrolizumab. 
5.3.1.2. 
Supply, Packaging, and Labeling 
Pembrolizumab is available as a 100 mg/4 mL solution for injection and will be provided by 
Incyte.  The contents of the label will be in accordance with all applicable regulatory 
requirements. 
5.3.1.3. 
Storage 
Vials should be stored under refrigeration at 2°C to 8°C (36°F to 46°F).  Vials should be 
protected from light by being stored in the original package until time of use.  Do not freeze or 
shake.  Sites are instructed to consult the Pharmacy Manual for additional information on storage 
of pembrolizumab. 
5.3.2. 
Oxaliplatin, Leucovorin, 5-Fluorouracil 
5.3.2.1. 
Description and Administration 
Subjects may receive premedications based on institutional guidelines, investigator practice, or 
local prescribing information or standards of care.  All premedications must be recorded in the 
eCRF.   
Subjects must meet minimum criteria for start of each chemotherapy cycle as outlined in 
Appendix H, Section H.1. 
Subjects will receive oxaliplatin 85 mg/m2 IV given concurrently with leucovorin 400 mg/m2 IV 
over 2 hours (± 15 min; or equivalent dose and schedule based on institutional practice), 
followed by a 5-fluorouracil 400 mg/m2 IV bolus (administration time per institutional practice), 
then a 5-fluorouracil 1200 mg/m2 per day IV continuous infusion over 46 hours (for a total dose 
of 2400 mg/m2).  These 3 agents will be administered on Days 1 and 15 of each 28-day cycle.  
There is no limit to the number of cycles of mFOLFOX6.  Investigators may reduce or 
discontinue oxaliplatin for peripheral neuropathy; if discontinued, investigators have the option 
to discontinue 5-fluorouracil and leucovorin.   
In Phase 1 and Phase 2 efficacy expansion subjects enrolled in Treatment Group A, mFOLFOX6 
will be administered after epacadostat and pembrolizumab (if applicable) on Cycle 1 Day 1 and 
Cycle 2 Day 1 
. 
For Phase 2 mandatory biopsy subjects enrolled in Treatment Group A, only IV chemotherapy 
will be administered during Cycle 1, and epacadostat, pembrolizumab, and IV chemotherapy will 
be administered starting on Cycle 2 Day 1.   
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Sites are instructed to consult local prescribing information for additional information and 
instructions for preparation and infusion of 5-fluorouracil, leucovorin, and oxaliplatin. 
Subjects may receive prophylactic G-CSF support with filgrastim per institutional guidelines.  
Prophylactic G-CSF should not be given in the first cycle unless discussed with the medical 
monitor. 
5.3.2.2. 
Supply, Packaging, and Labeling 
In countries where 5-fluorouracil, leucovorin, oxaliplatin, or their generic equivalents are 
available, investigators are responsible for ensuring that subjects receive commercially available 
supplies of these therapies for the entire duration of study participation.  Incyte 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 these therapies.  The contents of 
the labels will be in accordance with all applicable regulatory requirements. 
5.3.3. 
nab-Paclitaxel and Gemcitabine 
5.3.3.1. 
Description and Administration 
Subjects may receive premedications based on institutional guidelines, investigator practice, or 
local prescribing information or standards of care.  All premedications must be recorded in the 
eCRF. 
Subjects must meet minimum criteria for start of each chemotherapy cycle as outlined in 
Appendix I, Section I.1. 
Subjects will receive nab-paclitaxel 125 mg/m2 IV over 30 minutes (± 5 min) followed by 
gemcitabine 1000 mg/m2 IV over 30 minutes (± 5 min) on Days 1, 8, and 15 of each 28-day 
cycle.  The infusion of nab-paclitaxel should be completed before beginning the infusion of 
gemcitabine.  There is no limit to the number of cycles of nab-paclitaxel/gemcitabine. 
In Phase 1 and Phase 2 efficacy expansion subjects enrolled in Treatment Group B, 
nab-paclitaxel/gemcitabine will be administered after epacadostat and pembrolizumab (if 
applicable) on Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 2 Day 1 
 
. 
For Phase 2 mandatory biopsy subjects enrolled in Treatment Group B, only IV chemotherapy 
will be administered during Cycle 1, and epacadostat, pembrolizumab, and IV chemotherapy will 
be administered starting on Cycle 2 Day 1. 
Sites are instructed to consult local prescribing information for additional information and 
instructions for preparation and infusion of nab-paclitaxel and gemcitabine. 
Subjects may receive prophylactic G-CSF support with filgrastim per institutional guidelines.  
Prophylactic G-CSF should not be given in the first cycle unless discussed with the medical 
monitor. 
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5.3.3.2. 
Supply, Packaging, and Labeling  
In countries where nab-paclitaxel or gemcitabine (or generic equivalent of gemcitabine) are 
available, investigators are responsible for ensuring that subjects receive commercially available 
supplies of these therapies for the entire duration of study participation.  Incyte 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 these therapies.  The contents of 
the labels will be in accordance with all applicable regulatory requirements. 
5.3.4. 
Paclitaxel and Carboplatin 
5.3.4.1. 
Description and Administration 
Subjects must receive premedications (IV or PO) with corticosteroids, H1- and H2-antagonists, 
and antiemetics based on institutional guidelines, investigator practice, or local prescribing 
information or standards of care.  All premedications must be recorded in the eCRF. 
Subjects must meet minimum criteria for start of each chemotherapy cycle as outlined in 
Appendix J, Section J.1. 
Subjects will receive paclitaxel 200 mg/m2 IV over 3 hours (± 15 min) followed by carboplatin 
AUC 6 IV over 30 minutes (± 5 min) on Day 1 of each 21-day cycle for a minimum of 4 cycles 
and maximum of 6 cycles.  The dose of carboplatin should be calculated based on local or 
institutional standards, and the maximum dose may be limited based on these standards.  The 
infusion of paclitaxel should be completed before beginning the infusion of carboplatin. 
In Phase 1 subjects enrolled in Treatment Group C, paclitaxel and carboplatin will be 
administered after epacadostat and pembrolizumab on Cycle 1 Day 1 and Cycle 2 Day 1 
 
.  Premedications should be administered approximately 
30 minutes after completion of the pembrolizumab infusion. 
In Phase 2 efficacy expansion subjects enrolled in Treatment Group C, paclitaxel and carboplatin 
will be administered before pembrolizumab on Cycle 1 Day 1 and Cycle 2 Day 1 
 
. 
For Phase 2 mandatory biopsy subjects enrolled in Treatment Group C, only IV chemotherapy 
will be administered during Cycle 1, and epacadostat, pembrolizumab, and IV chemotherapy will 
be administered starting on Cycle 2 Day 1. 
Sites are instructed to consult local prescribing information for additional information and 
instructions for preparation and infusion of paclitaxel and carboplatin. 
Subjects may receive prophylactic G-CSF support with filgrastim per institutional guidelines.  
Prophylactic G-CSF should not be given in the first cycle unless discussed with the medical 
monitor. 
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5.3.4.2. 
Supply, Packaging, and Labeling 
In countries where carboplatin, paclitaxel, or their generic equivalents are available, investigators 
are responsible for ensuring that subjects receive commercially available supplies of these 
therapies for the entire duration of study participation.  Incyte 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 these therapies.  The contents of the labels will 
be in accordance with all applicable regulatory requirements. 
5.3.5. 
Pemetrexed and Platinum Agent 
5.3.5.1. 
Description and Administration 
Subjects must receive premedications (IV or PO) with corticosteroids, antiemetics, and vitamin 
B12 and folic acid supplementation based on institutional guidelines, investigator practice, or 
local prescribing information or standards of care.  All premedications must be recorded in the 
eCRF.  Subjects receiving cisplatin must also receive hydration as per institutional guidelines. 
Subjects must meet minimum criteria for start of each chemotherapy cycle as outlined in 
Appendix K, Section K.1. 
Subjects will receive pemetrexed 500 mg/m2 IV over 10 minutes (± 5 min) followed by a 
platinum agent (carboplatin AUC 5 IV over 30 minutes [± 5 min] or cisplatin 75 mg/m2 IV over 
2 hours [± 5 min]) on Day 1 of each 21-day cycle for a minimum of 4 cycles and a maximum of 
6 cycles.  The dose of carboplatin should be calculated based on local or institutional standards, 
and the maximum dose may be limited based on these standards.  Pemetrexed may continue as 
maintenance therapy after the 6 cycles. 
In Phase 1 subjects enrolled in Treatment Group D, pemetrexed and platinum agent will be 
administered after epacadostat and pembrolizumab on Cycle 1 Day 1 and Cycle 2 Day 1 
 
.  Premedications should be administered approximately 
30 minutes after completion of the pembrolizumab infusion. 
In Phase 2 efficacy expansion subjects enrolled in Treatment Group D, pemetrexed and platinum 
agent will be administered before pembrolizumab on Cycle 1 Day 1 and Cycle 2 Day 1 
 
. 
For Phase 2 mandatory biopsy subjects enrolled in Treatment Group D, only IV chemotherapy 
will be administered during Cycle 1, and epacadostat, pembrolizumab, and IV chemotherapy will 
be administered starting on Cycle 2 Day 1. 
Sites are instructed to consult local prescribing information for additional information and 
instructions for preparation and infusion of pemetrexed and the applicable platinum agent. 
Subjects may receive prophylactic G-CSF support with filgrastim per institutional guidelines.  
Prophylactic G-CSF should not be given in the first cycle unless discussed with the medical 
monitor. 
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5.3.5.2. 
Supply, Packaging, and Labeling 
In countries where pemetrexed or carboplatin or cisplatin (or platinum agent generic equivalents) 
are available, investigators are responsible for ensuring that subjects receive commercially 
available supplies of these therapies for the entire duration of study participation.  Incyte 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 these therapies.  The 
contents of the labels will be in accordance with all applicable regulatory requirements. 
5.3.6. 
Cyclophosphamide 
5.3.6.1. 
Description and Administration 
Subjects may receive premedications based on institutional guidelines, investigator practice, or 
local prescribing information or standards of care.  All premedications must be recorded in the 
eCRF. 
Subjects must meet minimum criteria for start of each chemotherapy cycle as outlined in 
Appendix L, Section L.1. 
Subjects will self-administer cyclophosphamide 50 mg PO once daily of each 21-day cycle.  
There is no limit to the number of cycles of cyclophosphamide.  Sites are instructed to consult 
local prescribing information for additional information on cyclophosphamide. 
In Phase 1 and Phase 2 efficacy expansion subjects enrolled in Treatment Group E, 
cyclophosphamide will be administered after epacadostat and pembrolizumab (if applicable) on 
Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 2 Day 1 
 
. 
For Phase 1, Phase 2 efficacy expansion, and Phase 2 mandatory biopsy subjects enrolled in 
Treatment Group E, epacadostat, pembrolizumab, and cyclophosphamide will be administered 
starting on Cycle 1 Day 1. 
Subjects may receive prophylactic G-CSF support with filgrastim per institutional guidelines.  
Prophylactic G-CSF should not be given in the first cycle unless discussed with the medical 
monitor. 
5.3.6.2. 
Supply, Packaging, and Labeling 
Cyclophosphamide will be obtained from commercial supplies and will be reimbursed by Incyte.  
Investigators are responsible for ensuring that subjects receive commercially available supplies 
of cyclophosphamide for the entire duration of study participation.  Incyte may provide 
cyclophosphamide where required by applicable law or regulation or under other limited 
circumstances when a subject may not otherwise have access to these therapies.  The contents of 
the label will be in accordance with all applicable regulatory requirements. 
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5.3.7. 
Gemcitabine and Platinum Agent 
5.3.7.1. 
Description and Administration 
Subjects must receive premedications (IV or PO) with corticosteroids and antiemetics based on 
institutional guidelines, investigator practice, or local prescribing information or standards of 
care.  All premedications must be recorded in the eCRF.  Subjects receiving cisplatin must also 
receive hydration as per institutional guidelines. 
Subjects must meet minimum criteria for start of each chemotherapy cycle as outlined in 
Appendix M, Section M.1. 
Gemcitabine and platinum agent will be administered in a 21-day cycle for a maximum of 
6 cycles.  Subjects will receive gemcitabine 1000 mg/m2 over 30 minutes (± 5 min) on Days 1 
and 8.  Administration of a platinum agent (carboplatin AUC 5 IV over 30 minutes [± 5 min] or 
cisplatin 70 mg/m2 IV over 2 hours [± 5 min]) will follow the gemcitabine infusion on Day 1.  
The dose of carboplatin should be calculated based on local or institutional standards, and the 
maximum dose may be limited based on these standards. 
In Phase 1 and Phase 2 efficacy expansion subjects enrolled in Treatment Group F, applicable 
chemotherapy agent will be administered after epacadostat and pembrolizumab (if applicable) on 
Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 2 Day 1 
 
. 
For Phase 2 mandatory biopsy subjects enrolled in Treatment Group F, only IV chemotherapy 
will be administered during Cycle 1, and epacadostat, pembrolizumab, and IV chemotherapy will 
be administered starting on Cycle 2 Day 1. 
Sites are instructed to consult local prescribing information for additional information and 
instructions for preparation and infusion of gemcitabine and the applicable platinum agent. 
Subjects may receive prophylactic G-CSF support with filgrastim per institutional guidelines.  
Prophylactic G-CSF should not be given in the first cycle unless discussed with the medical 
monitor. 
5.3.7.2. 
Supply, Packaging, and Labeling 
In countries where carboplatin, cisplatin, gemcitabine, or their generic equivalents are available, 
investigators are responsible for ensuring that subjects receive commercially available supplies 
of these therapies for the entire duration of study participation.  Incyte 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 these therapies.  The contents of 
the labels will be in accordance with all applicable regulatory requirements. 
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5.3.8. 
Platinum Agent and 5-Fluorouracil 
5.3.8.1. 
Description and Administration 
Subjects must receive premedications (IV or PO) with corticosteroids and antiemetics based on 
institutional guidelines, investigator practice, or local prescribing information or standards of 
care.  All premedications must be recorded in the eCRF.  Subjects receiving cisplatin must also 
receive hydration as per institutional guidelines. 
Subjects must meet minimum criteria for start of each chemotherapy cycle as outlined in 
Appendix N, Section N.1. 
Subjects will receive a platinum agent (carboplatin AUC 5 IV over 30 minutes [± 5 min] or 
cisplatin 100 mg/m2 IV over 60 minutes [± 5 min]) on Day 1 of each 21-day cycle followed by 
5-fluorouracil 1000 mg/m2 per day IV continuous infusion on Days 1 through 4 (for a total dose 
of 4000 mg/m2 over 96 hours) of each 21-day cycle for a maximum of 6 cycles.  The dose of 
carboplatin should be calculated based on local or institutional standards, and the maximum dose 
may be limited based on these standards. 
In Phase 1 and Phase 2 efficacy expansion subjects enrolled in Treatment Group G, platinum 
agent/5-fluorouracil will be administered after epacadostat and pembrolizumab on Cycle 1 Day 1 
and Cycle 2 Day 1 
. 
For Phase 2 mandatory biopsy subjects enrolled in Treatment Group G, only IV chemotherapy 
will be administered during Cycle 1, and epacadostat, pembrolizumab, and IV chemotherapy will 
be administered starting on Cycle 2 Day 1.   
Sites are instructed to consult local prescribing information for additional information and 
instructions for preparation and infusion of applicable platinum agent and 5-fluorouracil. 
Subjects may receive prophylactic G-CSF support with filgrastim per institutional guidelines.  
Prophylactic G-CSF should not be given in the first cycle unless discussed with the medical 
monitor. 
5.3.8.2. 
Supply, Packaging, and Labeling 
In countries where carboplatin, cisplatin, 5-fluourouracil, or their generic equivalents are 
available, investigators are responsible for ensuring that subjects receive commercially available 
supplies of these therapies for the entire duration of study participation.  Incyte 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 these therapies.  The contents of 
the labels will be in accordance with all applicable regulatory requirements. 
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5.4. 
Treatment Compliance 
Epacadostat and cyclophosphamide are oral medications, and 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 site staff should 
evaluate compliance at each visit and take appropriate steps to optimize compliance. 
Pembrolizumab, 5-fluorouracil, leucovorin, oxaliplatin, carboplatin, cisplatin, paclitaxel, 
pemetrexed, gemcitabine, and nab-paclitaxel 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. 
5.5. 
Treatment Interruptions and Adjustments 
5.5.1. 
Dose Modifications 
Modifications to epacadostat dosing are planned for the Phase 1 cohorts (see Section 4.1.1).  
Dose modifications in the form of reductions, interruption, or discontinuation of components of 
the chemotherapy regimen and/or interruption or discontinuation of pembrolizumab or 
epacadostat may also be needed for individual subjects in the event of a DLT or AE (related or 
unrelated to treatment).  Intrasubject dose escalation for epacadostat, pembrolizumab, or any 
chemotherapy drug is not permitted. 
5.5.1.1. 
Dose-Limiting Toxicity and Determination of Maximum Tolerated Dose 
A DLT will be defined as the occurrence of any of the toxicities in Table 3 occurring up to and 
including Day 28 for the cohorts where mFOLFOX6 and nab-paclitaxel/gemcitabine are 
administered and Day 21 for all other chemotherapy regimens in Phase 1, except those with a 
clear alternative explanation (eg, disease progression) or transient (≤ 72 hours) abnormal 
laboratory values without associated clinically significant signs or symptoms based on 
investigator determination.  Immune-related AEs of Grade 3 that improve to Grade 1 or lower 
within 14 days after the initiation of supportive care or corticosteroid therapy can be deemed a 
non-DLT.  All DLTs will be assessed by the investigator using CTCAE v4.0 criteria 
(Appendix E).  To be considered evaluable for dose tolerability, subjects should meet 1 of the 
following criteria:  1) receive the cohort-specified dose of epacadostat, pembrolizumab, and 
chemotherapy for at least 80% of planned doses (45 doses epacadostat/2 doses pembrolizumab 
for subjects who receive mFOLFOX6 or nab-paclitaxel/gemcitabine; 34 doses 
epacadostat/1 dose pembrolizumab for subjects who receive any other chemotherapy regimen) 
and complete the DLT observation period, or 2) had a DLT during the DLT observation period. 
It is recognized that certain toxicities due to chemotherapy (eg, including but not limited to 
gastrointestinal toxicity, including diarrhea; renal insufficiency; high-grade laboratory 
abnormalities; hypersensitivity/rash) may initially be clinically indistinguishable from toxicities 
due to immunotherapy.  Epacadostat will be held for these toxicities, and as a result, subjects 
may not receive at least 80% of the prescribed dose during Cycle 1.  In these cases, the SMC 
may assess subjects who receive dose intensities somewhat below 80% for the determination of 
DLTs, and consider in the adjudication process the specific toxicities encountered, likely cause 
of toxicities, and dose intensity and tolerability beyond Cycle 1. 
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Individual subject dose reductions may be made based on events observed at any time during 
treatment with epacadostat; however, for the purposes of dose cohort de-escalation, expanding a 
dose cohort, and determining the MTD of epacadostat, decisions will be made based on events 
that are observed from the first day of epacadostat administration through and including the final 
day of Cycle 1 (Day 28 for the cohorts where mFOLFOX6 and nab-paclitaxel/gemcitabine are 
administered and Day 21 for all other chemotherapy regimens).  A lower MTD of epacadostat 
may subsequently be determined based on relevant toxicities that become evident after Day 28 
for the cohorts where mFOLFOX6 and nab-paclitaxel/gemcitabine are administered and Day 21 
for all other chemotherapy regimens. 
Table 3: 
Definition of Dose-Limiting Toxicity 
Toxicity 
Nonhematologic 
• Grade 4 (life-threatening) irAE. 
• Grade 4 (life-threatening) vomiting or diarrhea. 
• Grade 4 (life-threatening) electrolyte abnormality. 
• Any ≥ Grade 3 nonhematologic toxicity EXCEPT: 
− Transient (≤ 72 hours) abnormal laboratory values without associated clinically significant signs or symptoms. 
− Grade 3 nausea, vomiting, and diarrhea adequately controlled with medical therapy within 48 hours. 
− Grade 3 rash in the absence of desquamation, with no mucosal involvement, that does not require systemic 
steroids and that resolves to Grade 1 in ≤ 14 days.  
− An event clearly associated with the underlying disease, disease progression, a concomitant medication, or 
comorbidity. 
− 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). 
− Grade 3 irAE that improves to ≤ Grade 1 in ≤ 14 days by appropriate care or with corticosteroid therapy. 
Hematologic 
• ≥ Grade 3 thrombocytopenia with clinically significant bleeding (requires hospitalization, transfusion of blood 
products, or other urgent medical intervention).  
• Grade 4 thrombocytopenia of any duration. 
• Grade 4 neutropenia lasting > 3 days. 
• ≥ Grade 3 febrile neutropenia (ANC < 1.0 × 109/L and fever > 101°F/38.3°C). 
• Grade 4 anemia not explained by underlying disease. 
5.5.1.1.1. Management of Dose-Limiting Toxicities or Other Urgent Situations 
In all cases, investigators may employ any measures or concomitant medications, after 
discussion with the sponsor (whenever possible), necessary to optimally treat the subject. 
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5.5.1.1.2. Follow-Up of Dose-Limiting Toxicities 
Any DLT should be followed until it resolves to baseline or appears to have stabilized for a 
minimum of 30 days, unless the subject discontinues epacadostat and pembrolizumab, in which 
case, the subject will be followed for 90 days after the last dose of epacadostat or pembrolizumab 
(whichever is later; see Section 8).  During follow-up, subjects should be seen as often as 
medically indicated to ensure safety. 
5.5.1.2. 
Procedures for Cohort Review and Dose De-Escalation 
Regular telephone conferences will be scheduled by the sponsor with study investigators in order 
to review cohort-specific data and overall safety data, agree on dose de-escalation, adjudicate 
individual high-grade AEs as potentially dose-limiting, and guide other major study decisions. 
5.5.2. 
Criteria and Procedures for Dose Reductions or Interruptions of Epacadostat 
and/or Pembrolizumab 
Dose reductions of epacadostat for the management of AEs are not permitted; however, 
administration may be delayed for management of toxicities (see Section 5.5.3 and Appendix G).  
Except in cases of emergency, it is recommended that the investigator consult with the medical 
monitor (or other representative of the sponsor) before temporarily interrupting therapy for 
reasons other than Protocol-mandated medication hold.  Additionally, the investigator must 
notify the sponsor's medical monitor and study project manager via email before restarting 
epacadostat that was temporarily interrupted because of an AE. 
For specific guidance for interruption of epacadostat in the event of SS, see Section 5.5.6. 
Dose reductions of pembrolizumab for the management of AEs is not permitted; however, 
administration may be delayed for management of toxicities (see Section 5.5.3 and Appendix G). 
Dose interruptions of epacadostat and/or pembrolizumab may be permitted in the case of 
medical/surgical events or logistical reasons not related to study therapy (eg, elective surgery, 
unrelated medical events, subject vacation, and/or holidays).  Subjects will be placed back on 
study therapy within 3 weeks of the scheduled interruption.  The reason for interruption should 
be documented in the eCRF. 
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5.5.3. 
Management of Immune-Related Adverse Events 
Adverse events associated with epacadostat and/or pembrolizumab exposure may represent an 
immunologic etiology.  These immune-related AEs (irAEs) may occur shortly after the first dose 
or several months after the last dose of epacadostat and/or pembrolizumab treatment and may 
affect more than 1 body system simultaneously.  Therefore, early recognition and initiation of 
treatment is critical to reduce complications.  Based on existing clinical study data, most irAEs 
were reversible and could be managed with interruptions of epacadostat and/or pembrolizumab, 
administration of corticosteroids and/or other supportive care.  For suspected irAEs, ensure 
adequate evaluation to confirm etiology or exclude other causes.  Additional procedures or tests 
such as bronchoscopy, endoscopy, or skin biopsy may be included as part of the evaluation.  
Based on the severity of irAEs, withhold or permanently discontinue epacadostat and/or 
pembrolizumab and administer corticosteroids.  Dose modification and toxicity management 
guidelines for irAEs associated with epacadostat and/or pembrolizumab are provided in 
Appendix G.  Subjects who develop a ≥ Grade 2 irAE should be discussed immediately with the 
sponsor. 
It is important to note that some chemotherapy-related AEs will overlap with potential irAEs 
(including but not limited to gastrointestinal toxicity, including diarrhea; renal insufficiency; 
high-grade laboratory abnormalities; rash/hypersensitivity).  In these cases, both the 
chemotherapy-related AE (see Section 5.5.4) and irAE management guidance (Appendix G) 
should be reviewed to determine the most appropriate management of therapy. 
5.5.4. 
Management of Chemotherapy-Related Adverse Events 
Dose modifications for hematologic and nonhematologic AEs related to chemotherapy may be 
managed per institutional guidelines.  In the absence of these, recommendations for dose 
modifications for the applicable chemotherapy regimen in the event of hematologic and 
nonhematologic AEs are provided in the Protocol appendices: 
• Appendix H for subjects who receive mFOLFOX6  
• Appendix I for subjects who receive nab-paclitaxel/gemcitabine  
• Appendix J for subjects who receive paclitaxel/carboplatin 
• Appendix K for subjects who receive pemetrexed/platinum agent 
• Appendix L for subjects who receive cyclophosphamide  
• Appendix M for subjects who receive gemcitabine/platinum agent 
• Appendix N for subjects who receive platinum agent/5-fluorouracil 
It is important to note that some chemotherapy-related AEs will overlap with potential irAEs 
(including but not limited to gastrointestinal toxicity, including diarrhea; renal insufficiency; 
high-grade laboratory abnormalities; rash/hypersensitivity).  In these cases, both the 
chemotherapy-related AE and irAE management guidance (Appendix G) should be reviewed to 
determine the most appropriate management of therapy. 
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5.5.5. 
Treatment After Initial Radiologic Evidence of Disease Progression  
Immunotherapeutic agents such as epacadostat and/or pembrolizumab may produce antitumor 
effects by potentiating endogenous cancer-specific immune responses.  The response patterns 
seen with immunotherapeutic agents may extend beyond the typical time course of responses 
seen with cytotoxic agents and can manifest as a clinical response after an initial increase in 
tumor burden or even the appearance of new lesions. 
RECIST v1.1 will be adapted for defining PD to account for the unique tumor response seen 
with immunotherapies.  This adaptation is known as irRECIST and will be used to guide 
treatment decisions for discontinuation of therapy due to disease progression.  These disease 
assessments will be performed by the study site. 
If radiographic imaging shows PD, it is at the discretion of the investigator to keep a subject on 
treatment or to stop treatment until imaging is repeated ≥ 4 weeks (but not ≥ 6 weeks) later in 
order to confirm PD.  When feasible, subjects should not be discontinued until progression is 
confirmed.  The decision to continue treatment after the first evidence of disease progression is at 
the investigator's discretion and should be based on the clinical status of the subject as described 
in Table 4. 
Subjects may receive treatment while waiting for confirmation of PD if they are clinically stable 
as defined by the following criteria: 
• Absence of clinically significant signs and symptoms (including worsening of 
laboratory values) indicating disease progression. 
• No decline in ECOG performance status. 
• Absence of rapid progression of disease. 
• Absence of progressive tumor at critical anatomical sites (eg, spinal cord 
compression) requiring urgent alternative medical intervention. 
Subjects who are clinically unstable are not required to have repeat imaging for the confirmation 
of PD. 
In subjects who discontinue study therapy without documented disease progression, every effort 
should be made to continue monitoring their disease status by radiologic imaging until the 
subject has confirmed PD, starts a new anticancer therapy, withdraws consent, or dies. 
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Table 4: 
Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
First radiologic 
evidence of PD  
Repeat imaging at 
≥ 4 weeks to confirm 
PD. 
May continue 
treatment at the 
investigator's 
discretion while 
awaiting 
confirmatory scan. 
Repeat imaging at 
≥ 4 weeks to confirm 
PD, if possible. 
Discontinue 
treatment. 
Repeat scan 
confirms PD  
No additional 
imaging required. 
Discontinue 
treatment. 
No additional 
imaging required. 
N/A 
Repeat scan shows 
SD, PR, or CR 
Continue regularly 
scheduled imaging 
assessments. 
Continue treatment 
at the investigator's 
discretion. 
Continue regularly 
scheduled imaging 
assessments. 
May restart 
treatment if 
condition has 
improved and/or is 
clinically stable per 
investigator's 
discretion. 
5.5.6. 
Procedure for Subjects Exhibiting Serotonin Syndrome 
There is a rare chance that epacadostat could cause an increase in serotonin levels in the brain 
that might trigger SS when administered in combination with other serotonergic agents.  This 
syndrome has been most closely associated with use of MAOIs, meperidine, linezolid, or 
methylene blue; all of these agents are prohibited during the study.  Selective serotonin reuptake 
inhibitors (SSRIs) and selective serotonin/norepinephrine reuptake inhibitors (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 (see Table 5) 
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, including tremor; 
hyperreflexia; and spontaneous, ocular, or inducible clonus, together with agitation, fever, 
diaphoresis, or muscle rigidity: 
• Immediately interrupt epacadostat, pembrolizumab, and chemotherapy (if applicable) 
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 SS are excluded, pembrolizumab and chemotherapy (if 
applicable) administration may be resumed unless other AE management guidelines 
apply for the specific event. 
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• 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 subject experiences moderate or severe unconfounded SS in the opinion of the 
investigator, without concomitant SSRI or SNRI usage, or serotonergic concomitant 
medications, only pembrolizumab administration may be resumed; epacadostat 
treatment should be permanently discontinued. 
Table 5: 
Sign and Symptoms of Serotonin Syndrome 
Seriousness 
Autonomic Signs 
Neurological Signs 
Mental Status 
Other 
Mild 
Afebrile or low-grade 
fever 
Intermittent tremor 
Restlessness 
– 
Tachycardia 
Akathisia 
Anxiety 
– 
Mydriasis 
Myoclonus 
– 
– 
Diaphoresis or 
shivering 
Mild hyperreflexia 
– 
– 
Moderate 
Increased tachycardia 
Hyperreflexia 
Easily startled 
Rhabdomyolysis 
Fever (up to 41ºC) 
Inducible clonus 
Increased 
confusion 
Metabolic acidosis 
Diarrhea with 
hyperactive bowel 
sounds 
Ocular clonus (slow 
continuous lateral eye 
movements) 
Agitation and 
hypervigilance 
Renal failure 
Diaphoresis with 
normal skin color 
Myoclonus 
– 
Disseminated 
intravascular 
coagulopathy 
(secondary to 
hyperthermia) 
Severe 
Temperature often 
more than 41ºC 
(secondary to increased 
tone) 
Increased muscle tone 
(lower limb > upper) 
Delirium 
As above 
– 
Spontaneous clonus 
Coma 
– 
– 
Substantial myoclonus 
or hyperreflexia 
 
– 
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5.6. 
Discontinuation of Subjects From Study Treatment 
5.6.1. 
Discontinuation Criteria 
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 in the study is inappropriate, the study 
plan is violated, or for administrative and/or other safety reasons.   
Subjects must be discontinued from treatment for the following reasons: 
• Unacceptable AEs as described in Appendix G, Table G-1 with a requirement to 
permanently discontinue. 
• The subject becomes pregnant.  
• Consent is withdrawn by the subject. 
Note:  Consent withdrawn means that the subject can no longer be followed and no 
additional data can be collected. 
• Further participation would be injurious to the subject's health or well-being, in the 
investigator's medical judgment. 
• Confirmed radiographic progression of disease per irRECIST.  See Section 5.5.5, 
Section 7.6.2.1, and Appendix F. 
• The subject has an unacceptable toxicity or a toxicity that does not recover in 
12 weeks.  Investigators who wish to continue treatment after a treatment delay of 
12 weeks should consult with the sponsor's medical monitor for approval. 
• The subject has completed 35 infusions of pembrolizumab and completed epacadostat 
treatment through the end of the cycle in which the 35th pembrolizumab infusion is 
administered.  If the subject has discontinued epacadostat for epacadostat-related 
toxicities but continued on pembrolizumab monotherapy, the subject must be 
discontinued after 35 infusions of pembrolizumab. 
• The study is terminated by the sponsor. 
• The study is terminated by the local health authority, IRB, or IEC. 
A subject may be discontinued from treatment as follows: 
• The subject has attained a confirmed CR and has been treated for at least 24 weeks 
with epacadostat and pembrolizumab and had at least 2 infusions of pembrolizumab 
beyond the date of initial CR. 
• If, during the course of the study, a subject is found not to have met eligibility 
criteria, the medical monitor, in collaboration with the investigator, will determine 
whether the subject should be withdrawn from the study. 
• If a subject is noncompliant with study procedures or epacadostat administration in 
the investigator's opinion, the sponsor should be consulted for instruction on handling 
the subject. 
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5.6.2. 
Discontinuation Procedures 
Discontinuation of epacadostat and pembrolizumab does not constitute study withdrawal or 
completion.  The subject will proceed to the safety follow-up period when epacadostat and 
pembrolizumab are permanently discontinued.  The EOT visit should be conducted whenever 
possible except when subjects are physically unable to travel to the site for the EOT visit, have 
withdrawn consent, or are lost to follow up.  Reasonable efforts should be made to have the 
subject return for the safety follow-up visit to have procedures completed as described in 
Section 6.  The date the subject was discontinued from epacadostat and pembrolizumab and the 
specific reason for discontinuation will be recorded in the eCRF. 
If a subject is discontinued from epacadostat and pembrolizumab: 
• The study monitor or sponsor must be notified. 
• The reason(s) for the discontinuation must be documented in the subject's medical 
record and in the eCRF. 
• The EOT or early termination visit should be performed. 
• The date epacadostat and pembrolizumab was discontinued should be recorded in the 
IRT. 
• Subjects must be followed for safety until the time of the follow-up visit or until 
epacadostat–related or pembrolizumab–related toxicities resolve, return to baseline, 
or are deemed irreversible, whichever is longer. 
5.7. 
Procedures for Withdrawal From Study 
If the subject discontinues epacadostat and pembrolizumab and actively withdraws consent for 
collection of follow-up data (ie, subsequent anticancer treatments and safety follow-up), then no 
additional data collection should occur.  The date the subject was withdrawn from the study will 
be recorded in the eCRF. 
5.8. 
Concomitant Medications 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the study.  If there is a clinical indication for one of these or other medications, 
discontinuation from study therapy may be required.  The investigator should discuss any 
questions regarding this with the sponsor.  The final decision on any supportive therapy rests 
with the investigator and/or the subject's primary physician.  However, the decision to continue 
the subject on study therapy requires the mutual agreement of the investigator, the sponsor, and 
the subject. 
All concomitant medications received within 28 days before Cycle 1 Day 1 and 90 days after the 
last dose of epacadostat or pembrolizumab (whichever is later) should be recorded.  Concomitant 
medications administered in the 90 days after the last dose of epacadostat or pembrolizumab 
(whichever is later) should be recorded for SAEs and AEs as defined in Section 8. 
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5.8.1. 
Permitted (Acceptable) 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. 
5.9. 
Restricted Medications 
• Systemic steroids may be used at doses ≤ 10 mg/day prednisone or equivalents. 
• 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 may require dose modification.  If an alternative to coumarin-based 
anticoagulants cannot be used, close INR monitoring is recommended. 
• 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. 
5.10. 
Prohibited Medications/Treatment 
Subjects are prohibited from receiving the following therapies starting from screening through 
EOT period of this study unless otherwise noted below: 
• Any investigational medication other than epacadostat, pembrolizumab, or the 
assigned chemotherapy regimen. 
• Any anticancer medications, including chemotherapy, immunotherapy, or biologic 
therapy other than epacadostat, pembrolizumab, or the assigned chemotherapy 
regimen. 
• Any chronic immunosuppressive treatment for any reason. 
Note:  Inhaled or topical steroids, systemic steroids at doses ≤ 10 mg/day of 
prednisone or equivalents, systemic steroids for short-term treatment of irAEs, or 
systemic steroids for prophylaxis of contrast allergy for imaging procedures, or 
systemic steroids for prophylaxis of chemotherapy-related AEs are allowed. 
• Radiation therapy. 
Note:  In the presence of a mixed response (some lesions improving or stable and 
other lesions progressing), radiation therapy to a symptomatic solitary lesion or to the 
brain may be allowed after discussion with the medical monitor.  
• Administration of a live attenuated vaccine within 30 days before the first dose of 
treatment and while participating in the study.  Examples of live vaccines include, but 
are not limited to, the following:  measles, mumps, rubella, chicken pox, yellow 
fever, rabies, BCG, and typhoid vaccine.  Seasonal influenza vaccines for injection 
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are generally killed virus vaccines and are allowed; however, intranasal influenza 
vaccines are live attenuated vaccines and are not allowed. 
• Any MAOI or drug associated with significant MAOI activity agents is prohibited 
from 21 days before Day 1 through 2 weeks after the final dose of epacadostat has 
been administered (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, 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 3.2) describe other medications that are prohibited during this 
study.  There are no prohibited therapies during the post-treatment follow-up period. 
5.10.1. 
Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Appendix G, Table G-1.  Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do not 
improve with administration of corticosteroids.  Several courses of steroid tapering may be 
necessary as symptoms may worsen when the steroid dose is decreased.  For each disorder, 
attempts should be made to rule out other causes such as metastatic disease or bacterial or viral 
infection, which might require additional supportive care.  It may be necessary to perform 
conditional procedures such as bronchoscopy, endoscopy, or skin photography as part of 
evaluation of the event. 
The dose modification and supportive care guidelines are intended to be applied when the 
investigator determines the events to be related to epacadostat and/or pembrolizumab.  If after 
the evaluation of the event, it is determined not to be related to pembrolizumab and/or 
epacadostat, the investigator does not need to follow the dose modification and supportive care 
guidelines.   
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Additionally, 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. 
• Diarrhea:  See Appendix G, Table G-1. 
• Infection:  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. 
• Infusion-related reactions with pembrolizumab:  See Appendix G, Section G.3. 
6. 
STUDY ASSESSMENTS 
NOTE:  As of Amendment 7, subjects will only be required to visit the clinic per standard of 
care.  Safety (including laboratory analytes) assessments that are consistent with the standard of 
care for the subject's condition should be performed via local labs.  Disease status should 
continue to be monitored by computerized tomography (CT), magnetic resonance imaging 
(MRI), or PET-CT scan as appropriate at a frequency consistent with the standard of care for the 
subject's disease. 
As of Amendment 7, data will only be collected for informed consent, SAEs, AEs leading to 
discontinuation, EOT disposition (reason for discontinuation), drug accountability, dosing 
information, end of study (EOS) disposition (end of study form), and death if it occurs within the 
safety reporting period.  See Table 6 for protocol-required assessments to limit clinic visits and 
procedures for subjects.  Only Table 6 should be followed by all subjects in all cohorts 
continuing on-treatment beyond Amendment 7.  All other tables in this section may be 
disregarded. 
All study assessments will be performed as indicated in the schedule of assessments (Table 7, 
Table 9, Table 11, Table 12, and Table 14) and all laboratory assessments will be performed as 
indicated in Table 8, Table 10, Table 13, and Table 15.  Table 16 presents a summary of clinical 
laboratory analytes to be assessed.  See Section 7 for instructions on each assessment.  Further 
details of study procedures and assessments can be found in the Study Reference Manual. 
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Table 6: 
Schedule of Assessments for ALL Ongoing Subjects After Amendment 7 Approval 
Procedures 
Treatment 
Period 
EOT 
Safety Follow Up 
30-Day 
Safety Follow up 
90-Day 
Comments 
Informed consent 
X 
 
