Clinical trial NCT02318277
Conditions: Solid Tumors Head and Neck Cancer Lung Cancer UC (Urothelial Cancer)
Sponsor: Incyte Corporation
Start date: 2015-01-05; Completion date: 2020-10-16
Enrollment: 176 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to explore the safety, tolerability, pharmacokinetics, immunogenicity and preliminary efficacy of INCB024360 administered in combination with MEDI4736 in subjects with selected advanced solid tumors.

Detailed description:

Arms: arm 1: MEDI4736 at selected dose levels every 2 weeks + INCB024360 25 mg BID as starting dose, followed by dose escalations until MTD or PAD is identified
Interventions: intervention 1: MEDI4736 intervention 2: INCB024360
Intervention descriptions: intervention 1: MEDI4736 administered intravenously (IV) every two weeks (q2w) intervention 2: INCB024360: Oral daily dosing

Protocol documents:
Prot_000.pdf: 
Incyte Corporation 
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Protocol INCB 24360-203 Amendment 7 
Version 7 
21 SEP 2018 
 
Clinical Study Protocol 
 
INCB 24360-203 
A Phase 1/2 Study Exploring the Safety, Tolerability, and Efficacy of 
Epacadostat in Combination With Durvalumab in Subjects With 
Selected Advanced Solid Tumors 
 
 
Product: 
Epacadostat and Durvalumab 
IND Number: 
 
EudraCT Number: 
2016-001911-19 
Phase of Study: 
1/2 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
Original Protocol (Version 0): 
18 AUG 2014 
Amendment (Version) 1: 
29 SEP 2014 
Amendment (Version) 2: 
20 FEB 2015 
Amendment (Version) 3: 
10 JUL 2015 
Amendment (Version) 4: 
12 JAN 2016 
Amendment (Version) 5: 
25 MAY 2016 
Amendment (Version) 6: 
28 JUN 2017 
Amendment (Version) 7: 
21 SEP 2018 
 
This study will be performed in accordance with ethical principles that have their origin in the Declaration of 
Helsinki and conducted in adherence to the study Protocol, Good Clinical Practices as defined in Title 21 of the US 
Code of Federal Regulations Parts 50, 54 56, 312, and Part 11 as well as ICH GCP consolidated guidelines (E6) and 
applicable regulatory requirements. 
The information in this document is confidential.  No part of this information may be duplicated, referenced, or 
transmitted in any form or by any means (electronic, mechanical, photocopy, recording, or otherwise) without the prior 
written consent of Incyte Corporation. 
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Protocol INCB 24360-203 Amendment 7 
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INVESTIGATOR'S AGREEMENT 
I have received and read the Investigator's Brochure for Epacadostat and Durvalumab.  I have 
read the INCB 24360-203 Protocol Amendment 7 (Version 7 dated 21 SEP 2018) and agree to 
conduct the study as outlined.  I agree to maintain the confidentiality of all information received 
or developed in connection with this Protocol. 
 
 
 
 
 
(Printed Name of Investigator) 
 
 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 
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Protocol INCB 24360-203 Amendment 7 
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Phase 1 Dose Escalation 
Phase 1 is the dose-escalation phase, which will include up to 6 cohorts of subjects treated with 
epacadostat at doses of 25 mg twice daily (BID), 50 mg BID, 75 mg BID, 100 mg BID, and 300 mg BID 
in combination with durvalumab 3 mg/kg or 10 mg/kg given on Day 1 of each 14-day cycle.  A minimum 
of 3 subjects will be enrolled and treated in each cohort, and all 3 subjects will be observed for a 
minimum of 42 days before the subsequent cohort begins enrollment.  Subjects must have received the 
cohort-specific dose of epacadostat for at least 75% of the doses (63 doses) and have received at least 
3 doses of durvalumab during the 42-day dose-limiting toxicity (DLT) observation period, or have 
experienced a DLT to be evaluable for dose tolerability.  Additional subjects will be enrolled in a cohort 
to achieve the minimum of 3 evaluable subjects if dropouts or dose interruptions/reductions occur that 
result in a subject being nonevaluable for DLTs. 
The dose of epacadostat will be escalated if 0 of the first 3 evaluable subjects enrolled experience a DLT.  
If 1 of the first 3 evaluable subjects enrolled experience a DLT, the cohort will be expanded to include 
3 additional evaluable subjects.  If 2 or more of either 3 or 6 subjects enrolled experience a DLT, the prior 
dose level will be considered the MTD.  If only 3 subjects were treated at this dose level, the dose will be 
confirmed as the MTD by evaluation of an additional 3 subjects before this dose is recommended for 
Phase 2 testing.   
The cohorts and dose levels are shown in the table below. 
Cohort 
Maximum Daily Dose of Epacadostat 
Dose of Durvalumab 
(Once Every 14 Days) 
1 
25 mg BID orally 
3 mg/kg IV 
2 
25 mg BID orally 
10 mg/kg IV 
3 
50 mg BID orally 
10 mg/kg IV 
4 
75 mg BID orally 
10 mg/kg IV 
5 
100 mg BID orally 
10 mg/kg IV 
6 
300 mg BID orallya 
10 mg/kg IV 
IV = intravenous. 
a Intermediate dose levels may be explored based on emerging PK or pharmacodynamic data. 
Phase 2 
Approximately 140 to 192 subjects with advanced melanoma, NSCLC, SCCHN, TNBC, gastric or 
GE junction cancer, or TCC of the GU tract will be enrolled at the MTD or PAD of epacadostat in 
combination with durvalumab.  The approximate number of subjects needed for the melanoma, TNBC, 
and gastric and GE junction cancer cohorts will be determined using the Simon 2-stage design:  Stage 1 
will be the initial number of subjects per tumor type, and the decision to proceed with Stage 2 will be 
determined by the response rate observed in Stage 1.  If more than 1 PAD is evaluated, the cohort may or 
may not be repeated for the specified tumor type as indicated in the table below.  The sponsor may limit 
enrollment of a specific tumor type to Stage 1. 
Tumor Type 
No. of Subjects Enrolled 
Stage 1  
Stage 2 
(If Study Proceeds to Stage 2) 
Total 
(Stage 1 + 2) 
Melanoma 
15 
25 
40 
TNBC 
13 
16 
29 
Gastric and GE junction cancer 
9 
11 
20 
Under Amendment 6, enrollment of the NSCLC, SCCHN, and TCC of the GU tract cohorts will be 
completed as expansion cohorts at the 300 mg BID dose level.  The sample size for each cohort will be 
increased to account for the heterogeneity of PD-1 pathway–treated and PD-1 pathway–naive subjects 
within the selected tumor types.  The approximate number of subjects per tumor type is listed in the table 
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below, and the number of PD-1 pathway–treated subjects in each cohort will be limited to 10 in order to 
reduce the risk of any cohort having a significant imbalance between PD-1 pathway–treated and PD-1 
pathway–naive subjects, thereby preserving the predicted levels of baseline efficacy observed with PD-1 
pathway monotherapy.  Subjects enrolled at the 100 mg BID will be analyzed independently. 
Tumor Type 
No. of Subjects Enrolled 
100 mg BIDa 
(n = 19) 
300 mg BIDb 
(n = 84) 
NSCLC 
8 
28 
SCCHN 
7 
28 
TCC of the GU tract 
4 
28 
a Subjects enrolled in the 100 mg BID dose level were enrolled before Amendment 5. 
b All subjects in the 300 mg BID NSCLC, SCCHN, and TCC of the GU tract cohorts enrolled in Amendment 5 or earlier are 
included in the total sample size. 
The study will consist of 3 periods: 
Screening:  Up to 28 days. 
Treatment Period:  The treatment period will continue every 14 days for up to 12 months as long as 
subjects are receiving benefit from treatment and have not met any criteria for study withdrawal.  Once 
subjects complete 12 months of study treatment or permanently discontinue study treatment for any other 
reason, the end-of-treatment (EOT) visit should be conducted, and they should enter the safety follow-up 
period of the study. 
Protocol Amendment 6 (28 JUN 2017) removed the option for subjects to receive epacadostat 
monotherapy once they completed 12 months of combination therapy with durvalumab.  However, 
subjects already receiving epacadostat monotherapy prior to Amendment 6 were allowed to continue if 
they were receiving clinical benefit and their investigator felt it was in the best interest of the subject.  
These subjects will be allowed to continue epacadostat monotherapy for up to an additional 12 months, 
and their maximum overall study treatment duration should not exceed 24 months.  Exceptions for these 
subjects to continue study treatment beyond 24 months will require medical monitor review and approval 
every 3 months. 
Follow-Up Period:  The safety follow-up visits will occur at 42 days and 90 days after the EOT visit or 
after the last dose of study treatment (if the EOT was not performed).   
Study Drugs, Dosages, and Modes of Administration: 
Epacadostat will be self-administered orally BID without regard to food and continued BID during each 
14-day cycle.  The MTD or PAD of epacadostat defined during Phase 1 will be used for Phase 2. 
All BID doses will be taken morning and evening, approximately 12 hours apart.  If a dose is missed by 
more than 4 hours, that dose should be skipped and the next dose should be taken at the scheduled time.  
If the subject vomits, an additional dose should not be taken.  Intrasubject dose escalation of epacadostat 
is not allowed. 
Durvalumab is an investigational agent and will be administered at 3 mg/kg or 10 mg/kg over 
60 minutes on Day 1 of each 14-day cycle for up to 12 months.  There will be an observation period of 
3 hours after the first dose of durvalumab is administered.  Intrasubject dose escalation of durvalumab is 
not allowed except as defined in the body of the Protocol. 
Reference Therapy, Dosage, and Mode of Administration:  Not applicable. 
Duration of Participation:  Subject participation is expected to average approximately 6 months. 
Study Population: 
Subjects with histologically or cytologically confirmed advanced melanoma, NSCLC, pancreatic cancer 
(Phase 1 only), SCCHN, TNBC, gastric or GE junction cancer, or TCC of the GU tract will be enrolled. 
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Key Inclusion Criteria: 
• Male or female subjects, age 18 years or older. 
• Histologically or cytologically confirmed diagnosis of melanoma, NSCLC, pancreatic cancer (Phase 1 
only), SCCHN, TNBC, gastric or GE junction cancer, or TCC of the GU tract that is locally advanced 
(not amenable to curative therapy such as surgical resection) or metastatic. 
• Must have failed at least 1 prior treatment regimen for locally advanced or metastatic disease or be 
intolerant to treatment or refuse standard treatment.  Investigational agents used in combination with 
standard therapies are allowed.  Adjuvant, neoadjuvant, or chemoradiation regimens given within 
6 months of screening would be counted as having received 1 prior systemic regimen and would not 
require an additional systemic regimen for advanced or metastatic disease. 
• For subjects with metastatic melanoma: 
− Must have known V600E activating BRAF mutation status or consent to BRAF V600E mutation 
testing during screening.  Testing should be performed in a CLIA certified laboratory.  BRAF 
mutation status determined as part of a panel of genetic tests performed in a gene expression analysis 
will also satisfy the inclusion criterion for BRAF mutation testing. 
− May be treatment-naive or have received prior treatment with an anti−cytotoxic T-lymphocyte-
associated antigen 4 (CTLA-4) or anti−programmed cell death receptor 1 (anti–PD-1) targeted agent.  
Note:  In Phase 1, subjects who are BRAF mutation positive must have received prior treatment with 
a BRAF inhibitor with or without a MEK inhibitor. 
− Ocular melanoma will be excluded. 
• For subjects with NSCLC: 
− Subjects who have tumors with driver mutations (eg, epidermal growth factor receptor [EGFR] 
mutation positive or anaplastic lymphoma kinase fusion oncogene positive) must have received 
treatment with a targeted therapy and have progressed or be intolerant, if a targeted agent is available 
for the specific driver mutation. 
− Subjects may have received prior treatment with an anti−PD-1 targeted agent. 
• For subjects with pancreatic cancer (Phase 1 only): 
− Subjects in Phase 1 must have an exocrine pancreatic neoplasm. 
Note:  Exocrine pancreatic neoplasms include all tumors related to the pancreatic ductal and ancinar 
cells and their stem cells. 
• For subjects with SCCHN: 
− Histology of squamous cell carcinoma. 
o Carcinoma of the nasopharynx and salivary gland will be excluded. 
− Prior systemic regimens must include a platinum-based therapy.  Investigational agents used in 
combination with standard therapies are allowed.  Subjects who relapse within 6 months of adjuvant 
therapy, including a platinum-containing regimen, may enroll. 
• For subjects with TNBC: 
− Histologically or cytologically confirmed breast adenocarcinoma that is unresectable or metastatic. 
− Subjects with breast cancer history of different phenotypes (ie, estrogen receptor [ER]/progesterone 
receptor [PgR]/human epidermal growth factor receptor 2 [HER2] positive) must have pathologic 
confirmation of triple-negative disease from the most current biopsy. 
− Pathologically confirmed as triple negative, source documented, defined as both of the following: 
o ER and PgR negative:  < 1% of tumor cell nuclei is immunoreactive in the presence of evidence 
that the sample can express ER or PgR (positive intrinsic controls). 
o HER2 negative as per American Society of Clinical Oncology/College of American Pathologists 
HER2 test guidelines. 
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Note:  HER2 test result should be reported as negative if a single test (or all tests) performed in a 
tumor specimen show the following: 
• Immunohistochemistry (IHC) 1+ as defined by incomplete membrane staining that is faint/barely 
perceptible and within > 10% of the invasive tumor cells. 
• IHC result is 0 as defined by no staining observed or membrane staining that is incomplete and is 
faint/barely perceptible and within ≤ 10% of the invasive tumor cells. 
• In situ hybridization (ISH) assay is negative based on a single probe average HER2 copy number 
< 4.0 signals/cell or dual probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number 
< 4.0 signals/cell. 
• If results are equivocal, reflex testing (same specimen using the alternative test or new specimen, 
if available) should be performed using an alternative assay (IHC or ISH). 
• For subjects with TCC of the GU tract: 
− Histologically or cytologically confirmed TCC of the bladder, ureter, or renal pelvis or mixed 
histology bladder cancer. 
− Metastatic or locally advanced and not amenable to curative therapy with disease progression on or 
after platinum-based chemotherapy or alternative therapy if platinum-based therapy is not 
appropriate. 
• For subjects with gastric or GE junction cancer: 
− Histologically or cytologically confirmed diagnosis of gastric or GE junction adenocarcinoma.  
− Progression on or after therapy containing platinum/fluoropyrimidine. 
− Documentation of HER2/neu status. 
• Presence of measurable disease per RECIST v1.1 guidelines. 
• ECOG performance status 0 to 1. 
• Fresh baseline tumor biopsies (fresh baseline biopsy is defined as a biopsy specimen taken within 
28 days prior to Cycle 1 Day 1) are required at baseline, except if inaccessible with medical monitor 
approval.  Archival tissue should also be submitted if available.  
Note:  If a fresh baseline biopsy is inaccessible, an archival specimen should be submitted. 
Key Exclusion Criteria: 
• Laboratory and medical history parameters not within the Protocol-defined range.  All screening 
laboratory tests should be performed within 7 days of treatment initiation. 
− Absolute neutrophil count < 1.5 × 109/L. 
− Platelets < 75 × 109/L. 
− Hemoglobin < 9 g/dL or < 5.6 mmol/L (transfusion is acceptable to meet this criterion). 
− Serum creatinine ≥ 1.5 × institutional upper limit of normal (ULN) OR measured or calculated 
creatinine clearance (glomerular filtration rate can also be used in place of creatinine or CrCl) 
< 50 mL/min for subjects with creatinine levels > 1.5 × institutional ULN. 
− AST or ALT > 2.5 × institutional ULN OR > 5 × ULN for subjects with liver metastases. 
− Total bilirubin > 1.5 × ULN OR direct bilirubin > institutional ULN for subjects with total bilirubin 
levels > 1.5 × ULN. 
o If there is no institutional normal range available for the direct bilirubin, the direct bilirubin should 
be < 40% of the total bilirubin. 
o In no case can total bilirubin exceed 3.0 × ULN. 
− International normalized ratio (INR) or prothrombin time (PT) > 1.5 × ULN (unless subject is 
receiving anticoagulant therapy, then subject may be included as long as PT or INR is within 
therapeutic range of intended use of anticoagulants). 
− Activated partial thromboplastin time (aPTT) > 1.5 × ULN (unless subject is receiving anticoagulant 
therapy, then subject may be included as long as aPTT is within therapeutic range of intended use of 
anticoagulants). 
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• Current pregnancy or breastfeeding. 
• Participation in any other study in which receipt of an investigational study drug occurred within 
28 days or 5 half-lives (whichever is longer) prior to first dose.  For investigational agents with long 
half-lives (eg, 5 days), enrollment prior to the fifth half-life requires medical monitor approval. 
• Receipt of prior immune checkpoint inhibitors (eg, anti−CTLA-4, anti−programmed cell death 
receptor 1 [anti–PD-1], anti−programmed cell death ligand 1 [anti−PD-L1], and any other antibody or 
drug specifically targeting T-cell costimulation) or an indoleamine 2,3-dioxygenase (IDO) inhibitor.  
Subjects who have received experimental vaccines or other immune therapies should be discussed with 
the medical monitor to confirm eligibility. 
Note:  The exception to this exclusion criterion would be subjects who have received a prior 
anti−CTLA-4 or PD-1 pathway targeted agent for indications in which an anti–CTLA-4 or PD-1 
pathway targeted agent has been approved (eg, melanoma).  In this case, the subject would be eligible 
to participate in the study. 
• Receipt of an immunologically based treatment for any reason, including chronic use of systemic 
steroid at doses ≥ 10 mg/day prednisone equivalent within 14 days prior to the first dose of study 
treatment.  Use of inhaled or topical steroids or systemic corticosteroids < 10 mg is permitted. 
• Receipt of any anticancer medication in the 21 days prior to receiving the first dose of study medication 
or any unresolved toxicity > Grade 1 from previous anticancer therapy, except for stable chronic 
toxicities not expected to resolve, such as peripheral neurotoxicity.  Prior treatment with nitrosureas 
(eg, carmustine or lomustine) require a 6-week washout prior to the first dose of study treatment. 
• Untreated central nervous system (CNS) metastases or carcinomatous meningitis, or CNS metastases 
that have progressed (eg, evidence of new or enlarging CNS metastasis or new neurological symptoms 
attributable to CNS metastases).  Subjects with treated, clinically stable CNS metastases (defined as 
2 brain images at least 4 weeks apart, both of which were obtained after treatment to the brain 
metastases) and who are off all corticosteroids for at least 2 weeks are eligible. 
• Any active or inactive autoimmune process or inflammatory disorder (including rheumatoid arthritis, 
moderate or severe psoriasis, multiple sclerosis, sarcoidosis syndrome, diverticulitis [with the exception 
of diverticulosis], inflammatory bowel disease, systemic lupus erythematosus, Wegener syndrome 
[granulomatosis with polyangiitis, Graves' disease, hypophysitis, uveitis, etc]) or receipt of systemic 
therapy for an autoimmune or inflammatory disease. 
Note:  Exceptions include subjects with vitiligo, hypothyroidism stable on hormone replacement, 
controlled asthma, Graves' disease, or Hashimoto's disease, celiac disease controlled by diet alone, or 
with medical monitor approval.  Subjects without active disease in the last 5 years may be included but 
only after consultation with medical monitor. 
• Evidence of interstitial lung disease or active, noninfectious pneumonitis. 
• Prior radiotherapy within 2 weeks of therapy.  Subjects must have recovered from all radiation-related 
toxicities, not require corticosteroids, and not have had radiation pneumonitis.  A 1-week washout is 
permitted for palliative radiation to non-CNS disease with medical monitor approval. 
• Receipt of monoamine oxidase inhibitors within the 21 days prior to the first dose of study treatment. 
• History of serotonin syndrome after receiving 1 or more serotonergic drugs. 
• History or presence of an abnormal electrocardiogram (ECG) that, in the investigator's opinion, is 
clinically meaningful.  Screening QTc interval > 480 msec is excluded (corrected by Fridericia or 
Bazett's formula).  In the event that a single QTc is > 480 msec, the subject may be enrolled if the 
average QTc for the 3 ECGs is ≤ 480 msec.  For subjects with an intraventricular conduction delay 
(QRS interval ≥ 120 msec), the JTc interval may be used in place of the QTc with sponsor approval.  
The JTc must be < 340 msec if JTc is used in place of the QTc.  Subjects with left bundle branch block 
are excluded. 
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TABLE OF CONTENTS 
SYNOPSIS ......................................................................................................................................3 
LIST OF ABBREVIATIONS ........................................................................................................20 
1. 
INTRODUCTION ......................................................................................................23 
1.1. 
Pharmaceutical and Therapeutic Background ............................................................23 
1.1.1. 
Inhibition of PD-1 Signaling as a Target for Cancer ..................................................23 
1.1.2. 
Inhibition of IDO1 as a Target for Cancer ..................................................................24 
1.1.3. 
Epacadostat .................................................................................................................25 
1.1.4. 
Durvalumab ................................................................................................................26 
1.1.5. 
Combined Immune Checkpoint Inhibition .................................................................26 
1.1.6. 
Melanoma ...................................................................................................................28 
1.1.7. 
Non−Small Cell Lung Cancer ....................................................................................29 
1.1.8. 
Pancreatic Cancer .......................................................................................................31 
1.1.9. 
Squamous Cell Carcinoma of the Head and Neck ......................................................32 
1.1.10. 
Triple-Negative Breast Cancer ...................................................................................32 
1.1.11. 
Gastric and Gastroesophageal Junction Cancer ..........................................................33 
1.1.12. 
Transitional Cell Carcinoma of the Genitourinary Tract ............................................34 
1.1.13. 
Preclinical and Clinical Study Data ............................................................................35 
1.1.13.1. 
Summary of Epacadostat Pharmacokinetics in Humans ............................................35 
1.1.13.2. 
Summary of Epacadostat Pharmacodynamics in Humans .........................................36 
1.1.13.3. 
Summary of Durvalumab Pharmacokinetics in Humans ............................................38 
1.2. 
Study Rationale ...........................................................................................................38 
1.3. 
Potential Risks and Benefits of the Treatment Regimen ............................................39 
1.3.1. 
Risks From Epacadostat .............................................................................................39 
1.3.2. 
Risks From Durvalumab .............................................................................................40 
1.3.2.1. 
Possible Risks Based on Mechanism of Action .........................................................40 
1.3.2.2. 
Possible Risks Based on Clinical Data .......................................................................41 
1.3.2.3. 
Possible Risks Based on Nonclinical Data .................................................................41 
1.3.2.4. 
Possible Risks Common to Any Immunoglobulin .....................................................42 
1.3.2.5. 
Possible Risks Associated With Immune Reactivity ..................................................42 
1.3.2.6. 
Possible Risks Associated With Administration ........................................................42 
1.3.3. 
Risks for Combination (Epacadostat and Durvalumab) .............................................42 
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1.4. 
Justification for Treatment Regimen ..........................................................................43 
1.5. 
Rationale for Endpoints ..............................................................................................45 
1.5.1. 
Efficacy Endpoints ......................................................................................................45 
2. 
STUDY OBJECTIVES AND PURPOSE ..................................................................47 
2.1. 
Primary Objectives .....................................................................................................47 
2.2. 
Secondary Objectives .................................................................................................47 
 
 
3. 
SUBJECT ELIGIBILITY ...........................................................................................48 
3.1. 
Study Population .........................................................................................................48 
3.2. 
Subject Inclusion Criteria ...........................................................................................48 
3.3. 
Subject Exclusion Criteria ..........................................................................................50 
4. 
INVESTIGATIONAL PLAN .....................................................................................54 
4.1. 
Overall Study Design ..................................................................................................54 
4.1.1. 
Phase 1 Dose Escalation .............................................................................................54 
4.1.2. 
Phase 2 ........................................................................................................................55 
4.2. 
Study Endpoints ..........................................................................................................56 
4.2.1. 
Primary Endpoints ......................................................................................................56 
4.2.2. 
Secondary Endpoints ..................................................................................................56 
 
 
4.3. 
Measures Taken to Avoid Bias ...................................................................................57 
4.4. 
Number of Subjects ....................................................................................................57 
4.5. 
Study Termination ......................................................................................................57 
5. 
TREATMENT OF SUBJECTS ..................................................................................58 
5.1. 
Treatment Groups and Administration of Study Drug ...............................................58 
5.1.1. 
Epacadostat .................................................................................................................58 
5.1.2. 
Durvalumab ................................................................................................................58 
5.1.2.1. 
Durvalumab Treatment Administration ......................................................................58 
5.1.2.2. 
Monitoring of Durvalumab Administration ................................................................58 
5.2. 
Treatment Compliance ................................................................................................59 
5.3. 
Randomization and Blinding ......................................................................................59 
5.4. 
Duration of Treatment and Subject Participation .......................................................59 
5.5. 
Rationale for Dose Modification ................................................................................60 
5.5.1. 
Definition of Dose-Limiting Toxicities ......................................................................60 
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5.5.2. 
Procedures for Cohort Review and Dose Escalation in Phase 1 ................................61 
5.5.2.1. 
Follow-Up for Dose-Limiting Toxicities ....................................................................62 
5.6. 
Dose Adjustment of Study Drug.................................................................................62 
5.6.1. 
Planned Dose Increases ..............................................................................................62 
5.6.2. 
Criteria and Procedures for Interruption or Dose Reduction ......................................62 
5.6.3. 
Criteria for Subjects Exhibiting Immune-Related Adverse Events ............................65 
5.6.3.1. 
Procedures and Guidelines for Pneumonitis ...............................................................65 
5.6.3.2. 
Procedures and Guidance for Enterocolitis ................................................................67 
5.6.3.3. 
Procedures and Guidance for Hepatitis ......................................................................69 
5.6.3.4. 
Procedures for Immune-Mediated Dermatitis ............................................................71 
5.6.3.5. 
Procedures for Immune-Mediated Neuropathies ........................................................73 
5.6.3.6. 
Procedures for Immune-Mediated Endocrinopathies .................................................76 
5.6.3.7. 
Procedures for Immune-Mediated Nephritis or Renal Dysfunction ...........................79 
5.6.3.8. 
Procedures and Guidelines for Lipase or Amylase Elevations ...................................81 
5.6.3.9. 
Procedures for Ocular Manifestations ........................................................................82 
5.6.3.10. 
Procedures and Guidelines for Myocarditis ...............................................................83 
5.6.3.11. 
Procedures and Guidelines for Myositis/Polymyositis ...............................................84 
5.6.3.12. 
Procedures for Immune-Related Adverse Events Not Specifically Described 
Above ..........................................................................................................................87 
5.6.4. 
Procedures for Subjects Exhibiting Serotonin Syndrome ..........................................88 
5.7. 
Withdrawal of Subjects From Study Treatment .........................................................90 
5.7.1. 
Withdrawal Criteria ....................................................................................................90 
5.7.2. 
Withdrawal Procedures ...............................................................................................91 
5.8. 
Study Completion .......................................................................................................91 
5.8.1. 
Study Completion Criteria ..........................................................................................91 
5.9. 
Beginning and End of the Study .................................................................................92 
5.10. 
Concomitant Medications and Measures ....................................................................92 
5.10.1. 
Restricted Medications and Measures ........................................................................92 
5.10.2. 
Prohibited Medications and Measures ........................................................................93 
6. 
STUDY ASSESSMENTS ..........................................................................................93 
6.1. 
Screening Period .........................................................................................................98 
6.2. 
Treatment Period ........................................................................................................99 
6.3. 
End of Treatment ........................................................................................................99 
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6.4. 
Follow-Up Period .......................................................................................................99 
6.4.1. 
Safety Follow-Up ........................................................................................................99 
6.5. 
Unscheduled Visits .....................................................................................................99 
6.6. 
Early Termination .......................................................................................................99 
7. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES .........................100 
7.1. 
Administration of Informed Consent Form ..............................................................100 
7.2. 
Demography and History ..........................................................................................100 
7.2.1. 
Demographics and Medical History .........................................................................100 
7.2.2. 
Prior and Concomitant Medications .........................................................................100 
7.3. 
Safety Assessments ...................................................................................................100 
7.3.1. 
Adverse Events .........................................................................................................100 
7.3.2. 
Comprehensive Physical Examination .....................................................................101 
7.3.3. 
Targeted Physical Examination ................................................................................101 
7.3.4. 
Vital Signs ................................................................................................................101 
7.3.5. 
Twelve-Lead Electrocardiograms .............................................................................101 
7.3.6. 
Laboratory Assessments ...........................................................................................102 
7.3.6.1. 
Chemistry ..................................................................................................................102 
7.3.6.2. 
Hematology ...............................................................................................................102 
7.3.6.3. 
Coagulation Panel .....................................................................................................103 
7.3.6.4. 
Endocrine Function Testing ......................................................................................103 
7.3.6.5. 
Serology ....................................................................................................................103 
7.3.6.6. 
Pregnancy Testing ....................................................................................................103 
7.3.6.7. 
Urinalysis ..................................................................................................................103 
7.3.7. 
Chest Radiograph ......................................................................................................103 
7.4. 
Efficacy Assessments ...............................................................................................103 
7.4.1. 
Initial Tumor Imaging ...............................................................................................103 
7.4.2. 
Tumor Imaging During the Study.............................................................................104 
7.4.3. 
RECIST v1.1.............................................................................................................104 
7.4.3.1. 
Tumor Assessments ..................................................................................................104 
7.4.3.2. 
Measurability of Tumor Lesions ..............................................................................105 
7.4.3.3. 
Response Criteria ......................................................................................................105 
7.5. 
Performance and Quality of Life Assessments .........................................................107 
7.6. 
Pharmacokinetic, Immunogenicity, 
 Assessments ...............107 
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7.6.1. 
Pharmacokinetics ......................................................................................................107 
7.6.1.1. 
Pharmacokinetic Assessment for Epacadostat ..........................................................107 
7.6.1.2. 
Pharmacokinetic Assessment for Durvalumab .........................................................108 
7.6.2. 
Immunogenicity for Durvalumab .............................................................................109 
 
 
 
 
7.6.3.2. 
Analysis of Tumor Samples ......................................................................................109 
 
 
7.7. 
Other Study Procedures ............................................................................................111 
7.7.1. 
Dispensing of Study Drug ........................................................................................111 
7.7.1.1. 
Dispensing of Epacadostat ........................................................................................111 
7.7.1.2. 
Dispensing of Durvalumab .......................................................................................111 
7.7.2. 
Administration of Study Drug ..................................................................................111 
7.7.2.1. 
Administration of and Compliance With Epacadostat .............................................111 
7.7.2.2. 
Administration of and Compliance With Durvalumab .............................................111 
7.7.3. 
Distribution of Subject Reminder Cards and Diaries ...............................................112 
8. 
SAFETY MONITORING AND REPORTING .......................................................112 
8.1. 
Adverse Events .........................................................................................................112 
8.1.1. 
Definitions and Reporting .........................................................................................112 
8.2. 
Laboratory Test Abnormalities .................................................................................113 
8.2.1. 
Definitions and Reporting .........................................................................................113 
8.2.2. 
Potential Drug-Induced Liver Injury (or Hy’s Law) ................................................113 
8.3. 
Serious Adverse Events ............................................................................................114 
8.3.1. 
Definitions ................................................................................................................114 
8.3.2. 
Reporting ..................................................................................................................115 
8.3.2.1. 
Hepatic Function Abnormalities (Hepatotoxicity) ...................................................115 
8.4. 
Emergency Unblinding of Treatment Assignment ...................................................116 
8.5. 
Pregnancy .................................................................................................................116 
8.6. 
Warnings and Precautions ........................................................................................116 
8.7. 
Data Monitoring Committee .....................................................................................117 
8.8. 
Adverse Events of Special Interest ...........................................................................117 
8.8.1. 
Pneumonitis ..............................................................................................................117 
8.8.2. 
Hypersensitivity Reactions .......................................................................................117 
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8.8.3. 
Hepatic Function Abnormalities (Hepatotoxicity) ...................................................118 
8.8.4. 
Serotonin Syndrome .................................................................................................118 
8.9. 
Product Complaints ..................................................................................................118 
9. 
STATISTICS ............................................................................................................119 
9.1. 
Study Populations .....................................................................................................119 
9.2. 
Selection of Sample Size ..........................................................................................119 
9.2.1. 
Cohort Size in Phase 1 ..............................................................................................119 
9.2.2. 
Sample Size for Phase 2 ...........................................................................................120 
9.3. 
Level of Significance ................................................................................................121 
9.4. 
Statistical Analyses ...................................................................................................121 
9.4.1. 
Primary Analyses ......................................................................................................121 
9.4.2. 
Secondary Analyses ..................................................................................................121 
9.4.3. 
Safety Analyses ........................................................................................................121 
9.4.4. 
Clinical Laboratory Tests .........................................................................................122 
9.5. 
Data Monitoring Committee .....................................................................................122 
9.6. 
Interim Analysis ........................................................................................................122 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT .........................................123 
10.1. 
Investigational Product Description .........................................................................123 
10.1.1. 
Packaging, Labeling, and Preparation of Study Drug ..............................................123 
10.1.1.1. 
Epacadostat ...............................................................................................................123 
10.1.1.2. 
Durvalumab ..............................................................................................................123 
10.1.2. 
Storage and Stability of Study Drug .........................................................................123 
10.1.2.1. 
Epacadostat ...............................................................................................................123 
10.1.2.2. 
Durvalumab ..............................................................................................................123 
10.2. 
Accountability, Handling, and Disposal of Study Drug ...........................................123 
11. 
STUDY ADMINISTRATION .................................................................................124 
11.1. 
Data Management .....................................................................................................124 
11.1.1. 
Data Collection .........................................................................................................124 
11.1.2. 
Data Management .....................................................................................................124 
11.2. 
Study Monitoring ......................................................................................................124 
11.3. 
Protocol Adherence ..................................................................................................125 
11.4. 
Financial Disclosure .................................................................................................125 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................126 
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12.1. 
Sponsor Audits..........................................................................................................126 
12.2. 
Inspection by Regulatory Authorities .......................................................................126 
13. 
ETHICS ....................................................................................................................127 
13.1. 
Ethical Conduct of the Study ....................................................................................127 
13.2. 
Written Informed Consent ........................................................................................127 
13.3. 
Ethics Review ...........................................................................................................127 
13.4. 
Data Privacy ..............................................................................................................128 
14. 
DATA HANDLING AND RECORDKEEPING .....................................................129 
14.1. 
Inspection of Records ...............................................................................................129 
14.2. 
Retention of Records ................................................................................................129 
14.3. 
Confidentiality ..........................................................................................................129 
15. 
PUBLICATION POLICY ........................................................................................130 
16. 
REFERENCES .........................................................................................................131 
APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS .............................................................................139 
APPENDIX B. EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS .....................................................................................140 
APPENDIX C. PROHIBITED MONOAMINE OXIDASE INHIBITORS AND 
DRUGS ASSOCIATED WITH SIGNIFICANT MONOAMINE OXIDASE 
INHIBITORY ACTIVITY .......................................................................................141 
APPENDIX D. PROHIBITED UGT1A9 INHIBITORS ..........................................................142 
APPENDIX E. PROTOCOL AMENDMENT SUMMARY OF CHANGES ..........................143 
 
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LIST OF TABLES 
Table 1: 
IDO1 Inhibition at Steady State in Study INCB 24360-101 ......................................37 
Table 2: 
IDO1 Inhibition at the Steady State in Studies INCB 24360-201 and 
INCB 24360-210 ........................................................................................................37 
Table 3: 
Summary of Epacadostat Steady-State Pharmacokinetic Parameters in 
Study INCB 24360-101 ..............................................................................................44 
Table 4: 
Dosing Cohorts ...........................................................................................................55 
Table 5: 
Approximate Number of Subjects by Tumor Type and Stage of Study .....................55 
Table 6: 
Approximate Number of Subjects for Expansion Cohorts .........................................56 
Table 7: 
Criteria for Defining Dose-Limiting Toxicities ..........................................................61 
Table 8: 
Dose Modification Guidelines of Epacadostat and Durvalumab for 
Non−Immune-Related Adverse Events ......................................................................63 
Table 9: 
Dose Reductions for Epacadostat ...............................................................................64 
Table 10: Recommended Approach for Handling Noninfectious Pneumonitis .........................66 
Table 11: Recommended Approach for Handling Enterocolitis .................................................68 
Table 12: Recommended Approach for Handling Hepatitis .......................................................70 
Table 13: Recommended Approach for Handling Dermatitis ....................................................72 
Table 14: Recommended Approach for Handling Neuropathies ................................................74 
Table 15: Recommended Approach for Handling Endocrinopathies .........................................77 
Table 16: Recommended Approach for Handling Nephritis or Renal Dysfunction ...................80 
Table 17: Recommended Approach to Handling Lipase or Amylase Elevations ......................82 
Table 18: Recommended Approach to Handling Myocarditis ...................................................83 
Table 19: Recommended Approach to Handling Myositis/Polymyositis...................................85 
Table 20: General Guidance for Diagnosis and Treatment of Immune-Related Adverse 
Events (Not Described in Previous Sections) .............................................................87 
Table 21: Recommended Approach for Handling Immune-Related Adverse Events 
(Not Described in Previous Sections) .........................................................................88 
Table 22: Signs and Symptoms of Serotonin Syndrome ............................................................89 
Table 23: Warfarin Dose Modification .......................................................................................92 
Table 24: Schedule of Assessments ............................................................................................94 
Table 25: Laboratory Assessments .............................................................................................96 
Table 26: Laboratory Tests:  Required Analytes ........................................................................98 
Table 27: Schedule and Timing of ECG Assessments .............................................................102 
Table 28: Evaluation of Overall Response ...............................................................................107 
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LIST OF ABBREVIATIONS 
The following abbreviations and special terms are used in this clinical study Protocol. 
Term 
Explanation 
ADA 
antidrug antibody 
AE 
adverse event 
ALK 
anaplastic lymphoma kinase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BID 
twice daily 
BRCA 
breast cancer gene 
CA19-9 
carbohydrate antigen 19-9 
CAP 
College of American Pathologists 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
maximum concentration 
Cmin 
minimum observed plasma or serum concentration over the dose interval 
CNS 
central nervous system 
CR 
complete response 
CRF 
case report form  
Css 
steady-state concentration 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T-lymphocyte-associated antigen 4 
DC 
dendritic cells 
DLCO 
diffusing capacity of the lung for carbon monoxide 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DM 
diabetes mellitus 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eDMC 
external data monitoring committee 
EGFR 
epidermal growth factor receptor 
Emax 
maximum effect 
EOT 
end of treatment 
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Term 
Explanation 
ER 
estrogen receptor 
FDA 
Food and Drug Administration 
FEF 
forced expiratory flow 
FEV1 
forced expiratory volume in 1 second 
FT4 
free thyroxine 
5-FU 
fluorouracil 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
GE 
gastroesophageal 
GI 
gastrointestinal 
gp100 
glycoprotein 100 
GU 
genitourinary 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDPE 
high-density polyethylene 
HER2 
human epidermal growth factor receptor 2 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HPV 
human papillomavirus 
HR 
hazard ratio 
Iave 
average inhibition 
IB 
Investigator's brochure 
IC50 
concentration that results in 50% inhibition 
ICF 
informed consent form  
ICH 
International Council on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IDO1 
indoleamine 2,3-dioxygenase 1 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin 
IHC 
immunohistochemistry 
IN 
Investigator Notification 
INR 
international normalized ratio 
irAE 
immune-related adverse event 
IRB 
Institutional Review Board 
 