 
 
For subjects treated beyond initial progression the date of the 
consent will also be collected. 
Concomitant medications 
X 
X 
 
 
Review to ensure no prohibited medications are being used.  
Provide data to Sponsor about SAEs only. 
Drug dispensing/contact IVRS 
X 
 
 
 
Dispense drug (epacadostat) on Day 1 of each cycle 
Assess compliance 
X 
X 
 
 
 
Administer pembrolizumab 
X 
 
 
 
Pembrolizumab should be administered every 3 weeks per standard 
of care from Cycle 1 Day 1 for up to 35 infusions. 
AE/SAE assessments 
X 
X 
X 
X 
AEs that lead to the discontinuation of study treatment and all SAEs 
must be recorded in the CRFs, regardless of the causal relationship. 
*Sites should follow up with subjects 90 days post-treatment to 
confirm any SAEs that occurred during the 90-day safety reporting 
period have been submitted and entered into the EDC system. 
Laboratory assessments 
X 
 
 
 
Local laboratory tests should be performed at each site as per 
standard of care for subject's condition and monitoring per 
investigator discretion (eg, hematology and chemistry).  Data will 
not be collected unless related to an SAE. 
Radiographic tumor assessments 
X 
 
 
 
Performed per standard of care schedule.  Data will not be collected 
beyond Week 18. 
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Table 7: 
Schedule of Assessments for Phase 1 or Phase 2 Efficacy Expansion Subjects in Treatment Group A or 
Treatment Group B 
Visit 
Screening 
Treatment
a 
EOT 
Follow-Up 
Comments 
Cycle 1, 4, 7+ 
Cycle 2, 5, 8+ 
Cycle 3, 6, 9+ 
Q9W 
Safety
b 
Disease 
Status 
Survival 
D1 
D8 D15 D22 D1 
D8 D15 D1 
D8 D15 
Evaluation Window 
Day -28  
to -1 
 
±3d ±3d ±3d ±3d ±3d ±3d ±3d ±3d ±3d 
±7d 
+7d 
30 d 
After 
EOT 
(±7d) 
90 d 
After 
EOT 
(±7d) 
Q9W 
After 
EOT 
(±7d) 
Q12W 
(±7d) 
Administrative procedures 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Contact IRT 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medical and cancer history 
(tumor-specific) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X* 
X 
X 
X 
X* 
X 
X 
X* 
X 
 
X 
X 
X 
 
 
* D8 for Cycles 1, 2, 3, 6, 9, 12, etc for 
all subjects.  D8 for Cycles 4, 5, 7, 8, 
10, 11, etc only for subjects who 
receive nab-paclitaxel/ gemcitabine. 
Dispense epacadostat 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
Post-treatment anticancer 
therapy status 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
Survival follow-up 
(Phase 2 only) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Clinical procedures/assessments 
Comprehensive physical 
examination and height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted physical examination 
 
X 
X* 
X 
X 
X 
X* 
X 
X 
X* 
X 
 
X 
X 
X 
 
 
* D8 for Cycles 1, 2, 3, 6, 9, 12, etc for 
all subjects.  D8 for Cycles 4, 5, 7, 8, 
10, 11, etc only for subjects who 
receive nab-paclitaxel/ gemcitabine.  
Vital signs and weight 
X 
X 
X* 
X 
X 
X 
X* 
X 
X 
X* 
X 
 
X 
X 
X 
 
 
* D8 for Cycles 1, 2, 3, 6, 9, 12, etc for 
all subjects.  D8 for Cycles 4, 5, 7, 8, 
10, 11, etc only for subjects who 
receive nab-paclitaxel/ gemcitabine. 
ECOG performance status 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
 
 
 
Laboratory assessments 
X 
X 
X* 
X 
X 
X 
X* 
X 
X 
X* 
X 
 
X 
X 
X 
 
 
* D8 for Cycles 1, 2, 3, 6, 9, 12, etc for 
all subjects.  D8 for Cycles 4, 5, 7, 8, 
10, 11, etc only for subjects who 
receive nab-paclitaxel/ gemcitabine. 
Tumor biopsy (Phase 2 only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsy is required for Phase 2 
efficacy expansion subjects at 
screening.  See Section 7.9 for biopsy 
requirements. 
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Table 7: 
Schedule of Assessments for Phase 1 or Phase 2 Efficacy Expansion Subjects in Treatment Group A or 
Treatment Group B (Continued) 
Visit 
Screening 
Treatmenta 
EOT 
Follow-Up 
Comments 
Cycle 1, 4, 7+ 
Cycle 2, 5, 8+ 
Cycle 3, 6, 9+ 
Q9W 
Safetyb 
Disease 
Status 
Survival 
D1 
D8 D15 D22 D1 
D8 D15 D1 
D8 D15 
Evaluation Window 
Day -28  
to -1 
 
±3d ±3d ±3d ±3d ±3d ±3d ±3d ±3d ±3d 
±7d 
+7d 
30 d 
After 
EOT 
(±7d) 
90 d 
After 
EOT 
(±7d) 
Q9W 
After 
EOT 
(±7d) 
Q12W 
(±7d) 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
All 12-lead ECGs will be performed 
with the subject in a recumbent or 
semirecumbent position after 5 minutes 
of rest and should not be performed 
within 15 minutes after a blood 
collection.  Electrocardiograms may be 
performed throughout the treatment 
period as clinically indicated. 
AE assessment 
X 
X 
X* 
X 
X 
X 
X* 
X 
X 
X* 
X 
 
X 
X 
X 
 
 
* D8 for Cycles 1, 2, 3, 6, 9, 12, etc for 
all subjects.  D8 for Cycles 4, 5, 7, 8, 
10, 11, etc only for subjects who 
receive nab-paclitaxel/ gemcitabine. 
Study drug or reference therapy administration 
Administer epacadostat in clinic 
 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Epacadostat will be administered in the 
clinic for any study visit 
 
.  Epacadostat should 
be administered before pembrolizumab 
and chemotherapy. 
Administer pembrolizumab 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
 
 
 
 
Pembrolizumab should be administered 
every 3 weeks from Cycle 1 D1 and 
before IV chemotherapy (mFOLFOX6 
or nab-paclitaxel/gemcitabine). 
Administer mFOLFOX6 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
 
 
 
 
 
See Section 5.3 for order of 
administration. 
Administer gemcitabine/ 
nab-paclitaxel 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
See Section 5.3 for order of 
administration. 
Efficacy measurements 
Radiologic tumor assessments 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
X 
 
The same imaging technique should be 
used in a subject throughout the study.  
If imaging shows PD, an imaging 
assessment should be performed at a 
minimum of 4 weeks and maximum of 
6 weeks later to confirm PD per 
irRECIST. 
See Section 7.6.2 for information on 
imaging frequency. 
a Treatment cycles are every 28 days (± 3 days). 
b The mandatory safety follow-up visits should be conducted approximately 30 days and 90 days after the EOT visit or before the initiation of a new anticancer treatment, whichever comes first.  If an 
EOT visit was not conducted, the last dose of epacadostat or pembrolizumab (whichever is later) should be used as the start of the safety follow-up period. 
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Table 8: 
Laboratory Assessments for Phase 1 or Phase 2 Efficacy Expansion Subjects in Treatment Group A or 
Treatment Group B 
Visit 
Screening
a 
Treatment 
EOT 
Safety Follow-Up 
Comments 
Cycle 1, 4, 7+ 
Cycle 2, 5, 8+ 
Cycle 3, 6, 9+ 
Q9W 
30 d 
After 
EOT 
(±7d) 
90 d 
After 
EOT  
(±7d) 
D1 D8 
D15 D22 D1 
D8 D15 D1 
D8 D15 
Evaluation Window 
Day -28  
to -1 
 
±3d ±3d ±3d ±3d ±3d ±3d ±3d ±3d ±3d 
±7d 
+7d 
Laboratory assessments
b 
Comprehensive serum 
chemistry 
X 
X 
X* 
X 
X 
X 
X* 
X 
X 
X* 
X 
 
X 
X 
X 
Additional assessment of serum chemistry may be 
conducted as clinically indicated. 
* D8 for Cycles 1, 2, 3, 6, 9, 12, etc for all subjects.  D8 for 
Cycles 4, 5, 7, 8, 10, 11, etc only for subjects who receive 
nab-paclitaxel/gemcitabine. 
Hematology with 
differential 
X 
X 
X* 
X 
X 
X 
X* 
X 
X 
X* 
X 
 
X 
X 
X 
Additional assessment of hematology with differential may 
be conducted as clinically indicated. 
* D8 for Cycles 1, 2, 3, 6, 9, 12, etc for all subjects.  D8 for 
Cycles 4, 5, 7, 8, 10, 11, etc only for subjects who receive 
nab-paclitaxel/gemcitabine. 
Liver chemistry tests 
X 
X 
X* 
X 
X 
X 
X* 
X 
X 
X* 
X 
 
X 
X 
X 
Additional assessment of liver chemistry may be conducted 
as clinically indicated. 
* D8 for Cycles 1, 2, 3, 6, 9, 12, etc for all subjects.  D8 for 
Cycles 4, 5, 7, 8, 10, 11, etc only for subjects who receive 
nab-paclitaxel/gemcitabine. 
Coagulation panel 
X 
X* 
 
 
 
 
 
 
 
 
 
 
X 
 
 
More frequent monitoring during treatment is required if 
subject is on warfarin. 
* Not required on D1 of Cycles 4, 7, 10, etc. 
Endocrine function tests 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
Required for D1 of Cycle 1, Cycle 2, and Cycle 3.  For D1 
of subsequent cycles, required every 3 cycles starting with 
Cycle 6 (ie, Cycles 6, 9, 12, etc).  Not required for D1 on 
Cycles 4, 5, 7, 8, 10, 11, etc. 
Urinalysis 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
Required for D1 of Cycle 1, Cycle 2, and Cycle 3.  For D1 
of subsequent cycles, required every 3 cycles starting with 
Cycle 6 (ie, Cycles 6, 9, 12, etc).  Not required for D1 on 
Cycles 4, 5, 7, 8, 10, 11, etc. 
Serum pregnancy test 
(childbearing females 
only) 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
A serum pregnancy test is required for all women of 
childbearing potential during screening and must be within 
72 hours of Cycle 1 D1. 
Urine pregnancy test 
(childbearing females 
only) 
 
X* 
 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
* Not required on Cycle 1 D1.  Required on D1 of each 
cycle starting on Cycle 2. 
See Section 7.5.5.7 for further details. 
Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 8: 
Laboratory Assessments for Phase 1 or Phase 2 Efficacy Expansion Subjects in Treatment Group A or 
Treatment Group B (Continued) 
Visit 
Screeninga 
Treatment 
EOT 
Safety Follow-Up 
Comments 
Cycle 1, 4, 7+ 
Cycle 2, 5, 8+ 
Cycle 3, 6, 9+ 
Q9W 
30 d 
After 
EOT 
(±7d) 
90 d 
After 
EOT  
(±7d) 
D1 D8 
D15 D22 D1 
D8 D15 D1 
D8 D15 
Evaluation Window 
Day -28  
to -1 
 
±3d ±3d ±3d ±3d ±3d ±3d ±3d ±3d ±3d 
±7d 
+7d 
a If screening safety and eligibility laboratory assessments are performed within 7 days of Cycle 1 Day 1, then the Cycle 1 Day 1 assessments may be omitted. 
b All safety laboratory assessments will be performed locally.  See Table 16 for a list of analytes. 
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Table 9: 
Schedule of Assessments for Phase 2 Mandatory Biopsy Subjects in Treatment Group A or Treatment Group B 
(Continued) 
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Table 9: 
Schedule of Assessments for Phase 2 Mandatory Biopsy Subjects in Treatment Group A or Treatment Group B 
(Continued) 
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Table 9: 
Schedule of Assessments for Phase 2 Mandatory Biopsy Subjects in Treatment Group A or Treatment Group B 
(Continued) 
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Table 10: 
Laboratory Assessments for Phase 2 Mandatory Biopsy Subjects in Treatment Group A or Treatment Group B 
Visit 
Screening
a 
Treatment 
EOT 
Safety Follow-
Up 
Comments 
Cycle 1 
Cycle 2, 5, 8+ 
Cycle 3, 6, 9+ 
Cycle 4, 7, 10+ 
Q9W 
30 d 
After 
EOT 
(±7d) 
90 d 
After 
EOT 
(±7d) 
D1 
D8 
D15 
D1 
D8 
D15 
D22 
D1 
D8 D15 D1 
D8 
D15 
Evaluation Window 
Day -28  
to -1 
 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d ±3d ±3d ±3d ±3d ±3d 
±3d 
±7d 
+7d 
Laboratory assessments
b 
Comprehensive 
serum chemistry 
X 
X 
X* 
X 
X 
X* 
X 
X 
X 
X* 
X 
X 
X* 
X 
 
X 
X 
X 
Additional assessment of serum chemistry 
may be conducted as clinically indicated. 
* D8 for Cycles 1, 2, 3, 4, 7, 10, 13, etc for 
all subjects.  D8 for Cycles 5, 6, 8, 9, 11, 
12, etc only for subjects who receive 
nab-paclitaxel/ gemcitabine. 
Hematology with 
differential 
X 
X 
X* 
X 
X 
X* 
X 
X 
X 
X* 
X 
X 
X* 
X 
 
X 
X 
X 
Additional assessment of hematology with 
differential may be conducted as clinically 
indicated. 
* D8 for Cycles 1, 2, 3, 4, 7, 10, 13, etc for 
all subjects.  D8 for Cycles 5, 6, 8, 9, 11, 
12, etc only for subjects who receive 
nab-paclitaxel/ gemcitabine. 
Liver chemistry tests 
X 
X 
X* 
X 
X 
X* 
X 
X 
X 
X* 
X 
X 
X* 
X 
 
X 
X 
X 
Additional assessment of liver chemistry 
may be conducted as clinically indicated. 
* D8 for Cycles 1, 2, 3, 4, 7, 10, 13, etc for 
all subjects.  D8 for Cycles 5, 6, 8, 9, 11, 
12, etc only for subjects who receive 
nab-paclitaxel/ gemcitabine. 
Coagulation panel 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
More frequent monitoring during treatment 
is required if subject is on warfarin. 
Endocrine function 
tests 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Required for D1 of Cycle 1, Cycle 2, and 
Cycle 3.  For D1 of subsequent cycles, 
required every 3 cycles starting with 
Cycle 6 (ie, Cycles 6, 9, 12, etc).  Not 
required for D1 on Cycles 5, 8, 11, etc. 
Urinalysis 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Required for D1 of Cycle 1, Cycle 2, and 
Cycle 3.  For D1 of subsequent cycles, 
required every 3 cycles starting with 
Cycle 6 (ie, Cycles 6, 9, 12, etc).  Not 
required for D1 on Cycles 5, 8, 11, etc. 
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Table 10: 
Laboratory Assessments for Phase 2 Mandatory Biopsy Subjects in Treatment Group A or Treatment Group B 
(Continued) 
Visit 
Screeninga 
Treatment 
EOT 
Safety Follow-
Up 
Comments 
Cycle 1 
Cycle 2, 5, 8+ 
Cycle 3, 6, 9+ 
Cycle 4, 7, 10+ 
Q9W 
30 d 
After 
EOT 
(±7d) 
90 d 
After 
EOT 
(±7d) 
D1 
D8 
D15 
D1 
D8 
D15 
D22 
D1 
D8 D15 D1 
D8 
D15 
Evaluation Window 
Day -28  
to -1 
 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d ±3d ±3d ±3d ±3d ±3d 
±3d 
±7d 
+7d 
Serum pregnancy test 
(childbearing females 
only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
A serum pregnancy test is required for all 
women of childbearing potential during 
screening and must be within 72 hours of 
Cycle 1 D1. 
Urine pregnancy test 
(childbearing females 
only) 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
Required on D1 of each cycle starting on 
Cycle 2.  See Section 7.5.5.7 for further 
details. 
Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Correlative samples 
Whole blood for 
correlative studies 
 
X 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Required for Cycle 1 (D1, D8, D15), 
Cycle 2 (D1), and Cycle 3 (D1).  For D1 of 
subsequent cycles, required every 3 cycles 
starting with Cycle 6 (ie, Cycles 6, 9, 12, 
etc).  Not required for D1 on Cycles 5, 8, 
11, etc. 
Plasma for 
correlative studies 
 
X 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Required for Cycle 1 (D1, D8, D15), 
Cycle 2 (D1), and Cycle 3 (D1).  For D1 of 
subsequent cycles, required every 3 cycles 
starting with Cycle 6 (ie, Cycles 6, 9, 12, 
etc).  Not required for D1 on Cycles 5, 8, 
11, etc. 
a If screening safety and eligibility laboratory assessments are performed within 7 days of Cycle 1 Day 1, then the Cycle 1 Day 1 assessments may be omitted. 
b All safety laboratory assessments will be performed locally.  See Table 16 for a list of analytes. 
CONFIDENTIAL 


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Table 11: 
Schedule of Assessments for Phase 1 or Phase 2 Efficacy Expansion Subjects in Treatment Group C, Treatment 
Group D, Treatment Group F, and Treatment Group G 
Visit 
Screening 
Treatment
a 
EOT 
Follow-Up 
Comments 
Cycle 1 
Cycle 2 
Cycle 3+ 
Q9W 
Safety
b 
Disease 
Status Survival 
D1 D8 D15 D1 
D8 D15 D1 
D8 
Evaluation Window 
Day -28  
to -1 
 
±3d ±3d ±3d ±3d ±3d ±3d ±3d 
±7d 
+7d 
30 d 
After 
EOT 
(±7d) 
90 d  
After 
EOT 
(±7d) 
Q9W 
After 
EOT 
(±7d) 
Q12W 
(±7d) 
Administrative procedures 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Contact IRT 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medical and cancer 
history (tumor-specific) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X* 
 
X 
X 
X 
 
 
* D8 visit for Cycles 3-6 is required for subjects in Treatment 
Group F only.  D8 visits from Cycle 7 onwards are not required, as 
subjects receive gemcitabine on D8 for a maximum of 6 cycles. 
Dispense epacadostat 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Post-treatment 
anticancer therapy status 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Survival follow-up 
(Phase 2 only) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical procedures/assessments 
Comprehensive physical 
examination and height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted physical 
examination 
 
X 
X 
X 
X 
X 
X 
X 
X* 
 
X 
X 
X 
 
 
* D8 visit for Cycles 3-6 is required for subjects in Treatment 
Group F only.  D8 visits from Cycle 7 onwards are not required, as 
subjects receive gemcitabine on D8 for a maximum of 6 cycles. 
Vital signs and weight 
X 
X 
X 
X 
X 
X 
X 
X 
X* 
 
X 
X 
X 
 
 
* D8 visit for Cycles 3-6 is required for subjects in Treatment 
Group F only.  D8 visits from Cycle 7 onwards are not required, as 
subjects receive gemcitabine on D8 for a maximum of 6 cycles. 
ECOG performance 
status 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
 
Laboratory assessments 
X 
X 
X 
X 
X 
X 
X 
X 
X* 
 
X 
X 
X 
 
 
* D8 visit for Cycles 3-6 is required for subjects in Treatment 
Group F only.  D8 visits from Cycle 7 onwards are not required, as 
subjects receive gemcitabine on D8 for a maximum of 6 cycles. 
Tumor biopsy  
(Phase 2 only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsy is required for Phase 2 efficacy expansion subjects at 
screening.  See Section 7.9 for biopsy requirements. 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
All 12-lead ECGs will be performed with the subject in a recumbent 
or semirecumbent position after 5 minutes of rest and should not be 
performed within 15 minutes after a blood collection.  
Electrocardiograms may be performed throughout the treatment 
period as clinically indicated. 
CONFIDENTIAL 


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Table 11: 
Schedule of Assessments for Phase 1 or Phase 2 Efficacy Expansion Subjects in Treatment Group C, Treatment 
Group D, Treatment Group F, and Treatment Group G (Continued) 
Visit 
Screening 
Treatmenta 
EOT 
Follow-Up 
Comments 
Cycle 1 
Cycle 2 
Cycle 3+ 
Q9W 
Safetyb 
Disease 
Status Survival 
D1 D8 D15 D1 
D8 D15 D1 
D8 
Evaluation Window 
Day -28  
to -1 
 
±3d ±3d ±3d ±3d ±3d ±3d ±3d 
±7d 
+7d 
30 d 
After 
EOT 
(±7d) 
90 d  
After 
EOT 
(±7d) 
Q9W 
After 
EOT 
(±7d) 
Q12W 
(±7d) 
AE assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X* 
 
X 
X 
X 
 
 
* D8 visit for Cycles 3-6 is required for subjects in Treatment 
Group F only.  D8 visits from Cycle 7 onwards are not required, as 
subjects receive gemcitabine on D8 for a maximum of 6 cycles. 
Study drug or reference therapy administration 
Administer epacadostat 
in clinic 
 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
For all Phase 1 subjects and Phase 2 efficacy expansion subjects in 
Treatment Groups F and G.  See Section 7.5.4 and Section 7.8.1.1 
for further details. 
Administer epacadostat 
in clinic 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
For Phase 2 efficacy expansion subjects in Treatment Group C and 
D.  See Section 7.5.4, Section 7.8.1.2, and Section 7.8.1.3 for further 
details. 
Administer 
pembrolizumab 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
For all Phase 1 subjects and Phase 2 efficacy expansion subjects in 
Treatment Groups F and G, pembrolizumab should be administered 
before IV chemotherapy.  
For Phase 2 efficacy expansion subjects in Treatment Groups C and 
D, pembrolizumab should be administered after IV chemotherapy. 
Administer carboplatin 
or cisplatin 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
See Section 5.3 for order of administration and maximum number 
of cycles. 
Administer paclitaxel 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
See Section 5.3 for order of administration and maximum number 
of cycles. 
Administer pemetrexed 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
See Section 5.3 for order of administration and maximum number 
of cycles. 
Administer gemcitabine 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
 
 
 
 
See Section 5.3 for order of administration and maximum number 
of cycles.   
Administer  
5-fluorouracil 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
See Section 5.3 for order of administration and maximum number 
of cycles. 
Efficacy measurements 
Radiologic tumor 
assessments 
X 
 
 
 
 
 
 
 
 
X 
X 
 
 
X 
 
The same imaging technique should be used in a subject throughout 
the study.  If imaging shows PD, an imaging assessment should be 
performed at a minimum of 4 weeks and maximum of 6 weeks later 
to confirm PD per irRECIST. 
See Section 7.6.2 for information on imaging frequency. 
a Treatment cycles are every 21 days (± 3 days). 
b The mandatory safety follow-up visits should be conducted approximately 30 days and 90 days after the EOT visit or before the initiation of a new anticancer treatment, whichever comes first.  If an 
EOT visit was not conducted, the last dose of epacadostat or pembrolizumab (whichever is later) should be used as the start of the safety follow-up period. 
CONFIDENTIAL 


Incyte Corporation 
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Protocol INCB 24360-207 Am 7 
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Table 12: 
Schedule of Assessments for Phase 1, Phase 2 Efficacy Expansion, or Phase 2 Mandatory Biopsy Subjects in 
Treatment Group E 
Visit 
Screening 
Treatment
a 
EOT 
Follow-Up 
Comments 
Cycle 1 
Cycle 2 
Cycle 3+ 
Q9W 
Safety
b 
Disease 
Status 
Survival 
D1 
D8 D15 D1 
D8 D15 D1 D10 
Evaluation Window 
Day -28  
to -1 
 
±3d ±3d ±3d ±3d ±3d ±3d ±3d 
±7d 
+7d 
30 d 
After 
EOT 
(±7d) 
90 d 
After 
EOT 
(±7d) 
Q9W 
After 
EOT 
(±7d) 
Q12W 
(±7d) 
Administrative procedures 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Contact IRT 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medical and 
cancer history 
(tumor-specific) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
 
Dispense epacadostat 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
Dispense 
cyclophosphamide 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
There is no limit to the maximum number of cycles of 
cyclophosphamide. 
Post-treatment 
anticancer therapy 
status 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
Survival follow-up 
(Phase 2 only) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Clinical procedures/assessments 
Comprehensive 
physical examination 
and height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted physical 
examination 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
 
Vital signs and 
weight 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
 
ECOG performance 
status 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
 
 
CONFIDENTIAL 


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Protocol INCB 24360-207 Am 7 
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Table 12: 
Schedule of Assessments for Phase 1, Phase 2 Efficacy Expansion, or Phase 2 Mandatory Biopsy Subjects in 
Treatment Group E (Continued) 
Visit 
Screening 
Treatmenta 
EOT 
Follow-Up 
Comments 
Cycle 1 
Cycle 2 
Cycle 3+ 
Q9W 
Safetyb 
Disease 
Status 
Survival 
D1 
D8 D15 D1 
D8 D15 D1 D10 
Evaluation Window 
Day -28  
to -1 
 
±3d ±3d ±3d ±3d ±3d ±3d ±3d 
±7d 
+7d 
30 d 
After 
EOT 
(±7d) 
90 d 
After 
EOT 
(±7d) 
Q9W 
After 
EOT 
(±7d) 
Q12W 
(±7d) 
Laboratory 
assessments 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
 
Tumor biopsy  
(Phase 2 only) 
X 
 
 
 
 
 
 
 
X* 
 
 
 
 
 
 
Screening biopsy is required for all Phase 2 efficacy 
expansion and mandatory biopsy subjects. 
* On-treatment biopsy is required for Phase 2 mandatory 
biopsy subjects only and will occur during Cycle 3 between 
D7 and D13. 
See Section 7.9 for biopsy requirements.   
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
All 12-lead ECGs will be performed with the subject in a 
recumbent or semirecumbent position after 5 minutes of 
rest and should not be performed within 15 minutes after a 
blood collection.  Electrocardiograms may be performed 
throughout the treatment period as clinically indicated. 
AE assessment 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
 
Study drug or reference therapy administration 
Administer 
epacadostat in clinic 
(Phase 1 and Phase 2 
efficacy expansion 
only) 
 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Section 7.8.1.1 for further details. 
Administer 
pembrolizumab 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
Efficacy measurements 
Radiologic tumor 
assessments 
X 
 
 
 
 
 
 
 
 
X 
X 
 
 
X 
 
The same imaging technique should be used in a subject 
throughout the study.  If imaging shows PD, an imaging 
assessment should be performed at a minimum of 4 weeks 
and maximum of 6 weeks later to confirm PD per 
irRECIST. 
See Section 7.6.2 for information on imaging frequency. 
a Treatment cycles are every 21 days (± 3 days). 
b The mandatory safety follow-up visits should be conducted approximately 30 days and 90 days after the EOT visit or before the initiation of a new anticancer treatment, whichever comes first.  If an 
EOT visit was not conducted, the last dose of epacadostat or pembrolizumab (whichever is later) should be used as the start of the safety follow-up period. 
CONFIDENTIAL 


Incyte Corporation 
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14 FEB 2019 
Table 13: 
Laboratory Assessments for Phase 1 or Phase 2 Efficacy Expansion Subjects in Treatment Group C, Treatment 
Group D, Treatment Group E, Treatment Group F, and Treatment Group G 
Visit 
Screening
a 
Treatment 
EOT 
Safety Follow-Up 
Comments 
Cycle 1 
Cycle 2 
Cycle 3+ 
Q9W 
30 d 
After 
EOT 
(±7d) 
90 d 
After 
EOT  
(±7d) 
D1 
D8 
D15 
D1 
D8 
D15 
D1 
D8 
Evaluation Window 
Day -28  
to -1 
 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±7d 
+7d 
Laboratory assessments
b 
Comprehensive serum chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X* 
 
X 
X 
X 
Additional assessment of serum chemistry may be 
conducted as clinically indicated. 
* D8 visit for Cycles 3-6 is required for subjects in 
Treatment Group F only.  D8 visits from Cycle 7 
onwards are not required, as subjects receive 
gemcitabine on D8 for a maximum of 6 cycles. 
Hematology with differential 
X 
X 
X 
X 
X 
X 
X 
X 
X* 
 
X 
X 
X 
Additional assessment of hematology with differential 
may be conducted as clinically indicated. 
* D8 visit for Cycles 3-6 is required for subjects in 
Treatment Group F only.  D8 visits from Cycle 7 
onwards are not required, as subjects receive 
gemcitabine on D8 for a maximum of 6 cycles 
Liver chemistry tests 
X 
X 
X 
X 
X 
X 
X 
X 
X* 
 
X 
X 
X 
Additional assessment of liver chemistry may be 
conducted as clinically indicated.  
* D8 visit for Cycles 3-6 is required for subjects in 
Treatment Group F only.  D8 visits from Cycle 7 
onwards are not required, as subjects receive 
gemcitabine on D8 for a maximum of 6 cycles 
Coagulation panel 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Endocrine function tests 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Required for D1 of Cycle 1, Cycle 2, and Cycle 3.  For 
D1 of subsequent cycles, required every 3 cycles 
starting with Cycle 6 (ie, Cycles 6, 9, 12, etc). 
Urinalysis 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Required for D1 of Cycle 1, Cycle 2, and Cycle 3.  For 
D1 of subsequent cycles, required every 3 cycles 
starting with Cycle 6 (ie, Cycles 6, 9, 12, etc). 
Serum pregnancy test  
(childbearing females only) 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
A serum pregnancy test is required for all women of 
childbearing potential during screening and must be 
within 72 hours of Cycle 1 D1. 
Urine pregnancy test 
(childbearing females only) 
 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
See Section 7.5.5.7 for further details. 
Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 


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Protocol INCB 24360-207 Am 7 
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Table 13: 
Laboratory Assessments for Phase 1 or Phase 2 Efficacy Expansion Subjects in Treatment Group C, Treatment 
Group D, Treatment Group E, Treatment Group F, and Treatment Group G (Continued) 
Visit 
Screeninga 
Treatment 
EOT 
Safety Follow-Up 
Comments 
Cycle 1 
Cycle 2 
Cycle 3+ 
Q9W 
30 d 
After 
EOT 
(±7d) 
90 d 
After 
EOT  
(±7d) 
D1 
D8 
D15 
D1 
D8 
D15 
D1 
D8 
Evaluation Window 
Day -28  
to -1 
 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±7d 
+7d 
a If screening safety and eligibility laboratory assessments are performed within 7 days of Cycle 1 D1, then the Cycle 1 D1 assessments may be omitted. 
b All safety laboratory assessments will be performed locally.  See Table 16 for a list of analytes. 
CONFIDENTIAL 


Incyte Corporation 
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Protocol INCB 24360-207 Am 7 
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14 FEB 2019 
Table 14: 
Schedule of Assessments for Phase 2 Mandatory Biopsy Subjects in Treatment Group C, Treatment Group D, 
Treatment Group F, and Treatment Group G 
Visit 
Screening 
Treatment
a 
EOT 
Follow-Up 
Comments 
Cycle 1 
Cycle 2 
Cycle 3+ 
Q9W 
Safety
b 
Disease 
Status 
Survival 
D1 
D8 
D15 D17 D1 
D8 D15 D1 
D8 D10 
Evaluation Window 
Day -28  
to -1 
 
±3d ±3d ±3d ±3d ±3d ±3d ±3d ±3d ±3d 
±7d 
+7d 
30 d 
After 
EOT 
(±7d) 
90 d 
After 
EOT 
(±7d) 
Q9W 
After 
EOT 
(±7d) 
Q12W 
(±7d) 
Administrative procedures 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Contact IRT 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medical and cancer 
history (tumor-specific) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
X 
X 
X 
 
X 
X 
X 
X 
X* 
 
X 
X 
X 
 
 
* D8 visit for Cycles 3-6 is required for subjects 
in Treatment Group F only.  D8 visits from 
Cycle 7 onwards are not required, as subjects 
receive gemcitabine on D8 for a maximum of 
6 cycles. 
Dispense epacadostat 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
Post-treatment 
anticancer therapy status 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Survival follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical procedures/assessments 
Comprehensive physical 
examination and height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted physical 
examination 
 
X 
X 
X 
 
X 
X 
X 
X 
X* 
 
 
X 
X 
X 
 
 
* D8 visit for Cycles 3-6 is required for subjects 
in Treatment Group F only.  D8 visits from 
Cycle 7 onwards are not required, as subjects 
receive gemcitabine on D8 for a maximum of 
6 cycles. 
Vital signs and weight 
X 
X 
X 
X 
 
X 
X 
X 
X 
X* 
 
 
X 
X 
X 
 
 
* D8 visit for Cycles 3-6 is required for subjects 
in Treatment Group F only.  D8 visits from 
Cycle 7 onwards are not required, as subjects 
receive gemcitabine on D8 for a maximum of 
6 cycles. 
ECOG performance 
status 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
 
 
Laboratory assessments 
X 
X 
X 
X 
 
X 
X 
X 
X 
X* 
 
 
X 
X 
X 
 
 
* D8 visit for Cycles 3-6 is required for subjects 
in Treatment Group F only.  D8 visits from 
Cycle 7 onwards are not required, as subjects 
receive gemcitabine on D8 for a maximum of 
6 cycles. 
CONFIDENTIAL 


Incyte Corporation 
Page 104 of 203 
Protocol INCB 24360-207 Am 7 
Version 7 
14 FEB 2019 
Table 14: 
Schedule of Assessments for Phase 2 Mandatory Biopsy Subjects in Treatment Group C, Treatment Group D, 
Treatment Group F, and Treatment Group G (Continued) 
Visit 
Screening 
Treatmenta 
EOT 
Follow-Up 
Comments 
Cycle 1 
Cycle 2 
Cycle 3+ 
Q9W 
Safetyb 
Disease 
Status 
Survival 
D1 
D8 
D15 D17 D1 
D8 D15 D1 
D8 D10 
Evaluation Window 
Day -28  
to -1 
 