 
ISH 
in situ hybridization 
IV 
intravenous 
IVIG 
intravenous immunoglobulin 
LFT 
liver function (chemistry) test 
LLN 
lower limit of normal 
MAOI 
monoamine oxidase inhibitor 
MedDRA 
Medical Dictionary for Regulatory Activities 
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Term 
Explanation 
mRECIST v1.1 
Modified Response Evaluation Criteria in Solid Tumors Version 1.1 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NSCLC 
non–small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PAD 
pharmacologically active dose 
PCP 
pneumocystis pneumonia 
PD-1 
programmed cell death receptor 1 
PD-L1 
programmed cell death ligand 1 
PD 
progressive disease  
PFS 
progression-free survival 
PgR 
progesterone receptor 
PK 
pharmacokinetic(s) 
PO 
orally 
PR 
partial response 
PT 
prothrombin time 
QD 
once daily 
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 
SNRI 
serotonin/norepinephrine reuptake inhibitor 
SS 
serotonin syndrome 
SSRI 
selective serotonin reuptake inhibitor 
t½  
half-life 
TCC 
transitional cell carcinoma 
Tmax 
time to maximum concentration 
TNBC 
triple-negative breast cancer 
Treg 
regulatory T cell 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal  
VA 
alveolar volume 
Vss  
volume of distribution at steady state 
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1. 
INTRODUCTION 
INCB 24360-203 is a Phase 1/2 study of epacadostat administered in combination with 
durvalumab in subjects with advanced melanoma, NSCLC, pancreatic cancer (Phase 1 only), 
SCCHN, TNBC, gastric or GE junction cancer, and TCC of the GU tract.  Phase 1 will be an 
open-label dose escalation to identify the MTD or PAD of epacadostat in combination with 
durvalumab.  Phase 2 will further explore the safety and efficacy of the MTD or PAD of 
epacadostat in combination with durvalumab determined in Phase 1.  Epacadostat represents a 
novel, potent, and selective inhibitor of the enzyme IDO1 in both human tumor cells and human 
DCs. 
Durvalumab is a human IgG1κ monoclonal antibody directed against human PD-L1.  The 
antibody is composed of 2 identical heavy chains of approximately 49,670 Da each, and 
2 identical light chains of approximately 23,390 Da each.  The fragment crystallizable domain of 
durvalumab contains a triple mutation in the constant domain of the IgG1 heavy chain that 
reduces binding to the complement component C1q and the fragment crystallizable gamma 
receptors responsible for mediating antibody-dependent cell-mediated cytotoxicity. 
For a thorough discussion of the pharmacology of epacadostat and durvalumab, refer to the 
epacadostat Investigator's Brochure (iIB) and the current durvalumab Investigator's 
Brochure (mIB). 
1.1. 
Pharmaceutical and Therapeutic Background 
The immune system has the innate ability to detect and eliminate aberrant cells, including tumor 
cells.  This occurs through T cells by recognizing the aberrant proteins of malignant cells and 
coordinating an immune response against them.  Tumor cells have been shown to evade the 
immune system by exploiting the immune checkpoint pathways that down regulate the immune 
response to avoid healthy tissue damage (Davies 2014).  Immune therapies targeting the immune 
checkpoint pathways have recently become an important therapeutic strategy for harnessing the 
immune system's ability to control malignancy.  The PD-1 pathway and the 
tryptophan-catabolizing enzyme, IDO1, are 2 components of the checkpoint pathways that have 
been shown to be present in the tumor microenvironment and appear to be valid immunotherapy 
targets for generating a successful immune response (Creelan 2014, Spranger et al 2014). 
1.1.1. 
Inhibition of PD-1 Signaling as a Target for Cancer 
The PD-1 receptor-ligand interaction is a key component to the immune checkpoint pathway.  
The normal function of PD-1, expressed on the cell surface of activated T cells under normal 
conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions.  Similar to CTLA-4, PD-1 is a surface receptor member of the B7-CD28 
superfamily.  It has been shown to induce T-cell tolerance by negatively regulating antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) (Talmadge et al 2007, 
Creelan 2014).  The mechanism by which PD-1 down-modulates T-cell responses is similar to 
but distinct from that of CTLA-4, as both molecules regulate an overlapping set of signaling 
proteins (Hiraoka 2010, Nobili et al 2008).  PD-1 has been shown to be expressed on activated 
lymphocytes, including peripheral CD4+ and CD8+ T cells, B cells, Tregs, and natural killer 
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cells (Hodi and Dranoff 2010, Kloor 2009).  The ligands for PD-1 (PD-L1 and PD-L2) are 
expressed in several cell types, including nonhematopoietic tissues and many tumors 
(Lee et al 2008, Leffers et al 2009, Nishimura et al 2000, Hiraoka 2010).  Binding of either PD-1 
ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor.  PD-L1 is 
expressed at low levels on various nonhematopoietic tissues, most notably on vascular 
endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting cells 
found in lymphoid tissue or chronic inflammatory environments.  PD-L2 is thought to control 
immune T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted 
T-cell function in peripheral tissues (Hiraoka 2010).  PD-L1 is expressed in many human tumors 
and has been associated with a poor prognosis (Thompson et al 2007, Konishi et al 2004, 
Hamanishi et al 2007, Nomi et al 2007, Boland et al 2013).  This evidence suggests that the 
PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and that upregulation of this 
pathway contributes to immune tolerance and tumor progression and should be considered as a 
target for the therapeutic intervention of cancer. 
1.1.2. 
Inhibition of IDO1 as a Target for Cancer 
Recent interest has focused on the role of IDO1 as a mechanism of immune tolerance in 
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 breakdown 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 DCs and macrophages at localized sites of inflammation (Munn and Mellor 2007). 
IDO1-driven oxidation of tryptophan results in a strong inhibitory effect on the development of 
T-cell mediated responses by blocking T-cell activation and inducing T-cell apoptosis 
(Mellor et al 2003).  Both the reduction in local tryptophan levels and the production of 
tryptophan catabolites that are inhibitory to cell proliferation contribute to the 
immunosuppressive effects (Frumento et al 2002).  IDO1 activity also promotes the 
differentiation of naive T cells to Tregs (Fallarino et al 2006).  Since increased Treg activity has 
been shown to promote tumor growth and Treg depletion has been shown to allow an otherwise 
ineffectual antitumor immune response to occur (Zou 2006), IDO1 expansion of Tregs may 
provide an additional mechanism whereby IDO1 could promote an immunosuppressive 
environment. 
A critical role for IDO1 in immune modulation 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 
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ipilimumab and nivolumab, respectively) in subjects with advanced melanoma.  In the Phase 1 
open-label, dose escalation study of nivolumab in combination with ipilimumab, ORR 
(according to the modified World Health Organization criteria) for all subjects in the concurrent 
regimen group was 40%.  Evidence of clinical activity (conventional, unconfirmed, or 
immune-related response or SD for ≥ 24 weeks) was observed in 65% of subjects.  In 17 subjects 
treated at the maximum doses that were associated with an acceptable level of AEs, 53% of 
subjects had an objective response compared with ipilimumab monotherapy (10.9%), all with 
tumor reduction of ≥ 80%.  Grade 3 or 4 AEs related to therapy occurred in 53% of subjects in 
the concurrent-regimen group but were qualitatively similar to previous experience with 
monotherapy and were generally reversible (Wolchok et al 2013). 
In the Phase 2 randomized, double-blinded study of nivolumab in combination with ipilimumab 
versus ipilimumab alone in subjects with previously untreated, unresectable or metastatic 
melanoma, the investigator-assessed ORR among subjects with BRAF wild-type tumors was 
61% (95% CI, 49 to 72) in the combination group versus 11% in the ipilimumab monotherapy 
group.  A CR was observed in 16 subjects (22%) in the combination group and no subjects in the 
ipilimumab monotherapy group.  In subjects with BRAF wild-type tumors, median PFS was not 
reached with the combination and was 4.4 months (95% CI, 2.8 to 5.7) with ipilimumab 
monotherapy (HR, 0.40; 95% CI, 0.23 to 0.68; p < 0.001).  Among subjects with BRAF mutation 
positive tumors, the ORR was 52% (12 of 23 subjects) in the combination group.  Median PFS 
for the combination was 8.5 months (95% CI, 2.8 to not estimable) and 2.7 months (95% CI, 
1.0 to 5.4) in the ipilimumab monotherapy group.  The rate of treatment-related AEs was 91% in 
the combination group and 93% in the ipilimumab monotherapy group.  Drug-related AEs of 
Grade 3 or 4 were reported more frequently in the combination group than in the ipilimumab 
monotherapy group (54% vs 24%).  Select AEs with potential immunological causes were 
consistent with the Phase 1 study, and most of the events resolved with immune-modulating 
medication (Postow et al 2015). 
As described above, IDO1 is another negative regulatory mechanism that contributes to 
tumor-derived immune suppression.  In preclinical models, IDO1 inhibition has been shown to 
synergize with blockade of either anti−CTLA-4 or anti−PD-1/PD-L1 in delaying tumor growth 
and increasing OS (Holmgaard et al 2013, Spranger et al 2014).  This effect was shown to be 
T-cell−dependent, leading to enhanced T-cell proliferation and interleukin-2 production within 
the tumor and to a marked increase in the effector-to-regulatory T-cell ratios in the tumors. 
In an ongoing Phase 1/2 open-label dose-escalation study of epacadostat in combination with 
ipilimumab (3 mg/kg IV), daily doses of epacadostat have been evaluated in 21-day cycles.  In 
the initial Phase 1 dose-escalation portion, 5 of 7 subjects receiving epacadostat 300 mg BID in 
combination with 4 doses of ipilimumab (3 mg/kg every 3 weeks) developed clinically 
significant ALT elevations; therefore, the study was amended to evaluate lower epacadostat 
doses.  At the 300 mg BID dose level, 6 of 7 subjects had evaluable scans and all showed SD as 
assessed by irRC.  Enrollment was restarted at 25 mg BID (n = 8), where 1 subject with 
progression of prior extensive liver metastases had a dose-limiting toxicity (DLT; Grade 3 AST 
elevation).  Subsequent cohorts received 50 mg BID continuous, 50 mg BID intermittent 
(2 weeks on, 1 week off), and 75 mg BID (50 mg every morning/25 mg every evening) in 
combination with 4 doses of ipilimumab 3 mg/kg every 3 weeks.  Eighteen subjects were 
enrolled in the 50 mg BID continuous dosing cohort, and 4 DLTs were reported (1 Grade 3 
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tumor.  Whenever possible, patients should have tumor tissue assessed for the presence of a 
driver mutation that stimulates tumor growth.  These mutations define subsets of patients likely 
to respond to specific inhibitors (NCCN Guidelines).  Patients with a known driver mutation in 
the EGFR are initially managed with an EGFR tyrosine kinase inhibitor (Moran and 
Sequist 2012, Gridelli et al 2012).  Those with an anaplastic lymphoma kinase fusion oncogene 
in their tumor are preferentially treated with crizotinib (Kwak et al 2010, Camidge et al 2012, 
Shaw et al 2013).  Patients without a driver mutation are generally treated with chemotherapy. 
Most patients with advanced NSCLC eventually develop PD and require additional treatment 
after their initial treatment with either chemotherapy or targeted therapy.  Currently approved 
cytotoxic chemotherapies for previously treated patients with NSCLC demonstrate few objective 
responses, which are generally of short duration, with limited impact on PFS and OS. 
Phase 1 studies of anti−PD-1 agents have demonstrated promising results.  The FDA granted 
approval for pembrolizumab for the treatment of metastatic NSCLC.  Pembrolizumab was 
approved for patients whose tumors express PD-L1 as determined by an FDA-approved test and 
who have disease progression on or after platinum-containing regimens (Garon et al 2015).  
Patients with EGFR or ALK genomic tumor aberrations should have disease progression on an 
FDA-approved therapy for these aberrations before receiving pembrolizumab.  In the Phase 1 
study by Garon et al (2015), an ORR of 19.4% was reported in the 495 NSCLC patients who 
received monotherapy pembrolizumab.  Median duration of response was 12.5 months, median 
PFS was 3.7 months, and OS was 12 months.  Nivolumab was also approved by the FDA and the 
EU for patients with locally advanced or metastatic NSCLC with progression after 
chemotherapy.  In the United States, patients with EGFR or ALK genomic tumor aberrations 
should also have disease progression on an FDA-approved therapy for these agents.  The Phase 3 
study comparing nivolumab to docetaxel resulted in an OS of 12.2 months (95% CI, 9.7 to 15.0) 
among 292 subjects in the nivolumab group and 9.4 months among the 290 subjects in the 
docetaxel group (HR, 0.73; 96% CI, 0.59 to 0.89; p = 0.002).  The response rate with nivolumab 
was 19% as compared with 12% in the docetaxel group (p = 0.02) (Borghaei et al 2015). 
In addition to PD-1 inhibition, drugs targeting PD-L1 have also shown promising data.  
MPDL3280A, a humanized monoclonal antibody that blocks PD-L1 from binding to its 
receptors, including PD-1 and B7.1, has shown similar efficacy.  In a Phase 1 study that included 
subjects with both squamous and nonsquamous NSCLC; ORR was 24% (9/37), and at the time 
of the abstract publication, all responses were ongoing and improving (Soria et al 2013).  The 
24-week PFS was 46%.  Analysis of biomarker data from tumor samples demonstrated a 
correlation between PD-L1 status and efficacy in both the MPDL3280A and pembrolizumab 
(MK-3475) studies. 
Targeting the IDO1 enzyme has been studied in subjects with metastatic NSCLC as well in the 
form of vaccination with an epitope derived from IDO1.  In the Phase 1 study, no severe 
toxicities occurred.  One of 15 HLA-A2−positive subjects treated developed a PR after 1 year of 
vaccine treatment, and SD of ≥ 8.5 months was reported in another 6 subjects.  The median 
survival was 25.9 months, and long-lasting PR + SD was seen in 47% of the subjects.  
Expression of IDO was detected in 9 of 10 tumor biopsy specimens by IHC (Iversen et al 2014). 
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1.1.8. 
Pancreatic Cancer 
Cancer of the exocrine pancreas is a highly lethal malignancy.  Pancreatic cancer is the 13th 
most common form of cancer worldwide, with 279,000 people diagnosed in 2008 (Ferlay 2008).  
Most die from the disease because it commonly presents in an advanced state. 
Chemotherapy represents the cornerstone of initial therapy for patients with advanced disease.  
Until recently, single-agent gemcitabine or gemcitabine in combination with erlotinib was 
considered the standard of care for most patients in the first-line advanced disease setting 
(Burris et al 1997, Moore et al 2007).  Two combination regimens have recently emerged as new 
standards of care based on Phase 3 studies in which the combinations were compared to 
gemcitabine monotherapy. 
Subjects treated with gemcitabine in combination with nab-paclitaxel showed a statistically 
significant improvement in OS compared with subjects receiving gemcitabine alone (median of 
8.5 months vs 6.7 months; HR 0.72, p = 0.000015).  Based on these results, the combination of 
gemcitabine plus nab-paclitaxel was approved by the FDA for the first-line treatment of 
metastatic adenocarcinoma of the pancreas and has emerged as a standard of care for the 
treatment of patients with advanced disease and good performance status (NCCN Guidelines). 
The superiority of FOLFIRINOX (a regimen that combines leucovorin-modulated 5-FU with 
irinotecan and/or oxaliplatin) over gemcitabine monotherapy was initially suggested in a 
randomized Phase 2 study that showed FOLFIRINOX was associated with a high ORR 
(39% vs 11%) and manageable toxicity (Ychou et al 2007).  The study was expanded to a 
Phase 3 study in which chemotherapy-naive subjects with metastatic pancreatic cancer were 
randomly assigned to gemcitabine alone versus the FOLFIRINOX regimen (Conroy et al 2011).  
The study was stopped when a preplanned interim analysis demonstrated that the primary 
endpoint of OS had been met (median 11.1 months vs 6.8 months; HR 0.57; p < 0.001).  These 
data establish FOLFIRINOX as another standard-of-care option in treatment-naive patients with 
advanced pancreatic cancer with a good performance status (NCCN Guidelines). 
The future role of immunotherapy in pancreatic cancer is less clear than the evidence shown in 
melanoma and NSCLC.  Experience in the clinical setting with immunotherapies is limited.  A 
Phase 2 study evaluated the efficacy of ipilimumab in subjects with pancreatic cancer.  
Twenty-seven subjects were enrolled, and although no responses by RECIST v1.1 were seen, 
1 subject did experience a delayed response and regression of the primary lesion and several 
hepatic metastases.  The subject also had an improvement in tumor markers and performance 
status (Royal et al 2010).  Pancreatic cancers have been shown to express PD-L1, which may be 
contributing to immune suppression and evasion.  PD-L1 expression in pancreatic cancer has 
also been shown to be associated with decreased tumor-infiltrating lymphocytes and poor 
prognosis (McDermott and Atkins 2013). 
As there are currently no approved standard of care for patients with pancreatic cancer who have 
PD despite first-line therapy, guidelines established by the NCCN in the United States and the 
European Society of Medical Oncology encourage the participation of patients with recurrent or 
refractory advanced pancreatic cancer and satisfactory performance status in clinical studies 
(NCCN Guidelines, Seufferlein et al 2012).  Because of the lack of effective therapies for this 
highly lethal malignancy, it is reasonable to provide an experimental therapy to patients who 
have failed approved first-line therapies in this setting. 
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1.1.9. 
Squamous Cell Carcinoma of the Head and Neck 
In the United States alone, approximately 55,070 people will develop head and neck cancer in 
the next year (Cancer.net 2014).  Tobacco use and drinking alcohol greatly increase the risk of 
developing head and neck cancer.  In addition, infection with HPV is associated with the 
development of head and neck cancer, and the incidence of HPV-associated SCCHN is on the 
rise.  Many patients present with localized disease that may be treated with either surgery or 
radiation therapy with curative intent (Vermorken and Specenier 2010).  Unfortunately, most 
patients will develop local recurrent disease, and about 20% to 30% of these patients will be 
diagnosed with distant metastases.  Treatment for recurrent/metastatic disease is typically not 
considered curative and includes chemotherapy or targeted agents.  Single agents most 
commonly used as monotherapy in this setting (eg, methotrexate, cisplatin, and 5-FU) typically 
have a short duration of response of only approximately 3 to 5 months.  Combination 
chemotherapy may be selected in patients with selected characteristics such as a good 
performance status (NCCN Guidelines).  Response rates of combination therapy are generally 
improved over monotherapy; however, clinical study data have not proven an OS benefit when 
compared to methotrexate, cisplatin, or 5-FU monotherapy (Vermorken and Specenier 2010), 
and these combinations may cause a significant increase in toxicity. 
Cetuximab, an agent targeting EGFR, is widely used in the United States and the EU in the 
setting of recurrent/metastatic disease.  In the United States and EU, cetuximab is approved for 
use in recurrent locoregional or metastatic squamous cell carcinoma of the head and neck in 
combination with platinum-based therapy with 5-FU.  In the United States, cetuximab is also 
approved for patients whose disease has progressed after platinum-based therapy.  A study of 
442 first-line subjects with SCCHN showed that the addition of cetuximab to platinum-based 
(cisplatin or carboplatin) therapy with 5-FU significantly improved OS from 7.4 months to 
10.1 months (HR = 0.80; p = 0.04).  Significant benefits were also seen in PFS and ORR; 
however, approximately 20% of subjects in each arm discontinued due to AEs. 
PD-L1 has been shown to be expressed in the tumor microenvironment of SCCHN.  PD-L1 
staining by IHC is seen in both HPV-positive tumors and HPV-negative tumors, although HPV 
positivity does appear to correlate with a higher probability of PD-L1 expression in the tumor 
microenvironment (Lyford-Pike et al 2013).  In early clinical studies, a subject with metastatic 
SCCHN was treated with the anti−PD-L1 monoclonal antibody MDPL3280A experienced a 
response by the second cycle of treatment (Herbst et al 2013).  More recent data studying the 
anti−PD-1 antibody MK-3475 in subjects with PD-L1−positive SCCHN has shown a best ORR 
of 19.6% using RECIST v1.1 (Seiwert et al 2014).  Additional studies of anti−PD-1 and 
anti−PD-L1 agents in the setting of metastatic SCCHN are ongoing. 
1.1.10. 
Triple-Negative Breast Cancer 
Triple-negative breast cancer accounts for approximately 20% of breast cancers diagnosed 
worldwide, or about 200,000 cases each year (Swain 2008).  A strong association has been found 
with African-American race, younger age, higher grade, premenopausal status, more advanced 
stage at diagnosis, and positive BRCA mutation status.  More than 75% of tumors displaying a 
positive BRCA mutation status are triple negative (Bayraktar et al 2011).  Despite initial 
responses to chemotherapy, TNBC has a poor prognosis as defined by low 5-year survival and 
high recurrence rates after adjuvant therapy. 
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Triple negative status is defined as tumors that lack expression of the ER and PgR but express 
HER2 at normal levels.  The ASCO/CAP panel guidelines for determining ER, PgR, and 
HER2 status were created to improve the accuracy of testing and are commonly used in clinical 
practice (Hammond et al 2010, Wolff et al 2013). 
Triple-negative breast cancer is described as "paradoxical" because of the relatively high 
likelihood of response and pathologic CR but poorer overall outcomes.  The risk of distant 
recurrence in TNBC and death peaks approximately 3 years after diagnosis and declines rapidly 
thereafter (Liedtke et al 2008).  As compared with ER-positive breast cancers, TNBC has a 
higher rate of relapse and a higher risk for metastases to the lung and brain (Lin et al 2012).  
Unfortunately, since endocrine therapy and HER2-directed therapies are ineffective, the only 
approved option for metastatic TNBC is chemotherapy, which is associated with a median 
survival of < 1 year. 
Recent studies suggest that PD-L1 is expressed in approximately 20% of patients with TNBC 
(Chawla et al 2014), and immunotherapy agents, including the anti-PD-1 antibody 
pembrolizumab, appear to be active in heavily pretreated patients with metastatic TNBC.  In a 
Phase 1b study, subjects with PD-L1+ metastatic TNBC were treated with monotherapy 
pembrolizumab every 2 weeks.  Approximately 50% of subjects on study had received ≥ 3 lines 
of therapy.  Of the 27 evaluable subjects, the ORR was 18.5%, median time to response was 
18 weeks, and the median duration of response had not been reached (range, 15-40+ weeks).  
Three of 5 responders at the time of analysis were on treatment for ≥ 11 months (Buisseret 
et al 2015).  Additional studies of both anti−PD-1 and anti−PD-L1 targeted agents are ongoing. 
1.1.11. 
Gastric and Gastroesophageal Junction Cancer 
In 2015, an estimated 24,590 and 16,980 patients will be diagnosed with gastric and esophageal 
cancer, respectively, and approximately 26,310 men and women will eventually succumb to their 
disease (NCCN 2015).  The prognosis for both gastric and GE junction cancers remains 
overwhelmingly poor.  Five-year survival rate rates for patients with proximal gastric cancer are 
only 10% to 15%.  Locally advanced unresectable and metastatic gastroesophageal cancers are 
not curable, and typically care is managed through a multidisciplinary approach including 
surgery, radiotherapy, and chemotherapy. 
Cisplatin is one of the most active agents for locally advanced metastatic esophageal cancer, with 
single-agent response rates of approximately 20% or higher.  Single-agent activity has also been 
observed with irinotecan, docetaxel, paclitaxel, and etoposide; however, cisplatin in combination 
with fluorouracil is the most commonly used regimen, resulting in response rates of 
approximately 20% to 50%.  Other combination chemotherapy regimens including oxaliplatin, 
carboplatin, mitomycin, and gemcitabine have been evaluated in advanced or metastatic 
esophageal cancer in the clinical trial setting; however, no consistent benefit was seen for any 
specific chemotherapy regimen (NCCN 2015). 
Recently, targeted therapies have shown clinical activity in the locally advanced or metastatic 
setting.  Ramucirumab, a vascular endothelial growth factor receptor-2 antibody, as a single 
agent or in combination with paclitaxel, was approved by the FDA and the EU for the treatment 
of patients with advanced gastric or adenocarcinoma of the esophagogastric junction for whom 
treatment in combination with paclitaxel is not appropriate or for patients who have progressed 
after therapy with platinum- or fluropyrimidine-based chemotherapy.  In the REGARD trial, 
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355 subjects were randomized to receive best supportive care plus ramucirumab or placebo.  
Median OS was 5.2 months in subjects treated in the ramucirumab group compared to 
3.8 months for those in the placebo group (p = 0.047) (Fuchs et al 2014).  In a second study of 
ramucirumab in combination with paclitaxel, the combination resulted in significantly higher 
OS, PFS, and ORR than paclitaxel alone.  The median OS for the combination was 9.63 months 
as compared to 7.63 months in the paclitaxel-alone arm (p = 0.0001) (NCCN 2015). 
In the near future, molecular characterization of upper GI tumors is expected to lead to additional 
treatment options for patients with advanced disease.  HER2-neu testing is currently 
recommended if metastatic disease is documented or suspected.  In the ToGA study, the addition 
of trastuzumab to chemotherapy in patients with HER2-neu overexpression or amplification 
resulted in a significant improvement in OS (13.8 vs 11.1 months, p = 0.046) (Bang et al 2010).  
This study established trastuzumab in combination with chemotherapy as a new standard of care 
for patients with HER2-neu−positive or metastatic gastric and esophagogastric junction 
adenocarcinoma. 
Recent clinical studies suggest that PD-1 and PD-L1 inhibitors may also have clinical activity in 
gastric and GE junction tumors.  In a Phase 1b study, subjects with metastatic adenocarcinoma of 
the stomach or GE junction received the anti−PD-1 treatment pembrolizumab every 2 weeks.  
The ORR was 22% (95% CI, 10-39) by central review and 33% by investigator review.  Median 
time to response was 8 weeks (range, 7-16 weeks), median duration of response was 24 weeks 
(range, 8+ to 33+ weeks), and the 6-month PFS rate was 24% (Muro et al 2015).  Additional 
studies with immunotherapy agents are ongoing. 
1.1.12. 
Transitional Cell Carcinoma of the Genitourinary Tract 
Urothelial carcinomas, also referred to as TCCs, are the most common histological subtype in the 
United States.  Transitional cell carcinoma may develop anywhere transitional epithelium is 
present, from the renal pelvis to the ureter, bladder, and proximal two-thirds of the urethra 
(NCCN 2015).  In the United States, approximately 75,000 new cases and 16,000 deaths occur 
each year due to bladder cancer (Siegel et al 2015).  Occupational and environmental 
carcinogens as well as tobacco use greatly increase risk of developing bladder cancer.  In 
addition, several studies have suggested a relationship between TCC and HPV infection.  
A recent meta-analysis found that approximately 17% of bladder cancers are HPV-positive 
(Li et al 2011).  The life expectancy for patients with metastatic urothelial cancer is poor, with a 
median OS of 12 to 18 months.  Treatment selection for advanced disease is dependent on a 
number of factors, including the presence of medical comorbidities, cardiac disease, renal 
functional, performance status, and disease extent.  There is no standard second-line therapy for 
patients who have progressed on first-line therapy for metastatic disease.  First-line therapy for a 
robust elderly patient often includes gemcitabine plus cisplatin or dose-dense methotrexate, 
vinblastine, doxorubicin, and cisplatin.  Alternatively, carboplatin, taxane-based regimens, or 
single-agent chemotherapy may be considered as well (NCCN 2015).  Second-line chemotherapy 
data are highly variable, and treatment choices in this setting largely depend on the patient's 
first-line treatment. 
More recently clinical activity has been observed with PD-1 and PD-L1 targeted agents.  In the 
Phase 2 study IMvigor210, subjects who progressed after treatment with a platinum-based 
chemotherapy were administered the anti−PD-L1 agent atezolizumab.  The ORR was 15% 
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(p = 0.0058) for all subjects on study, 18% (p = 0.0004) for subjects with PD-L1 expression 
≥ 1%, and 27% (p = 0.0001) in subjects with PD-L1 expression ≥ 5%.  Median duration of 
response at the time of analysis had not yet been reached; however, 92% (43 of 47) of responses 
were ongoing at 24 weeks (Rosenberg et al 2015).  In a separate Phase 1b study, 33 subjects with 
PD-L1+ urothelial tract tumors of mostly transitional cell histology were administered 
monotherapy pembrolizumab.  The ORR by central review was 24.1%, with 10.3% of subjects 
achieving CRs.  Duration of response was 16 to 40+ weeks (median not reached), with 6 of the 
7 responders ongoing at the time of analysis.  The median PFS was 8.6 weeks and the median OS 
in all subjects was 9.3 months (6-month OS rate, 58%; Plimack et al 2014).  Several additional 
studies are ongoing to further evaluate the activity of PD-1 and PD-L1 agents in TCC of the GU 
tract. 
1.1.13. 
Preclinical and Clinical Study Data 
Refer to the current Investigator's Brochures for both durvalumab (mIB) and epacadostat (iIB) 
for additional preclinical and clinical study data. 
1.1.13.1. Summary of Epacadostat Pharmacokinetics in Humans 
As of 29 OCT 2015, a total of 253 subjects were enrolled and received at least 1 dose of 
epacadostat in Incyte-sponsored studies, and 47 subjects were enrolled and received at least 
1 dose of epacadostat in investigator-sponsored studies. 
In Study INCB 24360-101, the multiple-dose PK of epacadostat was evaluated in subjects with 
refractory solid tumors at doses of 50 mg QD to 700 mg BID.  Pharmacokinetic observations 
include the following and are summarized in Figure 1. 
• After oral dose administration in the fasted state, the peak plasma concentration of 
epacadostat was typically attained at 2 hours postdose.  Epacadostat was eliminated 
with a geometric mean terminal disposition half-life of 2.9 hours. 
• Systemic accumulation after BID administration increased the mean epacadostat Cmax 
and AUC0-t by 16% and 33%, respectively, suggesting an "effective" half-life of 4 to 
6 hours. 
• Increases in epacadostat Cmax and AUC0-t were less than proportional to dose.  The 
slightly lower than dose-proportional relationship was most likely because of the 
limited rate and/or extent of intestinal absorption for this compound at higher doses. 
• A high-fat meal delayed epacadostat median Tmax by 4 hours but did not cause a 
clinically significant change in epacadostat plasma exposures.  Therefore, epacadostat 
may be administered without regard to food. 
• Moderate intersubject variability was observed for epacadostat plasma exposure at the 
steady state after administration in the fasted state. 
• The highest steady-state mean unbound 0- to 24-hour AUC (2.2 μM∙h) observed in 
this study (700 mg BID dose group) was well below the NOAEL unbound AUC0-24h 
of 7.9 μM∙h observed in the 28-day GLP toxicology study. 
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Figure 1: 
Epacadostat Plasma Concentrations (Mean ± SE) in Cancer Patients 
Receiving Multiple Doses of Epacadostat in the Fasted State 
 
1.1.13.2. Summary of Epacadostat Pharmacodynamics in Humans 
Tryptophan and kynurenine levels were measured in plasma and in stimulated whole blood 
samples from Studies INCB 24360-101, INCB 24360-201, and INCB 24360-210 as 
pharmacodynamic measures of the inhibition of IDO1 activity by epacadostat.  Whole blood 
samples were stimulated ex vivo with LPS and interferon-γ in order to increase the levels of 
IDO1 expression before measurement of tryptophan to kynurenine levels 24 hours later.  In 
addition, systemic changes in plasma markers of inflammation and lymphocyte subsets were 
monitored. 
Pharmacodynamic observations include the following: 
• Epacadostat administration effectively inhibits IDO1 enzyme activity, which is 
upregulated in many cancers and correlated with poor prognosis. 
• Inhibition of IDO1 is dose-dependent, and at doses at or above 300 mg BID, 
epacadostat effectively achieves maximal inhibition of IDO1 activity at trough, as 
assessed using changes in kynurenine levels. 
• Epacadostat inhibits IDO1 in all subjects, irrespective of cancer type. 
• The elevated kynurenine levels at baseline that are observed in cancer subjects are 
reduced at first measure after onset of treatment with epacadostat.  The elevated 
kynurenine levels are reduced back to the range noted in normal healthy individuals 
in most subjects. 
• The pharmacodynamic effects of epacadostat are consistent with the PK. 
• No significant changes in peripheral blood immune cell subsets or immune plasma 
proteins have been noted, suggesting that IDO1 inhibition does not elicit global 
changes in the peripheral immune system. 
Figure 2 summarizes the changes in plasma kynurenine levels observed in Study 
INCB 24360-101.  The levels of IDO1 inhibition are quantified in Table 1. 
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Figure 2: 
IDO1 Inhibition as a Function of Kynurenine Plasma Concentrations 
Attributable to IDO1 (Mean ± SEM) at the Steady State (on Cycle 1 Day 15) 
in Study INCB 24360-101 
 