±3d ±3d ±3d ±3d ±3d ±3d ±3d ±3d ±3d 
±7d 
+7d 
30 d 
After 
EOT 
(±7d) 
90 d 
After 
EOT 
(±7d) 
Q9W 
After 
EOT 
(±7d) 
Q12W 
(±7d) 
Tumor biopsy 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
Tumor biopsy is required for Phase 2 mandatory 
biopsy subjects at screening and on-treatment. 
Biopsies will occur during Cycle 1 between D14 
and D20 and Cycle 3 between D7 and D13. 
See Section 7.9 for biopsy requirements.   
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
All 12-lead ECGs will be performed with the 
subject in a recumbent or semirecumbent 
position after 5 minutes of rest and should not be 
performed within 15 minutes after a blood 
collection.  Electrocardiograms may be 
performed throughout the treatment period as 
clinically indicated. 
AE assessment 
X 
X 
X 
X 
 
X 
X 
X 
X 
X* 
 
 
X 
X 
X 
 
 
* D8 visit for Cycles 3-6 is required for subjects 
in Treatment Group F only.  D8 visits from 
Cycle 7 onwards are not required, as subjects 
receive gemcitabine on D8 for a maximum of 
6 cycles. 
Study drug or reference therapy administration 
Administer 
pembrolizumab 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
Pembrolizumab should be administered before 
IV chemotherapy. 
Administer carboplatin 
or cisplatin 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
See Section 5.3 for order of administration and 
maximum number of cycles. 
Administer paclitaxel 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
See Section 5.3 for order of administration and 
maximum number of cycles. 
Administer pemetrexed 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
See Section 5.3 for order of administration and 
maximum number of cycles. 
Administer gemcitabine 
 
X 
X 
 
 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
See Section 5.3 for order of administration and 
maximum number of cycles. 
Administer  
5-fluorouracil 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
See Section 5.3 for order of administration and 
maximum number of cycles. 
CONFIDENTIAL 


Incyte Corporation 
Page 105 of 203 
Protocol INCB 24360-207 Am 7 
Version 7 
14 FEB 2019 
Table 14: 
Schedule of Assessments for Phase 2 Mandatory Biopsy Subjects in Treatment Group C, Treatment Group D, 
Treatment Group F, and Treatment Group G (Continued) 
Visit 
Screening 
Treatmenta 
EOT 
Follow-Up 
Comments 
Cycle 1 
Cycle 2 
Cycle 3+ 
Q9W 
Safetyb 
Disease 
Status 
Survival 
D1 
D8 
D15 D17 D1 
D8 D15 D1 
D8 D10 
Evaluation Window 
Day -28  
to -1 
 
±3d ±3d ±3d ±3d ±3d ±3d ±3d ±3d ±3d 
±7d 
+7d 
30 d 
After 
EOT 
(±7d) 
90 d 
After 
EOT 
(±7d) 
Q9W 
After 
EOT 
(±7d) 
Q12W 
(±7d) 
Efficacy measurements 
Radiologic tumor 
assessments 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
X 
 
The same imaging technique should be used in a 
subject throughout the study.  If imaging shows 
PD, an imaging assessment should be performed 
at a minimum of 4 weeks and maximum of 
6 weeks later to confirm PD per irRECIST.   
See Section 7.6.2 for information on imaging 
frequency. 
a Treatment cycles are every 21 days (± 3 days). 
b The mandatory safety follow-up visits should be conducted approximately 30 days and 90 days after the EOT visit or before the initiation of a new anticancer treatment, whichever comes first.  If an 
EOT visit was not conducted, the last dose of epacadostat or pembrolizumab (whichever is later) should be used as the start of the safety follow-up period. 
CONFIDENTIAL 


Incyte Corporation 
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Table 15: 
Laboratory Assessments for Phase 2 Mandatory Biopsy Subjects in Treatment Group C, Treatment Group D, 
Treatment Group E, Treatment Group F, and Treatment Group G 
Visit 
Screening
a 
Treatment 
EOT 
Safety Follow-Up 
Comments 
Cycle 1 
Cycle 2 
Cycle 3+ 
Q9W 
30 d 
After 
EOT 
(±7d) 
90 d After 
EOT  
(±7d) 
D1 
D8 
D15 
D1 
D8 
D15 
D1 
D8 
Evaluation Window 
Day -28  
to -1 
 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±7d 
+7d 
Laboratory assessments
b 
Comprehensive serum 
chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X* 
 
X 
X 
X 
Additional assessment of serum chemistry may be 
conducted as clinically indicated.  
* D8 visit for Cycles 3-6 is required for subjects in 
Treatment Group F only.  D8 visits from Cycle 7 onwards 
are not required, as subjects receive gemcitabine on D8 for 
a maximum of 6 cycles. 
Hematology with differential 
X 
X 
X 
X 
X 
X 
X 
X 
X* 
 
X 
X 
X 
Additional assessment of hematology with differential may 
be conducted as clinically indicated. 
* D8 visit for Cycles 3-6 is required for subjects in 
Treatment Group F only.  D8 visits from Cycle 7 onwards 
are not required, as subjects receive gemcitabine on D8 for 
a maximum of 6 cycles. 
Liver chemistry tests 
X 
X 
X 
X 
X 
X 
X 
X 
X* 
 
X 
X 
X 
Additional assessment of liver chemistry may be conducted 
as clinically indicated. 
* D8 visit for Cycles 3-6 is required for subjects in 
Treatment Group F only.  D8 visits from Cycle 7 onwards 
are not required, as subjects receive gemcitabine on D8 for 
a maximum of 6 cycles. 
Coagulation panel 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Endocrine function tests 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Required for D1 of Cycle 1, Cycle 2, and Cycle 3.  For D1 
of subsequent cycles, required every 3 cycles starting with 
Cycle 6 (ie, Cycles 6, 9, 12, etc). 
Urinalysis 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Required for D1 of Cycle 1, Cycle 2, and Cycle 3.  For D1 
of subsequent cycles, required every 3 cycles starting with 
Cycle 6 (ie, Cycles 6, 9, 12, etc). 
Serum pregnancy test  
(childbearing females only) 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
A serum pregnancy test is required for all women of 
childbearing potential during screening and must be within 
72 hours of Cycle 1 D1. 
Urine pregnancy test 
(childbearing females only) 
 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
See Section 7.5.5.7 for further details. 
Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 15: 
Laboratory Assessments for Phase 2 Mandatory Biopsy Subjects in Treatment Group C, Treatment Group D, 
Treatment Group E, Treatment Group F, and Treatment Group G (Continued) 
Visit 
Screeninga 
Treatment 
EOT 
Safety Follow-Up 
Comments 
Cycle 1 
Cycle 2 
Cycle 3+ 
Q9W 
30 d 
After 
EOT 
(±7d) 
90 d After 
EOT  
(±7d) 
D1 
D8 
D15 
D1 
D8 
D15 
D1 
D8 
Evaluation Window 
Day -28  
to -1 
 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±7d 
+7d 
Correlative  samples 
Whole blood for correlative 
studies 
 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
Required for Cycle 1 (D1, D8, D15), Cycle 2 (D1), and 
Cycle 3 (D1).  For D1 of subsequent cycles, required every 
3 cycles starting with Cycle 6 (ie, Cycles 6, 9, 12, etc). 
Plasma for correlative studies 
 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
Required for Cycle 1 (D1, D8, D15), Cycle 2 (D1), and 
Cycle 3 (D1).  For D1 of subsequent cycles, required every 
3 cycles starting with Cycle 6 (ie, Cycles 6, 9, 12, etc). 
a If screening safety and eligibility laboratory assessments are performed within 7 days of Cycle 1 Day 1, then the Cycle 1 Day 1 assessments may be omitted. 
b All safety laboratory assessments will be performed locally.  See Table 16 for a list of analytes. 
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Table 16: 
Clinical Laboratory Analytes 
Serum Chemistries 
Hematology 
Other 
Albumin 
Amylase 
Bicarbonate 
Blood urea nitrogen 
Calcium 
Chloride 
Creatinine 
Glucose 
Iron 
Lactate dehydrogenase 
Lipase 
Magnesium 
Phosphate 
Potassium 
Sodium 
Total protein 
Uric acid  
Complete blood count, including:   
• Hemoglobin 
• Hematocrit 
• Platelet count 
• Red blood cell count 
• White blood cell count 
 
Differential count, including: 
• Basophils 
• Eosinophils 
• Lymphocytes 
• Monocytes 
• Neutrophils 
 
Absolute values must be provided for 
the following WBC differential 
laboratory results:  
• White blood cell count  
• Lymphocytes  
• Neutrophils 
Pregnancy test: 
Female subjects of 
childbearing potential only 
require a serum test at 
screening.  
Pregnancy tests (urine or 
serum) should be repeated on 
Day 1 of each cycle. 
 
Coagulation: 
PT  
aPTT or PTT 
INR 
Liver Chemistry Tests 
ALP 
ALT 
AST 
Total bilirubin 
Direct bilirubin (only if total 
bilirubin is elevated above 
ULN at screening) 
Urinalysis 
Hepatitis Screening Tests 
Endocrine Monitoring 
Color and appearance 
pH and specific gravity 
Bilirubin 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Occult blood 
Protein 
Urobilinogen 
Hepatitis B surface antigen 
HBV-DNA 
HCV-RNA  
HCV antibody 
 
Thyroid stimulating hormone 
Free thyroxine 
Total triiodothyronine 
6.1. 
Screening 
Screening is the interval between the signing of the ICF and the day that the subject is enrolled 
and received the first dose of treatment in the study (Cycle 1 Day 1) and must not exceed 
28 days.  The ICF must be obtained before performing any study-specific procedures.  
Assessments that are required to demonstrate eligibility may be performed over the course of 
1 or more days during screening process. 
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Procedures conducted as part of the subject's routine clinical management (eg, blood count, 
imaging) and obtained before signing the ICF may be used for screening, provided that the 
procedure meets the Protocol-defined criteria and has been performed within the required 
timeframe.  All information associated with eligibility requirements must be entered into the 
appropriate eCRF pages. 
Results from the screening visit evaluations will be reviewed to confirm subject eligibility before 
enrollment or the administration of epacadostat, pembrolizumab, or chemotherapy regimen.  
Tests with results that fail eligibility requirements may be repeated once during screening if the 
investigator believes the results to be in error.  For screening assessments that are repeated, the 
most recent available result before treatment assignment will be used to determine subject 
eligibility.  Treatment should start as soon as possible but within 7 days after the date of 
enrollment.  Additionally, a subject who fails screening may repeat the screening process 1 time 
if the investigator believes that there has been a change in eligibility status. 
6.2. 
Treatment 
The treatment period begins on the day that the subject receives the first dose of treatment in the 
study on Cycle 1 Day 1 and may continue in 28-day cycles (mFOLFOX6 or 
nab-paclitaxel/gemcitabine) or 21-day cycles (all other chemotherapy regimens) if, in the 
judgment of the investigator, the subject is receiving benefit from treatment and has not met any 
criteria for treatment discontinuation.  See Section 4.4 for details on the maximum duration of 
treatment.  
Cycle 1 Day 1 must be no more than 28 days after the subject has signed the ICF. 
6.3. 
End of Treatment 
The EOT visit will be conducted when the subject permanently discontinues epacadostat and 
pembrolizumab (+ 7 days).  As the discontinuation date of epacadostat may differ from that of 
pembrolizumab, the EOT visit should be conducted on the latter of the 2 dates.  
If the EOT visit coincides with a regular study visit, the EOT evaluations will supersede those of 
that scheduled visit, and the data will be entered in the EOT page in the eCRF.  The subject 
should be encouraged to return for the follow-up visits. 
6.4. 
Follow-Up 
6.4.1. 
Safety Follow-Up 
The safety follow-up period is the interval between the EOT visit and the scheduled safety 
follow-up visit(s), which should occur 30 days (± 7 days) and 90 days (± 7 days) after the EOT 
visit.  Adverse events and SAEs must be reported up until at least 90 days (120 days for 
pregnancy) after the EOT visit, the date of the follow-up visit, or until epacadostat- or 
pembrolizumab-related toxicities resolve, return to baseline, or are deemed irreversible, 
whichever is longer.  If an EOT visit was not conducted, the last dose of epacadostat or 
pembrolizumab (whichever is later) should be used as the start of the safety follow-up period. 
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.  If the subject cannot return to the site for the safety 
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follow-up visit, the subject should be contacted by telephone for assessment of AEs and SAEs, 
and this should be documented in the eCRF. 
Adverse events and SAEs before the start of the new anticancer therapy must be reported.  If a 
subject begins a new anticancer therapy before the end of the 30-day or 90-day safety follow-up 
period, the safety follow-up visit should be performed before the new anticancer therapy is 
started. 
6.4.2. 
Disease Status Follow-Up 
As of Amendment 7, disease status follow-up visits for subjects who discontinued for any reason 
other than disease progression are no longer required.  The last study visit will be the 90-day 
safety follow-up visit. 
6.4.3. 
Survival Follow-Up 
As of Amendment 7, survival follow-up visits for Phase 2 subjects are no longer required.  The 
last study visit will be the 90-day safety follow-up visit. 
6.5. 
End of Study 
Subjects will be considered as having completed the study if they meet any of the following 
criteria: 
• Subject dies and a date of death is available. 
• Subject is known to have died; however, the date of death cannot be obtained. 
Note:  Every effort must be made to obtain the date of death. 
• Consent is withdrawn for any further contact related to this study. 
− 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. 
NOTE:  As of Amendment 7, the 90-day safety follow-up visit will be considered the EOS 
for an individual subject unless any of the above conditions have been met before this visit. 
6.6. 
Unscheduled Visits 
Unscheduled study visits may occur at any time if medically warranted.  Any assessments 
performed at those visits should be recorded in the eCRF. 
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7. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES 
7.1. 
Administration of Informed Consent Form 
Valid informed consent must be obtained from the study subject before conducting any 
study-specific procedures, using an ICF approved by the local IRB/IEC that contains all elements 
required by ICH E6 and describes the nature, scope, and possible consequences of the study in a 
form understandable to the study subject.  Local and institutional guidelines for ICF content and 
administration must be followed; the original signed ICF must be retained by the investigator, 
and a copy of the signed ICF must be provided to the study subject.  The informed consent 
process for each subject must be documented in writing within the subject source documentation.  
Subjects of childbearing potential must agree to take appropriate measures to avoid pregnancy in 
order to participate in the study (see Appendix A). 
7.2. 
Interactive Response Technology Procedure 
The IRT will be contacted to obtain a subject identification number when a subject enters the 
screening period.  Upon determining that the subject is eligible for study entry, the IRT will be 
contacted to enroll the subject and obtain treatment group assignment.  Additionally, the IRT will 
be contacted at each regular study visit, as appropriate, to update the relevant treatment supply.  
The IRT will also be contacted when the subject permanently discontinues treatment. 
7.3. 
Demography and Medical History 
7.3.1. 
Demographics and General Medical History 
Demographic data and a complete medical and medication history will be collected at screening 
by the investigator or qualified designee and will include date of birth, race, ethnicity (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.   
7.3.2. 
Disease Characteristics and Treatment History 
Details regarding the disease for which the subject has enrolled in this study (eg, date of 
diagnosis, primary tumor histology, previous systemic therapies, surgeries, radiation therapy, and 
stage of cancer) will be collected at screening. 
 
 
 
 
 
 
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7.4. 
Prior and Concomitant Medications and Procedures 
NOTE:  As of Amendment 7, use of concomitant medications should be monitored for subjects 
to verify that subjects are not taking any concomitant medication prohibited per protocol; 
however, concomitant medications no longer need to be collected in the eCRF. 
Prior and concomitant medications and procedures will be reviewed to determine subject 
eligibility.  All concomitant medications and measures must be recorded in the eCRF, and any 
medication received or procedure performed within 28 days before enrollment and up until the 
subject discontinues from the study will be recorded in the eCRF.  The medication record will be 
maintained after signing the ICF to document concomitant medications, including any changes to 
the dose or regimen.  Concomitant medications include any prescription, over-the-counter 
medications, or natural/herbal preparations taken or administered during the study period.  
Concomitant treatments and/or procedures that are required to manage a subject's medical 
condition during the study will also be recorded in the eCRF. 
7.5. 
Safety Assessments 
NOTE:  As of Amendment 7, safety assessments should be as per site standard of care.  Only 
AEs leading to discontinuation and SAEs will be collected in the eCRF. 
7.5.1. 
Adverse Events 
Adverse events will be monitored from the time the subject signs the ICF.  Subjects will be 
instructed to report all AEs during the study and will be assessed for the 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 epacadostat, pembrolizumab, or chemotherapy regimen.  The definition, 
reporting, and recording requirements for AEs are described in Section 8. 
All AEs of unknown etiology associated with epacadostat or pembrolizumab exposure should be 
evaluated to determine if it is possibly an irAE.  See Section 5.5.3 and Appendix G regarding the 
identification, evaluation, and management of AEs of potential immunologic etiology. 
7.5.2. 
Physical Examinations 
7.5.2.1. 
Comprehensive Physical Examination 
Physical examinations must be performed by a medically qualified individual such as a licensed 
physician, physician's assistant, or an advanced registered nurse practitioner, as local law 
permits. 
The comprehensive physical examination will include height and 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 neurologic examination.  
Clinically significant abnormal findings during screening should be recorded as medical history. 
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7.5.2.2. 
Targeted Physical Examination 
The investigator or qualified designee will perform a directed physical examination as clinically 
indicated before 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 organs, as indicated by subject 
symptoms, AEs, or other findings.  New clinically significant abnormal findings should be 
recorded as AEs. 
7.5.3. 
Vital Signs 
Vital sign measurements include blood pressure, pulse, respiratory rate, body temperature, and 
weight.  Clinically significant abnormal findings during screening should be recorded as medical 
history.  New clinically significant abnormal findings should be recorded as AEs. 
7.5.4. 
Electrocardiograms 
All 12-lead ECGs will be performed with the subject in a recumbent or semirecumbent position 
after 5 minutes of rest and should not be performed within 15 minutes after a blood collection.  
Electrocardiograms must be obtained at screening for all subjects; subsequent ECGs may be 
obtained during the treatment period 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.  Clinically significant abnormal findings during screening should be recorded as 
medical history.  New clinically significant abnormal findings should be recorded as AEs. 
7.5.5. 
Laboratory Assessments 
NOTE:  As of Amendment 7, laboratory assessments only need to be performed in accordance 
with standard of care at each investigational site for the subject's condition and monitoring.  
Laboratory results do not need to be reported in the CRF, but all laboratory results corresponding 
with an SAE will be reported on the SAE form. 
Laboratory tests for screening period should be performed by the site's local laboratory within 
7 days before the first dose of treatment.  Clinically significant abnormal findings during 
screening should be recorded as medical history.  After Cycle 1, predose laboratory procedures 
can be conducted up to 72 hours before administration of epacadostat, pembrolizumab, and/or 
chemotherapy regimen.  Results must be reviewed by the investigator or qualified designee and 
found to be acceptable before each dose of treatment.  New clinically significant abnormal 
findings should be recorded as AEs. 
7.5.5.1. 
Serum Chemistry 
A comprehensive serum chemistry will be performed as clinically indicated.  Appropriate 
monitoring intervals should be discussed with the medical monitor in these circumstances.  
Serum chemistry tests will be performed by the site's local laboratory. 
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7.5.5.2. 
Hematology 
Hematology with differential will be performed as clinically indicated.  Appropriate monitoring 
intervals should be discussed with the medical monitor in these circumstances.  Hematology with 
differential will be performed by the site's local laboratory. 
7.5.5.3. 
Liver Chemistry  
Liver chemistry tests will be performed as clinically indicated.  Appropriate monitoring intervals 
should be discussed with the medical monitor in these circumstances.  Liver chemistry tests will 
be performed by the site's local laboratory. 
7.5.5.4. 
Coagulation Panel 
A coagulation panel will be performed as clinically indicated.  The coagulation panel will be 
performed by the site's local laboratory. 
7.5.5.5. 
Endocrine Function  
Endocrine function tests will be performed as clinically indicated.  Endocrine function testing 
analysis will be performed by the site's local laboratory. 
7.5.5.6. 
Urinalysis 
Urinalysis will be performed as clinically indicated.  Urinalysis will be performed by the site's 
local laboratory. 
7.5.5.7. 
Pregnancy Testing 
A serum pregnancy test will be required for all women of childbearing potential during screening 
and as clinically indicated. 
If a subject inadvertently becomes pregnant while on study, the subject will immediately be 
discontinued from study treatment.  The site will contact the subject at least monthly and 
document the subject's status until the first well-baby visit 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.  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. 
7.5.5.8. 
Serology 
Serology will be performed at screening only to assess eligibility for inclusion in the study. 
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7.6. 
Efficacy Assessments 
NOTE:  As of Amendment 7, no further efficacy assessment will be required beyond Week 18.  
Imaging for the study will only be required at Week 9 and Week 18 per RECIST v1.1.  After 
Week 18, CT/MRI or PET-CT assessments are only required to be performed as per standard of 
care guidelines for the subject's condition and monitoring.  Subjects must be withdrawn from the 
study if, in the opinion of the investigator, the disease has progressed and the subject is no longer 
having clinical benefit from the study treatment. 
7.6.1. 
Initial Tumor Imaging 
Initial tumor imaging must be performed within 28 days before the first dose of treatment.  The 
site study team must review prestudy images to confirm that the subject has measurable disease 
per RECIST v1.1. 
Scans performed as part of routine clinical management are acceptable for use as the screening 
scan if they are of diagnostic quality and performed within 28 days before the first dose of 
treatment.  The same imaging technique should be used in a subject throughout the study.  
Baseline scan must be a contrast CT or MRI, except in circumstances where there is a contrast 
allergy or with medical monitor approval.  When the CT component of a positron emission 
tomography/CT uses higher energy and thinner slices, it may be acceptable (with medical 
monitor approval).  A standard, full assessment for lesions should be conducted at baseline, 
including CT or MRI scans of chest, abdomen, and pelvis.  The same modality (CT or MRI) 
should be used for follow-up assessments every 9 weeks, including radiologic assessments of all 
sites of disease present at baseline.  In addition to radiologic monitoring, all other lesions 
observed at the screening visit should be followed. 
For selection of target lesions, RECIST v1.1 should be followed.  For example, RECIST 
discourages selection of target lesions inside the field of previous 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. 
7.6.2. 
Tumor Imaging During the Study 
Tumor imaging should be continued on treatment and assessed per RECIST v1.1, and the same 
imaging technique should be used in a subject throughout the study.  Imaging should be 
performed every 9 weeks (± 7 days) from Cycle 1 Day 1 for the first 12 months of treatment.  
After 12 months of treatment, the assessments should be performed every 12 weeks (± 7 days).  
Assessments should continue to be performed until disease progression, the start of new 
anticancer treatment, withdrawal of consent, death, or the end of the study, whichever occurs 
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first.  More frequent scanning is allowed, if clinically indicated.  Imaging should not be 
delayed for delays in cycle starts or extension of combination treatment cycle intervals. 
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 of 4 weeks after the first indication of response or at the next scheduled 
scan (9 weeks later), whichever is clinically indicated. 
Disease progression should be confirmed at least 4 weeks (but not later than 6 weeks) after the 
first scan indicating PD in clinically stable subjects.  Subjects who have unconfirmed disease 
progression may continue on treatment until progression is confirmed provided that they have 
met the conditions detailed in Section 7.6.2.1. 
7.6.2.1. 
Assessment of Progressive Disease According to Immune-Related RECIST 
Criteria 
RECIST v1.1 will be adapted for defining PD to account for the unique tumor response seen 
with immunotherapies.  This adaptation is known as irRECIST and will be used to guide 
treatment decisions for discontinuation of therapy due to disease progression. 
If imaging shows PD, it is at the discretion of the investigator to keep a subject on treatment or to 
stop treatment until imaging is repeated ≥ 4 weeks later, but not ≥ 6 weeks later, to confirm PD.  
When feasible, subjects should not be discontinued until progression is confirmed; however, the 
decision to continue treatment after the first evidence of disease progression is at the 
investigator's discretion based on the clinical status of the subject. 
Subjects may continue to receive treatment while waiting for confirmation of PD (see Table 4) if 
they are clinically stable as defined by the following criteria: 
• Absence of clinically significant signs and symptoms (including worsening of 
laboratory values) indicating disease progression. 
• No decline in ECOG performance status. 
• Absence of rapid progression of disease. 
• Absence of progressive tumor at critical anatomical sites (eg, spinal cord 
compression) requiring urgent alternative medical intervention. 
Subjects who are deemed clinically unstable are not required to have repeat imaging for 
confirmation.  If radiologic progression is confirmed, then the subject will be discontinued from 
treatment as specified in the Protocol, and the first radiographic evidence of PD should be the 
date of progression.  If radiologic progression is not confirmed, then the subject should 
resume/continue treatment and have their next scan according to the Protocol-specified schedule.  
If progression is not confirmed and the subject continues on treatment, the next scan that 
documents disease progression (and is confirmed by a second scan at least 4 weeks later) will be 
considered the date of disease progression. 
Note:  If a subject with confirmed radiographic progression (ie, 2 scans ≥ 4 weeks apart 
demonstrating progressive disease) is clinically stable or clinically improved, and there is no 
further increase in the tumor dimensions at the confirmatory scan, an exception may be 
considered to continue treatment upon consultation with the sponsor.  Clinically stable subjects 
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should also have at the confirmatory scan no further increase in the target lesions, no 
unequivocal increase in nontarget lesions, and no additional new lesions develop (nonworsening 
PD) to continue treatment. 
In determining whether the tumor burden has increased or decreased, investigators should 
consider all target lesions as well as nontarget lesions.   
Progressive disease is confirmed if ANY of the following conditions are met on the subsequent 
confirmatory scan: 
• Target lesions reach the PD threshold (increase in tumor burden ≥ 20% and absolute 
increase of at least 5 mm relative to nadir), OR if the threshold has already been 
reached on the initial scan showing PD, they remain above the threshold. 
• Nontarget lesions show unequivocal progression. 
• New lesions appear, OR if they appeared on the initial scan showing PD, they have 
grown. 
7.7. 
Performance and Quality-of-Life Assessments 
NOTE:  As of Amendment 7, ECOG performance status will no longer be collected and should 
be monitored only per the site's standard of care, if applicable. 
7.7.1. 
Eastern Cooperative Oncology Group Performance Status 
The investigator or qualified designee will assess ECOG performance status (Appendix C) at 
screening, before the administration of treatment on Day 1 of each cycle, and at the EOT and 
safety follow-up visits as specified in the schedules of assessments (Table 7, Table 9, Table 11, 
Table 12, and Table 14). 
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7.10. 
Other Study Procedures 
7.10.1. 
Distribution of Subject Reminder Cards and Subject Diaries 
Subjects will be provided with reminder cards at each visit.  All necessary instructions, such as 
administration instructions for epacadostat, concomitant medications, and reminders of visits to 
conduct laboratory tests, should be provided to the subject in writing on this reminder card, or on 
accompanying written materials.  Subject diaries may be used for the purpose of documenting 
epacadostat administration and AEs.  The subject diary should have an area on which the date 
and time of the last dose of epacadostat taken before each visit will be recorded as well as the 
time (and content, if applicable to the visit) of the last meal.  On Cycle 1 Day 1, 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. 
7.10.2. 
Post-Treatment Anticancer Therapy Status 
NOTE:  As of Amendment 7, post-treatment anticancer therapy will no longer be collected. 
The investigator or qualified designee will enter all new anticancer therapy initiated after the last 
dose of epacadostat or pembrolizumab (whichever is later) in the eCRF.  If a subject initiates a 
new anticancer therapy before the scheduled 30-day or 90-day safety follow-up visit, the 
appropriate safety follow-up visit should be rescheduled so it occurs before the first dose of the 
new anticancer therapy. 
7.10.3. 
Data Collection for Survival Follow-Up 
NOTE:  As of Amendment 7, data collection for survival follow-up visits for Phase 2 subjects 
are no longer required. 
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8. 
SAFETY MONITORING AND REPORTING 
8.1. 
Adverse Events 
NOTE:  As of Amendment 7, only AEs leading to discontinuation of study treatment and SAEs 
regardless of causality relationship will be reported in the eCRF. 
8.1.1. 
Definitions  
For the purposes of this Protocol, an adverse event (AE) is defined as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug related, 
that occurs after a subject provides informed consent.  Abnormal laboratory values or test results 
occurring after informed consent constitute AEs only if they induce clinical signs or symptoms, 
are considered clinically meaningful, require therapy (eg, hematologic abnormality that requires 
transfusion), or require changes in the study drug(s). 
8.1.2. 
Reporting 
Adverse events that begin or worsen after informed consent should be recorded on the Adverse 
Events form of the eCRF.  Conditions that were already present at the time of informed consent 
should be recorded on the Medical History form in the eCRF.  Monitoring for the occurrence of 
new AEs should be continued for at least 90 days after the last dose of epacadostat or 
pembrolizumab, or 30 days following cessation of study treatment if the subject initiates new 
anticancer therapy (whichever is earlier); monitoring for pregnancy should continue for 120 days 
after the last dose of epacadostat or pembrolizumab (whichever is later).  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. 
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The severity of AEs will be assessed using CTCAE v4.0 Grades 1 through 4.  The CTCAE v4.0 
severity of Grade 5 will not be used; AEs resulting in death will be graded accordingly using 
Grades 1 through 4 and have the outcome noted as fatal.  If an event is not classified by CTCAE, 
the severity of the AE will be graded according to the scale below to estimate the grade of 
severity: 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2 
Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate activities of daily living. 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
The occurrence of AEs should be sought by nondirective questioning of the subject during the 
screening process after signing the ICF and at each visit during the study.  Adverse events may 
also be detected when they are volunteered by the subject during the screening process or 
between visits, or through physical examination, laboratory test, or other assessments.  To the 
extent possible, each AE should be evaluated to determine: 
• The severity grade (CTCAE Grade 1 to 4). 
• Whether there is at least a reasonable possibility that the AE is related to the study 
treatment:  suspected (yes) or not suspected (no). 
NOTE:  Causality assessment for epacadostat, pembrolizumab, and the chemotherapy regimen 
must be indicated.  If appropriate, the relationship to the combination may be assessed as well. 
• The start and end dates, unless unresolved at final follow-up. 
• The action taken with regard to study drug. 
• The event outcome (eg, not recovered/not resolved, recovered/resolved, 
recovering/resolving, recovered/resolved with sequelae, fatal, unknown). 
• The seriousness, as per serious adverse event (SAE) definition provided in 
Section 8.3.1. 
Unlike routine safety assessments, SAEs are monitored continuously and have special reporting 
requirements (see Section 8.3.2). 
All AEs should be treated appropriately.  If an AE is treated with a concomitant medication or 
nondrug therapy, this action should be recorded on Adverse Event form and the treatment should 
be specified on the Prior/Concomitant Medications or Procedures and Non-Drug Therapy form 
in the eCRF. 
Once an AE is detected, it should be followed until it has resolved or until it is judged to be 
permanent; assessment should be made at each visit (or more frequently if necessary) of any 
changes in severity, the suspected relationship to the study drug, the interventions required to 
treat the event, and the outcome. 
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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. 
8.2. 
Laboratory Test Abnormalities 
Laboratory abnormalities that constitute an AE in their own right (considered clinically 
meaningful, induce clinical signs or symptoms, require concomitant therapy, or require changes 
in study drug) should be recorded on the Adverse Event form in the eCRF.  Whenever possible, a 
diagnosis rather than a symptom should be provided (eg, "anemia" instead of "low hemoglobin").  
Laboratory abnormalities that meet the criteria for AEs should be followed until they have 
returned to normal or an adequate explanation of the abnormality is found.  When an abnormal 
laboratory test result corresponds to a sign or symptom of a previously reported AE, it is not 
necessary to separately record the laboratory test result as an additional event. 
Laboratory abnormalities that do not meet the definition of an AE should not be reported as AEs.  
A Grade 3 or 4 AE does not automatically indicate an SAE unless it meets the definition of 
serious, as defined in Section 8.3.1.  A dose modification for the laboratory abnormality may be 
required (see Section 5.5) and should not contribute to the designation of a laboratory test 
abnormality as an SAE. 
8.2.1. 
Potential Drug-Induced Liver Injury (Hy's Law) 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur before the reporting of a potential DILI event (also known as Hy's Law).  All occurrences 
of potential DILIs 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 follows: 
1. AT (ALT or AST) elevation ≥ 3 times ULN 
AND 
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum 
ALP) 
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 drugs known to be hepatotoxic. 
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8.3. 
Serious Adverse Events 
8.3.1. 
Definitions 
An SAE is defined as an event that meets at least 1 of the following criteria: 
• Is fatal or life-threatening. 
• Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is a result of: 
− A routine treatment or monitoring of the studied indication not associated with 
any deterioration in condition.   
− An elective surgery or preplanned treatment for a pre-existing condition that is 
unrelated to the indication under study and has not worsened since signing the 
ICF. 
− A treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE and not resulting in hospital admission. 
− Any social reasons and respite care, in the absence of any deterioration in the 
subject's general condition. 
• Results in persistent or significant disability, incapacity, or a substantial disruption of 
a person's ability to conduct normal life functions. 
• Constitutes a congenital anomaly or birth defect. 
• Is considered to be an important medical event or a medically significant event that 
may not result in death, be immediately life-threatening, or require hospitalization but 
may be considered serious when, based on appropriate medical judgment, the event 
may jeopardize the subject or may require medical or surgical intervention to prevent 
1 of the outcomes listed above. 
8.3.2. 
Reporting 
Every SAE, regardless of suspected causality (eg, relationship to study drug[s] or study 
procedure or disease progression), occurring after the subject has signed the ICF through 90 days 
(120 days for pregnancy) after the last dose of epacadostat or pembrolizumab, or 30 days 
following cessation of study treatment if the subject initiates new anticancer therapy (whichever 
is earlier) must be reported to the sponsor (or designee) within 24 hours of learning of its 
occurrence, unless otherwise specified by the Protocol.  Any SAEs occurring more than 90 days 
(120 days for pregnancy) after the last dose of epacadostat or pembrolizumab (whichever is later) 
should be reported to the sponsor or its designee only if the investigator suspects a causal 
relationship to the study drug. 
Information about all SAEs is collected and recorded on the Adverse Event form of the eCRF.  
The investigator must assess and record the causal relationship of each SAE to the study 
treatment.  NOTE:  Causality assessment for epacadostat, pembrolizumab, and the chemotherapy 
regimen must be indicated.  If appropriate, the relationship to the combination may be assessed 
as well. 
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The investigator must also complete the Incyte Serious Adverse Event Report Form, in English, 
and send the completed and signed form to the sponsor or designee within 24 hours of becoming 
aware of the SAE.  The investigator must provide a causality assessment, that is, assess whether 
there is at least a reasonable possibility that the SAE is related to the study treatment:  suspected 
(yes) or not suspected (no).  Causality assessment for epacadostat, pembrolizumab, and each 
chemotherapy agent administered must be indicated.  If appropriate, the relationship to the 
combination may be assessed as well.  Refer to the Incyte Reference Guide for Completing the 
Serious Adverse Event Report Form. 
The contact information of the sponsor's study-specific representatives is listed in the 
investigator manual provided to each site.  The original copy of the SAE Report Form and the 
confirmation sheet must be kept at the study site. 
Investigational site personnel must report any new information regarding the SAE within 
24 hours of becoming aware of the information in the same manner that the initial SAE Report 
Form was sent.  Follow-up information is recorded on an amended or new SAE Report Form, 
with an indication that it is follow-up to the previously reported SAE and the date of the original 
report.  The follow-up report should include information that was not provided on the previous 
SAE Report Form, such as the outcome of the event (eg, resolved or ongoing), treatment 
provided, action taken with study drug because of the SAE (eg, interrupted or discontinued), or 
subject disposition (eg, continued or withdrew from study participation).  Each recurrence, 
complication, or progression of the original event should be reported as follow-up to that event, 
regardless of when it occurs. 
If the SAE (new occurrence) is not documented in the IBs for epacadostat or pembrolizumab or 
in the US prescribing information or EMA Summary of Product Characteristics for the 
chemotherapy agents and is thought to be related to epacadostat, pembrolizumab, or 
chemotherapy agent, then the sponsor or its designee may urgently require further information 
from the investigator for reporting to health authorities.  The sponsor or its designee may need to 
issue an Investigator Notification (IN) to inform all investigators involved in any study with the 
same drug that this SAE has been reported.  Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with Directive 2001/20/EC, or as per national regulatory requirements 
in participating countries. 
NOTE:  As of Amendment 7, all SAEs regardless of causality relationship will be submitted 
to the sponsor as described above and entered in the eCRF. 
8.4. 
Emergency Unblinding of Treatment Assignment 
Not applicable.  
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8.5. 
Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that study drug may 
have interfered with the effectiveness of a contraceptive medication or method.  When a 
pregnancy has been confirmed in a subject during maternal or paternal exposure to study drug, 
the following procedures should be followed in order to ensure subject safety: 
• The study drug must be discontinued immediately (female subjects only; see 
Section 5.5.2 for the maximum permitted duration of study drug interruption). 
• The investigator must complete and submit the Incyte Clinical Trial Pregnancy form 
to the sponsor or its designee within 24 hours of learning of the pregnancy. 
Data on fetal outcome and breastfeeding are collected for regulatory reporting and drug safety 
evaluation.  Follow-up should be conducted for each pregnancy to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence of any 
birth defects, congenital abnormalities, or maternal and/or newborn complications, by following 
until the first well-baby visit.  Pregnancy should be recorded on a Clinical Trial Pregnancy form 
and reported by the investigator to the sponsor or its designee.  Pregnancy follow-up information 
should be recorded on the same form and should include an assessment of the possible causal 
relationship to the sponsor's study drug to any pregnancy outcome, as well as follow-up to the 
first well-baby visit or the duration specified in local regulations, whichever is later.  Refer to the 
Incyte Reference Guide for Completing the Clinical Trial Pregnancy Form. 
Any SAE occurring during pregnancy must be recorded on the SAE report form and 
submitted to the sponsor or designee. 
8.6. 
Events of Clinical Interest 
Events of clinical interest (ECIs) must be recorded as such in the eCRF as an ECI. 
For this study, ECIs include: 
1. Potential drug-induced liver injury (or Hy's Law) – an elevated AST or ALT laboratory 
value that is ≥ 3 × the ULN and an elevated total bilirubin laboratory value that is 
≥ 2 × the ULN and, at the same time, an ALP laboratory value that is < 2 × the ULN, as 
determined by way of Protocol-specified laboratory testing or unscheduled laboratory 
testing. 
Note:  These criteria are based upon 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 the Investigator Trial File 
Binder (or equivalent). 
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2. An overdose of epacadostat or pembrolizumab that is not associated with clinical 
symptoms or abnormal laboratory results.  For this study, an overdose will be defined as 
≥ 1000 mg of epacadostat or ≥ 1000 mg (5 times the dose) of pembrolizumab.  No 
specific information is available on the treatment of overdose of epacadostat or 
pembrolizumab.  In the event of overdose, the subject should be observed closely for 
signs of toxicity.  Appropriate supportive treatment should be provided if clinically 
indicated. 
3. Serotonin syndrome (see Section 5.5.6 for further details). 
4. Any of the following AEs:  
a. ≥ Grade 3 diarrhea 
b. ≥ Grade 3 colitis 
c. ≥ Grade 2 pneumonitis 
d. ≥ Grade 3 rash or dermatitis 
e. Grade 4 laboratory abnormality  
Events of clinical interest that occur in any subject from the date of first dose of treatment 
through 90 days after EOT or the initiation of a new anticancer therapy, whichever is earlier, 
whether or not related to epacadostat or pembrolizumab, must be recorded in the eCRF.  A 
detailed narrative of the event should be reported to the sponsor within 24 hours of the event. 
8.7. 
Definition of an Overdose for This Protocol and Reporting of 
Overdose to the Sponsor 
For purposes of this study, an overdose is defined as an overdose will be defined as ≥ 1000 mg of 
epacadostat or ≥ 1000 mg (5 times the dose) of pembrolizumab.  All occurrences of overdose 
must be reported as an SAE (see Section 8.3.2 for reporting details). 
8.8. 
Warnings and Precautions 
Special warnings or precautions for the study drug, derived from safety information collected by 
the sponsor or its designee, are presented in the Investigator's Brochures (eIB, pIB).  Additional 
safety information collected between IB updates will be communicated in the form of 
Investigator Notifications (INs).  Any important new safety information should be discussed with 
the subject during the study, as necessary.  If new significant risks are identified, they will be 
added to the ICF. 
8.9. 
Safety Monitoring Committee 
Due to the complexity of the study, 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. 
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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 to the sponsor.  All product complaints associated with other 
study material will be reported directly to the respective manufacturer. 
The investigator or his/her designee is responsible for reporting a complete description of the 
product complaint via email or other written communication to the sponsor contact or respective 
manufacturer as noted in the packaging information.  Any AE associated with a product 
complaint should be reported as described in Section 8.1.2 of this Protocol. 
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint communication with the product. 
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9. 
STATISTICS 
9.1. 
Study Populations 
The safety population includes all subjects enrolled in the study who received at least 1 dose of 
epacadostat.  All safety analyses will be based on the safety population. 
The full analysis set includes all subjects enrolled in the study who received at least 1 dose of 
epacadostat and have at least 1 postbaseline assessment or who discontinued epacadostat.  All 
efficacy analyses will be based on the full analysis set. 
 
 
9.2. 
Selection of Sample Size 
9.2.1. 
Sample Size in Phase 1 
A 3 + 3 + 3 design will be used in Phase 1 to determine the MTD or PAD and DLT of 
epacadostat when given in combination with pembrolizumab and 7 chemotherapy regimens.  The 
total number of subjects will depend on the frequency of DLTs and number of dose levels tested 
before MTD or PAD is established.  Based on 3 + 3 + 3 design algorithm, within each treatment 
group, a minimum of 6 subjects and up to 9 subjects will be enrolled at each dose level. 
9.2.2. 
Sample Size in Phase 2 
9.2.2.1. 
Efficacy Expansion 
NOTE:  As of 25 OCT 2018, this study is closed to enrollment.  As of this date, no subjects were 
enrolled in Phase 2 efficacy expansion (all treatment groups) or Phase 2 mandatory biopsy 
Treatment Groups A, B, F, and G; therefore, disregard this section. 
Phase 2 consists of expansion cohorts (efficacy and mandatory biopsy) in specific tumor types 
(advanced or metastatic CRC, PDAC, squamous or nonsquamous NSCLC, UC, SCCHN, or any 
advanced or metastatic solid tumor that progressed on previous therapy with a PD-1 or PD-L1 
inhibitor).  A Simon 2-stage design will be used for the CRC and PDAC efficacy expansion 
cohorts.  The response rates for the historical control (p0), desired response rates for the 
combination (p1), number of subjects needed in Stage 1 (n1) and Stage 2 (n2), total number of 
subjects (n), first-stage threshold declaring cohort undesirable (r1), and the upper limit of the 
number of responses in n subjects such that futility of the drug is concluded (r) are provided for 
each expansion cohort in Table 21. 
In addition, a single-stage Phase 2 expansion will be used for all other efficacy expansion 
cohorts.  The sample sizes and decision rules are summarized in Table 22.  The definitions of p0, 
p1, n, and r are the same as those in Table 21. 
The calculation is based on a 1-sided Type I error of 0.1 and power of 80%, with the exception 
of the cohort enrolling solid tumors that progressed on previous treatment with a PD-1 or PD-L1 
inhibitor, which is based on a 1-sided Type I error of 0.1 and power of approximately 98%. 
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Table 21: 
Sample Size and Decision Rule for Simon 2-Stage Design Phase 2 Efficacy 
Expansion Cohorts 
Tumor Type 
p0 
p1 
n1 
n2 
n 
r1 
r 
CRC 
40% 
60% 
12 
26 
38 
5 
18 
PDAC 
25% 
45% 
15 
12 
27 
4 
9 
Table 22: 
Sample Size and Decision Rule for Single-Stage Design Phase 2 Efficacy 
Expansion Cohorts 
Tumor Type 
p0 
p1 
n 
r 
Squamous NSCLC 
30% 
50% 
33 
13 
Nonsquamous NSCLC 
50% 
70% 
33 
20 
Solid tumors that progressed on previous 
therapy with a PD-1 or PD-L1 inhibitor 
5% 
25% 
33 
3 
UC 
60% 
80% 
33 
23 
SCCHN 
50% 
70% 
33 
20 
9.2.2.2. 
Phase 2 Mandatory Biopsy Cohorts 
NOTE:  As of 25 OCT 2018, this study is closed to enrollment.  As of this date, only Phase 2 
mandatory biopsy Treatment Groups C, D, and E enrolled subjects, and the minimum number of 
subjects was not enrolled; therefore, disregard this section. 
• A minimum of 10 subjects will be enrolled in the CRC, PDAC, squamous NSCLC, 
nonsquamous NSCLC, UC, and SCCHN Phase 2 mandatory biopsy cohorts. 
• A minimum of 5 subjects will be enrolled in any advanced or metastatic solid tumor 
that progressed on previous therapy with a PD-1 or PD-L1 inhibitor mandatory 
biopsy cohorts. 
 
 
 
9.3. 
Level of Significance 
For the primary efficacy endpoints, the 1-sided Type I error will be controlled at 0.1 for each 
individual cohort expansion.  For other endpoints, CIs will be reported at a 95% confidence 
level.  Note that this level of significance does not account for the multiple expansion cohorts. 
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9.4. 
Statistical Analyses 
9.4.1. 
Primary Analyses 
• Phase 1:  The clinical safety data (AEs, vital signs, ECGs, routine laboratory tests) 
will be summarized using descriptive statistics (eg, mean, frequency) based on the 
safety population.  The analyses of safety data are described in Section 9.4.4. 
• Phase 2:  ORR, defined as the percentage of subjects having a CR or PR, per 
RECIST v1.1 will be estimated with a 95% CI. 
9.4.2. 
Secondary Analyses 
• Phase 1:  ORR, defined as the percentage of subjects having a CR or PR, per RECIST 
v1.1 will be estimated with 95% CI. 
• Phase 2:  The clinical safety data (AEs, vital signs, ECGs, routine laboratory tests) 
will be summarized using descriptive statistics (eg, mean, frequency) based on the 
safety population.  The analyses of safety data are detailed in Section 9.4.4. 
9.4.4. 
Safety Analyses 
9.4.4.1. 
Adverse Events 
A treatment-emergent AE is any AE either reported for the first time or worsening of a 
pre-existing event after the first dose of epacadostat, pembrolizumab, or chemotherapy.  Analysis 
of AEs will be limited to treatment-emergent AEs, but data listings will include all AEs 
regardless of their timing to treatment administration.  Adverse events will be tabulated by the 
MedDRA preferred term and system organ class.  Severity of AEs will be based on the NCI 
CTCAE v4.0 using Grades 1 through 4. 
The subset of AEs considered by the investigator to have a relationship to epacadostat will be 
considered to be treatment-related AEs.  If the investigator does not specify the relationship of 
the AE to epacadostat, the AE will be considered treatment-related.  The incidence of AEs and 
treatment-related AEs will be tabulated. 
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9.4.4.2. 
Clinical Laboratory Tests 
Laboratory test values outside the normal range will be assessed for severity based on the normal 
ranges for the clinical reference laboratory.  The incidence of abnormal laboratory values and 
shift tables relative to baseline will be tabulated. 
Laboratory data will be classified into Grades 1 through 4 using CTCAE v4.0.  The following 
summaries will be produced for the laboratory data: 
• Number and percentage of subjects with worst postbaseline CTCAE grade (regardless 
of baseline value).  Each subject will be counted only for the worst grade observed 
postbaseline. 
• Shift tables from baseline to the worst postbaseline value using CTCAE grade. 
• For laboratory parameters where CTCAE grades are not defined, shift tables to the 
worst postbaseline value using the low/normal/high classifications based on 
laboratory reference ranges. 
9.4.4.3. 
Vital Signs 
Descriptive statistics and mean change from baseline will be determined for vital signs (blood 
pressure, pulse, respiratory rate, and body temperature) at each assessment time.  Vital sign 
results will be reviewed for clinically notable abnormalities (see Table 23), and subjects 
exhibiting clinically notable vital sign abnormalities will be listed.  A value will be considered an 
"alert" value if it is outside the established range and shows a > 25% change from baseline. 
Table 23: 
Criteria for Clinically Notable Vital Sign Abnormalities 
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure 
> 155 mmHg 
< 85 mmHg 
Diastolic blood pressure 
> 100 mmHg 
< 40 mmHg 
Pulse 
> 100 bpm 
< 45 bpm 
Temperature 
> 38°C 
< 35.5°C 
Respiratory rate 
> 24/min 
< 8/min 
9.4.4.4. 
Electrocardiograms 
Descriptive statistics and mean change from baseline will be determined for each ECG parameter 
at each assessment time.  Electrocardiogram results will be reviewed for clinically notable 
abnormalities according to predefined criteria (Table 24).  Subjects exhibiting clinically notable 
ECG abnormalities will be listed. 
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Table 24: 
Criteria for Clinically Notable Electrocardiogram Abnormalities 
Parameter 
High Threshold 
Low Threshold 
QTcF 
> 480 msec 
< 295 msec 
PR 
> 220 msec 
< 75 msec 
QRS 
> 120 msec 
< 50 msec 
QT 
> 500 msec 
< 300 msec 
RR 
> 1330 msec 
< 600 msec 
QTcF = Fridericia correction. 
9.4.4.5. 
Events of Clinical Interest 
Events of clinical interest include potential drug-induced liver injury (or Hy's Law), an overdose 
of epacadostat or pembrolizumab that is not associated with clinical symptoms or abnormal 
laboratory results, SS, and any of the following AEs: ≥ Grade 3 diarrhea, ≥ Grade 3 colitis, 
≥ Grade 2 pneumonitis, ≥ Grade 3 rash or dermatitis, Grade 4 laboratory abnormality.  See 
Section 8.6 for further details. 
A summary of ECIs including the number (%) of subjects reporting any ECIs will be provided. 
9.5. 
Analyses for the Safety Monitoring Committee 
Details regarding safety data to be evaluated by the SMC will be addressed in the SMC charter. 
9.6. 
Interim Analysis 
Note:  As of 25 OCT 2018, this study is closed to enrollment.  As of this date, no subjects were 
enrolled in Phase 2 efficacy expansion (all treatment groups) or Phase 2 mandatory biopsy 
Treatment Groups A, B, F, and G; therefore, the interim analysis is no longer applicable. 
In Phase 2, there will be a planned interim analysis for futility in the CRC and PDAC expansion 
cohorts.  The Simon 2-stage design will be applied to each expansion cohort independently.  
According to Table 21, during Stage 1, n1 subjects with specific tumor types (advanced or 
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metastatic CRC or PDAC) will be enrolled in each cohort.  If ≤ r1 responses are observed, the 
cohort will be terminated for futility.  If more than r1 responses are observed within each cohort, 
additional n2 subjects will be enrolled for Stage 2 evaluation. 
Based on this early termination rule, the probabilities of early termination under the assumption 
of historical control response rates (H0) and desired response rates (HA) are shown in Table 25. 
Table 25: 
Probabilities of Early Termination for Simon 2-Stage Design 
Tumor Type 
p0 
p1 
Probability of Early Termination 
Under H0 
Under HA 
CRC 
40% 
60% 
0.6652 
0.1582 
PDAC 
25% 
45% 
0.6865 
0.1204 
The interim analysis for each expansion cohort will be conducted once the first postbaseline 
radiologic tumor assessments for Stage 1 subjects within the cohort are available.  Enrollment 
will be held at that time unless a sufficient number of responders have been observed before that 
time. 
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10. 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES 
10.1. 
Investigator Responsibilities 
This study will be performed in accordance with ethical principles that originate in the 
Declaration of Helsinki and conducted in adherence to the study Protocol; GCPs as defined in 
Title 21 of the US CFR Parts 11, 50, 54, 56, and 312; ICH E6 GCP consolidated guidelines; and 
local regulatory requirements as applicable to the study locations. 
The investigator will be responsible for: 
• Permitting study-related monitoring, sponsor audits, IRB/IEC review, and regulatory 
inspections by providing direct access to source data and other relevant clinical study 
documents. 
− Monitoring:  Qualified representatives of the sponsor or its designee, study 
monitors, will monitor the study according to a predetermined plan.  The 
investigator must allow the study monitors to review any study materials and 
subject records at each monitoring visit. 
− Auditing:  Qualified representatives of the sponsor or its designee may audit the 
clinical study site and study data to evaluate compliance with the Protocol, 
applicable local clinical study regulations, and overall study conduct.  The 
investigator must allow the auditors to review original source records and study 
documentation for all subjects. 
− Regulatory inspection:  Regulatory authorities may conduct an inspection of the 
study and the site at any time during the development of an investigational 
product.  The investigator and staff are expected to cooperate with the inspectors 
and allow access to all source documents supporting the eCRFs and other 
study-related documents.  The investigator must immediately notify the sponsor 
when contacted by any regulatory authority for the purposes of conducting an 
inspection. 
• Obtaining informed consent and ensuring that the study subjects' questions have been 
answered and the subjects fully understand study procedures: 
− Informed consent must be obtained before any study-related procedures are 
conducted, unless otherwise specified by the Protocol. 
− Informed consent must be obtained using the IRB/IEC-approved version in a 
language that is native and understandable to the subject.  A template will be 
provided by the sponsor or its designee.  The sponsor or its designee must review 
and acknowledge the site-specific changes to the ICF template.  The ICF must 
include a statement that the sponsor or its designee and regulatory authorities have 
direct access to subject records. 
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• Obtaining approval from the IRB/IEC before the start of the study and for any 
changes to the clinical study Protocol, important Protocol deviations, routine updates, 
and safety information in accordance with institutional requirements and local law. 
− The investigator is responsible for ensuring that the safety reports provided by the 
sponsor are reviewed and processed in accordance with regulatory requirements 
and with the policies and procedures established by the IRB/IEC. 
• Adhering to the Protocol as described in this document and agreeing that changes to 
the Protocol procedures, with the exception of medical emergencies, must be 
discussed and approved, first, by the sponsor or its designee and, second, by the 
IRB/IEC.  Each investigator is responsible for enrolling subjects who have met the 
specified eligibility criteria. 
• Retaining records in accordance with all local, national, and regulatory laws, but for a 
minimum period of at least 2 years after the last marketing application approval in an 
ICH region and until there are no pending or contemplated marketing applications in 
an ICH region, or if not approved, 2 years after the termination of the test article for 
investigation to ensure the availability of study documentation should it become 
necessary for the sponsor or a regulatory authority to review. 
− The investigator must not destroy any records associated with the study without 
receiving approval from the sponsor.  The investigator must notify the sponsor or 
its designee in the event of accidental loss or destruction of any study records.  If 
the investigator leaves the institution where the study was conducted, the sponsor 
or its designee must be contacted to arrange alternative record storage options. 
− All eCRF data entered by the site (including audit trail), as well as computer 
hardware and software (for accessing the data), will be maintained or made 
available at the site in compliance with applicable record retention regulations.  
The sponsor will retain the original eCRF data and audit trail. 
10.2. 
Accountability, Handling, and Disposal of Study Drug 
The investigator is responsible for drug accountability at the study site; however, some of the 
drug accountability duties may be assigned to an appropriate pharmacist or other designee.  
Inventory and accountability records must be maintained and readily available for inspection by 
the study monitor and are open to inspection at any time by any applicable regulatory authorities.  
The investigator or designee must maintain records that document: 
• Delivery of study treatment to the study site. 
• Inventory of study treatment at the site. 
• Subject use of the study treatment including pill or unit counts from each supply 
dispensed. 
• Return of study treatment to the investigator or designee by subjects. 
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The investigational product must be used only in accordance with the Protocol.  The investigator 
will also maintain records adequately documenting that the subjects were provided the specified 
study treatment.  These records should include dates, quantities, and any available batch or serial 
numbers or unique code numbers assigned to the investigational product and study subjects. 
Completed accountability records will be archived by the site.  The investigator or designee will 
be expected to collect and retain all used, unused, and partially used containers of study 
treatment until verified by the study monitor (unless otherwise agreed to by the sponsor).  At the 
conclusion of the study, the investigator or designee will oversee shipment of any remaining 
study treatment back to the sponsor or its designee for destruction according to institutional 
standard operating procedures.  If local procedures mandate on-site destruction of investigational 
supply, the site should (where local procedures allow) maintain the investigational supply until 
the study monitor inspects the accountability records in order to evaluate compliance and 
accuracy of accountability by the investigative site.  At sites where the study treatment is 
destroyed before monitor inspection, the monitors rely on documentation of destruction per the 
site SOP. 
10.3. 
Data Management 
Note:  As of Amendment 7, only SAEs, AEs leading to discontinuation, EOT disposition (reason 
for discontinuation), drug accountability, dosing information, EOS disposition (end of study 
form), informed consent, and death (if it occurs within the safety reporting period) will be 
collected in the eCRF. 
Data management will be performed in a validated database via an Electronic Data Capture 
(EDC) system.  All data entry, verification, and validation will be performed in accordance with 
the current standard operating procedures of the Data Management Department at the sponsor or 
its designee.  The database will be authorized for lock once all defined procedures are completed. 
The investigator will be provided with access to an EDC system so that an eCRF can be 
completed for each subject.  Entries made in the eCRF must be verifiable against source 
documents; if updates to the database are not possible, any discrepancies should be explained 
and documented.  The investigator will be responsible for reviewing all data and eCRF entries, 
and will sign and date the designated forms in each subject's eCRF, verifying that the 
information is true and correct.  The investigator is responsible for the review and approval of all 
query responses. 
Protocol deviations will be identified and recorded in the Protocol Deviation form of the eCRF.  
The study monitor will reference the Monitoring Plan in order to ensure that each issue identified 
is appropriately documented, reported, and resolved in a timely manner in accordance with the 
plan's requirements. 
10.4. 
Data Privacy and Confidentiality of Study Records 
The investigator and the sponsor or its designee must adhere to applicable data privacy laws and 
regulations.  The investigator and the sponsor or its designee are responsible for ensuring that 
sensitive information is handled in accordance with local requirements (eg, HIPAA).  
Appropriate consent and authorizations for use and disclosure and/or transfer (if applicable) of 
protected information must be obtained. 
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Subject names will not be supplied to the sponsor or its designee, if applicable.  Only the subject 
number will be recorded in the eCRF; if the subject's name appears on any other document 
(eg, laboratory report), it must be redacted from the copy of the document to be supplied to the 
sponsor or its designee.  Study findings stored on a computer will be stored in accordance with 
local data protection laws.  The subjects will be informed that representatives of the sponsor or 
its designee, IRB or IEC, or regulatory authorities may inspect their medical records to verify the 
information collected, and that all personal information made available for inspection will be 
handled in strictest confidence and in accordance with local data protection laws. 
10.5. 
Financial Disclosure 
Before study initiation, all clinical investigators participating in clinical studies subject to FDA 
Regulation Title 21 Code of Federal Regulations (CFR) Part 54 – Financial Disclosure by 
Clinical Investigators (ie, "covered studies") are required to submit a completed Clinical 
Investigator Financial Disclosure form that sufficiently details any financial interests and 
arrangements that apply.  For the purpose of this regulation, "clinical investigator" is defined as 
any investigator or subinvestigator who is directly involved in the treatment or evaluation of 
research subjects, including the spouse and each dependent child of the clinical investigator or 
subinvestigator.  These requirements apply to both US and foreign clinical investigators 
conducting covered clinical studies. 
Any new clinical investigators added to the covered clinical study during its conduct must also 
submit a completed Investigator Financial Disclosure Form.  During a covered clinical study, 
any changes to the financial information previously reported by a clinical investigator must be 
reported to the sponsor or its designee.  At the conclusion of the covered clinical study, the 
clinical investigators will be reminded of their obligations.  In the event that the clinical 
investigator is not reminded, they nevertheless will remain obligated to report to the sponsor or 
its designee any changes to the financial information previously reported, as well as any changes 
in their financial information for a period of 1 year after completion of the covered clinical study. 
10.6. 
Publication Policy 
By signing the study Protocol, the investigator and his or her institution agree that the results of 
the study may be used by the sponsor, Incyte Corporation (Incyte), for the purposes of national 
and international registration, publication, and information for medical and pharmaceutical 
professionals.  Study results will be published in accordance with applicable local and national 
regulations.  If necessary, the authorities will be notified of the investigator's name, address, 
qualifications, and extent of involvement.  The terms regarding the publication of study results 
are contained in the agreement signed with the sponsor or its designee.  A signed agreement will 
be retained by the sponsor or its designee. 
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11. 
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patients with advanced nonsquamous non-small cell lung cancer following pemetrexed plus 
cisplatin induction treatment: a cross-trial comparison of two phase III trials. Lung Cancer 
2014;85:408-414. 
Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine 
with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage 
non-small-cell lung cancer. J Clin Oncol 2008;26:3543-3551. 
Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for 
advanced non-small-cell lung cancer. N Engl J Med 2002;346:92-98. 
Sevko A, Michels T, Vrohlings M, et al. Antitumor effect of paclitaxel is mediated by inhibition 
of myeloid-derived suppressor cells and chronic inflammation in the spontaneous melanoma 
model. J Immunol 2013;190:2464-2471. 
Seiwert TY, Burtness B, Mehra R, et al. Safety and clinical activity of pembrolizumab for 
treatment of recurrent or metastatic squamous cell carcinoma of the head and neck 
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Shevchenko I, Karakhanova S, Soltek S, et al. Low-dose gemcitabine depletes regulatory T cells 
and improves survival in the orthotopic Panc02 model of pancreatic cancer. Int J Cancer 
2013;133:98-107. 
Smith DC, Gajewski T, Hamid O, et al. Epacadostat plus pembrolizumab in patients with 
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Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract 1071P. 
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APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS 
For Subjects Participating in the Study: 
The following methods that can achieve a failure rate of less than 1% per year when used 
consistently and correctly are considered as highly effective birth control methods.  
Such methods include: 
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation1 
− oral 
− intravaginal 
− transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation1 
− oral 
− injectable 
− implantable2 
• Intrauterine device (IUD)2 
• Intrauterine hormone-releasing system (IUS)2 
• Bilateral tubal occlusion2 
• Vasectomised partner2,3 
• Sexual abstinence4 
 
1  Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the 
contraception method. 
2  Contraception methods that in the context of this guidance are considered to have low user dependency. 
3  Vasectomised partner is a highly effective method of avoiding pregnancy provided 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. EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS 
Grade 
Performance Status 
0 
Fully active, able to carry on all predisease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, eg, light house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up and 
about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair. 
5 
Dead. 
Source:  Oken et al 1982. 
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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 (eg, phenelzine) 
Meperidine 
Caroxazone 
Linezolid 
Echinopsidine 
Methylene blue 
Furazolidone 
 
Tranylcypromine 
 
Brofaromine 
 
Metralindole 
 
Minaprine 
 
Moclobemide 
 
Pirlindole 
 
Toloxatone 
 
Lazabemide 
 
Pargyline 
 
Rasagiline 
 
Selegiline 
 
 
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APPENDIX E. COMMON TERMINOLOGY CRITERIA FOR ADVERSE 
EVENTS V4.0 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be used for adverse event reporting 
(http://ctep.cancer.gov/reporting/ctc.html). 
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APPENDIX F. RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS V1.1 
RECIST v1.1* will be used in this study for assessment of tumor response.  While either 
computed tomography or magnetic resonance imaging may be used, as per RECIST v1.1, 
computed tomography 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 G. DOSE MODIFICATIONS FOR EPACADOSTAT AND 
PEMBROLIZUMAB 
G.1. 
Dose Modifications for Epacadostat and Pembrolizumab for Immune-Related 
Adverse Events 
Adverse events (AEs) associated with epacadostat and/or pembrolizumab exposure may 
represent an immunologic etiology.  These immune-related AEs (irAEs) may occur shortly after 
the first dose or several months after the last dose of epacadostat and/or pembrolizumab 
treatment and may affect more than 1 body system simultaneously.  Therefore, early recognition 
and initiation of treatment is critical to reduce complications.  Based on existing clinical study 
data, most irAEs were reversible and could be managed with interruptions of epacadostat and/or 
pembrolizumab, administration of corticosteroids, and/or other supportive care.  For suspected 
irAEs, ensure adequate evaluation to confirm etiology or exclude other causes.  Additional 
procedures or tests such as bronchoscopy, endoscopy, or skin biopsy may be included as part of 
the evaluation.  Based on the severity of irAEs, withhold or permanently discontinue epacadostat 
and/or pembrolizumab and administer corticosteroids.  Dose modification and toxicity 
management guidelines for irAEs associated with pembrolizumab and/or epacadostat are 
provided in Table G-1. 
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Table G-1: 
Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Events Associated With 
Epacadostat and/or Pembrolizumab 
irAEs 
Toxicity Grade 
or Conditions 
(CTCAE v4.0) 
Study Treatment 
Action Taken with Study 
Treatment 
irAE Management 
With Corticosteroid 
and/or Other 
Therapies 
Monitor and Follow-Up 
Pneumonitis  
Grade 2 
Pembrolizumab 
Withhold until Grade 0-1  
• 
Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) 
followed by taper 
• 
Monitor subjects for signs and 
symptoms of pneumonitis. 
• 
Evaluate subjects with 
suspected pneumonitis with 
radiographic imaging and 
initiate corticosteroid 
treatment. 
• 
Add prophylactic antibiotics 
for opportunistic infections. 
Epacadostat 
Withhold until Grade 0-1 
Grade 3 or 4, or 
recurrent Grade 2 
Pembrolizumab 
Permanently discontinue 
Epacadostat  
Permanently discontinue 
Diarrhea/colitis 
Grade 2 or 3 
Pembrolizumab 
Withhold until Grade 0-1 
• 
Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) 
followed by taper 
• 
Monitor subjects for signs and 
symptoms of enterocolitis (ie 
diarrhea, abdominal pain, 
blood or mucus in stool with or 
without fever) and of bowel 
perforation (ie peritoneal signs 
and ileus). 
• 
Subjects with ≥ Grade 2 
diarrhea suspecting colitis 
should consider GI 
consultation and performing 
endoscopy to rule out colitis.  
• 
Subjects with diarrhea/colitis 
should be advised to drink 
liberal quantities of clear 
fluids.  If sufficient oral fluid 
intake is not feasible, fluid and 
electrolytes should be 
substituted via IV infusion. 
Epacadostat  
Withhold until Grade 0-1 
Grade 4 or 
recurrent Grade 3 
Pembrolizumab 
Permanently discontinue 
Epacadostat  
Permanently discontinue 
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Table G-1: 
Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Events Associated With 
Epacadostat and/or Pembrolizumab (Continued) 
irAEs 
Toxicity Grade 
or Conditions 
(CTCAE v4.0) 
Study Treatment 
Action Taken with Study 
Treatment 
irAE Management 
With Corticosteroid 
and/or Other 
Therapies 
Monitor and Follow-Up 
AST/ALT 
Elevation or 
Increased 
Bilirubin 
Grade 2 
Pembrolizumab 
Withhold until Grade 0-1 
• 
Administer 
corticosteroids 
(initial dose of 
0.5-1 mg/kg 
prednisone or 
equivalent) 
followed by taper 
• 
Monitor with liver function 
tests (consider weekly or more 
frequently until liver enzyme 
value returns to baseline or is 
stable). 
Epacadostat  
Withhold until Grade 0-1 
Grade 3 or 4  
Pembrolizumab 
Permanently discontinue 
• 
Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) 
followed by taper 
Epacadostat  
Permanently discontinue 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemiab 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure 
Pembrolizumab 
Withhold until Grade 0-1 
• 
Initiate insulin 
replacement 
therapy for subjects 
with T1DM  
• 
Administer anti-
hyperglycemic in 
subjects with 
hyperglycemia  
• 
Monitor subjects for 
hyperglycemia or other signs 
and symptoms of diabetes. 
Epacadostat  
Withhold until Grade 0-1 
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Table G-1: 
Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Events Associated With 
Epacadostat and/or Pembrolizumab (Continued) 
irAEs 
Toxicity Grade 
or Conditions 
(CTCAE v4.0) 
Study Treatment 
Action Taken with Study 
Treatment 
irAE Management 
With Corticosteroid 
and/or Other 
Therapies 
Monitor and Follow-Up 
Hypophysitis 
Grade 2 
Pembrolizumab 
Withhold until Grade 0-1 
• 
Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated. 
• 
Monitor for signs and 
symptoms of hypophysitis 
(including hypopituitarism and 
adrenal insufficiency). 
Epacadostat  
Withhold until Grade 0-1 
Grade 3 or 4  
Pembrolizumab 
Withhold until Grade 0-1 or 
permanently discontinuea  
Epacadostat  
Withhold until Grade 0-1 or 
permanently discontinuea 
Hyperthyroidismb 
Grade 2 
Pembrolizumab 
Continue 
• 
Treat with non-
selective beta-
blockers (eg 
propranolol) or 
thioamides as 
appropriate  
• 
Monitor for signs and 
symptoms of thyroid disorders. 
Epacadostat  
Continue 
Grade 3 or 4  
Pembrolizumab 
Withhold until Grade 0-1 or 
permanently discontinuea  
Epacadostat  
Withhold until Grade 0-1 or 
permanently discontinuea 
Hypothyroidismb 
Grade 2-4 
Pembrolizumab 
Continue 
• 
Initiate thyroid 
replacement 
hormones (eg 
levothyroxine or 
liothyronine) per 
standard of care 
• 
Monitor for signs and 
symptoms of thyroid disorders. 
Epacadostat  
Continue 
Nephritis and 
Renal 
Dysfunction 
Grade 2 
Pembrolizumab 
Withhold until Grade 0-1 
• 
Administer 
corticosteroids 
(prednisone 
1-2 mg/kg or 
equivalent) 
followed by taper. 
• 
Monitor changes of renal 
function 
Epacadostat  
Withhold until Grade 0-1 
Grade 3 or 4  
Pembrolizumab 
Permanently discontinue 
Epacadostat  
Permanently discontinue 
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Table G-1: 
Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Events Associated With 
Epacadostat and/or Pembrolizumab (Continued) 
irAEs 
Toxicity Grade 
or Conditions 
(CTCAE v4.0) 
Study Treatment 
Action Taken with Study 
Treatment 
irAE Management 
With Corticosteroid 
and/or Other 
Therapies 
Monitor and Follow-Up 
Myocarditis 
Grade 1 or 2 
Pembrolizumab 
Withhold until Grade 0 
• 
Based on severity 
of AE administer 
corticosteroids 
• 
Ensure adequate evaluation to 
confirm etiology and/or 
exclude other causes. 
Epacadostat 
Withhold until Grade 0 
Grade 3 or 4 
Pembrolizumab  
Permanently discontinue 
Epacadostat 
Permanently discontinue 
Rash 
Grade 1 or 2 
Pembrolizumab 
Continue 
• 
Manage with 
topical steroids 
with or without 
drug interruption. 
 