Table 1: 
IDO1 Inhibition at Steady State in Study INCB 24360-101 
Study/Cohort 
Dose 
No. of 
Subjects 
Mean ± SD 
Inhibition Max 
(%) 
Average Inhibition 
(0-6 h; %) 
Inhibition Trough 
(%) 
101/1 
50 mg QD 
3 
74 ± 18 
47 ± 18 
6 ± 10 
101/2 
50 mg BID 
4 
94 ± 3 
79 ± 12 
65 ± 18 
101/3 
100 mg BID 
5 
97 ± 1 
89 ± 6 
84 ± 6 
101/4 
300 mg BID 
4 
99 ± 1 
94 ± 4 
86 ± 11 
101/5 
400 mg BID 
7 
100 ± 1 
96 ± 3 
91 ± 10 
101/6 
500 mg BID 
5 
100 ± 1 
94 ± 7 
91 ± 9 
101/7 
700 mg BID 
4 
99 ± 1 
98 ± 1 
97 ± 1 
101/8 
600 mg BID 
7 
100 ± 4 
94 ± 6 
88 ± 11 
Preliminary data from Studies INCB 24360-201 and INCB 24360-210 demonstrated no 
differences in pharmacodynamic effects based on comparison with subjects in 
Study INCB 24360-101, as assessed using changes in kynurenine levels (see Table 2). 
Table 2: 
IDO1 Inhibition at the Steady State in Studies INCB 24360-201 and 
INCB 24360-210 
Study/Cohort 
Dose 
No. of 
Subjects 
Mean ± SD 
Inhibition Max 
(%) 
Average Inhibition 
(0-6 h; %) 
Inhibition Trough 
(%) 
201/1 
300 mg BID 
2 
99 ± 1 
93 ± 1 
92 ± 6 
201/2 
25 mg BID 
4 
86 ± 8 
66 ± 15 
40 ± 29 
201/3 
50 mg BID 
7 
93 ± 7 
81 ± 15 
64 ± 31 
210/1 
600 mg BID 
3 
99 ± 0 
97 ± 2 
94 ± 3 
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synergize with blockade of PD-1/PD-L1 in delaying tumor growth and increasing OS 
(Holmgaard et al 2013).  Many recent clinical results suggest that a common rate-limiting step is 
the expression of PD-L1 as a distal immune modulator expressed in 20% to 50% of human 
cancer (Hiraoka et al 2010, Herbst et al 2013), including but not limited to the ones selected for 
investigation in this study:  advanced or metastatic NSCLC, melanoma, pancreatic cancer 
(Phase 1 only), SCCHN, TNBC, gastric or GE junction cancer, and TCC of the GU tract.  
Expression of IDO and PD-1/L1 have been found to be increased in NSCLC as the disease 
progresses, and expression of these markers in tumor cells has been associated with shorter 
subject survival (Iversen et al 2014).  Anti−PD-L1 and anti−PD-1 monotherapy response rates of 
approximately 20% have been reported in refractory NSCLC (Garon et al 2015, Brahmer 
et al 2013) with a survival median of approximately 12 months.  In subjects with PD-L1 
expression in at least 50% of tumor cells, the reported response rate was 45.2% with a median 
PFS of 6.3 months.  At the time of analysis, OS had not yet been reached (Garon et al 2015). 
In APR 2018, the ECHO-301/KEYNOTE-252 study, a Phase 3 trial evaluating the anti–PD-1 
antibody pembrolizumab in combination with epacadostat vs pembrolizumab with placebo as 
first line treatment in subjects with unresectable or metastatic melanoma, underwent a 
preplanned eDMC review.  This eDMC review concluded that the co-primary endpoint of 
improvement in progression-free survival was not met (HR = 1.00; 95% CI 0.83 to 1.21) and that 
the co-primary endpoint of improvement in overall survival was also not expected to reach 
statistical significance (HR = 1.13; 95% CI 0.86 to 1.49).  Based on these results, and on the 
recommendation of the eDMC, the study was stopped.  The safety profile observed in the 
ECHO-301/KEYNOTE-252 study was consistent with that observed in previously reported 
studies of epacadostat in combination with pembrolizumab. 
1.3. 
Potential Risks and Benefits of the Treatment Regimen 
1.3.1. 
Risks From Epacadostat 
In 28-day toxicology studies, Cmax values have exceeded the 50% inhibitory concentration for the 
IDO1 enzyme in cells (7 nM) by up to 370-fold in the absence of any toxicity, so the risk of 
unintended pharmacological activity is expected to be low.  In the Phase 1 clinical study in 
subjects with refractory solid tumors (INCB 24360-101), epacadostat was well tolerated with a 
single SAE of radiation pneumonitis (also considered a DLT) in a subject with mediastinal 
metastasis of endometrial cancer, 1 report of asymptomatic and reversible hypopituitarism 
despite continued dosing of epacadostat, and 1 event of Grade 3 fatigue determined by the 
investigator to be related to study drug and considered a DLT.  Preliminary data from study 
INCB 24360-201 (evaluating the combination of epacadostat and ipilimumab) suggest that 
epacadostat doses ≤ 50 mg BID were well tolerated with ipilimumab.  In the 50 mg BID 
continuous cohort, 4 DLTs (Grade 3 diarrhea, Grade 3 ALT/AST elevation, Grade 3 colitis, and 
Grade 3 pneumonitis) in 18 subjects were reported.  Immune-related AEs were reversible with 
appropriate management.  The initial evaluation of epacadostat 300 mg BID in combination with 
ipilimumab was terminated due to the occurrence of Grade 3 or 4 ALT/AST elevation in 5 of 
7 subjects treated at this dose.  These AEs were reversible in all subjects upon discontinuation of 
study therapy and institution of corticosteroids based on an established protocol for the 
management of immune toxicities related to ipilimumab therapy.  Treatment-emergent AEs were 
reported in 100% of subjects administered 25 mg BID, 50 mg BID, 50 mg intermittent, 75 mg 
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total daily dose, and 300 mg BID of epacadostat in combination with ipilimumab.  
Treatment-emergent AEs occurring in ≥ 20% of patients overall included fatigue (n = 29 [69%]), 
constipation and nausea (n = 13 [31%] each), decreased appetite and headache (n = 11 [26%] 
each), and vomiting (n = 10 [24%]) (Gibney et al 2015). 
A potential concern of IDO1 inhibition is an increase in serotonin levels that could precipitate a 
cluster of AEs termed SS when administered alone or in combination with other serotonergic 
agents.  This rare syndrome has been associated with some MAOIs and combinations of 
serotonergic drugs (Boyer and Shannon 2005).  The clinical manifestations of SS range from 
barely perceptible to lethal; onset is rapid (within 12 hours of drug[s] administration).  
Preclinical data suggest that SS is unlikely after treatment with either epacadostat alone or with 
combination with MAOIs such as linezolid (Zhang et al 2016).  As of 27 FEB 2017, 2 subjects 
across the epacadostat program (958 subjects treated) have reported non-serious SS or symptoms 
of SS, and both were mild in their severity and resolved. 
1.3.2. 
Risks From Durvalumab 
Risks associated with durvalumab monotherapy and in combination are provided below.  
Additional safety information can be found in the durvalumab Investigator Brochure (mIB). 
1.3.2.1. 
Possible Risks Based on Mechanism of Action 
Durvalumab, an anti−PD-L1 antibody, binds with high affinity and specificity to PD-L1 and 
blocks its binding to PD-1 and CD80, thus promoting antitumor immunity and tumor cell killing.  
Potential risks based on the mechanism of action of durvalumab and related molecules include 
immune-mediated reactions such as enterocolitis, pneumonitis, dermatitis, hepatotoxicity, 
endocrinopathy, and neuropathy. 
A hypothetical risk exists for agents that activate the immune system by delivering agonistic 
signals through activating receptors, such as CD28 (Suntharalingam et al 2006).  Such agents 
have an increased potential to trigger systemic, nonspecific activation of T cells since they can 
exert their effects in the absence of any antigen-specific T-cell receptor signals.  In contrast, 
agents that act via antagonism of an inhibitory pathway modulate an existing antigen-specific 
T-cell receptor signal and have a limited potential to drive systemic, nonspecific activation of 
T cells.  This is exemplified clinically by molecules targeting CTLA-4 and PD-1, which are not 
associated with acute, severe adverse effects, such as cytokine storm (Brahmer et al 2010, 
Berger et al 2008, Wolchok et al 2010).  Like these molecules, durvalumab antagonizes an 
inhibitory receptor (PD-L1).  As such, in the absence of an antigen-specific T-cell receptor 
signal, inhibition of function of PD-L1 is not anticipated to elicit any response.  This expectation 
is supported by published data showing no effect for anti−PD-L1 antibodies in the absence of a 
T-cell receptor stimulus (Dong et al 2002).  To assess directly the potential of durvalumab to 
induce a release of cytokines, cytokine release assays were conducted in human whole blood.  
Durvalumab did not induce release of any cytokine from any donor at any concentration tested.  
These results support that, consistent with its mechanism of action as a PD-L1 antagonist, 
durvalumab is not expected to induce acute cytokine release in humans.  Nevertheless, the 
durvalumab first-time-in-human study design took into account the unlikely possibility of a 
cytokine release event by having a low starting dose, extensive monitoring, and cytokine 
sampling.  To further mitigate the risk to subjects, vital signs will be monitored every 15 minutes 
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throughout the infusion, at the end of the infusion, and 30 and 60 minutes postinfusion.  In 
addition, subjects will be observed for 3 hours following the first infusion of durvalumab.  Thus, 
the target occupancy will be well controlled with ample opportunity for observation, cessation of 
treatment, or intervention, if necessary. 
1.3.2.2. 
Possible Risks Based on Clinical Data 
As of 12 JUL 2015, > 1800 subjects have been treated across the ongoing durvalumab 
(MEDI4736) studies, including sponsored studies and collaborative studies.  The majority of 
subjects have been treated with monotherapy durvalumab (n = 1279); however, 440 subjects 
have received MEDI4736 in combination with tremelimumab or other anticancer agents, 
14 received other agents (1 gefitinib, 13 MEDI6383), and 150 subjects were blinded (mIB). 
The safety profile of durvalumab as monotherapy and combined with other anticancer agents 
was consistent with the pharmacology of the target and other agents in the immune checkpoint 
inhibitor class.  No tumor types appeared to be associated with unique AEs.  Immune-related 
AEs, which are important risks of immune checkpoint inhibitors, have been observed with 
durvalumab and include colitis, pneumonitis, hepatitis/hepatotoxicity, neuropathy/neuromuscular 
toxicity, endocrinopathy, dermatitis, and nephritis. 
1.3.2.2.1. Risks of Durvalumab Monotherapy 
Risks with durvalumab monotherapy include diarrhea, colitis, pneumonitis/interstitial lung 
disease, endocrinopathies (eg, hypo- and hyperthyroidism, Type I DM, diabetes insipidus, 
hypophysitis, and adrenal insufficiency), hepatitis/hepatotoxicity/increases in transaminases, 
neurotoxicities, nephritis/increases in creatinine, pancreatitis, rash/pruritus/dermatitis, 
infusion-related reactions, anaphylaxis, hypersensitivity or allergic reactions, myocarditis, and 
immune complex disease.  
Further information on the identified and potential risks can be found in the current version of 
the durvalumab IB (mIB). 
In monotherapy clinical studies, very commonly reported (≥ 10% of subjects) AEs of all grades 
are fatigue, nausea, decreased appetite, dyspnea, cough, constipation, diarrhea, vomiting, back 
pain, pyrexia, abdominal pain, anemia, arthralgia, peripheral edema, headache, rash, and pruritus.  
Approximately 8% of subjects experienced an AE that resulted in permanent discontinuation of 
durvalumab, and approximately 5% of subjects experienced an SAE that was considered to be 
related to durvalumab by the study investigator. 
The majority of treatment-related AEs were manageable with dose delays, symptomatic 
treatment, and, in the case of events suspected to have an immune basis, the use of established 
treatment guidelines for immune-mediated toxicity (see Section 5.6.3). 
A detailed summary of durvalumab monotherapy AE data can be found in the current version of 
the durvalumab IB (mIB). 
1.3.2.3. 
Possible Risks Based on Nonclinical Data 
Nonclinical studies have demonstrated that durvalumab partially suppressed the primary 
antibody response to a T-cell−dependent antigen (KLH).  Secondary antibody responses to this 
antigen were normal.  The relevance of this finding with respect to a human immune response is 
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1.4. 
Justification for Treatment Regimen 
The goal of the present study is to explore doses of epacadostat that may synergize or otherwise 
augment the efficacy observed with the PD-L1 inhibitor durvalumab in subjects with advanced 
cancer.  The established regimen of durvalumab (3 mg/kg or 10 mg/kg once every 14 days) will 
be combined with doses of epacadostat that provide partial and more complete IDO1 inhibition 
based on observations from the Phase 1 study (INCB 24360-101).  The initial dose selected for 
epacadostat in combination with durvalumab is 25 mg BID with escalation to 300 mg BID.  This 
is based on the preliminary observation that the average kynurenine inhibition for epacadostat 
25 mg BID and 300 mg BID are 66% and > 94%, respectively, and the safety of these doses, as 
well as doses up to 700 mg BID in the Phase 1 monotherapy study and in combination with 
ipilimumab in INCB 24360-201.  Dose escalation of epacadostat will evaluate 25 mg BID, 
50 mg BID, 75 mg BID, 100 mg BID, and 300 mg BID.  This dose range will span a range of 
average inhibition of IDO1 from approximately 40% (at 25 mg BID dosing) to 60% (50 mg BID 
dosing) to 89% (100 mg BID dosing) and 94% (300 mg BID dosing), based on 
pharmacodynamic testing.  Pharmacokinetic and pharmacodynamic observations from 
Studies INCB 24360-101 and INCB 24360-201 in cancer subjects support these doses, which 
provide a differential pharmacologic effect. 
The 200 mg dose level of epacadostat will not be explored in combination with durvalumab 
based on PK and pharmacodynamic considerations.  The results from Study INCB 24360-101 
demonstrated that epacadostat displays mildly sublinear exposure-dose response, as shown in 
Figure 3 and Table 3.  It is likely that there would be significant overlap in exposure at 200 mg 
compared to both 100 mg and 300 mg dose steps.  Furthermore, inhibition of IDO1 is well 
described by an Emax model that is fundamentally nonlinear, especially beyond the inhibition 
> 80%.  Any incremental increase in IDO1 inhibition begins to level off and would be insensitive 
to further increased epacadostat concentration.  Our pharmacodynamic model estimates Iave 
increases from 83% to 89% with dose stepping from 100 mg to 300 mg BID, which justifies not 
exploring the 200 mg intermediate dose in combination with durvalumab. 
Figure 3: 
INCB24360-101 Dose Response 
 
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Table 3: 
Summary of Epacadostat Steady-State Pharmacokinetic Parameters in Study INCB 24360-101 
Dose 
No. of 
Subjects 
Cmax (μM) 
Tmax (h) 
Cmin (μM) 
t½ (h) 
AUC0-t 
(μM∙h)  
AUC0-τ 
(μM∙h)
a 
CL/F (L/h) 
50 mg QD 
3 
0.396 ± 0.172 
0.365 
2.0 
(1.0- 4.0) 
0.00 ± 0.00 
NC 
2.4 ± 0.26 
2.4 
1.39 ± 0.256 
1.37 
1.58 ± 0.31 
1.56 
73.8 ± 14.7 
73.0 
50 mg BID 
4 
0.742 ± 0.212 
0.715 
2.0 
(1.0-3.9) 
0.084 ± 0.063 
NC 
2.4 ± 0.56 
2.3 
2.74 ± 1.08 
2.58 
3.05 ± 1.36 
2.83 
43.3 ± 19.2 
40.3 
100 mg BID 
5 
1.23 ± 0.348 
1.19 
2.0 
(1.0-2.2) 
0.201 ± 0.111 
0.171 
3.3 ± 0.75 
3.2 
5.32 ± 2.16 
4.97 
5.77 ± 2.34 
5.38 
45.8 ± 20.9 
42.4 
300 mg BID 
5 
2.48 ± 0.515 
2.44 
2.0 
(1.0-2.0) 
0.287 ± 0.146 
0.251 
3.9 ± 2.1 
3.5 
8.92 ± 0.841 
8.88 
9.78 ± 0.86 
9.75 
70.4 ± 6.19 
70.2 
400 mg BID 
8 
4.39 ± 2.02 
3.88 
2.0 
(1.0-6.0) 
0.624 ± 0.339 
0.523 
2.7 ± 0.62 
2.6 
16.7 ± 6.79 
15.0 
19.6 ± 7.43 
17.6 
62.3 ± 52.3 
51.8 
500 mg BID 
5 
4.82 ± 2.26 
4.48 
2.0 
(2.0-2.4) 
0.604 ± 0.260 
0.562 
2.4 ± 0.37 
2.4 
18.2 ± 6.46 
17.3 
20.6 ± 6.82 
19.7 
60.5 ± 19.1 
58.0 
600 mg BID 
12 
4.82 ± 2.16 
4.52 
2.0 
(1.0-2.1) 
0.932 ± 0.704 
0.731 
3.3 ± 0.97 
3.2 
19.5 ± 8.4 
18.3 
22.9 ± 10.0 
21.6 
66.4 ± 18.6 
63.5 
700 mg BID 
4 
6.23 ± 2.09 
6.00 
3.0 
(2.0-4.5) 
1.32 ± 0.417 
1.26 
3.0 ± 1.2 
2.9 
30.8 ± 10.5 
29.6 
35.8 ± 15.5 
33.9 
49.5 ± 17.1 
47.2 
P-values from a 1-factor ANOVA (factor = dose) of log-transformed exposures after dose normalization 
Dose 
 
0.0051 
 
 
 