Epacadostat  
Continue 
Grade 3c 
Pembrolizumab 
Withhold until Grade 0-1 
• 
Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) 
followed by taper. 
• 
Restart epacadostat at same 
dose if rash is mild and 
assessed as Grade 3 based only 
on body surface area and 
resolves without oral steroids.  
If oral steroids are required, or 
rash is severe, decrease by 
1 dose level once resolved to 
Grade 0-1. 
Epacadostat  
Withhold until Grade 0-1 
Grade 4 
Pembrolizumab 
Permanently discontinue 
Epacadostat  
Permanently discontinue 
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Table G-1: 
Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Events Associated With 
Epacadostat and/or Pembrolizumab (Continued) 
irAEs 
Toxicity Grade 
or Conditions 
(CTCAE v4.0) 
Study Treatment 
Action Taken with Study 
Treatment 
irAE Management 
With Corticosteroid 
and/or Other 
Therapies 
Monitor and Follow-Up 
Asymptomatic 
Amylase or 
Lipase Increased 
3 
Pembrolizumab 
May continue treatment with 
medical monitor approval 
 
• 
Permanently discontinue if 
clinical signs and symptoms of 
pancreatitis develop 
(abdominal pain, nausea, 
vomiting). 
• 
If toxicity does not resolve 
within 12 weeks of last dose 
after an interruption, must 
permanently discontinue unless 
approved by the medical 
monitor to continue. 
• 
If Grade 4 lipase/amylase 
elevation is asymptomatic and 
abdominal imaging suggests no 
pathology, study drug 
administration dosing may 
continue with medical monitor 
approval. 
Epacadostat  
May continue treatment with 
medical monitor approval 
4 
Pembrolizumab 
Withhold until toxicity resolves 
to Grade 0-1 
 
Epacadostat  
Withhold until toxicity resolves 
to Grade 0-1 
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Table G-1: 
Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Events Associated With 
Epacadostat and/or Pembrolizumab (Continued) 
irAEs 
Toxicity Grade 
or Conditions 
(CTCAE v4.0) 
Study Treatment 
Action Taken with Study 
Treatment 
irAE Management 
With Corticosteroid 
and/or Other 
Therapies 
Monitor and Follow-Up 
All Other irAEs 
Intolerable/ 
persistent Grade 2 
Pembrolizumab 
Withhold until Grade 0-1 
• 
Based on severity 
of AE administer 
corticosteroids  
• 
Ensure adequate evaluation to 
confirm etiology or exclude 
other causes. 
Epacadostat  
Withhold until Grade 0-1 
Grade 3 
Pembrolizumab 
Withhold until Grade 0-1, or 
discontinue based on the type of 
event.  Events that require 
discontinuation include and not 
limited to: Guillain-Barre 
Syndrome, encephalitis 
Epacadostat 
Withhold until Grade 0-1 
Events that require 
discontinuation include and not 
limited to: Guillain-Barre 
Syndrome, encephalitis   
Grade 4 or 
recurrent Grade 3  
Pembrolizumab 
Permanently discontinue 
Epacadostat 
Permanently discontinue 
AEs = adverse events; ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT) = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase); CTCAE = Common Terminology Criteria for Adverse Events; GI = gastrointestinal; irAE = immune-related adverse events; IV = intravenous; T1DM = Type 1 
diabetes mellitus. 
General Instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab and epacadostat have been withheld, pembrolizumab and epacadostat can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered.  Pembrolizumab and epacadostat should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids 
cannot be reduced to ≤ 10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid.  Other immunosuppressive treatment should be initiated if irAEs cannot 
be controlled by corticosteroids. 
NOTES: 
a. Withhold OR permanently discontinue pembrolizumab or epacadostat at the discretion of the investigator.   
b. For subjects with Grade 3 or 4 immune-related endocrinopathy where withholding of pembrolizumab and epacadostat is required, pembrolizumab and epacadostat may be 
resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM). 
c. Subjects with Grade 3 rash in the absence of desquamation, no mucosal involvement, does not require systemic steroids, and resolves to Grade 1 within 14 days does not have to 
hold study treatment. 
 
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G.2. 
Dose Modification and Toxicity Management of Infusion Reactions Related to 
Pembrolizumab 
Pembrolizumab may cause severe or life-threatening infusion reactions, including severe 
hypersensitivity or anaphylaxis.  Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion.  Dose 
modification and toxicity management guidelines on pembrolizumab-associated infusion 
reaction are provided in Table G-2. 
Table G-2: 
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated 
Increase monitoring of vital signs as medically indicated 
until the subject is deemed medically stable in the 
opinion of the investigator. 
None. 
Grade 2 
Requires therapy or 
infusion interruption 
but responds promptly 
to symptomatic 
treatment (eg, 
antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤ 24 hours 
Stop Infusion. 
Additional appropriate medical therapy may include, but 
is not limited to, the following: 
• IV fluids 
• Antihistamines 
• NSAIDs 
• Acetaminophen 
• Narcotics 
Increase monitoring of vital signs as medically indicated 
until the subject is deemed medically stable in the 
opinion of the investigator. 
If symptoms resolve within 1 hour of stopping drug 
infusion, the infusion may be restarted at 50% of the 
original infusion rate (eg, from 100 mL/h to 50 mL/h).  
Otherwise, dosing will be held until symptoms resolve, 
and the subject should be premedicated for the next 
scheduled dose. 
Subjects who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from 
further study drug treatment. 
Subject may be premedicated 
1.5 hours (± 30 minutes) 
before infusion of 
pembrolizumab with: 
Diphenhydramine 50 mg PO 
(or equivalent dose of 
antihistamine). 
Acetaminophen 500-1000 mg 
PO (or equivalent dose of 
analgesic). 
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Table G-2: 
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines (Continued) 
NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
Grades 3 or 4 
Grade 3: 
Prolonged (ie, not 
rapidly responsive to 
symptomatic 
medication and/or brief 
interruption of 
infusion); recurrence 
of symptoms after 
initial improvement; 
hospitalization 
indicated for other 
clinical sequelae (eg, 
renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; 
pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may include, but 
is not limited, to the following: 
• Epinephrine* 
*In cases of anaphylaxis, epinephrine should be used 
immediately. 
• IV fluids 
• Antihistamines 
• NSAIDs 
• Acetaminophen 
• Narcotics 
• Oxygen 
• Pressors 
• Corticosteroids 
Increase monitoring of vital signs as medically indicated 
until the subject is deemed medically stable in the 
opinion of the investigator. 
Hospitalization may be indicated. 
Subject should be permanently discontinued from further 
study drug treatment. 
No subsequent dosing. 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the 
period of drug administration. 
For further information, please refer to the CTCAE v4.0 at http://ctep.cancer.gov. 
NCI = National Cancer Institute; NSAID = nonsteroidal anti-inflammatory drug; PO = orally. 
G.3. 
Other Allowed Dose Interruption for Epacadostat and/or Pembrolizumab 
Epacadostat and/or pembrolizumab may be interrupted for situations other than treatment-related 
AEs, such as medical/surgical events or logistical reasons not related to study therapy.  Subjects 
should be placed back on study therapy within 3 weeks of the scheduled interruption, unless 
otherwise discussed with the sponsor.  The reason for interruption should be documented in the 
eCRF. 
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APPENDIX H. DOSE MODIFICATIONS FOR MFOLFOX6 
H.1. 
Criteria for Start of Cycle (Criteria for Administration on Day 1 of Each Cycle) 
After confirmation that each subject meets criteria for the start of each cycle described in 
Table H-1, mFOLFOX6 will be administered.  If any criteria are not met, administration of 
therapy will be postponed.  From the second cycle onwards, all treatments will be discontinued if 
therapy has not been initiated by 14 days after the estimated Day 1. 
Table H-1: 
Criteria for Administration of mFOLFOX6 on Day 1 of Each Cycle 
Parameter 
Criterion for Start 
WBC 
≥ 3.0 × 109/L 
Neutrophil count 
≥ 1.5 × 109/L 
Platelet count 
≥ 75 × 109/L 
Infection 
No fever (> 38.0°C or 100.4°F) suspect for infection 
Nonhematologic toxicities 
Diarrhea 
No watery diarrhea 
Others 
< Grade 2 (except for nausea, vomiting, anorexia, and fatigue) 
If mFOLFOX6 is held for any of the reasons noted in Table H-1 above, both epacadostat and 
pembrolizumab 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 H-2 and Table H-3 for hematologic toxicities, taking tolerability of 
the most recent dose into account. 
H.2. 
Management Guidelines for Hematologic Toxicities  
Table H-2 provides guidance for dose reductions for the first appearance of the hematologic 
toxicities.  Toxicities must be resolved to Grade 0 or 1 before resuming treatment.  When the 
dose of 5-FU is reduced, the dose of leucovorin will remain the same. 
Table H-2: 
Criteria for Dose Reductions for the First Appearance of Hematologic 
Toxicities 
Criteria 
Oxaliplatin 
5-FU Bolus 
5-FU Continuous 
Grade 3 leukopenia or neutropenia 
20% dose reduction 
Stop treatment 
No dose reduction 
Grade 4 leukopenia or neutropenia 
Grade 2 or 3 thrombocytopenia 
Grade 4 thrombocytopenia 
Note:  The dose of leucovorin remains the same. 
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Table H-3 provides guidance for dose reductions for the second appearance of the specified 
hematologic toxicities. 
Table H-3: 
Criteria for Dose Reductions for Recurrent Hematologic Toxicities 
Criteria 
Oxaliplatin 
5-FU Bolus 
5-FU Continuous 
Grade 3 leukopenia or neutropenia 
20% dose reduction 
N/A 
No dose reduction 
Grade 4 leukopenia or neutropenia 
Grade 2 or 3 thrombocytopenia 
Grade 4 thrombocytopenia 
Note:  The dose of leucovorin remains the same. 
After a second dose reduction, if any hematologic toxicities reoccur (third occurrence) and are 
clearly associated with chemotherapy, chemotherapy may be discontinued, and epacadostat and 
pembrolizumab may be continued at the same dose at the discretion of the investigator and 
approval of the medical monitor. 
H.3. 
Management Guidelines for Nonhematologic Toxicities 
Table H-4 provides guidance for dose reductions for the appearance of nonhematologic 
toxicities.  Toxicities must be resolved to Grade 0 or 1 before resuming treatment.  When the 
dose of 5-FU is reduced, the dose of leucovorin will remain the same.   
It is important to note that some chemotherapy-related AEs will overlap with potential irAEs 
(including but not limited to gastrointestinal toxicity, including diarrhea; renal insufficiency; 
high-grade laboratory abnormalities; rash/hypersensitivity).  In these cases, both the 
chemotherapy-related AE and irAE management guidance (Appendix G) should be reviewed to 
determine the most appropriate management of therapy. 
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Table H-4: 
Criteria for Dose Reductions for Nonhematologic Toxicities 
Criteria 
Oxaliplatin 
5-FU Bolus 
5-FU Continuous 
Allergic reaction to oxaliplatin 
Stop treatment 
No dose reduction 
No dose reduction 
AST/ALT 
Grade 1 (< 3 × ULN) 
No dose reduction 
No dose reduction 
No dose reduction 
Grade 2 (3 × to < 5 × ULN) 
No dose reduction 
No dose reduction 
No dose reduction 
Grade 3 or 4 (> 5× ULN) 
20% dose reduction 
Stop treatment 
No dose reduction 
Bilirubin 
Grade 2 (> 1.5 × to 3 × ULN) 
No dose reduction 
No dose reduction 
No dose reduction 
Grade 3 (> 3 × to 10 × ULN) 
20% dose reduction 
Stop treatment 
No dose reduction 
Grade 4 (> 10 × ULN) 
Stop treatment 
Stop treatment 
Stop treatment 
Hy's Law
a 
Stop treatment 
Stop treatment 
Stop treatment 
Diarrhea 
Grade 1 
No dose reduction 
No dose reduction 
No dose reduction 
Grade 2 
No dose reduction 
No dose reduction 
No dose reduction 
Grade 3 or 4 
20% dose reduction 
Stop treatment 
No dose reduction 
Neurologic toxicities 
Grade 2 
20% dose reduction 
No dose reduction. 
Stop treatment for hyperammonemic 
encephalopathy, acute cerebellar 
syndrome, confusion, disorientation, 
ataxia or visual disturbances 
Grade 3 
Stop treatment 
Respiratory symptoms indicative of pulmonary 
fibrosis due to oxaliplatin 
Stop treatment 
No dose reduction 
No dose reduction 
Other nonhematologic 
toxicity 
Grade 3 
20% dose reduction 
Stop treatment 
No dose reduction 
Grade 4 
Stop treatment 
Stop treatment 
Stop treatment 
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 I. DOSE MODIFICATIONS FOR 
GEMCITABINE/NAB-PACLITAXEL 
I.1. 
Criteria for Start of Cycle (Criteria for Administration on Day 1 of Each Cycle) 
A cycle of therapy may begin on a scheduled Day 1 if the following conditions are met: 
• ANC ≥ 1.5 × 109/L. 
• Platelet count ≥ 100 × 109/L. 
• Sensory neuropathy has improved to ≤ Grade 1. 
• Any other AE that occurred has resolved to ≤ Grade 1 severity or returned to baseline. 
The dose of each agent selected for use in the new cycle will follow the guidelines shown in 
Table I-1, taking tolerability of the most recent dose into account. 
If new cycle starting requirements are not met, regardless of dose modification, all treatments 
(epacadostat, pembrolizumab, gemcitabine, and nab-paclitaxel) will be held, and the subject will 
be evaluated at least weekly until the toxicity has resolved.  
From the second cycle onwards, all treatments will be discontinued if therapy has not been 
initiated within the 14 days after the scheduled Day 1. 
I.2. 
nab-Paclitaxel and Gemcitabine Dose Modifications  
Gemcitabine treatment cycles and those including nab-paclitaxel may be delayed or the dose 
may be reduced for laboratory parameters or AEs that are judged to be related to gemcitabine or 
nab-paclitaxel.  A maximum of 2 dose reductions are allowed:  for gemcitabine from 
1000 mg/m2 to 800 mg/m2 and 600 mg/m2, and for nab-paclitaxel from 125 mg/m2 to 100 mg/m2 
and 75 mg/m2 (Table I-1). 
Day 1 of each study cycle will correspond with the first day of chemotherapy administration.  
Thus, study cycles may become out of sync with the originally planned schedule.  All 
assessments will shift to coincide with the revised treatment (cycle) schedule. 
Table I-1: 
nab-Paclitaxel and Gemcitabine Dose Level Reductions 
Dose Reduction 
Gemcitabine 
nab-Paclitaxel 
Full dose 
1000 mg/m2 
125 mg/m2 
First dose reduction 
800 mg/m2 
100 mg/m2 
Second dose reduction 
600 mg/m2 
75 mg/m2 
If additional dose reduction required 
Discontinue 
Discontinue 
After a second dose reduction, if neutropenia or thrombocytopenia reoccur (third occurrence) 
and are clearly associated with chemotherapy, nab-paclitaxel and gemcitabine may be 
discontinued, and pembrolizumab and epacadostat may be continued at the discretion of the 
investigator and approval of the medical monitor. 
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I.3. 
Changes to Treatment Regimen During a Cycle for Hematologic Toxicities 
Mandatory dose interruptions and modifications of nab-paclitaxel and gemcitabine on Days 1, 8, 
and 15 of a cycle for hematologic toxicity are shown in Table I-2. 
Table I-2: 
Modifications for Neutropenia and/or Thrombocytopenia at the Start of a 
Cycle or Within a Cycle 
Cycle Day 
ANC  
(× 109/L) 
 
Platelet 
Count  
(× 109/L) 
nab-Paclitaxel and Gemcitabine 
Day 1 
< 1.5 
OR 
< 100 
Delay dose until recovery 
Day 8 
0.5 to < 1.0 
OR 
50 to < 75 
Reduce 1 dose level 
< 0.5 
OR 
< 50 
Withhold doses 
Day 15:  If Day 8 doses were reduced 
or given without modification 
0.5 to < 1.0 
OR 
50 to < 75 
Reduce 1 dose level from Day 8 
< 0.5 
OR 
< 50 
Withhold doses 
Day 15:  If Day 8 doses were 
withheld 
≥ 1.0 
OR 
≥ 75 
Reduce 1 dose level from Day 1 
0.5 to < 1.0 
OR 
50 to < 75 
Reduce 2 dose levels from Day 1 
< 0.5 
OR 
< 50 
Withhold doses 
I.4. 
Other Adverse Drug Reactions in Subjects With nab-Paclitaxel and Gemcitabine 
Dose interruptions and modifications for nab-paclitaxel and gemcitabine for other adverse drug 
reactions are described in Table I-3. 
Table I-3: 
Dose Modifications for nab-Paclitaxel and Gemcitabine Adverse Drug 
Reactions 
 
Gemcitabine 
nab-Paclitaxel 
Febrile neutropenia:  Grade 3 or 4 
Withhold until fever resolved and ANC ≥ 1.5 × 109/L; resume at next lower 
dose level. 
Peripheral neuropathy:  Grade 3 or 4 
No dose reduction. 
Withhold until improves to ≤ Grade 1; 
resume at next lower dose level. 
Cutaneous toxicity:  Grade 2 or 3 
Reduce to next lower dose level; discontinue treatment if toxicity persists. 
Gastrointestinal toxicity:  Grade 3 
mucositis or diarrhea 
Withhold until improves to ≤ Grade 1; resume at next lower dose level. 
Note:  If the subject meets more than 1 of the criteria listed, dose modifications should always be based on the system showing 
the greatest degree of toxicity.  Dose interruptions and modifications will be made at the discretion of the investigator. 
If the toxicities listed in Table I-3 persist or reoccur despite 2 dose reductions and are clearly 
associated with chemotherapy, nab-paclitaxel/gemcitabine may be discontinued, and 
pembrolizumab and epacadostat may be continued at the discretion of the investigator and 
approval of the medical monitor.  If nab-paclitaxel must be discontinued for peripheral 
neuropathy, gemcitabine, pembrolizumab, and epacadostat may be continued at the discretion of 
the investigator and approval of the medical monitor. 
I.4.1 
nab-Paclitaxel Hypersensitivity Reactions 
Hypersensitivity reactions are not expected with nab-paclitaxel.  If they do occur, minor 
symptoms such as flushing, skin reactions, dyspnea, hypotension, or tachycardia may require 
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temporary interruption of the infusion.  However, severe reactions, such as hypotension requiring 
treatment, dyspnea requiring bronchodilators, angioedema, or generalized urticaria, require 
immediate discontinuation of nab-paclitaxel and aggressive symptomatic therapy.  Subjects who 
experience a ≥ Grade 3 allergic reaction or anaphylaxis events will not be rechallenged with 
nab-paclitaxel.  Subjects with < Grade 3 infusion reactions can be rechallenged following 
premedication (per institutional guidelines).  If nab-paclitaxel is discontinued due to a 
hypersensitivity reaction, gemcitabine, pembrolizumab, and epacadostat may be continued at the 
discretion of the investigator and approval of the medical monitor. 
I.4.2. 
Management Guidelines for Nonhematologic Toxicities 
Table I-4 provides guidance for dose reductions for the appearance of nonhematologic toxicities.  
Toxicities must be resolved to Grade 0 or 1 before resuming treatment. 
It is important to note that some chemotherapy-related AEs will overlap with potential irAEs 
(including but not limited to gastrointestinal toxicity, including diarrhea; renal insufficiency; 
high-grade laboratory abnormalities; rash/hypersensitivity).  In these cases, both the 
chemotherapy-related AE and irAE management guidance (Appendix G) should be reviewed to 
determine the most appropriate management of therapy. 
Table I-4: 
Criteria for Dose Reductions for Nonhematologic Toxicities 
Criteria 
Gemcitabine 
nab-Paclitaxel 
Hypersensitivity reaction to 
nab-paclitaxel 
≤ Grade 2 
No dose reduction 
Rechallenge following 
premedication allowed 
≥ Grade 3 
No dose reduction 
Stop treatment 
AST/ALT 
Grade 1 (< 3 × ULN) 
No dose reduction 
No dose reduction 
Grade 2 (3 × to < 5 × ULN) 
No dose reduction 
Consider dose reduction 
Grade 3 or 4 (> 5 × ULN) 
No dose reduction 
Dose reduce 1 level 
Bilirubin 
Grade 2 (> 1.5 × to 3 × ULN) 
No dose reduction 
No dose reduction 
Grade 3 (> 3 × to 10 × ULN) 
No dose reduction 
Reduce dose 1 level 
Grade 4 (> 10 × ULN) 
Stop treatment 
Stop treatment 
Hy's Law
a 
Stop treatment 
Stop treatment 
Diarrhea 
Grade 1 
No dose reduction 
No dose reduction 
Grade 2 
No dose reduction 
No dose reduction 
Grade 3 or 4 
Reduce dose 1 level 
Reduce dose 1 level 
Neurologic toxicities 
Grade 2 
No dose reduction 
No dose reduction 
Grade 3 
No dose reduction 
Reduce dose 1 level 
Other nonhematologic toxicity 
Grade 3 
Reduce dose 1 level 
Reduce dose 1 level 
Grade 4 
Stop treatment 
Stop treatment 
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 
PACLITAXEL/CARBOPLATIN 
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, paclitaxel will be administered first, followed by carboplatin.  If any criteria are not 
met, administration of therapy (ie, epacadostat, pembrolizumab, carboplatin, paclitaxel) will be 
postponed.  From the second cycle onwards, all treatments 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 Paclitaxel and Carboplatin 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 
> 30 mL/min AND < 10% change in GFR from previous cycle 
Nonhematologic toxicities 
Bilirubin 
≤ ULN 
AST/ALT 
< 2.5 × ULN 
If carboplatin and/or paclitaxel are held for any of the reasons noted in Table J-1 above, both 
epacadostat and pembrolizumab 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 and Table J-3, taking tolerability of the most recent 
dose into account. 
J.2. 
Paclitaxel and Carboplatin Dose Modifications 
Table J-2 provides guidance for dose reductions for the first appearance of specified toxicities, 
and Table J-3 provides guidance for dose reductions for elevations of AST, ALT, and/or 
bilirubin. 
It is important to note that some chemotherapy-related AEs will overlap with potential irAEs 
(including but not limited to gastrointestinal toxicity, including diarrhea; renal insufficiency; 
high-grade laboratory abnormalities; rash/hypersensitivity).  In these cases, both the 
chemotherapy-related AE and irAE management guidance (Appendix G) should be reviewed to 
determine the most appropriate management of therapy. 
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Table J-2: 
Criteria for Dose Reductions for Specified Toxicities 
Hematologic 
toxicity 
Dose modifications based on neutrophil and/or platelet count on day of treatment (Day 1). 
ANC 
 
Platelet 
Count 
Action 
Dose Modification After 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 
No dose 
reduction 
Reduce by 1 AUC 
< 1.0 × 109/L AND < 100 × 109/L 
Delay 1 
week until 
recovery 
25% dose 
reduction 
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 with fever 
requiring IV antibiotics ± 
hospitalization 
20% reduction for carboplatin and dose 
paclitaxel at 135 mg/m2. 
Fatigue 
Grade 3 
First occurrence give 25% dose reduction; if 
persistent, 50% reduction or omit paclitaxel 
only. 
Neuropathy 
Grade 2 
Reduce paclitaxel to 135 mg/m2 in all 
subsequent cycles.  If persistent, reduce 
paclitaxel to 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 
If not contraindicated, consider giving 
diclofenac 50 mg TID for 5 days.  
Alternatively, consider prednisone 10 mg BID 
for 5 days starting 24 hours after paclitaxel.  If 
arthralgia and/or myalgia persists reduce 
subsequent paclitaxel doses 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.  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 
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Table J-3: 
Management Guidelines for Hepatic Toxicity 
AST/ALT 
Bilirubin 
Carboplatin 
Paclitaxel 
Grade 1 (< 3 × ULN) 
≤ ULN 
Continue same dose 
Continue same dose 
Grade 2 (3 × to < 5 × ULN) 
≤ ULN 
Continue same dose 
Continue same dose 
Grade 2 (3 × to < 5 × ULN) 
Grade 1 (ULN to 1.5 × ULN) 
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 
Continue same dose Reduce dose to 75 mg/m2 
ANY Grade 3 or Grade 4 
Permanently discontinue treatment 
Hy's Lawa 
Permanently discontinue treatment 
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 
PEMETREXED/PLATINUM AGENT 
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, pemetrexed and platinum agent (ie, carboplatin or cisplatin) may be administered.  If 
any criteria are not met, administration of therapy will be postponed.  From the second cycle 
onwards, the all treatments 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 Pemetrexed and Platinum Agent 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 
> 20 mL/min for carboplatin or > 50 mL/min for cisplatin 
AND 
< 10% change in GFR from previous cycle 
If pemetrexed/platinum agent are held for any of the reasons noted in Table K-1 above, both 
epacadostat and pembrolizumab 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, taking tolerability of the most recent dose into 
account. 
K.2. 
Pemetrexed and Platinum Agent Dose Modifications 
Table K-2 provides guidance for dose reductions for hematologic toxicities, and Table K-3 
provides guidance for nonhematologic toxicities. 
It is important to note that some chemotherapy-related AEs will overlap with potential irAEs 
(including but not limited to gastrointestinal toxicity, including diarrhea; renal insufficiency; 
high-grade laboratory abnormalities; rash/hypersensitivity).  In these cases, both the 
chemotherapy-related AE and irAE management guidance (Appendix G) should be reviewed to 
determine the most appropriate management of therapy. 
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Table K-2: 
Criteria for Dose Reductions for Hematologic Toxicities 
Hematologic 
toxicity 
Dose modifications based on neutrophil and/or platelet count on day of treatment (Day 1). 
Nadir 
ANC 
(× 109/L) 
 
Nadir Platelet Count 
(× 109/L) 
Dose Modification After Recovery 
Pemetrexed 
Platinum Agent 
(Carboplatin or 
Cisplatin) 
≥ 500 
AND 
≥ 50 
Full dose 
Full dose 
< 500 
AND 
≥ 50 
75% of previous dose 
75% of previous 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 
Table K-3: 
Criteria for Dose Reductions for Nonhematologic Toxicities 
Criteria 
Pemetrexed 
Platinum Agent 
(Carboplatin or 
Cisplatin) 
AST/ALT 
Grade 1 (< 3 × ULN) 
No dose reduction 
No dose reduction 
Grade 2 (3 × to < 5 × ULN) 
No dose reduction 
No dose reduction 
Grade 3 or 4 (> 5 × ULN) 
75% of previous dose 
75% of previous dose 
Bilirubin  
Grade 2 (> 1.5 × to 3 × ULN) 
No dose reduction 
No dose reduction 
Grade 3 (> 3 × to 10 × ULN) 
75% of previous dose 
75% of previous dose 
Grade 4 (> 10 × ULN) 
Stop treatment 
Stop treatment 
Hy's Law
a 
Stop treatment 
Stop treatment 
Diarrhea 
Any Grade requiring 
hospitalization OR Grade 3 or 4 
75% of previous dose 
75% of previous dose 
Neurotoxicity 
Grade 2 
No dose reduction 
50% of previous dose 
Grade 3 or 4 
Stop treatment 
Stop treatment 
Mucositis Grade 3 or 4 
50% of previous dose 
No dose reduction 
Other nonhematologic 
toxicity 
Grade 3 
75% of previous dose 
75% of previous dose 
Grade 4 
Stop treatment 
Stop treatment 
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. DOSE MODIFICATIONS FOR CYCLOPHOSPHAMIDE 
L.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 L-1, cyclophosphamide may be administered.  If any criteria are not satisfied, 
administration of the cycle will be postponed.  From the second cycle onwards, all treatments 
will be discontinued if administration of the cycle has not been initiated by 14 days after the 
estimated Day 1. 
Table L-1: 
Criteria for Administration of Cyclophosphamide on Day 1 of Each Cycle 
Parameter 
Criterion for Start 
Neutrophil count 
≥ 1.0 × 109/L 
Platelet count 
≥ 75 × 109/L 
Nonhematologic toxicities 
No ≥ Grade 2 anorexia, nausea, vomiting, diarrhea, stomatitis, 
and dryness of the mouth, epigastric pain or increase in bilirubin 
or transaminases 
If cyclophosphamide is held for any of the reasons noted in Table L-1, both epacadostat and 
pembrolizumab should be delayed as well.  The dose of each agent selected for use in the new 
cycle will follow the guidelines shown in Table L-2, taking tolerability of the most recent dose 
into account. 
L.2. 
Management Guidelines for Hematologic Toxicities  
Table L-2 provides guidance for dose reductions for the first appearance of specified 
hematologic toxicities. 
Table L-2: 
Criteria for Dose Reductions for the Hematologic Toxicities 
Criteria 
Cyclophosphamide 
Grade 3 leukopenia or neutropenia 
Reduce dose 50% OR change to every other day dosing if 
reduced dosage strength is unavailable 
Grade 4 leukopenia or neutropenia 
Reduce dose 50% OR change to every other day dosing if 
reduced dosage strength is unavailable 
Grade 2 or 3 thrombocytopenia 
Reduce dose 50% OR change to every other day dosing if 
reduced dosage strength is unavailable 
Grade 4 thrombocytopenia 
Reduce dose 50% OR change to every other day dosing if 
reduced dosage strength is unavailable 
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Table L-3 provides guidance for dose reductions for recurrent specified hematologic toxicities. 
Table L-3: 
Criteria for Dose Reductions for Recurrent Hematologic Toxicities 
Criteria 
Cyclophosphamide 
Grade 3 leukopenia or neutropenia 
Stop treatment 
Grade 4 leukopenia or neutropenia 
Stop treatment 
Grade 2 or 3 thrombocytopenia 
Stop treatment 
Grade 4 thrombocytopenia 
Stop treatment 
L.3. 
Management Guidelines for Nonhematologic Toxicities 
Table L-4 provides guidance for dose reductions for the appearance of nonhematologic toxicities 
for subjects who receive cyclophosphamide.  Toxicities must be resolved to Grade 0 or 1 before 
resuming treatment. 
It is important to note that some chemotherapy-related AEs will overlap with potential irAEs 
(including but not limited to gastrointestinal toxicity, including diarrhea; renal insufficiency; 
high-grade laboratory abnormalities; rash/hypersensitivity).  In these cases, both the 
chemotherapy-related AE and irAE management guidance (Appendix G) should be reviewed to 
determine the most appropriate management of therapy. 
Table L-4: 
Criteria for Dose Reductions for Nonhematologic Toxicities 
Criteria 
Cyclophosphamide 
AST/ALT 
Grade 1 (< 3 × ULN) 
No dose reduction 
Grade 2 (3 × to < 5 × ULN) 
No dose reduction 
Grade 3 or 4 (> 5 × ULN) 
50% dose reduction 
Bilirubin 
Grade 2 (> 1.5 × to 3 × ULN)  
No dose reduction 
Grade 3 (> 3 × to 10 × ULN) 
50% dose reduction 
Grade 4 (> 10 × ULN) 
Stop treatment 
Hy's Law
a 
Stop treatment 
Diarrhea 
Grade 1 
No dose reduction 
Grade 2 
No dose reduction 
Grade 3 or 4 
50% dose reduction 
Neurologic toxicities 
Grade 2 
No dose reduction 
Grade 3 
50% dose reduction 
Other nonhematologic toxicity 
Grade 3 
50% dose reduction 
Grade 4 
Stop treatment 
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 M. DOSE MODIFICATIONS FOR 
GEMCITABINE/PLATINUM AGENT 
M.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 M-1, gemcitabine and platinum agent (ie, carboplatin or 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 M-1: 
Criteria for Administration of Gemcitabine and Platinum Agent 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 
Infection 
No fever (> 38.0°C or 100.4°F) suspect for infection 
Renal function 
> 20 mL/min for carboplatin or > 50 mL/min for cisplatin 
AND 
< 10% change in GFR from previous cycle 
If gemcitabine/platinum agent is held for any of the reasons noted in Table M-1 above, both 
epacadostat and pembrolizumab 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 M-2 and Table M-3 for hematologic toxicities, taking 
tolerability of the most recent dose into account. 
M.2. 
Management Guidelines for Hematologic Toxicities 
Table M-2 provides guidance for dose reductions for the first appearance of the hematologic 
toxicities.  Toxicities must be resolved to Grade 0 or 1 before resuming treatment. 
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Table M-2: 
Criteria for Dose Reductions for the First Appearance of 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 After Recovery 
Gemcitabine 
Platinum Agent 
(Carboplatin or 
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 
Reduce 1 dose level 
75% dose 
< 1.0 × 109/L AND ≤ 100 × 109/L 
Delay 1 week until 
recovery 
Reduce 2 dose levels 
75% dose 
Table M-3 provides guidance for dose reductions for the recurrent specified hematologic 
toxicities.  A maximum of 2 dose reductions for gemcitabine is allowed (Table M-4).  After a 
second dose reduction, if any hematologic toxicities reoccur (third occurrence) and are clearly 
associated with chemotherapy, chemotherapy may be discontinued, and epacadostat and 
pembrolizumab may be continued at the same dose at the discretion of the investigator and 
approval of the medical monitor. 
Table M-3: 
Criteria for Dose Reductions for Recurrent 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 After Recovery 
Gemcitabine 
Platinum Agent 
(Carboplatin or 
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 
Reduce 1 dose level 
75% dose 
< 1.0 × 109/L AND ≤ 100 × 109/L 
Delay 1 week until 
recovery 
Reduce 2 dose levels 
75% dose 
Table M-4: 
Gemcitabine Dose Level Reductions 
Dose Reduction 
Gemcitabine 
Full dose 
1000 mg/m2 
First dose reduction 
800 mg/m2 
Second dose reduction 
600 mg/m2 
If additional dose reduction required 
Discontinue 
M.3. 
Management Guidelines for Nonhematologic Toxicities 
Table M-5 provides guidance for dose reductions for the appearance of nonhematologic 
toxicities.  Toxicities must be resolved to Grade 0 or 1 before resuming treatment. 
It is important to note that some chemotherapy-related AEs will overlap with potential irAEs 
(including but not limited to gastrointestinal toxicity, including diarrhea; renal insufficiency; 
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high-grade laboratory abnormalities; rash/hypersensitivity).  In these cases, both the 
chemotherapy-related AE and irAE management guidance (Appendix G) should be reviewed to 
determine the most appropriate management of therapy. 
Table M-5: 
Criteria for Dose Reductions for Nonhematologic Toxicities 
Criteria 
Gemcitabine 
Platinum Agent 
(Carboplatin or Cisplatin) 
Diarrhea 
Grade 1 
No dose reduction 
No dose reduction 
Grade 2 
Reduce 1 dose level 
No dose reduction 
Grade 3 or 4 
Reduce 2 dose levels 
75% dose 
Neurologic toxicities 
Grade 2 
No dose reduction 
75% dose 
Grade 3 
Stop treatment 
Other nonhematologic toxicity 
Grade 3 
Reduce 1 dose level 
75% dose 
Grade 4 
Stop treatment 
Stop treatment 
Table M-6 provides guidance for dose reductions for platinum agent in the event of renal 
impairment.  If the calculated GFR falls by more than 10% from the previous cycle, consider 
dose reduction. 
Table M-6: 
Criteria for Dose Reductions of Platinum Agent for Renal Impairment 
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 5 (discuss with 
medical monitor prior to switching) 
20-30 mL/min 
EDTA, then use AUC as per 
protocol or consider 
discontinuing carboplatin 
< 30 mL/min 
Discontinue cisplatin, continue 
paclitaxel 
< 20 mL/min 
Discontinue carboplatin, 
continue paclitaxel 
Table M-7 provides guidance for dose reductions for elevations of AST, ALT, and/or bilirubin. 
Table M-7: 
Criteria for Dose Reductions for Hepatic Toxicity 
AST/ALT 
Bilirubin 
Gemcitabine 
Platinum Agent 
Grade 1 (< 3× ULN) 
≤ ULN 
No dose reduction 
Continue same dose 
Grade 2 (3 × to < 5 × ULN) 
≤ ULN 
No dose reduction 
Continue same dose 
Grade 2 (3 × to < 5 × ULN) 
Grade 1 (ULN to 1.5 × ULN) 
No dose reduction 
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 
No dose reduction 
Continue same dose 
ANY Grade 3 or Grade 4 
Permanently discontinue treatment 
Hy's Lawa 
Permanently discontinue treatment 
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 N. DOSE MODIFICATIONS FOR PLATINUM 
AGENT/5-FLUOROURACIL 
N.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 N-1, platinum agent (ie, carboplatin or cisplatin) and 5-fluorouracil 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 N-1: 
Criteria for Administration of Platinum Agent and 5-Fluorouracil 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 
Infection 
No fever (> 38.0°C or 100.4°F) suspect for infection 
Nonhematologic toxicities 
Diarrhea 
No watery diarrhea 
Renal function 
> 20 mL/min for carboplatin or > 50 mL/min for cisplatin 
AND 
< 10% change in GFR from previous cycle 
Others 
< Grade 2 (except for nausea, vomiting, anorexia, and fatigue) 
If platinum agent/5-fluorouracil is held for any of the reasons noted in Table N-1 above, both 
epacadostat and pembrolizumab 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 N-2 and Table N-3 for hematologic toxicities, taking 
tolerability of the most recent dose into account. 
N.2. 
Management Guidelines for Hematologic Toxicities 
Table N-2 provides guidance for dose reductions for the first appearance of the hematologic 
toxicities.  Toxicities must be resolved to Grade 0 or 1 before resuming treatment. 
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Table N-2: 
Criteria for Dose Reductions for the First Appearance of 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 
Platinum Agent 
(Carboplatin or 
Cisplatin) 
5-Fluorouracil 
≥ 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% dose 
75%-100% dose 
< 1.0 × 109/L AND ≤ 100 × 109/L Delay 1 week until recovery 
75% dose 
75% dose 
Table N-3 provides guidance for dose reductions for the specified recurrent hematologic 
toxicities.  After a second dose reduction, if any hematologic toxicities reoccur (third occurrence) 
and are clearly associated with chemotherapy, chemotherapy may be discontinued, and 
epacadostat and pembrolizumab may be continued at the same dose at the discretion of the 
investigator and approval of the medical monitor. 
Table N-3: 
Criteria for Dose Reductions for Recurrent 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 
Platinum Agent 
(Carboplatin or 
Cisplatin) 
5-Fluorouracil 
≥ 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% dose 
75%-100% dose 
< 1.0 × 109/L AND ≤ 100 × 109/L Delay 1 week until recovery 
75% dose 
75% dose 
N.3. 
Management Guidelines for Nonhematologic Toxicities 
Table N-4 provides guidance for dose reductions for the appearance of nonhematologic 
toxicities.  Toxicities must be resolved to Grade 0 or 1 before resuming treatment. 
It is important to note that some chemotherapy-related AEs will overlap with potential irAEs 
(including but not limited to gastrointestinal toxicity, including diarrhea; renal insufficiency; 
high-grade laboratory abnormalities; rash/hypersensitivity).  In these cases, both the 
chemotherapy-related AE and irAE management guidance (Appendix G) should be reviewed to 
determine the most appropriate management of therapy. 
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Table N-4: 
Criteria for Dose Reductions for Nonhematologic Toxicities 
Criteria 
Platinum Agent  
(Carboplatin or Cisplatin) 
5-Fluorouracil 
Diarrhea 
Grade 1 
No dose reduction 
No dose reduction 
Grade 2 
No dose reduction 
No dose reduction 
Grade 3 or 4 
75% dose 
75% dose 
Neurologic toxicities 
Grade 2 
No dose reduction. 
Stop treatment for hyperammonemic 
encephalopathy, acute cerebellar 
syndrome, confusion, disorientation, 
ataxia, or visual disturbances 
75% dose 
Grade 3 
 
Stop treatment 
Other nonhematologic toxicity 
Grade 3 
75% dose 
75% dose 
Grade 4 
Stop treatment 
Stop treatment 
Table N-5 provides guidance for dose reductions for platinum agent in the event of renal 
impairment.  If the calculated GFR falls by more than 10% from the previous cycle, consider 
dose reduction. 
Table N-5: 
Criteria for Dose Reductions of Platinum Agent for Renal Impairment 
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 5 (discuss with 
medical monitor prior to switching) 
20-30 mL/min 
EDTA then use AUC as per 
protocol, or consider 
discontinuing carboplatin 
< 30 mL/min 
Discontinue cisplatin, 
continue paclitaxel. 
< 20 mL/min 
Discontinue carboplatin, 
continue paclitaxel 
Table N-6 provides guidance for dose reductions for elevations of AST, ALT, and/or bilirubin. 
Table N-6: 
Criteria for Dose Reductions for Hepatic Toxicity 
AST/ALT 
Bilirubin 
5-Fluorouracil 
Platinum Agent 
(Carboplatin or 
Cisplatin) 
Grade 1 (< 3× ULN) 
≤ ULN 
Continue same dose 
Continue same dose 
Grade 2 (3 × to < 5 × ULN) 
≤ ULN 
Continue same dose 
Continue same dose 
Grade 2 (3 × to < 5 × ULN) 
Grade 1 (ULN to 1.5 × ULN) 
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 
Continue same dose 
Continue same dose 
ANY Grade 3 or Grade 4 
Permanently discontinue treatment 
Hy's Lawa 
Permanently discontinue treatment 
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 O. PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document 
Date 
Amendment (Version) 1: 
10 JAN 2017 
Amendment (Version) 2: 
28 MAR 2017 
Amendment (Version) 3: 
18 MAY 2017 
Amendment (Version) 4: 
31 JUL 2017 
Amendment (Version) 5: 
02 FEB 2018 
Amendment (Version) 6: 
31 AUG 2018 
Amendment (Version) 7: 
14 FEB 2019 
Amendment 7 (14 FEB 2019) 
Overall Rationale for the Amendment:  The primary purpose of this amendment is to provide 
guidance for the management of ongoing subjects as enrollment has been terminated for the 
study as of 25 OCT 2018. 
1. Synopsis; Section 2, Study Objectives and Endpoints; Section 4.1, Overall Study 
Design; Section 9.2.2, Sample Size in Phase 2; Section 9.4, Statistical Analyses; 
Section 9.6, Interim Analysis 
Description of changes: 
• Removed text describing secondary objectives/endpoints for DOR and PFS by 
RECIST 1.1 and irRECIST for Phase 1 and Phase 2. 
 