 
0.0961 
 
NC = not calculable. 
Note:  Values are mean ± SD and geometric mean, except Tmax is reported as median (range).  
a The t½ and hence AUC0-12h values could not be estimated for 4 subjects. 
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In general, as single agents, epacadostat and durvalumab have been well tolerated in this study 
population that has significant comorbidities. 
It should be noted that the initial evaluation of epacadostat at 300 mg BID in combination with 
ipilimumab (Study INCB 24360-201) was terminated due to the occurrence of Grade 3 or 4 
ALT/AST elevation in 5 of 7 subjects treated at this dose.  These AEs were reversible in all 
subjects upon discontinuation of study therapy and institution of corticosteroids based on an 
established protocol for the management of immune toxicities related to ipilimumab therapy.  
The study was subsequently amended, and preliminary data suggest that doses of epacadostat up 
to 50 mg BID are well tolerated with ipilimumab.  In the 25 mg cohort, 1 DLT of Grade 3 AST 
elevation was observed.  Four DLTs (Grade 3 diarrhea, Grade 3 colitis, Grade 3 pneumonitis, 
and Grade 3 ALT/AST elevation) have been observed in the 50 mg BID continuous dosing 
cohort among 18 evaluable subjects, and 1 occurrence of Grade 3 colitis has been observed in the 
50 mg BID intermittent dosing cohort (2 weeks on/1 week off) among 9 evaluable patients.  In 
the 75 mg total daily dose cohort (50 mg every morning and 25 mg every evening), there was 
1 DLT of Grade 3 rash among 7 evaluable subjects.  The most common all-grade irAEs were 
rash (52.4%), pruritus (38.1%), diarrhea (33.3%), increased ALT and AST (21.4% and 16.7%), 
and hypothyroidism (11.9%).  irAEs ≥ Grade 3 occurring in > 1 subject were AST elevation and 
colitis (n = 4 [9.5%] each) and ALT elevation (n = 3 [7.1%]).  Other treatment-emergent AEs 
occurring in ≥ 20% of subjects overall included fatigue (n = 29 [69%]); constipation and nausea 
(n = 13 [31%] each); decreased appetite and headache (n = 11 [26%] each); and vomiting (n = 10 
[24%]; Gibney et al 2015).  Adverse events reported in this study were consistent with what has 
been reported previously in subjects treated with ipilimumab monotherapy (iIB).  Complete 
inhibition of the IDO1 target is not required for maximally effective activity in preclinical 
models.  As monotherapy, maximally effective doses in nonclinical models result in exposures 
that are comparable to doses of 25 to 50 mg BID in humans. 
1.5. 
Rationale for Endpoints 
1.5.1. 
Efficacy Endpoints 
The primary efficacy objective of this study is to evaluate activity of study treatment using ORR 
as per investigator assessed response using modified RECIST v1.1 (mRECIST v1.1).  Modified 
RECIST v1.1 will also be used by the local site to determine eligibility and make treatment 
decisions.  Imaging will be collected and held for possible future central imaging vendor 
assessment. 
Immunotherapeutic agents such as durvalumab work to enhance antitumor immune responses 
and these response patterns may lead to a clinical benefit (eg, CR, PR, SD) after an initial 
increase in tumor burden that may be classified as PD by standard RECIST criteria 
(Wolchok et al 2009).  Standard RECIST criteria may not provide an adequate response 
assessment of immunotherapeutic agents such as durvalumab.  Therefore, RECIST v1.1 will be 
used with the following modification (and defined as mRECIST v1.1). 
Progressive disease should be confirmed a minimum of 4 weeks after the initial radiologic 
indication of PD.  If the confirmation scan shows a decrease in the tumor burden, study treatment 
may be continued or resumed.  If PD is confirmed the subject will be discontinued from study 
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treatment.  Clinically stable subjects have the option of continuing study treatment per the 
investigator's discretion while waiting for radiologic confirmation of progression. 
Clinically stable for this purpose is defined by the following criteria: 
• Absence of signs and symptoms indicating disease progression. 
• No decline in ECOG performance status. 
• Absence of rapid progression of disease. 
• Absence of progressive tumor at critical anatomical sites (eg, spinal cord 
compression) requiring urgent alternative medical intervention. 
Subjects who are deemed clinically unstable are not required to have repeat imaging for 
confirmation of PD.  Additional information regarding mRECIST v1.1 is provided in 
Section 7.4. 
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3. 
SUBJECT ELIGIBILITY 
3.1. 
Study Population 
Subjects with histologically or cytologically confirmed advanced melanoma, NSCLC, pancreatic 
cancer (Phase 1 only), SCCHN, TNBC, gastric or GE junction cancer, and TCC of the GU tract 
will be enrolled. 
3.2. 
Subject Inclusion Criteria 
The following criteria are required for inclusion in the study: 
1. Male or female subjects, age 18 years or older. 
2. Ability to comprehend and willingness to sign an ICF. 
3. Histologically or cytologically confirmed diagnosis of melanoma, NSCLC, pancreatic 
cancer (Phase 1 only), SCCHN, TNBC, gastric or GE junction cancer, or TCC of the GU 
tract that is locally advanced (not amenable to curative therapy such as surgical resection) 
or metastatic. 
4. Must have failed at least 1 prior treatment regimen for locally advanced or metastatic 
disease or be intolerant to treatment or refuse standard treatment.  Investigational agents 
used in combination with standard therapies are allowed.  Adjuvant, neoadjuvant, or 
chemoradiation regimens given within 6 months of screening would be counted as having 
received 1 prior systemic regimen and would not require an additional systemic regimen 
for advanced or metastatic disease. 
5. For subjects with metastatic melanoma: 
a. Must have known V600E activating BRAF mutation status or consent to BRAF 
V600E mutation testing during screening.  Testing should be performed in a CLIA 
certified laboratory.  BRAF mutation status determined as part of a panel of genetic 
tests performed in gene expression analysis will also satisfy the inclusion criterion for 
BRAF mutation testing. 
b. May be treatment-naive or have received prior treatment with an anti–CTLA-4 or 
anti–PD-1 targeted agent.  Note:  In Phase 1, subjects who are BRAF mutation 
positive must have received prior treatment with a BRAF inhibitor with or without a 
MEK inhibitor. 
c. Ocular melanoma will be excluded. 
6. For subjects with NSCLC: 
a. Subjects who have tumors with driver mutations (eg, EGFR mutation positive or 
anaplastic lymphoma kinase fusion oncogene positive) must have received treatment 
with a targeted therapy and have progressed or be intolerant, if a targeted agent is 
available for the specific driver mutation. 
b. Subjects may have received prior treatment with an anti–PD-1 targeted agent. 
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7. For subjects with pancreatic cancer (Phase 1 only): 
a. Subjects in Phase 1 must have an exocrine pancreatic neoplasm. 
Note:  Exocrine pancreatic neoplasms include all tumors related to the pancreatic 
ductal and ancinar cells and their stem cells. 
8. For subjects with SCCHN: 
a. Histology of squamous cell carcinoma. 
b. Carcinoma of the nasopharynx and salivary gland will be excluded. 
c. Prior systemic regimens must include a platinum-based therapy.  Investigational 
agents used in combination with standard therapies are allowed.  Subjects who 
relapse within 6 months of adjuvant therapy, including a platinum-containing 
regimen, may enroll. 
9. For subjects with TNBC: 
a. Histologically or cytologically confirmed breast adenocarcinoma that is unresectable 
or metastatic. 
b. Subjects with breast cancer history of different phenotypes (ie, ER/PgR/HER2 
positive) must have pathologic confirmation of triple-negative disease from the most 
current biopsy. 
c. Pathologically confirmed as triple negative, source documented, defined as both of 
the following: 
i) ER and PgR negative:  < 1% of tumor cell nuclei is immunoreactive in the 
presence of evidence that the sample can express ER or PgR (positive intrinsic 
controls). 
ii) HER2 negative as per ASCO/CAP HER2 test guidelines. 
Note:  HER2 test result should be reported as negative if a single test or all 
tests performed in a tumor specimen show the following: 
• IHC 1+ as defined by incomplete membrane staining that is faint/barely 
perceptible and within > 10% of the invasive tumor cells. 
• IHC result is 0 as defined by no staining observed or membrane staining 
that is incomplete and is faint/barely perceptible and within ≤ 10% of the 
invasive tumor cells. 
• In situ hybridization (ISH) assay is negative based on a single probe 
average HER2 copy number < 4.0 signals/cell or dual probe 
HER2/CEP17 ratio < 2.0 with an average HER2 copy number < 4.0 
signals/cell. 
• If results are equivocal, reflex testing (same specimen using the 
alternative test or new specimen, if available) should be performed using 
an alternative assay (IHC or ISH). 
10. For subjects with TCC of the GU tract: 
a. Histologically or cytologically confirmed TCC of the bladder, ureter, or renal pelvis 
or mixed histology bladder cancer. 
b. Metastatic or locally advanced and not amenable to curative therapy with disease 
progression on or after platinum-based chemotherapy or alternative therapy if 
platinum-based therapy is not appropriate. 
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11. For subjects with gastric or GE junction cancer: 
a. Histologically or cytologically confirmed diagnosis of gastric or GE junction 
adenocarcinoma. 
b. Progression on or after therapy containing platinum/fluoropyrimidine. 
c. Documentation of HER2/neu status. 
12. Presence of measurable disease per RECIST v1.1 guidelines. 
13. Life expectancy > 12 weeks. 
14. ECOG performance status 0 to 1. 
15. Fresh baseline tumor biopsies (fresh baseline biopsy is defined as a biopsy specimen 
taken within 28 days prior to Cycle 1 Day 1) are required at baseline as specified in 
Section 7.6.3.2, except if inaccessible with medical monitor approval.  Archival tissue 
should also be submitted if available.  
Note:  If a fresh baseline biopsy is inaccessible, an archival specimen should be 
submitted. 
16. Female subjects of childbearing potential (defined as women who have not undergone 
surgical sterilization with a hysterectomy and/or bilateral oophorectomy, and are not 
postmenopausal, defined as ≥ 12 months of amenorrhea) must have a negative serum 
pregnancy test at screening.  All female subjects of childbearing potential (and male 
subjects) must agree to take appropriate precautions to avoid pregnancy (or fathering 
children) (with at least 99% certainty) from screening through the 90-day safety 
follow-up visit.  Permitted methods that are at least 99% effective in preventing 
pregnancy (Appendix A) should be communicated to the subject and their understanding 
confirmed.  
Note:  Male subjects should refrain from sperm donation from screening through 90 days 
after the last dose of study drug. 
3.3. 
Subject Exclusion Criteria 
If met, any of the following criteria will lead to exclusion from the study: 
1. Laboratory and medical history parameters not within the Protocol-defined range.  All 
screening laboratory tests should be performed within 7 days of treatment initiation. 
a. ANC < 1.5 × 109/L. 
b. Platelets < 75 × 109/L. 
c. Hemoglobin < 9 g/dL or < 5.6 mmol/L (transfusion is acceptable to meet this 
criterion). 
d. Serum creatinine ≥ 1.5 × institutional ULN OR measured or calculated creatinine 
clearance (glomerular filtration rate can also be used in place of creatinine or CrCl) 
< 50 mL/min for subjects with creatinine levels > 1.5 × institutional ULN. 
e. AST or ALT > 2.5 × institutional ULN OR > 5 × ULN for subjects with liver 
metastases. 
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f. Total bilirubin > 1.5 × ULN OR direct bilirubin > institutional ULN for subjects with 
total bilirubin levels > 1.5 × ULN. 
-  If there is no institutional normal range available for the direct bilirubin, the direct 
bilirubin should be < 40% of the total bilirubin. 
-  In no case can total bilirubin exceed 3.0 × ULN. 
g. INR or PT > 1.5 × ULN (unless subject is receiving anticoagulant therapy, then 
subject may be included as long as PT or INR is within therapeutic range of intended 
use of anticoagulants). 
h. aPTT > 1.5 × ULN (unless subject is receiving anticoagulant therapy, then subject 
may be included as long as aPTT is within therapeutic range of intended use of 
anticoagulants). 
2. Current pregnancy or breastfeeding. 
3. Participation in any other study in which receipt of an investigational study drug occurred 
within 28 days or 5 half-lives (whichever is longer) prior to the first dose.  For 
investigational agents with long half-lives (eg, 5 days), enrollment prior to the fifth 
half-life requires medical monitor approval. 
4. Receipt of prior immune checkpoint inhibitors (eg, anti-CTLA-4, anti–PD-1, anti–PD-L1, 
and any other antibody or drug specifically targeting T-cell costimulation) or an IDO 
inhibitor.  Subjects who have received experimental vaccines or other immune therapies 
should be discussed with the medical monitor to confirm eligibility. 
Note:  The exception to this exclusion criterion would be subjects who have received a 
prior anti–CTLA-4 or PD-1 pathway targeted agent for indications in which an  
anti–CTLA-4 or PD-1 pathway targeted agent has been approved (eg, melanoma).  In 
this case, the subject would be eligible to participate in the study. 
5. Receipt of an immunologically based treatment for any reason, including chronic use of 
systemic steroid at doses ≥ 10 mg/day prednisone equivalent within 14 days prior to the 
first dose of study treatment.  Use of inhaled or topical steroids or systemic 
corticosteroids < 10 mg is permitted. 
6. Receipt of any anticancer medication in the 21 days prior to receiving their first dose of 
study medication or any unresolved toxicity > Grade 1 from previous anticancer therapy, 
except for stable chronic toxicities not expected to resolve, such as peripheral 
neurotoxicity.  Prior treatment with nitrosureas (eg, carmustine or lomustine) require a 
6-week washout prior to the first dose of study treatment. 
7. Major surgical procedure (as defined by the investigator, with the exception of local 
surgery of isolated lesions for palliative intent) within 28 days of starting study treatment 
OR inadequate recovery from toxicity and/or complications from major surgery before 
starting study treatment. 
8. History of other malignancy within 2 years of study entry, with the exception of cured 
basal cell or squamous cell carcinoma of the skin, superficial bladder cancer, prostate 
intraepithelial neoplasm, carcinoma in situ of the cervix, or other noninvasive or indolent 
malignancy, or cancers from which the subject has been disease-free for ≥ 1 year 
following treatment with curative intent. 
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9. Untreated CNS metastases or carcinomatous meningitis, or CNS metastases that have 
progressed (eg, evidence of new or enlarging CNS metastasis or new neurological 
symptoms attributable to CNS metastases).  Subjects with treated and clinically stable 
CNS metastases (defined as 2 brain images at least 4 weeks apart, both of which were 
obtained after treatment to the brain metastases) and who are off all corticosteroids for at 
least 2 weeks are eligible. 
Any active or inactive autoimmune process or inflammatory disorder (including  
rheumatoid arthritis, moderate or severe psoriasis, multiple sclerosis, sarcoidosis 
syndrome, diverticulitis [with the exception of diverticulosis], inflammatory bowel 
disease, systemic lupus erythematosus, Wegener syndrome [granulomatosis with 
polyangiitis, Graves' disease, hypophysitis, uveitis, etc]) or receipt of systemic therapy 
for an autoimmune or inflammatory disease. 
Note:  Exceptions include subjects with vitiligo, hypothyroidism stable on hormone 
replacement, controlled asthma, Graves' disease, or Hashimoto's disease, celiac disease 
controlled by diet alone, or with medical monitor approval.  Subjects without active 
disease in the last 5 years may be included but only after consultation with medical 
monitor. 
10. Evidence of interstitial lung disease or active, noninfectious pneumonitis. 
11. Prior radiotherapy within 2 weeks of therapy.  Subjects must have recovered from all 
radiation-related toxicities, not require corticosteroids, and not have had radiation 
pneumonitis.  A 1-week washout is permitted for palliative radiation to non-CNS disease 
with medical monitor approval. 
12. Active infection requiring systemic therapy. 
13. History of organ transplant that requires use of immunosuppressives. 
14. Presence of a gastrointestinal condition that may affect drug absorption. 
15. Known history of human immunodeficiency virus infection or known history of or is 
positive for hepatitis B (eg, HBsAg reactive or HBV DNA detected) or hepatitis C 
(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. 
16. Receipt of MAOIs within the 21 days prior to the first dose of study treatment. 
17. History of SS after receiving 1 or more serotonergic drugs. 
18. Any condition that would jeopardize the safety of the subject or compliance with the 
Protocol. 
19. Receipt of live attenuated vaccination within 30 days prior to study entry or within 
30 days of receiving durvalumab. 
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20. History or presence of an abnormal ECG that, in the investigator's opinion, is clinically 
meaningful.  Screening QTc interval > 480 msec is excluded (corrected by Fridericia or 
Bazett's formula).  In the event that a single QTc is > 480 msec, the subject may be 
enrolled if the average QTc for the 3 ECGs is ≤ 480 msec.  For subjects with an 
intraventricular conduction delay (QRS interval ≥ 120 msec), the JTc interval may be 
used in place of the QTc with sponsor approval.  The JTc must be < 340 msec if JTc is 
used in place of the QTc.  Subjects with left bundle branch block are excluded. 
21. Clinically significant cardiac disease, including unstable angina, acute myocardial 
infarction within 6 months from Day 1 of study drug administration, New York Heart 
Association Class III or IV congestive heart failure, and arrhythmia requiring therapy. 
Note:  A subject with an arrhythmia may enroll if the subject is on anti-arrhythmic 
medication and is in sinus rhythm on the screening ECG. 
22. Any prior ≥ Grade 3 irAE while receiving immunotherapy, including anti−PD-1, 
anti−PD-L1, or anti−CTLA-4 treatment, or any unresolved irAE > Grade 1.  Must not 
have experienced a toxicity that led to permanent discontinuation of prior 
immunotherapy.  Subjects with endocrine AEs ≤ Grade 2 are permitted to enroll if they 
are stably maintained on appropriate replacement therapy and are asymptomatic.  
Subjects with prior anti−PD-1, anti−PD-L1, or anti−CTLA-4 therapy must not have 
required the use of additional immunosuppression other than corticosteroids for the 
management of an AE, not have experienced recurrence of an AE if rechallenged, and not 
currently require maintenance doses of > 10 mg prednisone or equivalent per day. 
Note:  Previous immune-related ocular or neurologic toxicity of any grade is excluded. 
23. Known allergy or reaction to any component of either study drug formulation. 
24. Subjects who require ongoing thoracentesis or paracentesis for palliation must be 
discussed with the medical monitor to determine eligibility. 
25. History of primary immunodeficiency. 
26. History of leptomeningeal carcinomatosis. 
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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
This is a Phase 1/2 open-label study of epacadostat administered in combination with 
durvalumab in subjects with advanced melanoma, NSCLC, pancreatic cancer (Phase 1 only), 
SCCHN, TNBC, gastric or GE junction cancer, or TCC of the GU tract.  The dose-escalation 
part of the study (Phase 1) uses a 3 + 3 design to identify the MTD or PAD of epacadostat in 
combination with durvalumab.  Phase 2 will further explore the safety and efficacy of the MTD 
or PAD of epacadostat in combination with durvalumab determined in Phase 1. 
The study will consist of 3 periods: 
Screening:  Up to 28 days. 
Treatment Period:  The treatment period will continue every 14 days for up to 12 months as 
long as subjects are receiving benefit from treatment and have not met any criteria for study 
withdrawal as defined in Section 5.7.1.  Once subjects complete 12 months of study treatment or 
permanently discontinue study treatment for any other reason, the EOT visit should be 
conducted, and they should enter the follow-up period of the study. 
Follow-Up Period:  The safety follow-up visits will occur at 42 days (±7 days) and 90 days 
(± 7 days) after the EOT visit or the last dose of study treatment if the EOT visit is not 
completed. 
4.1.1. 
Phase 1 Dose Escalation 
Phase 1 is the dose-escalation phase, which will include up to 6 cohorts of subjects treated with 
epacadostat at doses of 25 mg BID, 50 mg BID, 75 mg BID, 100 mg BID, and 300 mg BID in 
combination with durvalumab 3 mg/kg or 10 mg/kg given on Day 1 of each 14-day cycle.  A 
minimum of 3 subjects will be enrolled and treated in each cohort, and all 3 subjects will be 
observed for a minimum of 42 days before the subsequent cohort begins enrollment. 
Subjects must have received the cohort-specific dose of epacadostat for at least 75% of the doses 
(63 doses) and have received at least 3 doses of durvalumab during the 42-day DLT observation 
period, or have experienced a DLT to be evaluable for dose tolerability.  Additional subjects will 
be enrolled in a cohort to achieve the minimum of 3 evaluable subjects if dropouts or dose 
interruptions/reductions occur that result in a subject being nonevaluable for DLTs. 
The dose of epacadostat will be escalated if 0 of the first 3 evaluable subjects enrolled experience 
a DLT.  If 1 of the first 3 evaluable subjects enrolled experience a DLT, the cohort will be 
expanded to include 3 additional evaluable subjects.  If 2 or more of either 3 or 6 subjects 
enrolled experience a DLT, the prior dose level will be considered the MTD.  If only 3 subjects 
were treated at this dose level, the dose will be confirmed as the MTD by evaluation of an 
additional 3 subjects before this dose is recommended for Phase 2 testing. 
The cohorts and dose levels are shown in Table 4. 
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Table 4: 
Dosing Cohorts 
Cohort 
Maximum Daily Dose of Epacadostat 
Dose of Durvalumab (Once Every 14 Days) 
1 
25 mg BID orally 
3 mg/kg IV 
2 
25 mg BID orally 
10 mg/kg IV 
3 
50 mg BID orally 
10 mg/kg IV 
4 
75 mg BID orally 
10 mg/kg IV 
5 
100 mg BID orally 
10 mg/kg IV 
6 
300 mg BID orally
a 
10 mg/kg IV 
a Intermediate dose levels may be explored based on emerging PK or pharmacodynamic data. 
During the study, dose interruptions and/or dose decreases may be implemented based on 
toxicity as described in Section 5.6. 
For the definition of DLT, see Section 5.5.1. 
All subjects who received epacadostat and durvalumab in the dose-escalation phase and remain 
on study treatment will be observed for at least 42 days from the first dose prior to enrolling 
subjects in Phase 2 of the study. 
4.1.2. 
Phase 2 
Approximately 140 to 192 subjects with advanced melanoma, NSCLC, SCCHN, TNBC, gastric 
or GE junction cancer, and TCC of the GU tract will be enrolled at the MTD or PAD of 
epacadostat in combination with durvalumab.  More than 1 PAD may be evaluated in Phase 2.  
The approximate number of subjects needed for the melanoma, TNBC, and gastric and GE 
junction cancer cohorts will be determined using the Simon 2-stage design:  Stage 1 will be the 
initial number of subjects per tumor type, and the decision to proceed with Stage 2 will be 
determined by the response rate observed in Stage 1 (further number of subjects to be enrolled in 
each stage per tumor type is detailed in Table 5).  If more than 1 PAD is evaluated, the cohort 
may or may not be repeated for the specified tumor type as indicated in Table 5.  The sponsor 
may limit enrollment of a specific tumor type to Stage 1. 
Table 5: 
Approximate Number of Subjects by Tumor Type and Stage of Study 
Tumor Type 
No. of Subjects Enrolled 
Stage 1 
Stage 2 
(If Study Proceeds to Stage 2) 
Total 
(Stage 1 + 2) 
Melanoma 
15 
25 
40 
TNBC 
13 
16 
29 
Gastric and GE junction cancer 
9 
11 
20 
Under Amendment 6, enrollment of the NSCLC, SCCHN, and TCC of the GU tract cohorts will 
be completed as expansion cohorts at the 300 mg BID dose level.  The sample size for each 
cohort will be increased to account for the heterogeneity of PD-1 pathway–treated and PD-1 
pathway–naive subjects within the selected tumor types.  The approximate number of subjects 
per tumor type is listed in Table 6, and the number of PD-1 pathway–treated subjects in each 
cohort will be limited to 10 in order to reduce the risk of any cohort having a significant 
imbalance between PD-1 pathway–treated and PD-1 pathway–naive subjects, thereby preserving 
the predicted levels of baseline efficacy observed with PD-1 pathway monotherapy.  Subjects 
enrolled at the 100 mg BID dose level will be analyzed independently. 
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Table 6: 
Approximate Number of Subjects for Expansion Cohorts 
Tumor Type 
No. of Subjects Enrolled 
100 mg BID
a 
(n = 19) 
300 mg BID
b 
(n = 84) 
NSCLC 
8 
28 
SCCHN 
7 
28 
TCC of the GU tract 
4 
28 
a Subjects enrolled in the 100 mg BID dose level were enrolled before Amendment 5. 
b All subjects in the 300 mg BID NSCLC, SCCHN, and TCC of the GU tract cohorts enrolled in Amendment 5 or earlier are 
included in the total sample size. 
4.2. 
Study Endpoints 
4.2.1. 
Primary Endpoints 
• Phase 1:  MTD or PAD.  The MTD is defined by the highest dose cohort where no 
more than 1 of 6 subjects experience a DLT, or the highest Protocol-defined dose for 
each agent in the absence of exceeding the MTD.  Alternatively, the PAD is defined 
as a tolerated dose of epacadostat (in combination with durvalumab) that produces 
substantial pharmacological target inhibition.  Safety and tolerability will be assessed 
by monitoring the frequency, duration, and severity of AEs, through physical 
examinations, by evaluating changes in vital signs and ECGs, and through clinical 
laboratory blood and urine sample evaluations. 
• Phase 2:  Objective response rate determined by radiographic disease assessments per 
mRECIST v1.1 described in Sections 1.5.1 and 7.4. 
4.2.2. 
Secondary Endpoints 
• Phase 1:  Objective response rate determined by radiographic disease assessments per 
mRECIST v1.1. 
• Phase 2:  Safety and tolerability of the combination as assessed by monitoring the 
frequency, duration, and severity of AEs, through physical examinations, by 
evaluating changes in vital signs and ECGs, and through clinical laboratory blood and 
urine sample evaluations. 
• Phases 1 and 2:  Durability of response determined by radiographic disease 
assessment defined as the time from earliest date of disease response until earliest 
date of disease progression 
• Phases 1 and 2:  PFS determined from the date of randomization until disease 
progression or death. 
• Phases 1 and 2:  The endpoints for assessment of PK of durvalumab and epacadostat 
include individual durvalumab and epacadostat concentrations and PK parameters. 
• Phases 1 and 2:  The endpoints for assessment of immunogenicity of durvalumab 
include the number and percentage of subjects who develop detectable ADAs. 
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5. 
TREATMENT OF SUBJECTS 
5.1. 
Treatment Groups and Administration of Study Drug 
Subjects in Phase 1 will receive doses according to cohort enrollment.  Subjects in Phase 2 will 
receive the dose or doses selected by the sponsor upon review of Phase 1 data.  Study treatment 
should begin as close as possible to the date of enrollment. 
5.1.1. 
Epacadostat 
All BID doses of epacadostat will be taken orally morning and evening, approximately 12 hours 
apart without regard to food.  If the morning or evening dose is missed by more than 4 hours, 
that dose should be skipped and the next scheduled dose should be taken at the usual time.  If the 
subject vomits, an additional dose should not be taken.  Doses of epacadostat will be 
self-administered except the days scheduled to be given at the study clinic (see Section 7.6).  
Epacadostat should be taken just prior to beginning the infusion of durvalumab on days given in 
clinic.  Epacadostat will be given daily in combination with durvalumab for up to 12 months.  
Intrasubject dose escalation of epacadostat is not permitted. 
5.1.2. 
Durvalumab 
The dose of durvalumab will be calculated based on the subject's weight in kilograms.  
Durvalumab will be administered in the clinic as an IV infusion of 3 mg/kg or 10 mg/kg once 
every 14 days for up to 12 months.  Intrasubject dose escalation of durvalumab is not permitted 
except as defined in Section 5.6.1. 
5.1.2.1. 
Durvalumab Treatment Administration 
Durvalumab will be administered as an IV infusion over approximately 60 minutes 
(± 5 minutes).  The IV line will be flushed with a volume of normal saline equal to the priming 
volume of the infusion set used after the contents of the IV bag are fully administered (unless 
prohibited by institutional practice).  No incompatibilities have been observed between 
durvalumab and polypropylene, polyethylene, polyolefin copolymers, or polyvinylchloride. 