 
 
 
Rationale for changes:  Update based on sponsor decision to terminate enrollment, not 
all cohorts have been fully enrolled, and Phase 2 efficacy expansion cohorts, where 
overall survival was to be collected, will not be open for enrollment.  Therefore, it will 
not be possible to adequately complete analysis for some objectives. 
2. Synopsis; Section 4.1.2, Phase 2:  Efficacy Expansion and Mandatory Biopsy 
Cohorts; Section 7.9.4.1, Tumor Biopsy in the Phase 2 Mandatory Biopsy Subjects 
Section 7.9.4.2, Tumor Biopsy in the Phase 2 Efficacy Expansion Subjects  
Description of changes: 
• Removed text regarding optional on-treatment biopsies in Phase 2 efficacy 
expansion subjects. 
• Added text indicating that on-treatment biopsies are no longer required for 
subjects enrolled in Phase 2 mandatory biopsy cohorts. 
Rationale for changes:  Update to study assessments based on enrollment termination.  
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3. Synopsis; Section 4.3.1, Planned Number of Subjects 
Description of change:  The number of subjects enrolled has been updated. 
Rationale for change:  Enrollment has been terminated by the sponsor; therefore, the 
number of subjects planned and enrolled has been updated. 
4. Section 4.4, Duration of Treatment and Subject Participation 
Description of change:  Clarification was added for the required length of contraception 
after chemotherapy. 
Rationale for change:  For consistency with Inclusion Criterion #5. 
5. Section 4.5, Overall Study Duration 
Description of change:  The text in this section was revised to clearly define an end of 
the study for subject management and data analysis. 
Rationale for change:  Given enrollment has been terminated by the sponsor and all 
subjects have been followed for at least 18 weeks (2 imaging assessments), the sponsor is 
considering this the end of the study for the purpose of database lock and study analysis.  
Subjects will continue receive study treatment if none of the discontinuation criteria are 
met. 
6. Section 5.2.1.2, Supply, Packaging, and Labeling; Section 5.5.1, Dose Modifications; 
Section 5.5.2, Criteria and Procedures for Dose Reductions or Interruptions of 
Epacadostat and/or Pembrolizumab; Section 5.6.1, Discontinuation Criteria; 
Appendix G, Dose Modifications for Epacadostat and Pembrolizumab (Table G-1:  
Dose Modification and Toxicity Management Guidelines for Immune-Related 
Adverse Events Associated With Epacadostat and/or Pembrolizumab) 
Description of change:  Dose reductions of epacadostat will no longer be permitted and 
the 25-mg tablet has been removed.  If the subject has a toxicity and it resolves to 
Grade 0-1, treatment may resume at the starting dose of epacadostat.  If they cannot 
restart at that dose then they must discontinue treatment. 
Rationale for change:  Sponsor decision to require therapy to be resumed at current dose 
to maintain target inhibition.  No dose reductions are permitted and all subjects are 
currently using the 100-mg tablets. 
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7. Synopsis; Section 5.6.1, Discontinuation Criteria; Section 5.6.2, Discontinuation 
Procedures; Section 5.7, Procedures for Withdrawal From Study; Section 6, Study 
Assessments; Section 7.4, Prior and Concomitant Medications and Procedures; 
Section 7.5, Safety Assessments; Section 7.6, Efficacy Assessments; Section 7.6.2, 
Tumor Imaging During the Study; Section 7.7, Performance and Quality-of-Life 
Assessments; Section 7.8.1, Blood Sample Collection; Section 7.10.2, Post-Treatment 
Anticancer Therapy Status; Section 7.10.3, Data Collection for Survival Follow-Up; 
Section 8.1, Adverse Events; Section 8.3.2, Reporting; Section 10.3 Data 
Management 
Description of change:  Study procedures for all subjects remaining on study treatment 
have been limited to standard of care for the subject's condition via local labs and disease 
status should continue to be monitored by CT, MRI, or PET-CT scan as appropriate at a 
frequency consistent with the standard of care for the subject's disease.  Data will only be 
collected for informed consent, SAEs, AEs leading to discontinuation, EOT disposition 
(reason for discontinuation), drug accountability, dosing information only, EOS 
disposition (end of study form), and death if it occurs within the safety reporting period. 
Rationale for change:  Update to study assessments based on enrollment termination, 
and all on-going subjects have met the updated definition of EOS as defined in 
Section 4.5. 
8. 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 6 (31 AUG 2018) 
Overall Rationale for the Amendment:  The primary purpose of this amendment is to update 
the study design based on recent developments in the epacadostat clinical development program. 
1. Synopsis; Section 4.1.2, Phase 2:  Efficacy Expansion and Mandatory Biopsy 
Cohorts (Figure 1:  Study Design); Section 7.9.4.1, Tumor Biopsy in the Phase 2 
Mandatory Biopsy Subjects; Section 9.2.2.2, Phase 2 Mandatory Biopsy Cohorts 
Description of change:  Removed text regarding the opening of the Phase 2 mandatory 
biopsy cohorts for squamous and nonsquamous NSCLC cohorts being at the discretion of 
the sponsor.  Figure 1 was updated accordingly. 
Rationale for change:  Based on the Study INCB 24360-301 results, the sponsor 
believes obtaining translational data from tumor tissue samples of subjects with NSCLC 
will allow for a better understanding of mechanisms of action for epacadostat, 
pembrolizumab, and chemotherapy in the tumor microenvironment.  
2. Synopsis; Section 3.1, Inclusion Criteria 
Description of change:  Updated inclusion criterion #24 for subjects enrolling in the 
Phase 2 mandatory biopsy cohort who have any solid tumor that progressed on previous 
therapy with a PD-1 or PD-L1 inhibitor.  
Rationale for change:  To provide additional clarity for primary refractory versus 
secondary relapsed subjects. 
3. Synopsis; Section 3.2, Exclusion Criteria 
Description of changes: 
• Updated exception to exclusion criterion #4 for subjects who have known active CNS 
and/or carcinomatous meningitis. 
• Added history of allogeneic stem cell transplant to exclusion criterion #10. 
• Updated heading for exclusion criterion #24 to include subjects in Treatment 
Groups A and G in Phase 1 and 2. 
Rationale for changes: 
• To provide additional clarity. 
• Subjects with a history of allogeneic stem cell transplant are immunocompromised 
and should be excluded from the study.  
• 5-Fluorouracil is administered as a prolonged infusion in both Treatment Groups A 
and G; therefore, subjects with a known dihydropyrimidine dehydrogenase deficiency 
in these treatment groups are at a greater risk of experiencing toxicities. 
4. Synopsis; Section 6, Study Assessments (Tables 7, 11, and 12); Section 7.5.4, 
Electrocardiograms 
Description of change:  Removed requirement for ECG measurement on Cycle 1 Day 1 
and Cycle 1 Day 8 for all Phase 1 subjects and Phase 2 efficacy expansion subjects.   
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Rationale for change:  To update the schedule of ECG assessments, as Study 
INCB 24360-103 met the requirements for a negative QT study, and the FDA agreed that 
extensive ECG monitoring in ongoing clinical studies with epacadostat is no longer 
needed. 
5. Synopsis; Section 6.4.2, Disease Status Follow-Up; Section 7.6.2, Tumor Imaging 
During the Study 
Description of change:  Updated text describing imaging frequency for subjects who are 
on study treatment and for subjects who discontinued treatment for a reason other than 
disease progression. 
Rationale for change:  To provide clarity on imaging schedule. 
6. Section 1.2, Overview of Epacadostat; Section 1.11.12, Risks From Combining 
Epacadostat and Pembrolizumab 
Description of change:  Added information about Study INCB 24360-301.   
Rationale for change:  To provide updated information on efficacy and safety of the 
combination of epacadostat and pembrolizumab based on recent published data. 
7. Section 5.3.1.2, Supply Packaging, and Labeling 
Description of change:  Updated text regarding pembrolizumab supply. 
Rationale for change:  To reflect use of only investigational supply of pembrolizumab. 
8. Section 5.10, Prohibited Medications/Treatment 
Description of change:  Removed mefenamic acid from the list of UGT1A9 inhibitors. 
Rationale for change:  To align with current clinical information from the epacadostat 
IB. 
9. Section 5.10.1, Supportive Care Guidelines 
Description of change:  Removed guidance on the management of diarrhea. 
Rationale for change:  To avoid conflict with guidance for managing diarrhea/colitis 
that is included in Appendix G, Table G-1.  
10. Section 7.5.5.4, Coagulation Panel; Section 7.5.5.5, Endocrine Function; 
Section 7.5.5.6, Urinalysis 
Description of change:  Added a statement indicating that more frequent monitoring 
may be performed for these analytes if clinically indicated. 
Rationale for change:  For consistency with other laboratory monitoring. 
11. 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 5 (02 FEB 2018) 
Overall Rationale for the Amendment:  The primary purpose of this amendment is to update 
the dose modification guidance for epacadostat and pembrolizumab for the management of 
immune-related adverse events. 
1. Synopsis 
Description of change:  Revised text regarding the timing of laboratory 
 
 
Rationale for change:  To more accurately describe the Protocol-defined assessments. 
2. Synopsis; Section 3.1, Subject Inclusion Criteria 
Description of change:  Revised inclusion criterion 5 to clarify that contraception 
methods should continue for 120 days from the last dose of epacadostat and 
pembrolizumab and that if a subject continues on chemotherapy after discontinuation of 
epacadostat and pembrolizumab, contraception methods should continue for 180 days 
after the last dose of chemotherapy. 
Rationale for change:  To make consistent with other studies that are investigating 
epacadostat and pembrolizumab in combination. 
3. Synopsis; Section 3.2, Subject Exclusion Criteria 
Description of change:  Updated exclusion criterion 18 to state that subjects who have 
feeding tubes are eligible. 
Rationale for change:  To reflect that medical monitor approval is no longer needed, 
given submission of appropriate regulatory documents outside of the United States. 
4. Synopsis; Section 4.1.1, Phase 1 
Description of change:  Revised the first rule for cohort expansion in the event of a DLT 
from no DLTs to ≤ 1 DLT. 
Rationale for change:  To make consistent with Section 4.1.2. 
5. Section 1.3, Overview of Pembrolizumab; Section 1.11.2, Risks From 
Pembrolizumab 
Description of change:  Removed text for approved pembrolizumab indications in the 
United States and the European Union.  Updated text describing risks of pembrolizumab 
to reflect information from the pembrolizumab Investigator's Brochure.  Updated 
references to pembrolizumab prescribing information and summary of product 
characteristics to the pembrolizumab Investigator's Brochure. 
Rationale for change:  To ensure that the most up-to-date information is referenced in 
the pembrolizumab Investigator's Brochure, given that approvals and risk language may 
change during the course of this study and because approvals may have regional 
differences. 
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6. Section 1.11.1, Risks From Epacadostat; Section 5.5.6, Procedure for Subjects 
Exhibiting Serotonin Syndrome 
Description of change:  Updated text on SS. 
Rationale for change:  To reflect revised text on SS included in Version 10 of the 
epacadostat Investigator's Brochure and to update the management procedure of subjects, 
study treatments, and concomitant medications in the event of SS. 
7. Section 4.5, Overall Study Duration 
Description of change:  Added text to allow for data analysis of individual treatment 
groups, provided the treatment group has been completed. 
Rationale for change:  To allow for flexibility with data analysis of individual treatment 
groups, should enrollment times differ among the groups. 
8. Section 5.3.1.2, Supply, Packaging, and Labeling 
Description of change:  Updated text regarding pembrolizumab supply. 
Rationale for change:  To reflect use of investigational supply of pembrolizumab. 
9. Section 5.6.1, Discontinuation Criteria 
Description of change:  Added unacceptable adverse events as described in Appendix G, 
Table G-1 with a requirement to permanently discontinue. 
Rationale for change:  To update discontinuation criteria for accuracy. 
10. Section 5.9, Restricted Medications 
Description of change:  Updated text on use of coumarin-based anticoagulants and 
removed Table 7, Recommendations for Warfarin Dose Modifications. 
Rationale for change:  To clarify, as Table 7 was redundant; both target international 
normalized ratio regimens require only close monitoring when given with epacadostat 
100 mg twice daily. 
11. Section 5.10, Prohibited Medications/Treatment 
Description of change:  Removed restriction on the use of melatonin supplements and 
certain UGT1A9 inhibitors while on study treatment.  
Rationale for change:  To align with recent literature or evidence indicating 1) a lack of 
a confirmed association between melatonin use and SS and 2) that certain UGT1A9 
inhibitors may not interfere with the metabolism of epacadostat.  
12. Section 6, Study Assessments (Table 7 through Table 15) 
Description of change:  Updated Schedule of Assessment and Laboratory Assessment 
tables. 
Rationale for change:  To correct inconsistencies and provide additional clarity with 
corresponding sections within the Protocol. 
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13. Section 6, Study Assessments (Table 11); Section 7.5.4, Electrocardiograms 
Description of change:  Revised Table 11 and updated text in Section 7.5.4 on ECG 
requirements for subjects in Phase 2 efficacy expansion Treatment Groups C and D. 
Rationale for change:  To provide additional clarity that 1) ECGs are not required on 
Cycle 1 Day 1 for Phase 2 efficacy expansion subjects in Treatment Groups C and D, as 
these subjects do not receive the first dose of epacadostat in the clinic and 2) ECGs are 
not required for any Phase 2 mandatory biopsy subject, as these subjects do not receive 
epacadostat during Cycle 1. 
14. Section 8.6, Events of Clinical Interest; Section 9.4.4.5, Events of Clinical Interest 
Description of change:  Revised to reflect ECIs only. 
Rationale for change:  To refine the list of ECIs to provide clarity for investigative sites. 
15. Appendix G, Dose Modifications for Epacadostat and Pembrolizumab (Table G-1) 
Description of change:  Updated Table G-1. 
Rationale for change:  To provide updated dose management guidance for epacadostat 
and pembrolizumab in the event of immune-related adverse events.  
16. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment, including the addition of all summary of changes to Appendix O. 
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Amendment 4 (31 JUL 2017) 
Overall Rationale for the Amendment:  The primary purpose of this amendment is to update 
the study design. 
1. Title; Synopsis; Section 1, Introduction; Section 2.1, Study Objectives; Section 4, 
Investigational Plan; Section 5, Treatment; Section 6, Study Assessments; 
Section 7.6, Efficacy Assessments 
Description of change:  Replaced nivolumab/programmed cell death protein 1 (PD-1) 
inhibitor in Treatment Groups A and B with pembrolizumab. 
Rationale for change:  Change in study design.  
2. Title; Synopsis; Section 1.10.1, Justification for Treatment Regimen; Section 4.1, 
Overall Study Design; Section 4.3.1, Planned Number of Subjects; Section 5.9, 
Restricted Medications 
Description of change:  Modified Phase 1 study design to remove dose-escalation and to 
allow for the start of Phase 2 if a minimum of 6 subjects have been treated with 
epacadostat 100 mg twice daily and there are ≤ 1 of 6 dose-limiting toxicities in all 
treatment groups (previously limited to only Treatment Groups C and D). 
Rationale for change:  Change in study design. 
3. Synopsis; Section 1.8, Overview of Gemcitabine/Platinum Agent in Urothelial 
Carcinoma; Section 1.9, Overview of Platinum Agent/5-Fluorouracil in Squamous 
Cell Carcinoma of the Head and Neck; Section 1.11.8, Risks From 
Gemcitabine/Platinum Agent; Section 1.11.9, Risks From Platinum 
Agent/5-Fluorouracil; Section 2.1, Study Objectives; Section 3, Subject Eligibility; 
Section 4, Investigational Plan; Section 5.3.7, Gemcitabine and Platinum Agent; 
Section 5.3.8, Platinum Agent and 5-Fluorouracil; Section 6, Study Assessments; 
Section 9.2, Selection of Sample Size; Appendix M, Dose Modifications for 
Gemcitabine/Platinum Agent; Appendix N, Dose Modifications for Platinum 
Agent/5-Fluoroucil 
Description of change:  Added 2 new chemotherapy regimens to evaluate in 
combination with epacadostat and pembrolizumab in Phase 1, which will be limited to 
2 tumor-specific cohorts in Phase 2.   
Rationale for change:  Update to study design. 
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5. Synopsis; Section 2, Study Objectives and Endpoints; Section 4.2, Measures Taken 
to Avoid Bias; Section 9.4, Statistical Analyses  
Description of change:  Clarified that primary and secondary efficacy measurements are 
per RECIST v1.1 and that efficacy by immune-related RECIST (irRECIST) 
 
 
Rationale for change:  Update to study design. 
6. Synopsis; Section 5.5.5, Treatment After Initial Radiologic Evidence of Disease 
Progression; Section 5.6.1, Discontinuation Criteria; Section 6, Study Assessments; 
Section 7.6.2.1, Assessment of Progressive Disease According to Immune-Related 
RECIST Criteria 
Description of change:  Edited text to show that the adaptation of RECIST v1.1 is 
known as irRECIST and that irRECIST should be used to guide treatment decisions for 
discontinuation of therapy. 
Rationale for change:  To provide additional clarification. 
7. Synopsis; Section 3, Subject Eligibility 
Description of change:  Updated to provide a clear definition on eligibility criteria for 
the Phase 2 subjects who received previous treatment with a PD-1 or programmed cell 
death ligand 1 inhibitor, and provided clarifications for other criterion.  
Rationale for change:  To provide additional guidance on eligibility criteria.  
8. Synopsis; Section 3.1, Subject Inclusion Criterion; Section 4.1.2, Phase 2:  Efficacy 
Expansion and Mandatory Biopsy Cohorts; Section 6, Study Assessments; 
Section 7.9.4, Tumor Biopsy 
Description of change:  Added requirement that all Phase 2 efficacy expansion subjects 
are required to provide a biopsy at screening and updated timing of collection of 
on-treatment biopsies in the Phase 2 mandatory biopsy subjects.  
Rationale for change:  Update to study design.  
9. Synopsis; Section 4.4, Duration of Treatment and Subject Participation; 
Section 5.6.1, Discontinuation Criteria; Section 6.2, Treatment 
Description of change:  Updated the duration of treatment of with pembrolizumab to be 
35 infusions of pembrolizumab and duration of treatment with epacadostat to be the end 
of the cycle in which the 35th infusion of pembrolizumab is administered.  
Rationale for change:  Update to study design.  
10. Synopsis; Section 5.3, Background Therapies 
Description of change:  Updated text on order of administration of background 
therapies. 
Rationale for change:  To provide additional clarification on order of administration of 
pembrolizumab and individual agents of the chemotherapy regimen.  
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11. Synopsis; Section 6, Study Assessments 
Description of change:  Updated timing of collection of 
 assessments. 
Rationale for change:  To provide additional alignment with frequency of study visits as 
a subject progresses through the study.  
12. Synopsis; Section 6.4.2, Disease Status Follow-Up; Section 7.6.2.1, Assessment of 
Progressive Disease According to Immune-Related RECIST Criteria 
Description of change:  Updated text on timeframe for when disease status follow-up 
should continue and when scan frequency can change to longer intervals. 
Rationale for change:  To provide additional clarification.  
13. Section 1.11.1, Risks From Epacadostat; Section 5.5.6, Procedure for Subjects 
Exhibiting Serotonin Syndrome 
Description of change:  Included updated information on serotonin syndrome events in 
epacadostat studies and updated the table describing signs/symptoms that may be 
indicative of serotonin syndrome  
Rationale for change:  To provide the most recent information on serotonin syndrome 
with epacadostat treatment and provide additional guidance on signs and symptoms.   
14. Section 5.5.3, Management of Immune-Related Adverse Events; Section 5.5.4, 
Management of Chemotherapy-Related Adverse Events; Appendices G through M 
Description of change:  Revised protocol sections and appendices so that dose 
modifications for epacadostat and pembrolizumab for immune-related adverse events are 
described in 1 appendix and dose modifications for individual components of the 
chemotherapy regimen are described in the corresponding appendices. 
Rationale for change:  To provide simplified guidance for the management of adverse 
events.  
15. Section 5.10.1, Supportive Care Guidelines 
Description of change:  Added text on the management of diarrhea and reference to 
management of infusion reactions with pembrolizumab in Appendix G.  
Rationale for change:  To provide additional clarification. 
16. Section 8.6, Events of Clinical Interest and Adverse Events of Special Interest; 
Section 8.7, Definition of an Overdose for This Protocol and Reporting of Overdose 
to the Sponsor 
Description of change:  Updated to include the definition of an overdose for epacadostat 
and pembrolizumab. 
Rationale for change:  To provide clear guidance on overdose thresholds.  
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 3 (18 MAY 2017) 
Overall Rationale for the Amendment:  The primary purpose of this amendment is to update 
the study design of Phase 1 and provide flexibility in DLT determination in Phase 1. 
1. Synopsis; Section 3.1, Subject Inclusion Criteria; Section 4.1, Overall Study Design 
(including Figure 1, Study Design); Section 4.1.1, Phase 1:  Dose Escalation in 
Selected Chemotherapy Regimens; Section 4.3.1, Planned Number of Subjects; 
Section 9.2.1.2, Safety Expansion 
Description of change:  Removed text related to the 2 safety expansion cohorts in 
Phase 1 and added text to indicate that for Treatment Groups C and D, at least 6 subjects 
must be treated at epacadostat 100 mg BID before opening Phase 2 at that dose. 
Rationale for change:  Change in study design after further assessment following 
feedback from the FDA. 
2. Synopsis; Section 4.1.1, Phase 1:  Dose Escalation in Selected Chemotherapy 
Regimens 
Description of change:  Text has been added to allow for determination of a dose-
limiting toxicity (DLT) by the Data Monitoring Committee in certain cases where 
chemotherapy toxicities are indistinguishable from immune-related toxicities.   
Rationale for change:  To allow for flexibility with determining a DLT in situations 
where there are overlapping toxicities between chemotherapy and immunotherapy and 
the subject has received < 80% dose intensity. 
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Amendment 2 (28 MAR 2017) 
Overall Rationale for the Amendment:  The primary purpose of this amendment is to update 
the study design of both Phase 1 and Phase 2 and provide clarity within the Protocol with respect 
to definition of study drug. 
1. Synopsis, Overall Study Design; Section 4.1, Overall Study Design; Section 5.5.1.1, 
Dose-Limiting Toxicity and Determination of Maximum Tolerated Dose 
Description of change:  Text has been added to 1) address the inclusion of 2 safety 
expansion cohorts of subjects with NSCLC at epacadostat 100 mg BID for Treatment 
Group C and Treatment Group D in Phase 1; 2) clarify the criteria for determining 
evaluability for dose tolerability, 3) clarify the rules for dose escalation or de-escalation, 
and 4) address the change in Phase 2 from a Simon 2-stage design to a single stage for all 
cohorts treated with pembrolizumab, and 5) include the cumulative incidence of 
treatment-related serious adverse events (SAEs) within a Phase 2 cohort as part of the 
threshold for evaluating toxicity in Phase 2. 
Rationale for change:  To address changes in study design in Phase 1 and Phase 2 and 
provide clarification on evaluation of tolerability in Phase 1 and Phase 2.  
2. Synopsis, Study Population (Key Inclusion Criteria); Section 3.1, Subject Inclusion 
Criteria 
Description of change:  Text has been added to provide details on inclusion criterion for 
the Phase 1 safety expansion NSCLC subjects (criterion 21). 
Rationale for change:  To provide clarification on prior immunotherapies that are 
allowed and not allowed for the Phase 1 safety expansion NSCLC subjects. 
3. Section 3.1, Subject Inclusion Criteria; Section 4.4, Duration of Treatment and 
Subject Participation; Section 6.2, Treatment 
Description of change:  Updated to indicate that if a subject continues on a PD-1 
inhibitor or chemotherapy after discontinuing epacadostat, contraception methods should 
continue according to guidance outlined in the prescribing information of each therapy 
(criterion 5). 
Rationale for change:  To inform investigators and site staff that appropriate 
contraception measures must continue after subject is discontinued from epacadostat but 
continues on background therapy. 
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4. Synopsis, Study Population (Key Exclusion Criteria); Section 3.2, Subject Exclusion 
Criteria  
Description of change:  Text has been added to (1) allow for the use of partial 
thromboplastin time (PTT) in place of activated PTT (aPTT) results to determine 
eligibility (criterion 1g), (2) clarify windows for meeting exclusion criteria must be 
within various thresholds of Cycle 1 Day 1 (criteria 2-4 and 15), and (3) provide details 
on gastrointestinal conditions that affect drug absorption that would qualify as 
exclusionary and that subjects with feeding tubes would require medical monitor 
approval (criterion 18). 
Rationale for change:  To allow for flexibility for coagulation tests per institutional 
standards, clarify the window for thresholds is within Cycle 1 Day 1 so that criteria apply 
to all subjects enrolled in the study (including the Phase 2 mandatory biopsy cohorts who 
start epacadostat on Cycle 2 Day 1), and provide guidance on types of subjects with 
gastrointestinal conditions that may or may not be included in the study. 
5. Synopsis, Combination Therapy, Dosage, and Mode of Administration; Section 5.3, 
Background Therapies  
Description of change:  The PD-1 inhibitors have been reclassified as background 
therapies.  Additionally, text has been added to clarify the start date of the PD-1 inhibitor 
and timing of administration after epacadostat and before premedications or 
chemotherapy, and to provide additional clarity on timing of administration of 
chemotherapy regimens.  Text has been added to the carboplatin/paclitaxel and 
carboplatin/pemetrexed sections to allow for sites to have the option to use equivalent 
alternatives for the listed premedications as per institutional guidelines, investigator 
practice, or availability of similar medications on the investigative site's formulary. 
Rationale for change:  To clarify timing of administration of PD-1 inhibitors and 
chemotherapy regimens, and to allow for alternatives to required premedications if those 
that are described in the Protocol are not available. 
6. Synopsis, Study Schedule/Procedures; Section 6.3, End of Treatment; Section 6.4, 
Follow-Up 
Description of change:  Revised to clarify that the end of treatment is defined as the end 
of epacadostat treatment and that follow-up assessments (safety, disease status, survival) 
will occur from the end of treatment date of epacadostat based on the respective windows 
defined in the Protocol.   
Rationale for change:  To clearly define the end of treatment for purposes of subject 
entry in to the follow-up portion of the study. 
7. Synopsis, Estimated Number of Subjects and Statistical Methods; Section 4.3.1, 
Planned Number of Subjects; Section 9, Statistics 
Description of change:  Updated the anticipated total number of subjects and selection 
of sample sizes/statistical methods. 
Rationale for change:  To account for changes in study design.  
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8. Section 1.3, Overview of Nivolumab; Section 1.4, Overview of Pembrolizumab; 
Section 1.10.1, Risks from Epacadostat; Section 1.10.2, Risks from Nivolumab; 
Section 1.10.3, Risks From Pembrolizumab 
Description of change:  Updated preclinical data for epacadostat and to reflect recent 
approvals and risk language in US prescribing information for nivolumab and 
pembrolizumab.   
Rationale for change:  To provide the most updated information. 
9. Section 5.7, Procedures for Withdrawal From Study 
Description of change:  New section added detailing procedures for subject withdrawal 
from the study.  
Rationale for change:  To clarify that subjects have the option to discontinue treatment 
and/or study assessments but allow collection of information in the follow-up period of 
the study or discontinue. 
10. Section 5.10, Prohibited Medications/Treatment 
Description of change:  Section revised to update criteria for allowed steroid use and 
radiation therapy, to prohibit melatonin supplements, and to remove redundancy with 
exception for immunologic treatment. 
Rationale for change: To provide additional information on exceptions to prohibited 
medications while on study.   
11. Section 6, Study Assessments (Table 8 and Table 10)  
Description of change:  Additional evaluations of concomitant medications, targeted 
physical examination, and vital signs and weight have been added for the cohorts where 
nivolumab is administered. 
Rationale for change:  To provide consistency with frequency of assessments in the 
cohorts where pembrolizumab is administered. 
12. Section 6, Study Assessments (Tables 9, 11, 14, 16, 17) 
Description of change:  Urine pregnancy test is now required in all women of 
childbearing potential at the intervals noted within the tables and not just per 
country-specific requirements.  
Rationale for change:  To ensure appropriate monitoring for pregnancy while on study. 
13. Section 5.5.5.1, Dose-Limiting Toxicity and Determination of Maximum Tolerated 
Dose (Table 3); Section 6, Study Assessments (Tables 9, 11, 14, 16); Section 7.5.5.5, 
Lipid Panel 
Description of change:  Lipid panel testing has been removed. 
Rationale for change:  Alterations in lipids is not common with epacadostat, and routine 
monitoring is not necessary. 
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14. Section 6, Study Assessments (Tables 10, 13, and 15); Section 7.5.4, 
Electrocardiograms; Section 
, 
 
Description of change:  ECGs on Cycle 1 Day 1 and Cycle 1 Day 8, 
 
 
 should only be collected for Phase 1 and the Phase 2 efficacy expansion subjects.  
ECGs on Cycle 1 Day 1 and Cycle 1 Day 8 do not need to be conducted in subjects 
enrolled in the Phase 2 mandatory biopsy cohorts. 
Rationale for change:  To clarify ambiguity in Protocol text. 
15. Section 6, Study Assessments (Table 17: Clinical Laboratory Analytes) 
Description of change:  Under Serum Chemistries, magnesium has been added to the list 
of analytes and phosphorus has been corrected to phosphate.  Collection of reticulocytes 
has been removed from Hematology.  The header for liver enzyme analytes has been 
updated to "Liver Chemistry Tests."  
Rationale for change:  To update recommended analytes that are needed to monitor 
safety in this study. 
16. Clarification of study drug.  Wherever possible throughout the Protocol, epacadostat 
replaced "study drug" to provide clarity.  All changes are noted in the redline version of 
the amendment.   
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 1 (10 JAN 2017) 
Overall Rationale for the Amendment:  The primary purpose of this amendment is to address 
FDA's correspondence from 03 JAN 2017. 
1. Synopsis, Key Inclusion Criteria; Section 3.1, Subject Inclusion Criteria 
(Criterion #20) 
Description of change:  Text describing inclusion criterion for Phase 2 subjects with 
non−small cell lung cancer (NSCLC) who have driver mutations (EGFR, ALK fusion 
oncogene, or ROS1) was clarified to indicate these subjects must have received prior 
treatment with an approved tyrosine kinase inhibitor. 
Rationale for change:  FDA request. 
2. Section 5.5.1.1, Dose-Limiting Toxicity and Determination of Maximum Tolerated 
Dose (Table 3, Definition of Dose-Limiting Toxicity) 
Description of change:  Two new criteria for dose-limiting toxicities (DLTs) were 
added:  Grade 4 (life-threatening) immune-related adverse event (irAE) and Grade 4 
(life-threatening) electrolyte abnormality.  Additionally, the criterion for DLT exceptions 
related to nausea, vomiting, and diarrhea adequately controlled with medical therapy 
within 48 hours was limited to Grade 3 events. 
Rationale for change:  FDA request. 
3. Synopsis, Data Monitoring Committee; Section 8.9, Data Monitoring Committee; 
Section 9.5, Analyses for the Data Monitoring Committee 
Description of change:  Text describing the establishment of a Data Monitoring 
Committee to monitor patient safety was added. 
Rationale for change:  FDA request. 
4. Synopsis, Estimated Number of Subjects; Section 4.3.1, Planned Number of 
Subjects 
Description of change:  Text added to Phase 2 Expansion to clarify that this will include 
subjects from the Simon 2-stage and Biopsy cohorts. 
Rationale for change:  FDA request. 
5. Section 4.4, Duration of Treatment and Subject Participation; Section 5.2.1.1, 
Description and Administration; Section 5.2.2.1, Description and Administration; 
Section 5.2.3.1, Description and Administration; Section 6.2, Treatment 
Description of change:  Text on the maximum duration of treatment with epacadostat 
and applicable PD-1 inhibitor was revised. 
Rationale for change:  To correct inconsistencies within various Protocol sections. 
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6. Synopsis, Overall Study Design; Section 4.1.2, Phase 2: Expansion Cohorts; 
Section 7.9.4, Tumor Biopsy 
Description of change:  Text on optional biopsies for subjects enrolled in the Simon 
2-stage portion of Phase 2 was revised.  Additional text indicating that subjects who 
provide a biopsy that does not meet minimum standards for evaluation (as outlined in the 
Laboratory Manual) may still enroll in the study but may be replaced in order to enroll 
sufficient numbers of biopsy evaluable subjects.   
Rationale for change:  To provide guidance on the collection and timing of optional 
biopsies for subjects enrolled in the Simon 2-stage portion of Phase 2 who receive IV 
chemotherapy, and flexibility to replace nonevaluable biopsy samples. 
7. Section 9.6, Interim Analysis 
Description of change:  Text describing interim analyses for futility in the Simon 
2-stage portion of Phase 2 was added. 
Rationale for change:  To provide guidance on assumptions, probabilities, and timing of 
interim analyses. 
8. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 
CONFIDENTIAL 