Since the compatibility of durvalumab with other IV medications and solutions, other than 
normal saline (0.9% [w/v] sodium chloride for injection), is not known, the durvalumab solution 
should not be infused through an IV line in which other solutions or medications are being 
administered.  The date, start time, interruption, and completion time of durvalumab 
administration must be recorded in the source documents. 
5.1.2.2. 
Monitoring of Durvalumab Administration 
Subjects will be monitored during and after infusion with assessment of vital signs at the 
beginning of the infusion (± 5 minutes), every 15 minutes (± 5 minutes) during the infusion of 
durvalumab, at the end of infusion (± 5 minutes), and at 30 minutes (± 5 minutes) and 
60 minutes (± 5 minutes) postinfusion.  Subjects will be monitored during a 3-hour 
(± 15 minutes) postinfusion period of observation after the first dose of durvalumab only.  For 
subsequent doses, the 3-hour observation period will not be required unless a subject experiences 
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an infusion-related reaction.  If the infusion takes longer than 60 minutes, then the vital signs 
assessments should follow the principles as described above. 
In the event of ≤ Grade 2 infusion-related reaction, the infusion rate of durvalumab may be 
decreased by 50% or interrupted until resolution of the event (up to 4 hours) and reinitiated at 
50% of the initial rate until completion of the infusion.  In subjects experiencing ≤ Grade 2 
infusion-related reaction, subsequent infusions may be administered at 50% of the initial rate.  
Acetaminophen and/or an antihistamine (eg, diphenhydramine) or equivalent medications per 
institutional standard may be administered at the discretion of the investigator.  If the 
infusion-related reaction is ≥ Grade 3 in severity, treatment with durvalumab will be 
discontinued.  As with any antibody, allergic reactions to dose administration are possible.  
Appropriate drugs and medical equipment to treat acute anaphylactic reactions must be 
immediately available, and study personnel must be trained to recognize and treat anaphylaxis.  
The study site must have immediate access to emergency resuscitation teams and equipment in 
addition to the ability to admit subjects to an intensive care unit if necessary. 
5.2. 
Treatment Compliance 
Treatment compliance with all study-related medications should be emphasized to the subject by 
the site personnel, and appropriate steps should be taken to optimize compliance during the 
study.  Subjects will bring all unopened, empty, and unused bottles of epacadostat with them to 
each study visit.  Investigative site staff will perform a count of returned tablets to assess 
compliance, and this information will be entered into the CRF.  Bottles of study drug, including 
unopened, partially opened, or empty bottles cannot be destroyed or returned to the depot until a 
monitor reviews and verifies all tablet counts for compliance.  Compliance with durvalumab will 
also be documented in the medical record and monitored by the sponsor or its designee. 
5.3. 
Randomization and Blinding 
This is not a randomized or blinded study. 
5.4. 
Duration of Treatment and Subject Participation 
Each subject enrolled in the study will continue receiving combination study treatment in 
continuous 14-day cycles for up to 12 months as long as subjects are receiving clinical benefit 
and have not met any criteria for study withdrawal.  When a subject discontinues all study 
treatment, the treatment period will end, the EOT visit should be conducted, and the subject will 
enter the safety follow-up period (see Section 6.4). 
Protocol Amendment 6 (28 JUN 2017) removed the option for subjects to receive epacadostat 
monotherapy once they completed 12 months of combination therapy with durvalumab.  
However, subjects already receiving epacadostat monotherapy prior to Amendment 6 were 
allowed to continue if they were receiving clinical benefit and their investigator felt it was in the 
best interest of the subject.  These subjects will be allowed to continue epacadostat monotherapy 
for up to an additional 12 months, and their maximum overall study treatment duration should 
not exceed 24 months.  Exceptions for these subjects to continue study treatment beyond 
24 months will require medical monitor review and approval every 3 months. 
Study participation is expected to average about 6 months. 
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5.5. 
Rationale for Dose Modification 
The purpose of the dose-escalation portion of the study (Phase 1) is to establish a suitable dose of 
epacadostat in combination with durvalumab. 
A 42-day DLT window, along with regular internal reviews of safety events, will be used for the 
dose-escalation phase of the study.  While the rules for adjudicating DLTs in the context of dose 
escalation/cohort expansion are specified in Section 5.5.1, an AE not listed above, or an AE 
meeting the DLT criteria above but occurring outside of the DLT period, may be defined as a 
DLT after consultation between the sponsor and investigator, based on the emerging safety 
profile.  The final recommended dose for the dose-expansion phase will be based on the review 
of the safety and tolerability data, including cumulative toxicity from available cohorts. 
Independent of the determination of tolerability during Phase 1 of the study, subjects may require 
individual modification or interruption of epacadostat or durvalumab if necessitated by AEs, 
including irAEs.  Dose adjustments are summarized in Section 5.6. 
5.5.1. 
Definition of Dose-Limiting Toxicities 
Dose-limiting toxicities will be evaluated during the dose-escalation phase.  The period for 
evaluating DLTs will be from the time of first administration of study treatment until the planned 
administration of the fourth dose of durvalumab, 42 days from receiving the first doses of 
epacadostat and durvalumab.  Subjects who do not remain on the study up to this time for 
reasons other than DLT will be replaced with another subject at the same dose level.  Grading of 
DLTs will be according to the NCI CTCAE v4.0.  A DLT will be defined as the occurrence of 
any treatment-related toxicity described in Table 7 occurring up to and including Study Day 42 
(6-week observation period).  Only toxicities with a clear alternative explanation (eg, due to 
disease progression, comorbid conditions, concomitant medications) or transient (≤ 72 hours) 
abnormal laboratory values without associated clinically significant signs or symptoms based on 
investigator determination can be deemed non-DLT.  Grade 3 irAEs (excluding ocular, 
pneumonitis, or colitis) that improve to ≤ Grade 1 by appropriate care or corticosteroid therapy 
within 14 days after the initiation of supportive care or corticosteroid therapy will not count as 
DLTs.  Subjects who may not have experienced a DLT but who experienced intolerable, lower 
grade persistent toxicity determined to be due to study drug or have experienced recurrent dose 
interruptions and/or reductions will be considered in the determination of the study drug doses to 
be used in Phase 2. 
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Table 7: 
Criteria for Defining Dose-Limiting Toxicities 
Hematologic Toxicities: 
• Grade 4 thrombocytopenia related to either drug 
• ≥ Grade 3 neutropenia lasting > 5 days related to either drug 
• Grade 4 anemia related to either drug 
• Febrile neutropenia (ANC < 1.0 × 109/L and fever > 101°F/38.3°C) related to either drug 
• Thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, disseminated intravascular coagulation, 
idiopathic thrombocytopenic purpura, ≥ Grade 3 hemolysis 
Nonhematologic Toxicities: 
• Any drug-related/immune-related
a Grade 4 toxicity  
• Any Grade 3 or 4 AST, ALT, or total bilirubin elevation 
• Any other drug-related/immune-relateda Grade 3 toxicity, EXCLUDING: 
− Grade 3 nausea/vomiting controlled by medical intervention within 72 hours 
− Grade 3 immune-related AEa (other than ocular events, colitis, and pneumonitis) that improves to Grade ≤ 1 or 
baseline within 14 days after the initiation of supportive care or corticosteroid therapy 
− Grade 3 endocrinopathy that is managed with or without systemic corticosteroid therapy and/or hormone 
replacement therapy and the subject is asymptomatic or minimally or transiently symptomatic based on 
Investigator assessment 
− Grade 3 fatigue lasting ≤ 7 days from onset 
− Grade 3 rash in the absence of desquamation, with no mucosal involvement, that does not require systemic 
steroids, that does not interfere with activities of daily living and resolves to Grade 1 by the next dose of 
durvalumab or 14 days, whichever is longer 
− Any grade vitiligo or alopecia 
• Grade 2 or higher episcleritis, uveitis, or iritis 
• Grade 2 pneumonitis that does not resolve to ≤ Grade 1 within 3 days of initiation of maximal supportive care 
General: 
• Greater than 2-week delay in starting Cycle 4 because of a treatment-related toxicity even if the toxicity does not 
meet DLT criteria defined above. 
• If subjects are unable to receive 75% of epacadostat or 3 doses of durvalumab during the DLT observation period 
because of drug-related toxicity, even if the toxicity does not meet DLT criteria defined above. 
• While the rules for adjudicating DLTs in the context of dose escalation are specified above, an AE not listed 
above may be defined as a DLT after a consultation with the sponsor and investigators, based on the emerging 
safety profile. 
a Immune-related AEs are defined as AEs of an immune nature (ie, inflammatory) in the absence of a clear alternative etiology.  
In the absence of a clinically significant abnormality, repeat laboratory testing will be conducted to confirm significant 
laboratory findings prior to designation as a DLT. 
5.5.2. 
Procedures for Cohort Review and Dose Escalation in Phase 1 
Telephone conferences will be scheduled by the sponsor with Phase 1 investigators in order to 
review cohort-specific data, overall safety data from prior cohorts (if applicable), and to agree on 
dose escalation.  For additional safety oversight, this group will review and adjudicate individual 
high-grade AEs as potentially dose-limiting and for guiding the study team on decisions 
regarding dose escalation and cohort expansion.  The same method will be employed for 
reviewing data in Phase 1 to determine the recommended dose for Phase 2. 
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5.5.2.1. 
Follow-Up for Dose-Limiting Toxicities 
Subjects whose treatment is discontinued due to a DLT must be followed until resolution or 
stabilization of the DLT event, whichever comes first. 
5.6. 
Dose Adjustment of Study Drug 
5.6.1. 
Planned Dose Increases 
Cohort dose escalation is described in Section 4.1.1. 
Intrasubject dose escalations of epacadostat are not permitted. 
Intrasubject dose escalation of durvalumab to 10 mg/kg every 2 weeks will be allowed only for 
subjects who were enrolled into the study at a dose of durvalumab 3 mg/kg every 2 weeks, 
provided that the following criteria are met: 
• The Protocol inclusion criteria are met. 
• The subject has not experienced related or possibly related toxicity ≥ Grade 2. 
• The next dose level of epacadostat 25 mg BID and durvalumab 10 mg/kg has been 
determined to be safe based on DLT rules (eg, no DLTs during the DLT observation 
period). 
• The subject is willing to submit to the PK
 sampling schedule and 
durvalumab infusion observation as in Cycle 1. 
• In the opinion of the investigator, the subject does not have any concurrent condition 
or circumstance that would complicate the dose escalation or PK sampling, or pose 
increased risk to the subject. 
• The intrasubject dose escalation has been approved by the sponsor. 
Note that if a subject dose escalates and experiences toxicity, guidance for dose interruption is 
provided in Sections 5.6.2 and 5.6.3.  In cases of persistent toxicity, dose de-escalation may be 
considered if approved by the medical monitor. 
5.6.2. 
Criteria and Procedures for Interruption or Dose Reduction 
In some circumstances, it may be necessary to temporarily interrupt treatment as a result of 
adverse experiences that may have an unclear relationship to study drug. 
Table 8 summarizes the dosing actions for epacadostat and durvalumab that must be 
implemented with the indicated related AEs.  Additional information related to dose changes and 
AE management for irAEs can be found in Section 5.6.3. 
In general, treatment with both study drugs should be withheld for ≥ Grade 3 irAEs or non-irAEs 
and may be withheld for ≥ Grade 2 irAEs.  Additional details for irAEs are provided in 
Section 5.6.3. 
If a criterion for dose reduction of epacadostat is met, refer to Table 9 to determine the 
appropriate dose for the subject.  There will be no dose reductions of durvalumab allowed for the 
management of toxicities of individual subjects (exception noted in Section 5.6.1).  Doses of 
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durvalumab may be delayed for toxicity management.  In general, study treatment should be 
discontinued for toxicities that do not resolve to Grade 1 or less within 4 weeks of onset.  
Exceptions to this must be discussed with the medical monitor. 
Note:  There may be some circumstances where, due to toxicity attributed to epacadostat, a 
subject may not tolerate the combination therapy but may benefit from monotherapy with 
durvalumab.  These cases must be discussed and approved by the medical monitor before the 
subject may receive durvalumab monotherapy on study. 
Any interruptions of > 4 weeks or for LFT abnormalities must be discussed with the medical 
monitor prior to resuming treatment. 
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 study 
drug that was interrupted for > 4 weeks due to an AE. 
Table 8: 
Dose Modification Guidelines of Epacadostat and Durvalumab for 
Non−Immune-Related Adverse Events 
Adverse Event 
CTCAE v4.0 
Grade 
Action With Respect to 
Epacadostat 
Action With Respect to 
Durvalumab 
Non-irAE (first 
occurrence) 
3 
Hold study treatment until 
resolution to ≤ Grade 1 or 
baseline.
a 
For AEs that downgrade to 
≤ Grade 2 within 7 days or 
resolve to ≤ Grade 1 or baseline 
within 14 days, resume study 
treatment administration. 
Otherwise, discontinue study 
treatment. 
Hold study treatment until 
resolution to ≤ Grade 1 or 
baseline.
a 
For AEs that downgrade to 
≤ Grade 2 within 7 days or 
resolve to ≤ Grade 1 or baseline 
within 14 days, resume study 
treatment administration. 
Otherwise, discontinue study 
treatment. 
Non-irAE (second 
occurrence) 
3 
Hold study treatment until 
resolution to ≤ Grade 1 or 
baseline.
a 
For AEs that downgrade to 
≤ Grade 2 within 7 days or 
resolve to ≤ Grade 1 or baseline 
within 14 days, resume study 
treatment administration. 
Otherwise, discontinue study 
treatment. 
Hold study treatment until 
resolution to ≤ Grade 1 or 
baseline.
a 
For AEs that downgrade to 
≤ Grade 2 within 7 days or 
resolve to ≤ Grade 1 or baseline 
within 14 days, resume study 
treatment administration. 
Otherwise, discontinue study 
treatment. 
Non-irAE (third 
occurrence) 
3 
Discontinue epacadostat. 
Hold study treatment until 
resolution to ≤ Grade 1 or 
baseline.
a 
For AEs that downgrade to 
≤ Grade 2 within 7 days or 
resolve to ≤ Grade 1 or baseline 
within 14 days, resume study 
treatment administration. 
Otherwise, discontinue study 
treatment. 
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Table 8: 
Dose Modification Guidelines of Epacadostat and Durvalumab for 
Non−Immune-Related Adverse Events (Continued) 
Adverse Event 
CTCAE v4.0 
Grade 
Action With Respect to 
Epacadostat 
Action With Respect to 
Durvalumab 
Non-irAE 
4 
Discontinue epacadostat. 
Discontinue durvalumab. 
Infusion-related 
reactions 
1 or 2 
Not applicable. 
The infusion rate of durvalumab 
may be decreased by 50% or 
temporarily interrupted until 
resolution of the event.  
For Grade 2 infusion-related 
reactions, subsequent infusions 
may be given at 50% of the initial 
infusion rate. 
• Acetaminophen and/or 
antihistamines may be 
administered per institutional 
standards at the discretion of 
the investigator. 
• Consider premedication prior 
to subsequent doses. 
• Steroids should not be used for 
routine premedication of 
≤ Grade 2 infusion reactions. 
Infusion-related 
reactions 
≥ 3 
Discontinue epacadostat. 
Discontinue durvalumab. 
Manage severe infusion-related 
reactions per institutional 
standards (eg, intramuscular 
epinephrine followed by IV 
diphenhydramine and ranitidine, 
and IV glucocorticoid). 
a If event is a laboratory AE without associated clinically significant signs or symptoms, as determined by the principal 
investigator, the subject may continue study treatment administration with approval from the medical monitor as long as steroid 
treatment has not been planned or initiated.  Laboratory testing should be repeated within 72 hours.  If the AE does not resolve 
to ≤ Grade 1 in 7 days, the subject should then interrupt study treatment until event has resolved to ≤ Grade 1 and restart at the 
next lower dose level. 
Table 9: Dose Reductions for Epacadostat 
Current Dose 
Dose Reduction 
25 mg BID 
Discontinue epacadostat 
50 mg BID 
25 mg BID 
75 mg BID 
50 mg BID 
100 mg BID 
75 mg BID 
300 mg BID 
100 mg BID 
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5.6.3. 
Criteria for Subjects Exhibiting Immune-Related Adverse Events 
This section is meant to apply to suspected irAEs from epacadostat, durvalumab, or the 
combination.  Immune-related AEs may be predicted based on the nature of the durvalumab or 
epacadostat compounds, their mechanism of action, and reported experience with 
immunotherapies that have a similar mechanism of action.  Special attention should be paid to 
AEs that may be suggestive of potential irAEs.  An irAE can occur shortly after the first dose or 
several months after the last dose of treatment. 
If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, 
toxin, or other etiologic causes prior to labeling an AE as an irAE.  Subjects who develop a 
≥ Grade 2 irAE should be discussed immediately with the medical monitor. 
Recommendations for management of specific immune-mediated AEs such as pneumonitis 
(see Section 5.6.3.1), enterocolitis (see Section 5.6.3.2), hepatitis (see Section 5.6.3.3), dermatitis 
(see Section 5.6.3.4), immune-mediated neuropathies (see Section 5.6.3.5), immune-mediated 
endocrinopathies (see Section 5.6.3.6), immune-mediated nephritis or renal dysfunction 
(see Section 5.6.3.7), and ocular manifestations (see Section 5.6.3.8) are detailed in the sections 
below. 
General recommendations to managing irAEs not detailed elsewhere in this section are detailed 
in Section 5.6.3.12. 
5.6.3.1. 
Procedures and Guidelines for Pneumonitis 
Subjects with symptomatic pneumonitis should immediately stop receiving durvalumab and 
epacadostat and have an evaluation.  Subjects should be monitored for signs and symptoms of 
pneumonitis or interstitial lung disease.  The evaluation may include imaging (high resolution 
CT scan), bronchoscopy, and pulmonary function tests such as monitoring of oxygenation via 
pulse oximetry (resting and exertion) and laboratory work-up to rule out other causes such as 
infection.  If the subject is determined to have study drug−associated pneumonitis, the suggested 
treatment plan is detailed in Table 10. 
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Table 10: 
Recommended Approach for Handling Noninfectious Pneumonitis 
Toxicity 
Grade 
Withhold/Discontinue 
Durvalumab and 
Epacadostat 
Guidance for Restarting 
Study Treatment 
Supportive Care 
Grade 1 
(asymptomatic) 
No action. 
Note:  Consider 
holding study treatment 
as clinically 
appropriate during 
diagnostic work-up for 
other etiologies. 
Not applicable. 
For Grade 1 (radiographic changes 
only): 
• Monitor and closely follow up in 
2-4 days for clinical symptoms, 
pulse oximetry (resting and 
exertion), and laboratory work-up 
and then as clinically indicated. 
• Consider pulmonary and infectious 
disease consult. 
Grade 2 
Withhold epacadostat 
and durvalumab. 
Note:  Permanently 
discontinue study 
treatment if upon 
rechallenge subject 
develops pneumonitis 
≥ Grade 2. 
Hold treatment until 
resolution to ≤ Grade 1 or 
baseline. 
• If toxicity improves to 
≤ Grade 1 or baseline, then 
the decision to reinitiate 
study treatment will be 
based on treating 
physician's clinical 
judgment and after 
completion of steroid taper. 
• If toxicity worsens, treat as 
Grade 3 or Grade 4. 
For Grade 2 (mild to moderate new 
symptoms): 
• Monitor symptoms daily and 
consider hospitalization. 
• Promptly start systemic steroids 
(eg, prednisone 1-2 mg/kg per day 
PO or IV equivalent). 
• Reimaging as clinically indicated. 
• If no improvement within 3-5 days, 
additional work-up should be 
considered, and prompt treatment 
with IV methylprednisolone 
2-4 mg/kg per day should be started. 
• If still no improvement within 
3-5 days despite IV 
methylprednisone at 2-4 mg/kg per 
day, promptly start 
immunosuppressive therapy such as 
tumor necrosis factor inhibitors 
(eg, infliximab 5 mg/kg every 
2 weeks). 
Caution:  Important to rule out 
sepsis and refer to infliximab label 
for general guidance before using 
infliximab. 
• Once improving, gradually taper 
steroids over ≥ 28 days and consider 
prophylactic antibiotics, antifungal 
or anti-PCP treatment (refer to 
current NCCN Guidelines for 
treatment of cancer-related 
infections [Category 2B 
recommendation]). 
• Consider pulmonary and infectious 
disease consult. 
• Consider discussing with medical 
monitor as necessary. 
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Table 10: 
Recommended Approach for Handling Noninfectious Pneumonitis 
(Continued) 
Toxicity 
Grade 
Withhold/Discontinue 
Durvalumab and 
Epacadostat 
Guidance for Restarting 
Study Treatment 
Supportive Care 
Grade 3 and 
Grade 4 
Discontinue 
epacadostat and 
durvalumab. 
Not applicable. 
For Grade 3 or Grade 4 (severe or 
new symptoms, new/worsening 
hypoxia, life threatening): 
• Promptly initiate empiric IV 
methylprednisolone 1-4 mg/kg per 
day or equivalent. 
• Obtain pulmonary and infectious 
disease consult. 
• Hospitalize the subject. 
• Supportive care (oxygen, etc). 
• If no improvement within 3-5 days, 
additional work-up should be 
considered and prompt treatment 
with additional immunosuppressive 
therapy such as tumor necrosis 
factor inhibitors (eg, infliximab at 
5 mg/kg every 2 weeks) started. 
Caution:  Rule out sepsis and refer 
to infliximab label for general 
guidance before using infliximab. 
• Once improving, gradually taper 
steroids over ≥ 28 days and consider 
prophylactic antibiotics, antifungals, 
and, in particular, anti-PCP 
treatment (refer to current 
NCCN Guidelines for treatment of 
cancer-related infections 
[Category 2B recommendation]). 
PCP = pneumocystis pneumonia. 
5.6.3.2. 
Procedures and Guidance for Enterocolitis 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such 
as sepsis, peritoneal signs, and ileus).  In symptomatic subjects, rule out infectious etiologies and 
consider endoscopic evaluation for persistent or severe symptoms. 
Subjects should be thoroughly evaluated to rule out any alternative etiology (eg, disease 
progression, other medications, infections including testing for clostridium difficile toxin, etc).  
Steroids should be considered in the absence of clear alternative etiology, even for low grade 
events, in order to prevent potential progression to higher grade event.  Use analgesics carefully; 
they can mask symptoms of perforation and peritonitis.  The recommended approach for 
handling enterocolitis is detailed in Table 11. 
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Table 11: 
Recommended Approach for Handling Enterocolitis 
Toxicity 
Grade  
Withhold/Discontinue 
Durvalumab and 
Epacadostat 
Guidance for Restarting 
Study Treatment 
Supportive Care 
Grade 1 
No action. 
Not applicable. 
• Closely monitor for worsening 
symptoms. 
• Consider symptomatic treatment, 
including hydration, electrolyte 
replacement, dietary changes 
(eg, American Dietetic Association 
colitis diet), and loperamide.  Use of 
probiotics as per treating physician's 
clinical judgment. 
Grade 2 
Withhold durvalumab 
and epacadostat. 
Hold treatment until 
resolution to ≤ Grade 1 or 
baseline. 
• If toxicity improves to 
≤ Grade 1, then study 
treatment can be 
resumed after 
completion of steroid 
taper.  Epacadostat will 
be reduced by 1 dose 
level, and durvalumab 
will resume at the same 
dose/schedule. 
• If toxicity worsens, 
treat as Grade 3 or 
Grade 4. 
• Consider symptomatic treatment, 
including hydration, electrolyte 
replacement, dietary changes 
(eg, American Dietetic Association 
colitis diet), and loperamide and/or 
budesonide. 
• Promptly start prednisone 1-2 mg/kg 
per day PO or IV equivalent. 
• If event is not responsive within 
3-5 days or worsens despite 
prednisone 1-2 mg/kg per day PO or 
IV equivalent, GI consult should be 
obtained for consideration of further 
work-up such as imaging and/or 
colonoscopy to confirm colitis and 
rule out perforation, and prompt 
treatment with IV methylprednisolone 
2-4 mg/kg per day started. 
• If still no improvement within 
3-5 days despite 2-4 mg/kg IV 
methylprednisolone, promptly start 
immunosuppressives such as 
infliximab at 5 mg/kg once every 
2 weeks. 
Caution:  Important to rule out bowel 
perforation and refer to infliximab 
label for general guidance before using 
infliximab. 
• Consult with medical monitor if no 
resolution to ≤ Grade 1 in 3-4 days. 
• Once improving, gradually taper 
steroids over ≥ 28 days and consider 
prophylactic antibiotics, antifungals, 
and anti-PCP treatment (refer to 
current NCCN Guidelines for 
treatment of cancer-related infections 
[Category 2B recommendation]). 
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Table 11: 
Recommended Approach for Handling Enterocolitis (Continued) 
Toxicity 
Grade 
Withhold/Discontinue 
Durvalumab and 
Epacadostat 
Guidance for Restarting 
Study Treatment 
Supportive Care 
Grade 3 and 
Grade 4 
Discontinue epacadostat 
and durvalumab. 
Not applicable. 
• Treatment with systemic 
corticosteroids (IV administration) 
should be initiated promptly at a dose 
of 2-4 mg/kg per day of prednisone or 
equivalent. 
• Monitor stool frequency and volume 
and maintain hydration. 
• Urgent GI consult and imaging and/or 
colonoscopy as appropriate. 
• If still no improvement within 
3-5 days of IV methylprednisolone 
2-4 mg/kg per day or equivalent, 
promptly start further 
immunosuppressives (eg, infliximab at 
5 mg/kg once every 2 weeks). 
Caution:  Ensure GI consult to rule out 
bowel perforation and refer to 
infliximab label for general guidance 
before using infliximab. 
• Once improving, gradually taper 
steroids over ≥ 28 days and consider 
prophylactic antibiotics, antifungals, 
and anti-PCP treatment (refer to 
current NCCN Guidelines for 
treatment of cancer-related infections 
[Category 2B recommendation]). 
5.6.3.3. 
Procedures and Guidance for Hepatitis 
Monitor LFTs (hepatic transaminase, alkaline phosphatase, and bilirubin levels) and assess 
subjects for signs and symptoms of hepatotoxicity on Day 1 of each cycle before dosing of 
durvalumab.  In subjects with hepatotoxicity, rule out infectious or malignant causes and 
increase frequency of LFT monitoring to twice per week until resolution.  Recommendations for 
management of hepatitis are shown in Table 12. 
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Table 12: 
Recommended Approach for Handling Hepatitis 
Toxicity Grade 
Withhold/Discontinue 
Epacadostat and 
Durvalumab 
Guidance for Restarting 
Study Treatment 
Supportive Care 
Grade 1 
No dose modifications.  
If it worsens, then treat 
as Grade 2 event. 
Not applicable. 
Increase frequency of LFT monitoring 
to twice per week until LFTs return to 
baseline. 
Grade 2 
elevation in 
AST/ALT or 
total bilirubin 
Withhold epacadostat 
and durvalumab. 
Hold treatment until 
resolution to ≤ Grade 1 or 
baseline. 
• If improves to ≤ Grade 1 
or baseline, resume 
study treatment after 
completion of steroid 
taper.  Epacadostat will 
be reduced by 1 dose 
level, and durvalumab 
will resume at the same 
dose/schedule. 
• If toxicity worsens, then 
treat as Grade 3 or 
Grade 4. 
• Regular and frequent checking of 
liver chemistries (eg, every 
1-2 days) until improving or 
resolved. 
• Rule out viral and other etiologies. 
• If event is persistent (> 3-5 days) or 
worsens, promptly start prednisone 
1-2 mg/kg per day PO or IV 
equivalent. 
• If still no improvement within 
3-5 days despite prednisone 
1-2 mg/kg per day PO or IV 
equivalent, consider additional 
work-up and start prompt treatment 
with IV methylprednisolone 
2-4 mg/kg per day. 
• If still no improvement within 
3-5 days despite 1-4 mg/kg per day 
methylprednisolone IV or 
equivalent, promptly start 
immunosuppressives 
(mycophenolate mofetil).  Discuss 
with medical monitor if 
mycophenolate mofetil is not 
available.  Infliximab should NOT 
be used. 
• Once improving, gradually taper 
steroids over ≥ 28 days and consider 
prophylactic antibiotics, antifungals, 
and anti-PCP treatment (refer to 
current NCCN Guidelines for 
treatment of cancer-related 
infections [Category 2B 
recommendation]). 
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Table 12: 
Recommended Approach for Handling Hepatitis (Continued) 
Toxicity 
Grade 
Withhold/Discontinue 
Epacadostat and 
Durvalumab 
Guidance for Restarting 
Study Treatment 
Supportive Care 
Grade 3 
elevation in 
AST/ALT of 
> 5 × ULN but 
< 8  × ULN 
 