Signature Manifest
Document Number: IC-DEV-PROT-AMEND-0448
Revision: 0
Title: INCB 24360-207 Protocol Amendment 7
All dates and times are in Eastern Standard Time.
INCB 24360-207 Protocol AM7
Approval and Release
Name/Signature
Title
Date
Meaning/Reason
13 Feb 2019, 03:27:08 PM
Approved
13 Feb 2019, 03:34:52 PM
Approved
13 Feb 2019, 03:42:49 PM
Approved
14 Feb 2019, 10:37:59 AM
Approved
INCB 24360-207 Protocol AM7
Approval and Release
Name/Signature
Title
Date
Meaning/Reason
14 Feb 2019, 03:00:40 PM
Approved
14 Feb 2019, 03:02:48 PM
Approved
14 Feb 2019, 03:38:38 PM
Approved
14 Feb 2019, 03:44:52 PM
Approved

SAP_001.pdf: 
Incyte Corporation 
Page 1 of 40 
INCB 24360-207 SAP Amendment 1 
12 MAR 2019 
STATISTICAL ANALYSIS PLAN 
INCB 24360-207 / NCT03085914 
A Phase 1/2, Open-Label, Safety, Tolerability, and Efficacy Study of 
Epacadostat in Combination With Pembrolizumab and 
Chemotherapy in Subjects With Advanced or Metastatic Solid 
Tumors (ECHO-207/KEYNOTE-723) 
IND Number: 
132,309 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
Protocol Version: 
Protocol Amendment 7 dated 14 FEB 2019 
CRF Approval Date: 
14 AUG 2018 
SAP Version: 
Amendment 1 
SAP Author: 
 
, 
 
Date of Plan: 
12 MAR 2019 
This study is being conducted in compliance with good clinical practice, 
including the archiving of essential documents. 
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INCB 24360-207 SAP Amendment 1 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
INTRODUCTION ........................................................................................................8 
2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS.................................9 
2.1. 
Protocol and Case Report Form Version ......................................................................9 
2.2. 
Study Objectives ...........................................................................................................9 
2.2.1. 
Primary Objectives .......................................................................................................9 
2.2.2. 
Secondary Objectives ...................................................................................................9 
 
9 
2.3. 
Study Endpoints ..........................................................................................................10 
2.3.1. 
Primary Endpoints ......................................................................................................10 
2.3.2. 
Secondary Endpoints ..................................................................................................10 
 
10 
3. 
STUDY DESIGN .......................................................................................................11 
3.1. 
Overall Study Design ..................................................................................................11 
3.1.1. 
Phase 1 ........................................................................................................................11 
3.1.2. 
Phase 2:  Efficacy Expansion and Mandatory Biopsy Cohorts ..................................13 
3.2. 
Control of Type I Error ...............................................................................................16 
3.3. 
Sample Size Considerations .......................................................................................16 
3.3.1. 
Sample Size in Phase 1 ...............................................................................................16 
3.3.2. 
Sample Size in Phase 2 ...............................................................................................16 
3.3.2.1. 
Efficacy Expansion .....................................................................................................16 
3.3.2.2. 
Mandatory Biopsy Cohorts .........................................................................................17 
3.4. 
Schedule of Assessments ............................................................................................17 
4. 
DATA HANDLING DEFINITIONS AND CONVENTIONS ..................................18 
4.1. 
Scheduled Study Evaluations and Study Periods .......................................................18 
4.1.1. 
Day 1 ...........................................................................................................................18 
4.1.2. 
Study Day ...................................................................................................................18 
4.1.3. 
Baseline Value ............................................................................................................18 
4.1.4. 
Handling of Missing and Incomplete Data .................................................................18 
4.1.5. 
Cycle Length and Duration .........................................................................................19 
4.2. 
Variable Definitions ....................................................................................................20 
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4.2.1. 
Age ..............................................................................................................................20 
4.2.2. 
Body Surface Area ......................................................................................................20 
4.2.3. 
Prior and Concomitant Medication .............................................................................20 
5. 
STATISTICAL METHODOLOGY ...........................................................................21 
5.1. 
General Methodology .................................................................................................21 
5.2. 
Treatment Groups .......................................................................................................21 
5.3. 
Analysis Populations ..................................................................................................22 
5.3.1. 
Full Analysis Set .........................................................................................................22 
5.3.2. 
Safety Population ........................................................................................................22 
6. 
BASELINE, EXPOSURE, AND DISPOSITION VARIABLES AND 
ANALYSES ...............................................................................................................23 
6.1. 
Baseline and Demographics, Physical Characteristics, and Disease History .............23 
6.1.1. 
Demographics .............................................................................................................23 
6.1.2. 
Baseline Disease Characteristics and Disease History ...............................................23 
6.1.3. 
Prior Therapy ..............................................................................................................23 
6.1.4. 
Medical History ..........................................................................................................24 
6.2. 
Disposition of Subjects ...............................................................................................24 
6.3. 
Protocol Deviations ....................................................................................................24 
6.4. 
Exposure .....................................................................................................................24 
6.4.1. 
Exposure for Epacadostat ...........................................................................................24 
6.4.2. 
Exposure for Pembrolizumab .....................................................................................24 
6.4.3. 
Exposure for Cyclophosphamide ................................................................................25 
6.4.4. 
Exposure for Intravenous Chemotherapies .................................................................25 
6.4.4.1. 
Exposure for Carboplatin ............................................................................................25 
6.4.4.2. 
Exposure for Other Intravenous Chemotherapies .......................................................25 
6.5. 
Prior and Concomitant Medication .............................................................................26 
7. 
EFFICACY .................................................................................................................27 
7.1. 
General Considerations ...............................................................................................27 
7.2. 
Efficacy Hypotheses ...................................................................................................27 
7.3. 
Analysis of the Efficacy Parameters ...........................................................................27 
7.3.1. 
Response Criteria ........................................................................................................27 
7.3.2. 
Objective Response Rates and Best Overall Response ..............................................27 
7.3.2.1. 
Objective Response Rate Under RECIST v1.1 ..........................................................28 
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7.3.3. 
Largest Percentage Reduction in Sum of Diameters of Target Lesions .....................29 
8. 
SAFETY AND TOLERABILITY ..............................................................................29 
8.1. 
General Considerations ...............................................................................................29 
8.2. 
Adverse Events ...........................................................................................................30 
8.2.1. 
Adverse Event Definitions ..........................................................................................30 
8.2.2. 
Dose-Limiting Toxicities ............................................................................................30 
8.2.3. 
Maximum Tolerated Dose ..........................................................................................30 
8.2.4. 
Events of Clinical Interest and Adverse Events of Special Interest ...........................30 
8.2.5. 
Adverse Event Summaries ..........................................................................................31 
8.3. 
Clinical Laboratory Tests ...........................................................................................32 
8.3.1. 
Laboratory Value Definitions .....................................................................................32 
8.3.2. 
Laboratory Value Summaries .....................................................................................32 
8.4. 
Vital Signs ..................................................................................................................33 
8.5. 
Electrocardiograms .....................................................................................................33 
9. 
INTERIM ANALYSES ..............................................................................................34 
10. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN ........................36 
10.1. 
Changes to Protocol-Defined Analyses ......................................................................36 
10.2. 
Changes to the Statistical Analysis Plan .....................................................................36 
10.2.1. 
Amendment 1 ..............................................................................................................36 
11. 
REFERENCES ...........................................................................................................37 
APPENDIX A. PLANNED TABLES AND LISTINGS ............................................................38 
 
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LIST OF TABLES 
Table 1: 
Epacadostat Dose Cohorts ..........................................................................................12 
Table 2: 
Treatment Groups .......................................................................................................12 
Table 3: 
Sample Size and Decision Rule for Simon 2-Stage Design Phase 2 Efficacy 
Expansion Cohorts ......................................................................................................16 
Table 4: 
Sample Size and Decision Rule for Single-Stage Design Phase 2 Efficacy 
Expansion Cohorts ......................................................................................................17 
Table 5: 
Best Overall Response When Confirmation of CR and PR is Required ....................28 
Table 6: 
RECIST Evaluation Criteria for Overall Response:  Measurable Disease at 
Baseline .......................................................................................................................29 
Table 7: 
Criteria for Clinically Notable Vital Sign Abnormalities ...........................................33 
Table 8: 
Criteria for Clinically Notable Electrocardiogram Abnormalities .............................34 
Table 9: 
Probability of Early Termination for Simon 2-Stage Design .....................................35 
Table 10: Probability of Early Termination at Stage 1 for Simon 2-Stage Design ....................35 
Table 11: Statistical Analysis Plan Versions ..............................................................................36 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................15 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
adverse event 
AEOSI 
adverse event of special interest 
 
 
 
 
 
 
BID 
twice daily 
BSA 
body surface area 
CI 
confidence interval 
 
 
 
 
CR 
complete response 
CRC 
colorectal cancer 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
dose-limiting toxicity 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ECOG 
Eastern Cooperative Oncology Group 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
irRECIST 
immune-related Response Evaluation Criteria in Solid Tumors 
IV 
intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities  
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute  
NE 
not evaluable 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
PAD 
pharmacologically active dose 
PD 
progressive disease 
PD-1 
programmed cell death protein 1 
PD-L1 
programmed cell death ligand 1 
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Abbreviation 
Term 
PDAC 
pancreatic ductal adenocarcinoma 
 
 
PO 
orally 
PR 
partial response 
PT 
preferred term 
Q3W 
every 3 weeks 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAP 
statistical analysis plan 
SCCHN 
squamous cell carcinoma of the head and neck 
SD 
stable disease 
SI unit 
International System of Units 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
 
 
UC 
urothelial carcinoma 
WHO 
World Health Organization 
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1. 
INTRODUCTION 
This is an open-label, nonrandomized, Phase 1/2 study to determine the safety, tolerability, and 
efficacy of epacadostat when given in combination with pembrolizumab and 7 chemotherapy 
regimens.  Phase 1 will consist of a 3 + 3 + 3 design and will determine the MTD or PAD of 
epacadostat when given in combination with pembrolizumab and chemotherapy; efficacy will 
also be explored.  Subjects with advanced or metastatic solid tumors who have progressed after 
receiving at least 1 previous standard therapy for advanced or metastatic disease (or who are 
intolerant to or refuse standard of care) and for whom treatment with 1 of the chemotherapy 
regimens is appropriate will be enrolled in Phase 1.  Phase 2 will further evaluate the safety, 
tolerability, and efficacy of the MTD or PAD of epacadostat selected in Phase 1 when given in 
combination with pembrolizumab and chemotherapy.  Subjects with advanced or metastatic 
CRC, PDAC, NSCLC (squamous or nonsquamous), UC, or SCCHN who have not previously 
received chemotherapy as first-line therapy for advanced or metastatic disease and have not 
previously received immune checkpoint inhibitors nor an indoleamine 2,3-dioxygenase inhibitor 
will be enrolled in Phase 2.  A separate cohort of subjects with any advanced or metastatic solid 
tumor who progressed on previous therapy with a PD-1 or PD-L1 inhibitor will also be enrolled 
in Phase 2.  Protocol Amendment 7, Section 1 provides a detailed description of the 
investigational product, target patient population, rationale for doses to be examined, and 
potential risks and benefits of treatment with the combination of epacadostat, pembrolizumab, 
and chemotherapy regimens. 
The purpose of this SAP is to provide details of the statistical analyses that have been outlined in 
Study INCB 24360-207 Protocol Amendment 7 dated 14 FEB 2019.  The scope of this plan 
includes the interim and final analyses that are planned and will be executed by the Biostatistics 
and Programming department or designee.  
 
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2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS 
2.1. 
Protocol and Case Report Form Version 
This SAP is based on INCB 24360-207 Protocol Amendment 7 dated 14 FEB 2019 and CRFs 
approved 14 AUG 2018.  Unless superseded by an amendment, this SAP will be effective for all 
subsequent Protocol amendments and eCRF versions. 
2.2. 
Study Objectives 
2.2.1. 
Primary Objectives 
• Phase 1:  To evaluate the safety, tolerability, and DLTs and to define an MTD and/or 
PAD of epacadostat in combination with pembrolizumab and chemotherapy in 
subjects with advanced or metastatic solid tumors. 
• Phase 2:  To evaluate the efficacy of epacadostat in combination with pembrolizumab 
and chemotherapy in subjects with advanced or metastatic CRC, PDAC, NSCLC, 
UC, SCCHN, or any advanced or metastatic solid tumor who progressed on previous 
therapy with a PD-1 or PD-L1 inhibitor by assessing ORR per RECIST v1.1. 
2.2.2. 
Secondary Objectives 
• Phase 1:  To explore the efficacy of epacadostat in combination with pembrolizumab 
and chemotherapy in subjects with advanced or metastatic solid tumors by assessing 
ORR per RECIST v1.1. 
• Phase 2:  To further evaluate the safety and tolerability of epacadostat at the MTD 
and/or PAD in combination with pembrolizumab and chemotherapy in subjects with 
selected advanced or metastatic solid tumors. 
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2.3. 
Study Endpoints 
2.3.1. 
Primary Endpoints 
• Phase 1:  Safety and tolerability will be assessed by monitoring frequency, duration, 
and severity of AEs through physical examinations, by evaluating changes in vital 
signs and ECGs, and through clinical laboratory blood and urine sample evaluations. 
• Phase 2:  ORR, defined as the percentage of subjects having a CR or PR, will be 
determined by investigator assessment of radiographic disease per RECIST v1.1. 
2.3.2. 
Secondary Endpoints 
• Phase 1:  ORR, defined as the percentage of subjects having a CR or PR, will be 
determined by investigator assessment of radiographic disease per RECIST v1.1. 
• Phase 2:  Safety and tolerability will be assessed by monitoring frequency, duration, 
and severity of AEs through physical examinations, by evaluating changes in vital 
signs and ECGs, and through clinical laboratory blood and urine sample evaluations. 
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3. 
STUDY DESIGN 
3.1. 
Overall Study Design 
This is an open-label, nonrandomized, Phase 1/2 study to determine the safety, tolerability, and 
efficacy of epacadostat when given in combination with pembrolizumab and 7 chemotherapy 
regimens (see Figure 1).  In Phase 1, the MTD or PAD of epacadostat when given in 
combination with pembrolizumab and chemotherapy will be determined by a 3 + 3 + 3 design.  
In Phase 2, the safety, tolerability, and efficacy of the MTD or PAD of epacadostat selected in 
Phase 1 when given in combination with pembrolizumab and chemotherapy will be further 
evaluated. 
3.1.1. 
Phase 1 
A 3 + 3 + 3 design will be used, in which 7 treatment groups will be explored in parallel.  A 
minimum of 3 evaluable subjects will be enrolled in each treatment group beginning with 
Cohort 1 (epacadostat 100 mg BID; starting dose), and the first 3 evaluable subjects will be 
observed for a minimum of 28 days in the cohorts where mFOLFOX6 or 
nab-paclitaxel/gemcitabine are administered or 21 days for all other chemotherapy regimens. 
The scenarios for de-escalation and expansion are summarized below, and the doses of 
epacadostat to be evaluated are summarized in Table 1. 
1. If 0 DLTs occur in 3 subjects in Cohort 1, 3 additional subjects will be treated in 
Cohort 1.  If there are no DLTs in these 6 subjects, enrollment in Phase 2 for that 
treatment group may proceed. 
2. If 1 of 3 subjects in Cohort 1 has a DLT, 3 additional subjects will be enrolled in 
Cohort 1.  If there are no additional DLTs (≤ 1 DLTs in 6 subjects), enrollment in Phase 2 
for that treatment group may proceed. 
3. If 2 of 6 subjects in Cohort 1 have a DLT, 3 additional subjects will be enrolled in 
Cohort 1.  If there are no additional DLTs (≤ 2 DLTs in 9 subjects), enrollment in Phase 2 
for that treatment group may proceed. 
4. If ≥ 2 of 3, 3 of 6, or 3 of 9 subjects have DLTs within a cohort, de-escalation of 
epacadostat to 50 mg BID (Cohort ‒1) will be evaluated using the same criteria. 
If Cohort ‒1 is not tolerated within a given treatment group, that treatment group will not be 
pursued further.  The study will be terminated if Cohort ‒1 is not tolerated in all treatment 
groups. 
Dose interruptions and/or modifications may be implemented based on toxicity as described in 
Protocol Amendment 7, Section 5.5.1.1.  Dose modifications should not be made during the DLT 
observation period without discussion with the medical monitor.  
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Table 1: 
Epacadostat Dose Cohorts 
Epacadostat Dose Cohort 
Epacadostat Dose 
–1 
50 mg BID 
1 (starting dose) 
100 mg BID
a 
a If epacadostat 100 mg BID is not tolerated within a treatment group, epacadostat 50 mg BID will be evaluated. 
Subjects will be assigned to a treatment group (see Table 2) based on the chemotherapy regimen 
most appropriate for the subject's tumor type. 
Table 2: 
Treatment Groups 
Treatment 
Group A 
Epacadostat 
Pembrolizumab 
mFOLFOX6 
BID PO continuous 
daily dosing 
(see Table 1) 
200 mg IV Q3W 
• Oxaliplatin 85 mg/m2 IV on Days 1 and 15 
• Leucovorin 400 mg/m2 IV on Days 1 and 
15 
• 5-Fluorouracil 400 mg/m2 IV bolus, then 
1200 mg/m2 per day IV infusion over 
46 hours for a total dose of 2400 mg/m2, on 
Days 1 and 15 
Treatment 
Group B 
Epacadostat 
Pembrolizumab 
nab-paclitaxel and Gemcitabine 
BID PO continuous 
daily dosing 
(see Table 1) 
200 mg IV Q3W 
• nab-Paclitaxel 125 mg/m2 IV on Days 1, 8, 
and 15 
• Gemcitabine 1000 mg/m2 IV on Days 1, 8, 
and 15 
Treatment 
Group C 
Epacadostat 
Pembrolizumab 
Paclitaxel and Carboplatin 
BID PO continuous 
daily dosing 
(see Table 1) 
200 mg IV Q3W 
• Paclitaxel 200 mg/m2 IV on Day 1 Q3W 
• Carboplatin AUC 6 IV on Day 1 Q3W 
Treatment 
Group D 
Epacadostat 
Pembrolizumab 
Pemetrexed and Platinum Agent 
BID PO continuous 
daily dosing 
(see Table 1) 
200 mg IV Q3W 
• Pemetrexed 500 mg/m2 IV on Day 1 Q3W 
• Investigators choice of platinum agent:  
Carboplatin AUC 5 IV on Day 1 Q3W or 
Cisplatin 75 mg/m2 on Day 1 Q3W 
Treatment 
Group E 
Epacadostat 
Pembrolizumab 
Cyclophosphamide 
BID PO continuous 
daily dosing 
(see Table 1) 
200 mg IV Q3W 
50 mg PO once daily 
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Table 2: 
Treatment Groups (Continued) 
Treatment 
Group F 
Epacadostat 
Pembrolizumab 
Gemcitabine and Platinum Agent 
BID PO continuous 
daily dosing 
(see Table 1) 
200 mg IV Q3W 
• Gemcitabine 1000 mg/m2 IV on Days 1 and 
8 Q3W 
Investigators choice of platinum agent:  
Carboplatin AUC 5 IV on Day 1 Q3W or 
Cisplatin 70 mg/m2 on Day 1 Q3W 
Treatment 
Group G 
Epacadostat 
Pembrolizumab 
Platinum Agent and 5-Fluorouracil 
BID PO continuous 
daily dosing 
(see Table 1) 
200 mg IV Q3W 
• Investigators choice of platinum agent:  
Carboplatin AUC 5 IV on Day 1 Q3W or 
Cisplatin 100 mg/m2 IV 
• 5-Fluorouracil 1000 mg/m2 per day IV 
infusion on Days 1 to 4 Q3W 
3.1.2. 
Phase 2:  Efficacy Expansion and Mandatory Biopsy Cohorts 
Note:  As of 25 OCT 2018, this study is closed to enrollment.  As of this date, no subjects 
were enrolled in Phase 2 efficacy expansion (all treatment groups) and Phase 2 mandatory 
biopsy Treatment Groups A, B, F, and G.  Any text included in the body of this SAP that 
references these treatment groups and cohorts have not been deleted but should be 
disregarded. 
Phase 2 efficacy expansion cohorts will evaluate the efficacy of the MTD or PAD of epacadostat 
determined in Phase 1 in combination with pembrolizumab and chemotherapy and to further 
evaluate the safety and tolerability of the combination.  The efficacy expansion cohorts will be 
limited to the following advanced or metastatic tumor types:  
1. CRC (Treatment Group A:  epacadostat + pembrolizumab + mFOLFOX6):  Simon 
2-Stage design 
2. PDAC (Treatment Group B:  epacadostat + pembrolizumab + 
nab-paclitaxel/gemcitabine):  Simon 2-Stage design 
3. Squamous NSCLC (Treatment Group C:  epacadostat + pembrolizumab + 
paclitaxel/carboplatin) 
4. Nonsquamous NSCLC (Treatment Group D:  epacadostat + pembrolizumab + 
pemetrexed/platinum agent) 
5. Any solid tumor that progressed on previous therapy with a PD-1 or PD-L1 inhibitor 
(Treatment Group E:  epacadostat + pembrolizumab + cyclophosphamide) 
6. UC (Treatment Group F:  epacadostat + pembrolizumab + gemcitabine/platinum agent) 
7. SCCHN (Treatment Group G:  epacadostat + pembrolizumab + platinum agent/ 
5-fluorouracil) 
In addition to the efficacy expansion cohorts listed above, separate mandatory biopsy cohorts 
will be enrolled to evaluate changes in the tumor microenvironment.  For the cohorts where 
IV chemotherapy is administered, subjects will receive IV chemotherapy only during Cycle 1 
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followed by epacadostat + pembrolizumab + IV chemotherapy starting with Cycle 2 Day 1.  For 
the CRC and PDAC cohorts, a minimum of 10 subjects with evaluable paired biopsy specimens 
will be enrolled.  A fresh tumor biopsy will be collected during screening.  On treatment biopsies 
are mandatory and will be collected between Days 21 and 27 of Cycle 1 (IV chemotherapy only) 
and Cycle 2 (epacadostat + pembrolizumab + IV chemotherapy).  For the squamous NSCLC, 
nonsquamous NSCLC, UC, or SCCHN cohorts, a minimum of 10 subjects with evaluable paired 
biopsy specimens will be enrolled.  A fresh tumor biopsy will be collected during screening.  
On-treatment biopsies are mandatory and will be collected between Days 14 and 20 of Cycle 1 
(IV chemotherapy only) and Days 7 and 13 of Cycle 3 (epacadostat + pembrolizumab + IV 
chemotherapy).  For subjects with any advanced or metastatic solid tumor that progressed on 
previous therapy with a PD-1 or PD-L1 inhibitor, a minimum of 5 subjects with evaluable paired 
biopsy specimens will be enrolled in the mandatory biopsy cohort; however, this cohort will be 
administered epacadostat, pembrolizumab, and cyclophosphamide starting on Cycle 1 Day 1.  A 
fresh tumor biopsy will be collected during screening, and an on treatment biopsy is mandatory 
and will be collected between Days 7 and 13 of Cycle 3. 
Note:  As of 25 OCT 2018, on-treatment tumor biopsies are no longer required for subjects 
who already enrolled in the mandatory biopsy cohorts. 
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Figure 1: 
Study Design 
 
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3.2. 
Control of Type I Error 
For the primary efficacy endpoint in Phase 2, the 1-sided Type I error will be controlled at 
0.1 for each individual treatment group.  For other endpoints, CIs will be reported at a 
95% confidence level.  Note that this level of significance does not account for the multiple 
treatment groups. 
3.3. 
Sample Size Considerations 
3.3.1. 
Sample Size in Phase 1 
A 3 + 3 + 3 design will be used in Phase 1 to determine the MTD or PAD and DLT of 
epacadostat when given in combination with pembrolizumab and 7 chemotherapy regimens.  The 
total number of subjects will depend on the frequency of DLTs and number of dose levels tested 
before MTD or PAD is established.  Based on 3 + 3 + 3 design algorithm, within each treatment 
group, a minimum of 6 subjects and up to 9 subjects will be enrolled at each dose level. 
3.3.2. 
Sample Size in Phase 2 
3.3.2.1. 
Efficacy Expansion 
NOTE:  As of 25 OCT 2018, this study is closed to enrollment.  As of this date, no subjects 
were enrolled in Phase 2 efficacy expansion (all treatment groups) or Phase 2 mandatory 
biopsy Treatment Groups A, B, F, and G; therefore, disregard this section. 
Phase 2 consists of expansion cohorts (efficacy and mandatory biopsy) in specific tumor types 
(advanced or metastatic CRC, PDAC, squamous or nonsquamous NSCLC, UC, SCCHN, or any 
advanced or metastatic solid tumor that progressed on previous therapy with a PD-1 or PD-L1 
inhibitor).  A Simon 2-stage design will be used for the CRC and PDAC efficacy expansion 
cohorts.  The response rates for the historical control (p0), desired response rates for the 
combination (p1), number of subjects needed in Stage 1 (n1) and Stage 2 (n2), total number of 
subjects (n), first-stage threshold declaring cohort undesirable (r1), and the upper-limit of the 
number of responses in n subjects such that futility of the drug is concluded (r) are provided for 
each expansion cohort in Table 3. 
In addition, a single-stage Phase 2 expansion will be used for all other efficacy expansion 
cohorts.  The sample sizes and decision rules are summarized in Table 4.  The definitions of p0, 
p1, n, and r are the same as those in Table 3. 
The calculation is based on a 1-sided Type I error of 0.1 and power of 80%, with the exception 
of the cohort enrolling solid tumors that progressed on previous treatment with a PD-1 or PD-L1 
inhibitor, which is based on a 1-sided Type I error of 0.1 and power of approximately 98%. 
Table 3: 
Sample Size and Decision Rule for Simon 2-Stage Design Phase 2 Efficacy 
Expansion Cohorts 
Tumor Type 
p0 
p1 
n1 
n2 
n 
r1 
r 
CRC 
40% 
60% 
12 
26 
38 
5 
18 
PDAC 
25% 
45% 
15 
12 
27 
4 
9 
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Table 4: 
Sample Size and Decision Rule for Single-Stage Design Phase 2 Efficacy 
Expansion Cohorts 
Tumor Type 
p0 
p1 
n 
r 
Squamous NSCLC 
30% 
50% 
33 
13 
Nonsquamous NSCLC 
50% 
70% 
33 
20 
Solid tumors that progressed on previous 
therapy with a PD-1 or PD-L1 inhibitor 
5% 
25% 
33 
3 
UC 
60% 
80% 
33 
23 
SCCHN 
50% 
70% 
33 
20 
3.3.2.2. 
Mandatory Biopsy Cohorts 
NOTE:  As of 25 OCT 2018, this study is closed to enrollment.  As of this date, only Phase 2 
mandatory biopsy Treatment Groups C, D, and E enrolled subjects, and the minimum number of 
subjects was not enrolled; therefore, disregard this section. 
• A minimum of 10 subjects will be enrolled in the CRC, PDAC, squamous NSCLC, 
nonsquamous NSCLC, UC, and SCCHN Phase 2 mandatory biopsy cohorts. 
• A minimum of 5 subjects will be enrolled in any advanced or metastatic solid tumor 
that progressed on previous therapy with a PD-1 or PD-L1 inhibitor mandatory 
biopsy cohorts. 
In Phase 2 mandatory biopsy cohorts, assuming the true rate of subjects positive for the 
biomarker is 50%, the probability of observing ≥ 4 subjects out of 10 with the biomarker is 83% 
for CRC, PDAC, squamous NSCLC, non-squamous NSCLC, UC and SCCHN cohorts and the 
probability of observing ≥ 2 subjects out of 5 with the biomarker is 81% for previous PD-1 or 
PD-L1 inhibitor therapy cohort. 
3.4. 
Schedule of Assessments 
See Protocol Amendment 7 dated 14 FEB 2019 for a full description of all study procedures and 
assessment schedules for this study. 
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4. 
DATA HANDLING DEFINITIONS AND CONVENTIONS 
4.1. 
Scheduled Study Evaluations and Study Periods 
4.1.1. 
Day 1 
Day 1 is the date that the first dose of epacadostat, pembrolizumab, or chemotherapy is 
administered to the subjects. 
4.1.2. 
Study Day 
If a visit/reporting date is on or after Day 1, then the study day at the visit/reporting date will be 
calculated as 
Day # = (Visit/Reporting Date – Day 1 date + 1). 
If the visit/reporting date is before Day 1, then the study day at the visit/reporting date will be 
calculated as  
Day # = (Visit/Reporting Date – Day 1 date). 
A study day of -1 indicates 1 day before Day 1. 
4.1.3. 
Baseline Value 
Baseline is the last nonmissing measurement obtained before the first administration of 
epacadostat, pembrolizumab, or chemotherapy. 
When scheduled assessments and unscheduled assessments occur on the same day and time of 
the assessment or time of first dose is not available, use the following convention to determine 
baseline: 
• If both a scheduled and an unscheduled visit are available on the day of the first dose 
and the time is missing, use the scheduled assessment as baseline. 
• If all scheduled assessments are missing on the day of the first dose and an 
unscheduled assessment is available, use the unscheduled assessment as baseline. 
4.1.4. 
Handling of Missing and Incomplete Data  
In general, values for missing data will not be imputed unless methods for handling missing data 
are specified in this section or relevant sections. 
Partial disease/cancer diagnosis date will be handled as follows: 
• If only the day is missing, then the imputed day will be the first of the month. 
• If both the month and day are missing, then the imputed day and month will be 
01 JAN. 
• No imputation will be done if the date is completely missing. 
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Missing or partial date of last dose will be handled as follows: 
• If only the day is missing, then the imputed date of the last dose will be the earlier 
date of the first day of the month or the date that the subject discontinued treatment. 
• Otherwise, the date that the subject discontinued treatment will be used as the date of 
the last dose. 
For relevant efficacy endpoints, partial death date will be imputed as follows: 
• If mmyyyy for the last contact date = mmyyyy for the death date, then the death date 
will be set to the day after the last contact date. 
• If mmyyyy for the last contact date < mmyyyy for the death date, then the death date 
will be set to the first day of the death month. 
• Otherwise, the partial death date will not be imputed. 
For prior and concomitant medications: 
The start/stop dates recorded in the eCRF by the investigator and his or her research staff will be 
used to identify when a concomitant medication was taken during the study.  Any missing start 
date must be queried for resolution.  Unresolved missing start dates will be handled as follows: 
• If the date is completely missing, the medication will be considered both prior and 
concomitant. 
• If only the day is missing, and the last day of the month is before the first dose date 
on Day 1, then the concomitant medication will be considered as starting before 
Day 1, and the incomplete date will be imputed as the last day of the month. 
• If only the day is missing, and the first day of the month is after the first dose date on 
Day 1, then the concomitant medication will be considered as starting after Day 1, 
and the incomplete date will be imputed as the first day of the month. 
• If only the day is missing, and the month is equal to the month of the first dose date 
on Day 1, then the incomplete date will be imputed as the first day of the month. 
• If both the month and day are missing, and the last day of the year is before the first 
dose date on Day 1, then the concomitant medication will be considered as starting 
before Day 1, and the incomplete date will be imputed as if it is the last day of the 
year.  Otherwise, the incomplete date will be imputed as if it is the first day of the 
year. 
4.1.5. 
Cycle Length and Duration 
Cycle 1 Day 1 is the day that the first dose of epacadostat, pembrolizumab, or chemotherapy is 
administered.  Scheduled cycle length is 21 or 28 days depending on the chemotherapy 
administered.  For mFOLFOX6 and nab-paclitaxel/gemcitabine regimens, the scheduled cycle 
length is 28 days.  For all other chemotherapy regimens, the scheduled cycle length is 21 days. 
For Phase 1 and Phase 2 efficacy expansion subjects enrolled in Treatment Groups A, B, C, D, E, 
F, and G and the Phase 2 mandatory biopsy subjects enrolled in Treatment Group E, epacadostat 
will be administered beginning on Cycle 1 Day 1 and continuously thereafter.  For Phase 2 
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subjects enrolled in the mandatory biopsy cohorts where IV chemotherapy is administered 
(Treatment Groups A, B, C, D, F, and G), epacadostat will be administered beginning on Cycle 2 
Day 1 and continuously thereafter.  Treatment will continue through the end of the cycle in 
which the 35th pembrolizumab infusion is administered if, in the investigator's judgment, the 
subject is receiving benefit from therapy and has not met any criteria for treatment 
discontinuation (see Protocol Amendment 7, Section 5.6.1). 
For Phase 1 and Phase 2 efficacy expansion subjects enrolled in Treatment Groups A, B, C, D, E, 
F, and G and for Phase 2 mandatory biopsy subjects enrolled in Treatment Group E, 
pembrolizumab will be administered starting on Cycle 1 Day 1.  For subjects enrolled in the 
Phase 2 mandatory biopsy cohorts where IV chemotherapy is administered (Treatment 
Groups A, B, C, D, F, and G), pembrolizumab will be administered starting on Cycle 2 Day 1.  
Treatment will continue for a total of 35 pembrolizumab infusions if, in the investigator's 
judgment, the subject is receiving benefit from therapy and has not met any criteria for treatment 
discontinuation (see Protocol Amendment 7, Section 5.6.1). 
Actual Day 1 of subsequent cycles will correspond with the first day of administration of 
epacadostat, pembrolizumab, or chemotherapy in that cycle; thus, treatment cycles may become 
out of sync with the originally planned schedule and cycle length may be different from 21 or 
28 days.  The date of Day 1 of subsequent cycles recorded on the eCRF will be used as Day 1 of 
the subsequent cycles. 
4.2. 
Variable Definitions 
The following variables will only be calculated if not reported on the eCRF. 
4.2.1. 
Age 
Subject age will be calculated as the integer part of the number of years from date of birth to the 
date of signing the IC, using the following formula: 
Age = integer part of (date of informed consent – date of birth + 1) / 365.25. 
When date of birth was not collected for a subject and the age of the subject was reported on the 
eCRF, the reported age will substitute for the calculated age. 
4.2.2. 
Body Surface Area 
Body surface area will be calculated based on the Mosteller (1987) formula as follows: 
BSA (m2) = {[weight (kg) × height (cm)] / 3600}½ 
Sites will also record the BSA calculated per institutional standards. 
4.2.3. 
Prior and Concomitant Medication 
Prior medication is defined as any nonstudy medication started before the first dose of 
epacadostat, pembrolizumab, or the assigned chemotherapy regimen. 
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Concomitant medication is defined as any nonstudy medication that is started accordingly: 
• Before the date of first administration of epacadostat, pembrolizumab, or the assigned 
chemotherapy regimen and is ongoing throughout the study or ends on/after the date 
of first study drug administration. 
• On/after the date of first administration of epacadostat, pembrolizumab, or the 
assigned chemotherapy regimen and is ongoing or ends during the course of study 
drug. 
A prior medication could also be classified as "both prior and concomitant medication" if the end 
date is on or after first dose of epacadostat, pembrolizumab, or chemotherapy regimen.  In the 
listing, it will be indicated whether a medication is prior-only, concomitant-only, or both prior 
and concomitant medication. 
For the purposes of analysis, all medications will be considered concomitant medications unless 
the medications can unequivocally be defined as not concomitant. 
5. 
STATISTICAL METHODOLOGY 
5.1. 
General Methodology 
Unless otherwise noted, SAS® software (SAS Institute Inc, Cary, NC; v9.4 or later) will be used 
for the generation of all tables, graphs, and statistical analyses.  Descriptive summaries for 
continuous variables will include, but not be limited to, the number of observations, mean, 
standard deviation, median, minimum, and maximum.  Descriptive summaries for categorical 
variables will include the number and percentage of subjects in each category. 
Interim analyses are planned for this study as defined in Section 9. 
5.2. 
Treatment Groups 
Note:  As of 25 OCT 2018, this study is closed to enrollment.  As of this date, no subjects were 
enrolled in Phase 2 efficacy expansion (all treatment groups) or Phase 2 mandatory biopsy 
Treatment Groups A, B, F, and G.  Any text that references these treatment groups and cohorts 
has not been deleted but should be disregarded. 
This is an open-label, nonrandomized, Phase 1/2 study to determine the safety, tolerability, and 
efficacy of epacadostat when given in combination with pembrolizumab and 7 chemotherapy 
regimens. 
In Phase 1, subjects will be enrolled into 7 treatment groups.  Subjects will be assigned to a 
treatment group (see Table 2) based on the chemotherapy regimen most appropriate for their 
tumor type.  The initial dose level for epacadostat in each treatment group will be 100 mg BID.  
The doses of epacadostat to be evaluated and the scenarios for dose de-escalation are 
summarized in Table 1. 
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In Phase 2, the efficacy expansion + cohorts and the mandatory biopsy cohorts will be limited to 
the following advanced or metastatic tumor types: 
1. CRC (Treatment Group A:  epacadostat + pembrolizumab+ mFOLFOX6) 
2. PDAC (Treatment Group B:  epacadostat + pembrolizumab+ nab-paclitaxel/gemcitabine) 
3. Squamous NSCLC (Treatment Group C:  epacadostat + pembrolizumab + 
paclitaxel/carboplatin) 
4. Nonsquamous NSCLC (Treatment Group D:  epacadostat + pembrolizumab + 
pemetrexed/platinum agent) 
5. Any solid tumor that progressed on previous therapy with a PD-1 or PD-L1 inhibitor 
(Treatment Group E:  epacadostat + pembrolizumab + cyclophosphamide) 
6. UC (Treatment Group F:  epacadostat + pembrolizumab + gemcitabine/platinum agent) 
7. SCCHN (Treatment Group G:  epacadostat + pembrolizumab + platinum agent/5-
fluorouracil) 
Data will be summarized by treatment group for Phase 1 and Phase 2 combined. 
5.3. 
Analysis Populations 
5.3.1. 
Full Analysis Set 
The FAS includes subjects enrolled in the study who received at least 1 dose of epacadostat, 
pembrolizumab, or applicable chemotherapy agent and have at least 1 postbaseline assessment or 
who discontinued treatment. 
The FAS population will be used for the summary of all efficacy data. 
5.3.2. 
Safety Population 
The safety population includes all subjects enrolled in the study who received at least 1 dose of 
epacadostat, pembrolizumab, or applicable chemotherapy agent. 
Specific safety analysis populations to be used for drug-specific tables include the following 
subgroups: 
• epacadostat safety population 
• pembrolizumab safety population 
• mFOLFOX6 safety population 
• nab-paclitaxel and gemcitabine safety population 
• paclitaxel and carboplatin safety population 
• pemetrexed and platinum agent safety population 
• cyclophosphamide safety population 
• gemcitabine and platinum agent safety population 
• 5-fluorouracil and platinum agent safety population 
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All of the chemotherapy safety populations are defined as all subjects enrolled in the study who 
received at least 1 dose of any chemotherapy agent.  For example, the mFOLFOX6 safety 
population includes all subjects enrolled in the study who received at least 1 dose of oxaliplatin, 
leucovorin, or fluorouracil. 
The safety population will be used for the summary of safety analyses. 
6. 
BASELINE, EXPOSURE, AND DISPOSITION VARIABLES AND 
ANALYSES 
Appendix A provides a list of planned tables and listings.  Sample data displays are provided in a 
separate document.  The list of tables and listings and the shells are to be used as a guideline.  
Modifications of the list or shells that do not otherwise affect the nature of the analysis will not 
warrant an amendment to the SAP. 
6.1. 
Baseline and Demographics, Physical Characteristics, and Disease 
History 
6.1.1. 
Demographics 
The following demographics will be summarized for all subjects in the safety population by 
treatment group:  age, sex, race, and ethnicity. 
6.1.2. 
Baseline Disease Characteristics and Disease History 
The baseline disease characteristics include tumor types, current stage, current number of 
metastatic organ/tissue sites, current sites of disease, and types prior therapies for cancer 
(eg, radiotherapy, surgery, systemic therapy or prior PD1/L1 therapy), will be summarized by 
treatment group. 
ECOG performance status will be summarized for all subjects in the safety population by 
treatment group. 
6.1.3. 
Prior Therapy 
Number of subjects who received prior systemic cancer therapy regimens will be summarized for 
all subjects in the safety population by treatment group.  Regimen name, component drugs, start 
and stop date, purpose of the regimen, best response, reason for discontinuation, and date of 
relapse/progression will be listed. 
Number of subjects who received prior radiation will be summarized for all subjects in the safety 
population by treatment group.  Radiotherapy type, body site, start and stop date, reason for 
regimen, number of fractions, total dose, and best response will be listed. 
Number of subjects who had prior surgery or surgical procedure for the malignancies under 
study will be summarized for all subjects in the safety population by treatment group.  Date and 
description of the surgery/procedure will be listed. 
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6.1.4. 
Medical History 
Medical history will be summarized by assigned treatment group for all subjects in the safety 
population by treatment group.  This summation will include the number and percentage of 
subjects with significant medical history for each body system/organ class as documented on the 
eCRF. 
6.2. 
Disposition of Subjects 
The number and percentage of subjects who were enrolled, treated, completed the study, 
discontinued study treatment with a primary reason for discontinuation, and discontinued from 
the study with a primary reason for withdrawal will be summarized for all subjects in the safety 
population by treatment group.  The number of subjects enrolled by site will also be provided by 
treatment group. 
6.3. 
Protocol Deviations 
Protocol deviations recorded on the eCRF will be presented in the subject data listings.  If data 
warrant, protocol deviations will be summarized for all subjects in the safety population by 
treatment group. 
6.4. 
Exposure 
6.4.1. 
Exposure for Epacadostat 
The following variables will be summarized for epacadostat: 
• Duration of treatment (days):  Date of last dose of epacadostat – date of first dose 
of epacadostat + 1. 
• Total dose administered (mg):  Total dose administered (mg) for each subject will 
be the sum of epacadostat administered (mg) across cycles. 
• Average Daily Dose (mg/day):  Total dose administered (mg) divided by the 
duration of treatment in days. 
6.4.2. 
Exposure for Pembrolizumab 
The following variables will be summarized for pembrolizumab: 
• Total number of infusions:  Total number of infusions per subject will be the total 
number of infusions per subject with a nonzero dose of pembrolizumab. 
• Dose administered per cycle (mg):  The actual dose administered (mg) per cycle. 
• Total dose administered (mg):  Total dose (mg) administered is the sum of the 
cumulative dose of pembrolizumab that has been administered to the subject. 
For an infusion i, let Ci be the concentration (mg/mL) of pembrolizumab and Vi be the 
total volume administered (in mL) reported on the pembrolizumab dosing eCRF; let 
N be the total number of infusions: 
Total dose administered (mg) = 
. 
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• Average dose (mg):  The average dose (mg) will be the total dose administered (mg) 
divided by the total number of infusions. 
• Duration of treatment (days):  Date of last dose of pembrolizumab – date of first 
dose of pembrolizumab + 1. 
6.4.3. 
Exposure for Cyclophosphamide 
The exposure for cyclophosphamide will be summarized the same as that for epacadostat in 
Section 6.4.1. 
6.4.4. 
Exposure for Intravenous Chemotherapies 
6.4.4.1. 
Exposure for Carboplatin 
The following variables will be summarized for the exposure for carboplatin at AUC5, AUC6, 
and other dose levels separately: 
• Total number of infusions:  Total number of infusions per subject will be the total 
number of infusions per subject with a nonzero dose of carboplatin. 
• Dose administered per cycle (mg):  The actual dose administered (mg) per cycle. 
• Total dose administered (mg):  Total dose (mg) administered is the sum of the 
BSA-adjusted cumulative dose of carboplatin that has been administered to the 
subject. 
For an infusion i, let Ci be the concentration (mg/mL) of carboplatin and Vi be the 
total volume administered (in mL) reported on carboplatin dosing eCRF and let N be 
the total number of infusions: 
Total dose administered (mg) = 
. 
• Average dose (mg):  The average dose (mg) will be the total dose administered (mg) 
divided by the total number of infusions. 
• Duration of treatment (days):  Date of last dose of carboplatin – date of first dose of 
carboplatin + 1. 
6.4.4.2. 
Exposure for Other Intravenous Chemotherapies 
The following variables will be summarized for each component of all other IV chemotherapies: 
• Total number of infusions:  Total number of infusions per subject will be the total 
number of infusions per subject with a nonzero dose of each IV chemotherapy agent. 
• Dose administered per cycle (mg/m2):  The actual dose administered (mg/m2) per 
cycle. 
• Total dose administered (mg/m2):  Total dose (mg/m2) administered is the sum of 
the BSA-adjusted cumulative dose of each IV chemotherapy agent that has been 
administered to the subject. 
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For an infusion i, let Ci be the concentration (mg/mL) of each IV chemotherapy agent 
and Vi be the total volume administered (in mL) reported on each IV chemotherapy 
agent dosing eCRF; let B be the subject's baseline BSA (m2), and let N be the total 
number of infusions: 
Total dose administered (mg/m2) = 
. 
• Average dose (mg/m2):  The average dose (mg/m2) will be the total dose 
administered (mg/m2) divided by the total number of infusions. 
• Duration of treatment (days):  Date of last dose – date of first dose + 1. 
Other IV chemotherapies in this study include the following:  5-fluorouracil, leucovorin, 
oxaliplatin, gemcitabine, nab-paclitaxel, paclitaxel, pemetrexed, and cisplatin. 
6.5. 
Prior and Concomitant Medication 
For subjects in the safety population, prior medications and concomitant medications will be 
coded using the WHO Drug Dictionary and summarized by WHO drug class and WHO drug 
term.  Results will be summarized as number and percentage of subjects with prior and 
concomitant medications by preferred term and WHO drug class. 
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7. 
EFFICACY 
NOTE:  As of 25 OCT 2018, this study is closed to enrollment.  As of this date, no subjects 
were enrolled in Phase 2 efficacy expansion (all treatment groups); therefore, no efficacy 
tables or listings will be provided. 
7.1. 
General Considerations 
The efficacy endpoint of this study is ORR by investigator assessment based on RECIST v1.1.  
The primary efficacy assessment is based on RECIST v1.1.  Listings of response assessment at 
each visit will be provided. 
7.2. 
Efficacy Hypotheses 
A Simon 2-stage design (Simon 1989) will be applied to Phase 2 efficacy expansion subjects in 
Treatment Groups A and B in testing the null hypothesis that the true ORR is less than or equal 
to the clinically insignificant response rates of p0 against the alternative hypothesis that the true 
ORR is equal to the target ORR of p1.  The values of p0 and p1 for each tumor type are displayed 
in Table 3. 
7.3. 
Analysis of the Efficacy Parameters 
7.3.1. 
Response Criteria 
Overall disease status will be categorized using RECIST v1.1.  Subjects will have their overall 
response evaluated as CR, PR, SD, PD, or NE at each postbaseline radiological assessment based 
on changes in target lesions, nontarget lesions, and appearance of new lesions. 
7.3.2. 
Objective Response Rates and Best Overall Response 
A subject is defined as an objective responder if the subject has an overall response of CR or PR 
at any postbaseline visit prior to first PD.  Objective responders will be assessed based on 
RECIST v1.1. 
Objective response rate is defined as the proportion of subjects with objective responses.  
Objective response rate will be estimated with 95% CIs overall by cohort-specific tumor type.  
Confidence intervals will be calculated based on the method for Simon-2-Stage CIs of response 
rates outlined in Koyama and Chen (2008).  Subjects who do not have sufficient baseline 
information will be included in the denominators in the calculation of ORR. 
In general, best overall response is the best response recorded postbaseline prior to and including 
the first PD, in the order of CR, PR, SD, PD, and NE.  In the case of SD, measurements must 
meet the SD criteria at least once after the date of first dose at a minimum interval of 
56 (63-7) days.  Subjects that fail to meet this criterion will have best overall response of PD if 
the next available assessment indicates PD or NE if there is no additional assessment available.  
Under RECIST v1.1, if radiologic imaging shows CR or PR, a tumor assessment should be 
repeated at a minimum of 4 weeks to confirm the response in order to claim the CR or PR as the 
best overall response.  If there is no second CR or PR tumor assessment in the minimum 
21 (28-7)-day follow-up time, the CR or PR will be unconfirmed.  Table 5 lists the scenarios of 
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responses that can occur after an unconfirmed CR or PR in the 4-week follow-up time and 
provides a rule for determining the best overall response in each scenario. 
Table 5: 
Best Overall Response When Confirmation of CR and PR is Required 
Overall Response 
at First Timepoint 
Overall Response at Subsequent 
Timepoint 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PR
a 
CR 
SD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
CR 
NE
b 
SD provided minimum criteria for SD 
duration met, otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
PR 
NEb 
SD provided minimum criteria for SD 
duration met, otherwise NE 
NE 
NE 
NE 
a If a CR is truly met at the first timepoint, then any disease seen at a subsequent timepoint, even disease meeting 
PR criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR).  
Best overall response would depend on whether the minimum duration for SD was met.  However, sometimes CR 
may be claimed when subsequent scans suggest small lesions were likely still present, and in fact, the subject had a 
PR, not a CR at the first timepoint.  Under these circumstances, the original CR should be changed to a PR and the 
best overall response is PR. 
b In cases where confirmatory scans with NEs are subsequently followed by another scan confirming the response, 
for example, a subject with timepoint responses of PR-NE-PR, it is reasonable to consider PR as a confirmed 
response. 
7.3.2.1. 
Objective Response Rate Under RECIST v1.1 
Under RECIST v1.1, the best response is determined by subject using the highest overall 
response achieved postbaseline prior to and including the first PD, in the order of CR, PR, SD, 
PD, and NE.  Responses of CR, PR, or SD after a response of PD will not be considered in 
determining best response by RECIST v1.1 criteria.  In the case of SD, measurements must meet 
the SD criteria at least after the date of first dose at a minimum of 56 (63-7) days.  Subjects who 
fail to meet this criterion will have best overall response of PD if the next available assessment 
indicated PD or NE if there is no additional assessment available. 
For subjects with measurable disease at baseline, the RECIST v1.1 assessment criteria presented 
in Table 6 can be used to determine the overall disease status at a given timepoint based on the 
target lesion, nontarget lesion, and new lesion assessment. 
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Table 6: 
RECIST Evaluation Criteria for Overall Response:  Measurable Disease at 
Baseline 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non-PD or NE 
No 
PR 
SD 
Non-PD or NE 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
7.3.3. 
Largest Percentage Reduction in Sum of Diameters of Target Lesions 
For each subject in the FAS population with target lesions at baseline, target lesion sizes will be 
measured by sum of diameters.  The best percent change from baseline, defined as the largest 
decrease in target lesion size for each subject, will be summarized descriptively, and a waterfall 
plot of the best percent change will be generated. 
Per RECIST criteria, target lesions considered "too small to measure" will be assigned a default 
value of 5 mm for purposes of this analysis.  Likewise, target lesions identified as "not present" 
at postbaseline assessments will be assigned 0 mm for this analysis.  In the event a target lesion 
is unaccounted for in a particular postbaseline timepoint (ie, assessment missing or NE), then the 
overall sum of diameters for target lesions will not be evaluable for that postbaseline timepoint. 
8. 
SAFETY AND TOLERABILITY 
Appendix A provides a list of planned tables and listings.  Sample data displays are provided in a 
separate document.  The list of tables and listings and the shells are to be used as a guideline.  
Modifications of the list or shells that do not otherwise affect the nature of the analysis will not 
warrant an amendment to the SAP. 
8.1. 
General Considerations 
Summary tables may be replaced with listings when appropriate.  For instance, an AE frequency 
table may be replaced with a listing if it only contains a few unique PTs reported on relatively 
few subjects. 
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8.2. 
Adverse Events 
8.2.1. 
Adverse Event Definitions 
A TEAE is any AE either reported for the first time or worsening of a pre-existing event after 
first dose of study drug.  Analysis of AEs (as discussed below) will be limited to TEAEs, but 
data listings will include all AEs regardless of their timing in relation to study drug 
administration. 
Adverse events will be tabulated by MedDRA PT and SOC.  Severity of AEs will be graded 
using the NCI CTCAE.  The CTCAE v4.03 is used for this study.  The CTCAE reporting 
guidelines and grading details are available on the Cancer Therapy Evaluation Program website. 
The subset of AEs considered by the investigator to be related to study treatment will be 
considered to be treatment-related AEs.  The incidence of AEs and treatment-related AEs will be 
tabulated.  In addition, serious TEAEs will also be tabulated. 
Any missing onset date, causality, or severity must be queried for resolution.  Unresolved 
missing causality and severity will be handled according to the following rules: 
• An unresolved missing causality will be considered treatment-related. 
• An unresolved missing severity will be identified as an unknown severity. 
For purposes of analysis, all AEs will be considered TEAEs unless the AE can unequivocally be 
defined as not treatment emergent. 
8.2.2. 
Dose-Limiting Toxicities 
The number of subjects with DLTs and the type of DLT will be listed by dose level. 
8.2.3. 
Maximum Tolerated Dose 
In Phase 1, the MTD is defined as the highest dose level at which ≤ 1/6 or ≤ 2/9 subjects 
experience a DLT. 
8.2.4. 
Events of Clinical Interest and Adverse Events of Special Interest 
Events of clinical interest must be recorded as such on the eCRF. 
For this study, events of clinical interests include: 
1. Potential drug-induced liver injury (or Hy's Law) – an elevated AST or ALT laboratory 
value that is ≥ 3 × the ULN and an elevated total bilirubin laboratory value that is 
≥ 2 × the ULN and, at the same time, an ALP laboratory value that is < 2 × the ULN, as 
determined by way of Protocol-specified laboratory testing or unscheduled laboratory 
testing. 
2. An overdose of epacadostat or pembrolizumab that is not associated with clinical 
symptoms or abnormal laboratory results.  For this study, an overdose will be defined as 
≥ 1000 mg of epacadostat or ≥ 1000 mg (5 × the dose) of pembrolizumab.  No specific 
information is available on the treatment of overdose of epacadostat or pembrolizumab.  
In the event of overdose, the subject should be observed closely for signs of toxicity.  
Appropriate supportive treatment should be provided if clinically indicated. 
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3. Serotonin syndrome (see Protocol Section 5.5.6 for further details). 
4. Any of the following AEs: 
a. ≥ Grade 3 diarrhea 
b. ≥ Grade 3 colitis 
c. ≥ Grade 2 pneumonitis 
d. ≥ Grade 3 rash or dermatitis 
e. Grade 4 laboratory abnormality 
An overall summary of sponsor-determined AEOSIs will include number (%) of subjects 
reporting any immune-related AEs. 
Subjects meeting the criteria of Hy's Law will be listed with study visit and assigned treatment 
group. 
8.2.5. 
Adverse Event Summaries 
An overall summary of AEs by treatment group will include: 
• Number (%) of subjects reporting any TEAEs 
• Number (%) of subjects reporting any DLTs 
• Number (%) of subjects reporting any serious TEAEs 
• Number (%) of subjects reporting any Grade 3 or 4 TEAEs 
• Number (%) of subjects reporting any TEAEs related to any study drug 
• Number (%) of subjects who temporarily interrupted epacadostat and/or 
pembrolizumab because of TEAEs 
• Number (%) of subjects who permanently discontinued epacadostat and/or 
pembrolizumab because of TEAEs 
• Number (%) of subjects with epacadostat dose reductions because of TEAEs 
• Number (%) of subjects who had a fatal TEAE 
The following summaries will be produced by MedDRA term (if 10 or fewer subjects appear in a 
table, a listing may be appropriate): 
• Summary of TEAEs by SOC and PT 
• Summary of TEAEs by PT in decreasing order of frequency 
• Summary of Grade 3 or 4 TEAEs by SOC and PT 
• Summary of Grade 3 or 4 TEAEs by PT in decreasing order of frequency 
• Summary of any treatment-related TEAEs by SOC and PT 
• Summary of any treatment-related TEAEs by PT in decreasing order of frequency 
• Summary of TEAEs with a fatal outcome by SOC and PT 
• Summary of serious TEAEs by SOC and PT 
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• Summary of serious TEAEs by PT in decreasing order of frequency 
• Summary of TEAEs leading to any dose reduction by SOC and PT 
• Summary of TEAEs leading to any dose interruption by SOC and PT 
• Summary of TEAEs leading to discontinuation of study drug by SOC and PT 
• Summary of sponsor-determined AEOSIs by category and PT 
8.3. 
Clinical Laboratory Tests 
8.3.1. 
Laboratory Value Definitions 
Laboratory values and change from baseline values will be summarized descriptively by visit.  
The baseline value will be determined according to Section 4.1.3 using the nonmissing values 
collected before the first dose, prioritizing scheduled assessments for baseline identification over 
unscheduled visits.  The last record before administration in the highest priority will be 
considered the baseline record.  For baseline laboratory candidates with the same date and time 
in the same priority category, additional rules may be provided after consultation with the 
medical monitor to delineate which value will be defined as baseline. 
Laboratory test values outside the normal range will be assessed for severity based on CTCAE 
grade or similar criteria where clinical intervention is required for CTCAE grading.  The 
incidence of abnormal laboratory values and shift tables relative to baseline will be tabulated. 
8.3.2. 
Laboratory Value Summaries 
All test results and associated normal ranges from central laboratories will be reported in SI 
units.  All tests with numeric values will have a unique unit per test.  Any laboratory test results 
and associated normal ranges from local laboratories will be converted to SI units.  For the 
limited number of cases where the associated normal ranges from a local laboratory cannot be 
obtained despite due diligence, associated central laboratory normal ranges will be applied.  In 
the event that central laboratory normal ranges are not available, a set of standard normal ranges 
based on documented reference ranges will be applied to facilitate reporting the test results. 
When there are multiple laboratory nonmissing values for a subject's particular test at a 
scheduled visit, the laboratory value with the smallest laboratory sequence number will be used 
in by-visit summaries. 
Numeric laboratory values will be summarized descriptively in SI units, and non-numeric test 
values will be tabulated when necessary. 
For test results that will be summarized with available normal ranges, the number and percentage 
of subjects with the laboratory values being low (but never high), normal, high (but never low), 
and both low and high will be calculated for each test.  This shift summary will be produced for 
each test for the safety population.  The denominator for the percentage calculation will use the 
number of subjects in the baseline category (ie, low, high, normal, and missing) as the 
denominator for the percentage in each of the categories during the treatment period. 
Shift tables will be presented showing change in CTCAE grade from baseline to worst grade 
postbaseline.  Separate summaries for abnormally high and abnormally low laboratory values 
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will be provided when the laboratory parameter has both high and low grading criteria.  The 
denominator for the percentage calculation will be the number of subjects in the baseline 
category. 
In cases where differentials of hematology parameters are obtained without corresponding 
absolute count data, efforts will be made to investigate if the conversion to an absolute value will 
lead to additional abnormalities.  This will be discussed with the clinical team regarding 
appropriate documentation and action. 
8.4. 
Vital Signs 
Values at each scheduled visit, change, and percent change from baseline for vital signs, 
including systolic blood pressure, diastolic blood pressure, pulse, respiration rate, body 
temperature, and weight will be summarized descriptively. 
Criteria for clinically notable vital sign abnormalities are defined in Table 7.  The abnormal 
values for subjects exhibiting clinically notable vital sign abnormalities will be listed along with 
their assigned treatment group.  Alert vital signs are defined as an absolute value outside the 
defined range and percentage change greater than 25%.  The abnormal values for subjects 
exhibiting alert vital sign abnormalities will be listed. 
Table 7: 
Criteria for Clinically Notable Vital Sign Abnormalities 
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure 
> 155 mmHg 
< 85 mmHg 
Diastolic blood pressure 
> 100 mmHg 
< 40 mmHg 
Pulse 
> 100 bpm 
< 45 bpm 
Temperature 
> 38°C 
< 35.5°C 
Respiratory rate 
> 24 breaths/min 
< 8 breaths/min 
8.5. 
Electrocardiograms 
Twelve-lead ECGs including heart rate, PR, QRS, QT, QTc (QTcF or QTcB), and JTc (if 
applicable) intervals will be obtained for each subject during the study. 
Criteria for clinically notable ECG abnormalities are defined in Table 8.  The number of subjects 
with clinically significant ECGs will be summarized by treatment group.  Subjects exhibiting 
clinically notable ECG abnormalities will also be listed with study visit and assigned treatment 
group.  Abnormal values for subjects with alert ECG values, defined as both the absolute value 
and the percentage change from baseline being outside normal ranges, will be identified and 
listed. 
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Table 8: 
Criteria for Clinically Notable Electrocardiogram Abnormalities 
Parameter 
High Threshold 
Low Threshold 
QTcF 
> 450 ms 
< 295 ms 
PR 
> 220 ms 
< 75 ms 
QRS 
> 120 ms 
< 50 ms 
QT 
> 500 ms 
< 300 ms 
RR 
> 1330 ms 
< 600 ms 
Heart rate 
> 100 bpm 
< 45 bpm 
QTcF = Fridericia correction. 
Twelve-lead ECGs will be obtained for each subject during the study.  Electrocardiogram 
abnormalities, both at baseline and postbaseline visits, will be tabulated by treatment group.  
Incidences of abnormalities will be listed with study visit, assigned treatment group, and a 
description of the abnormality. 
9. 
INTERIM ANALYSES 
NOTE:  As of 25 OCT 2018, this study is closed to enrollment.  As of this date, no subjects 
were enrolled in Phase 2 efficacy expansion (all treatment groups) or Phase 2 mandatory 
biopsy Treatment Groups A, B, F, and G; therefore, interim analysis is no longer 
applicable. 
There are no planned, formal interim analyses for Phase 1.  Periodic review of accrued clinical 
data will be conducted by Incyte and provided to study investigators via teleconferences at the 
end of each part.  Based on review of the most current safety data, the sponsor (in consultation 
with the study investigators) will determine if and at what dose additional subjects should be 
treated in the study. 
In Phase 2, there will be 2 interim analyses for futility in the CRC and PDAC efficacy expansion 
cohorts.  The Simon 2-stage design (Simon 1989) will be applied to each efficacy expansion 
cohort independently.  During Stage 1, 12 CRC subjects and 15 PDAC subjects will be enrolled.  
If ≤ 5 responses are observed in CRC efficacy expansion cohort, the cohort will be terminated 
for futility.  If ≥ 6 responses are observed in the CRC efficacy expansion cohort, an additional 
26 CRC subjects will be enrolled for Stage 2 evaluation.  Similarly, if ≤ 4 responses are observed 
in the PDAC efficacy expansion cohort, the cohort will be terminated for futility.  If 
≥ 5 responses are observed in PDAC expansion cohort, an additional 12 PDAC subjects will be 
enrolled for Stage 2 evaluation. 
Based on this early termination rule, the probabilities of early termination under the assumption 
of historical control response rates (H0) and desired response rates (HA) are shown in Table 9. 
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Table 9: 
Probability of Early Termination for Simon 2-Stage Design 
Tumor Type 
p0 
p1 
Probability of Early Termination 
Under H0 
Under HA 
CRC 
40% 
60% 
0.6652 
0.1582 
PDAC 
25% 
45% 
0.6865 
0.1204 
The probability of early termination for Stage 1 is summarized in Table 10. 
Table 10: 
Probability of Early Termination at Stage 1 for Simon 2-Stage Design 
True Response Rate 
Probability of Early Termination at Stage 1 
CRC 
PDAC 
25% 
0.9456 
0.6865 
30% 
0.8822 
0.5155 
35% 
0.7873 
0.3519 
40% 
0.6652 
0.2173 
45% 
0.5269 
0.1204 
50% 
0.3872 
0.0592 
55% 
0.2607 
0.0255 
60% 
0.1582 
0.0093 
65% 
0.0846 
0.0028 
70% 
0.0386 
0.0007 
The interim analysis for each expansion cohort will be conducted once the first postbaseline 
radiologic tumor assessments for Stage 1 subjects within the cohort are available.  Enrollment 
will be held at that time unless a sufficient number of responders have been observed before that 
time. 
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10. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN 
All versions of the SAP are listed in Table 11. 
Table 11: 
Statistical Analysis Plan Versions 
SAP Version 
Date 
Original 
14 NOV 2017 
Amendment 1 
12 MAR 2019 
10.1. 
Changes to Protocol-Defined Analyses 
Not applicable. 
10.2. 
Changes to the Statistical Analysis Plan 
10.2.1. 
Amendment 1 
The primary purpose of this amendment is to update the statistical analyses as enrollment has 
been terminated for the study as of 25 OCT 2018. 
• Secondary 
 efficacy objectives and endpoints including duration of 
response, progression-free survival, and overall survival per RECIST v1.1 and all 
efficacy objectives and endpoints per irRECIST were removed.  Corresponding 
statistical analyses were removed. 
• Safety analyses were simplified to meet the requirement of abbreviated Clinical Study 
Report. 
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11. 
REFERENCES 
Koyama T, Chen H. Proper inference from Simon's two-stage designs. Stat Med 2008;27:3145-
154. 
Mosteller RD. Simplified calculation of body-surface area. N Engl J Med 1987;317:1098. 
Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989;10:1-10. 
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APPENDIX A. PLANNED TABLES AND LISTINGS 
This appendix provides a list of the planned tables and listings for the Clinical Study Report.  
Standard tables will follow the conventions in the Standard Safety Tables v1.1.  Shells are 
provided for nonstandard tables in a separate document.  In-text tables are identical in structure 
and content as appendix tables, but follow a Rich Text Format. 
The lists of tables and listings are to be used as guidelines.  Modifications of the lists that do not 
otherwise affect the nature of the analysis will not warrant an amendment to the SAP. 
Tables 
Table No. 
Title 
Population 
Baseline and Demographic Characteristics 
1.1  Disposition 
1.1.1 
Analysis Populations 
Safety 
1.1.2 
Summary of Subject Disposition 
Safety 
1.1.3 
Summary of Number of Subjects Enrolled By Site 
Safety 
1.2  Demography 
1.2.1 
Summary of Demographics 
Safety 
1.3  Baseline Characteristics 
1.3.1 
Summary of Cancer History and Baseline Disease Characteristics 
Safety 
1.4  Prior Medication and Concomitant Medication 
1.4.1 
Summary of Prior Systemic Cancer Therapy 
Safety 
1.4.2 
Summary of Prior Medications 
Safety 
1.4.3 
Summary of Concomitant Medications 
Safety 
1.5  Others 
1.5.1 
Summary of General Medical History 
Safety 
1.5.2 
Summary of Protocol Deviations 
Safety 
Safety 
3.1  Dose Exposure 
3.1.1.1 
Summary of Exposure to Epacadostat 
Epacadostat Safety 
3.1.1.2 
Summary of Exposure to Pembrolizumab 
Pembrolizumab Safety 
3.1.1.3 
Summary of Exposure to Components of mFOLFOX6 
mFOLFOX6 Safety 
3.1.1.4 
Summary of Exposure to nab-Paclitaxel and Gemcitabine 
nab-Paclitaxel and 
Gemcitabine Safety 
3.1.1.5 
Summary of Exposure to Paclitaxel and Carboplatin 
Paclitaxel and Carboplatin 
Safety 
3.1.1.6 
Summary of Exposure to Pemetrexed and Platinum Agent 
Pemetrexed and Platinum 
Agent Safety 
3.1.1.7 
Summary of Exposure to Cyclophosphamide 
Cyclophosphamide Safety 
3.1.1.8 
Summary of Exposure to Gemcitabine and Platinum Agent 
Gemcitabine and Platinum 
Agent Safety 
3.1.1.9 
Summary of Exposure to 5-Fluorouracil and Platinum Agent 
5-Fluorouracil and Platinum 
Agent Safety 
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Table No. 
Title 
Population 
3.2  Adverse Events 
3.2.1 
Overall Summary of Treatment-Emergent Adverse Events 
Safety 
3.2.2.1 
Summary of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term 
Safety 
3.2.2.2 
Summary of Treatment-Emergent Adverse Events by MedDRA 
Preferred Term in Decreasing Order of Frequency 
Safety 
3.2.3.1 
Summary of Grade 3 or 4 Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term 
Safety 
3.2.3.2 
Summary of Grade 3 or 4 Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of Frequency 
Safety 
3.2.4.1 
Summary of any Treatment-Related Adverse Events by MedDRA 
System Organ Class and Preferred Term 
Safety 
3.2.4.2 
Summary of any Treatment-Related Adverse Events by MedDRA 
Preferred Term in Decreasing Order of Frequency  
Safety 
3.2.5 
Summary of Treatment-Emergent Adverse Events With a Fatal 
Outcome by MedDRA System Organ Class and Preferred Term 
Safety 
3.2.6 
Summary of Serious Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term 
Safety 
3.2.7 
Summary of Serious Treatment-Emergent Adverse Events by 
Preferred Term in Decreasing Order of Frequency 
Safety 
3.2.8.1 
Summary of Treatment-Emergent Adverse Events Leading to any 
Dose Reduction By MedDRA System Organ Class and Preferred 
Term 
Safety 
3.2.8.2 
Summary of Treatment-Emergent Adverse Events Leading to any 
Dose Interruption by MedDRA System Organ Class and Preferred 
Term 
Safety 
3.2.8.3 
Summary of Treatment-Emergent Adverse Events Leading to 
Discontinuation of Study Drug by MedDRA System Organ Class 
and Preferred Term 
Safety 
3.2.9 
Summary of Sponsor-Determined Adverse Events of Special Interest 
by Category and MedDRA Preferred Term 
Safety 
3.3  Laboratory 
3.3.1 
Summary of Laboratory Values - Hematology 
Safety 
3.3.2 
Shift Summary of Hematology Laboratory Values in CTC Grade - to 
the Worst Abnormal Value  
Safety 
3.3.3 
Summary of Laboratory Values - Chemistry 
Safety 
3.3.4 
Shift Summary of Chemistry Laboratory Values in CTC Grade - to 
the Worst Abnormal Value 
Safety 
3.4  Vital Signs 
3.4.1 
Summary of Pulse 
Safety 
3.4.2 
Summary of Systolic Blood Pressure 
Safety 
3.4.3 
Summary of Diastolic Blood Pressure  
Safety 
3.4.4 
Summary of Respiration Rate 
Safety 
3.4.5 
Summary of Body Temperature 
Safety 
3.4.6 
Summary of Weight 
Safety 
3.5  ECG 
3.5.9 
Summary of Clinically Significant ECGs 
Safety 
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Listings 
Listing No. 
Title 
2.1  Discontinued Subjects (Subject Disposition) 
2.1.1 
Subject Enrollment and Disposition Status 
2.2  Protocol Deviation 
2.2 
Protocol Deviations 
2.3  Data Excluded From 
 Efficacy, and/or Safety Analyses 
2.3 
Analysis Population 
2.4  Demography and Baseline (Including Prior and Concomitant Medications) 
2.4.1 
Demographic and Baseline Disease Characteristics 
2.4.2 
Disease History 
2.4.3 
Prior Radiation Treatment 
2.4.4 
Prior Systemic Therapy 
2.4.5 
Prior Surgery or Surgical Procedure 
2.4.6 
Medical History 
2.4.7 
Prior and Concomitant Medication 
2.5  Exposure 
2.5 
Study Drug Administration 
2.7  Adverse Events (and Exposure) 
2.7.1 
Treatment-Emergent Adverse Events 
2.7.2 
Dose-Limiting Toxicities 
2.7.3 
Serious Treatment-Emergent Adverse Events 
2.7.4 
Fatal Treatment-Emergent Adverse Events 
2.7.5 
Treatment-Emergent Adverse Events Leading to Discontinuation of Epacadostat/Pembrolizumab 
2.7.6 
Treatment-Emergent Adverse Events Leading to Interruption of Epacadostat/Pembrolizumab 
2.7.7 
Treatment-Emergent Adverse Events Leading to Dose Reduction of Epacadostat 
2.8  Laboratory Data 
2.8.1 
Clinical Laboratory Values - Hematology 
2.8.2 
Clinical Laboratory Values - Chemistry 
2.8.4 
Clinical Laboratory Values - Coagulation 
2.8.7 
Abnormal Clinical Laboratory Values 
2.8.8 
Hy's Law 
2.9  Vital Signs 
2.9.1 
Vital Signs 
2.10  ECG 
2.10.1 
12-Lead ECG Values 
 
CONFIDENTIAL 


Signature Manifest
Document Number: IC-STS-SAP-0130
Revision: 0
Title: INCB 24360-207 SAP Amendment 1
All dates and times are in Eastern Standard Time.
INCB 24360-207 SAP Amendment 1
Approval
Name/Signature
Title
Date
Meaning/Reason
19 Mar 2019, 02:36:01 PM
Approved
19 Mar 2019, 02:49:48 PM
Approved
22 Mar 2019, 04:02:02 PM
Approved
22 Mar 2019, 04:14:14 PM
Approved