OR  
 
Grade 3 
elevation in 
total bilirubin 
of ≤ 5 × ULN 
Withhold epacadostat 
and durvalumab. 
Hold treatment until resolution 
to ≤ Grade 1 or baseline. 
•  Resume study treatment if 
elevations downgrade 
≤ Grade 1 or baseline within 
14 days; epacadostat will be 
reduced by 1 dose level, and 
durvalumab will resume at 
the same dose/schedule. 
• If AE does not resolve to 
≤ Grade 1 or baseline within 
14 days:  Discontinue study 
treatment (exceptions may 
be made by the medical 
monitor on a case by case 
basis). 
• Permanently discontinue 
study treatment for any case 
meeting Hy’s law criteria 
(AST and/or ALT > 3 × 
ULN + bilirubin > 2 × ULN 
without initial findings of 
cholestasis (ie, elevated 
alkaline P04) and in the 
absence of any alternative 
cause. 
• Promptly initiate empiric IV 
methylprednisolone 1-4 mg/kg per 
day or equivalent  
• If still no improvement within 
3-5 days despite IV 
methylprednisolone 1-4 mg/kg per 
day or equivalent, promptly start 
treatment with immunosuppressive 
therapy (mycophenolate mofetil).  
Discuss with medical monitor if 
mycophenolate is not available.   
Infliximab should NOT be used. 
• Hepatology consult, abdominal 
work-up, and imaging, as 
appropriate. 
• Once improving, gradually taper 
steroids over ≥ 28 days and 
consider prophylactic antibiotics, 
antifungals, and anti-PCP treatment 
(refer to current NCCN Guidelines 
for treatment of cancer-related 
infections [Category 2B 
recommendation]). 
Elevation in 
AST/ALT of 
> 8 × ULN 
 
OR 
 
Elevation of 
total bilirubin 
of > 5 × ULN 
Discontinue 
epacadostat and 
durvalumab. 
Not applicable. 
5.6.3.4. 
Procedures for Immune-Mediated Dermatitis 
Monitor subjects for signs and symptoms of dermatitis such as rash and pruritus.  Unless an 
alternate etiology has been identified, signs or symptoms of dermatitis should be considered 
immune-mediated.  Recommendations for management of immune-mediated dermatitis are 
shown in Table 13.  If there is any bullous formation, the medical monitor should be contacted 
and the study drug should be discontinued. 
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Table 13: 
Recommended Approach for Handling Dermatitis 
Toxicity 
Grade 
Withhold/Discontinue 
Epacadostat and 
Durvalumab 
Guidance for Restarting Study 
Treatment 
Supportive Care 
Grade 1 
No action. 
Not applicable. 
• For mild to moderate dermatitis, 
such as localized rash and pruritus, 
treat symptomatically, including oral 
antipruritics (eg, diphenhydramine 
or hydroxyzine) and topical therapy 
(eg, urea cream).  Administer topical 
or systemic corticosteroids if there is 
no improvement of symptoms within 
1 week. 
Grade 2 
May withhold epacadostat 
and durvalumab per 
investigator discretion. 
If persistent (> 1-2 weeks), hold 
treatment until resolution to 
≤ Grade 1 or baseline. 
• If toxicity worsens, then treat 
as Grade 3. 
• If toxicity improves to 
≤ Grade 1 or baseline, then 
resume drug/study regimen 
after completion of steroid 
taper. 
• Obtain dermatology consult. 
• Consider symptomatic treatment 
including oral antipruritics 
(eg, diphenhydramine or 
hydroxyzine) and topical therapy 
(eg, urea cream). 
• Consider moderate-strength topical 
steroid. 
• If no improvement of rash/skin 
lesions occurs within 3-5 days or 
worsens despite symptomatic 
treatment and/or use of moderate-
strength topical steroid, discuss with 
medical monitor and promptly start 
systemic steroids, such as prednisone 
1-2 mg/kg per day PO or IV 
equivalent. 
• Consider skin biopsy if persistent for 
> 1-2 weeks or recurs. 
Grade 3 
Withhold epacadostat and 
durvalumab. 
Note:  Permanently 
discontinue epacadostat 
and durvalumab in 
subjects with 
Stevens-Johnson 
syndrome, toxic epidermal 
necrolysis, or rash 
complicated by full 
thickness dermal 
ulceration or necrotic, 
bullous, or hemorrhagic 
manifestations. 
Hold treatment until resolution 
to ≤ Grade 1 or baseline. 
• If AE resolves within 
4 weeks:  Restart study 
treatment at same 
dose/schedule. 
• If AE does not resolve within 
4 weeks:  Approval to restart 
study treatment by medical 
monitor required; epacadostat 
will be reduced by 1 dose 
level, and durvalumab will 
resume at the same 
dose/schedule. 
For Grade 3 or 4: 
• Consult dermatology. 
• Promptly initiate empiric IV 
methylprednisolone 1-4 mg/kg per 
day or equivalent. 
• Consider hospitalization. 
• Monitor extent of rash. 
• Consider skin biopsy (preferably 
> 1) as clinically feasible. 
• Once improving, gradually taper 
steroids over ≥ 28 days and consider 
prophylactic antibiotics, antifungals, 
and anti-PCP treatment (refer to 
current NCCN Guidelines for 
treatment of cancer-related 
infections [Category 2B 
recommendation]). 
• Discuss with medical monitor. 
Grade 4 
Discontinue epacadostat 
and durvalumab. 
Not applicable. 
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5.6.3.5. 
Procedures for Immune-Mediated Neuropathies 
Subjects should be evaluated to rule out any alternative etiology (eg, disease progression, 
infections, metabolic syndromes, or medications).  Monitor subjects for symptoms of motor or 
sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, behavior 
changes, headache, nausea, vertigo, or paresthesia.  Consider appropriate diagnostic testing 
(eg, electromyogram and nerve conduction investigations).  Perform symptomatic treatment with 
neurological consult as appropriate.  Recommendations for the management of 
immune-mediated neuropathies are shown in Table 14. 
For any grade immune-mediated peripheral neuromotor syndromes, such as Guillain-Barré 
syndrome and myasthenia gravis, the following precautions should be followed: 
• The prompt diagnosis of immune-mediated peripheral neuromotor syndromes is 
important, since certain subjects may unpredictably experience acute 
decompensations that can result in substantial morbidity or, in the worst case, death.  
Special care should be taken for certain sentinel symptoms that may predict a more 
severe outcome, such as prominent dysphagia, rapidly progressive weakness, and 
signs of respiratory insufficiency or autonomic instability. 
• Subjects should be evaluated to rule out any alternative etiology (eg, disease 
progression, infections, metabolic syndromes, and medications).  It should be noted 
that the diagnosis of immune-mediated peripheral neuromotor syndromes can be 
particularly challenging in patients with underlying cancer, due to the multiple 
potential confounding effects of cancer (and its treatments) throughout the neuraxis.  
Given the importance of prompt and accurate diagnosis, it is essential to have a low 
threshold to obtain a neurological consult. 
• Neurophysiologic diagnostic testing (eg, electromyogram, nerve conduction 
investigations, and "repetitive stimulation," if myasthenia is suspected) is routinely 
indicated upon suspicion of such conditions and may be best facilitated by means of a 
neurology consultation. 
• It is important to consider that the use of steroids as the primary treatment of 
Guillain-Barré syndrome is not typically considered effective.  Subjects requiring 
treatment should be started with IVIG, followed by plasmapheresis if not responsive 
to IVIG. 
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Table 14: 
Recommended Approach for Handling Neuropathies 
Toxicity 
Grade 
Withhold/Discontinue 
Epacadostat and 
Durvalumab 
Guidance for Restarting Study 
Treatment 
Supportive Care 
Immune-mediated neurotoxicity (to include but not limited to limbic encephalitis, autonomic neuropathy, 
excluding myasthenia gravis and Guillain-Barré syndrome) 
Grade 1 
No action. 
Not applicable. 
Provide symptomatic treatment. 
Grade 2 
May withhold 
epacadostat and 
durvalumab per 
investigator discretion. 
• For acute motor neuropathies or 
neurotoxicity, hold study 
treatment until resolution to 
≤ Grade 1. 
• For sensory neuropathy/ 
neuropathic pain, consider 
holding study treatment until 
resolution to ≤ Grade 1. 
− If toxicity worsens, then treat 
as Grade 3 or Grade 4. 
− Study treatment can be 
resumed once event improves 
to ≤ Grade 1 or baseline and 
after completion of steroid 
taper.  Epacadostat will be 
reduced by 1 dose level, and 
durvalumab will resume at the 
same dose/schedule. 
• Consider systemic corticosteroids 
in addition to appropriate 
symptomatic treatment. 
• If no improvement within 3-5 days 
despite prednisone 1-2 mg/kg per 
day PO or IV equivalent, consider 
additional work-up and promptly 
treat with additional 
immunosuppressive therapy 
(eg, IVIG). 
Grade 3 
and 
Grade 4 
Discontinue epacadostat 
and durvalumab. 
Not applicable. 
• Discuss with medical monitor and 
consider hospitalization. 
• Obtain neurology consult. 
• Consider prompt initiation of 
systemic corticosteroids (IV 
administration should be strongly 
considered) at a dose of 1-2 mg/kg 
per day prednisone or equivalent. 
• Institute medical intervention as 
appropriate for management of 
severe neuropathy. 
• If no improvement within 3-5 days 
despite IV corticosteroids, consider 
additional work-up and promptly 
treat with additional 
immunosuppressants (eg, IVIG). 
•  Once stable, gradually taper 
steroids over ≥ 28 days. 
Immune-mediated peripheral neuromotor syndromes (eg, Guillain-Barré syndrome and myasthenia gravis) 
Grade 1 
No action. 
• Not applicable. 
• Provide symptomatic treatment. 
• Discuss with the study physician. 
• Care should be taken to monitor 
subjects for sentinel symptoms of a 
potential decompensation as 
described above. 
• Obtain a neurology consult, unless 
the symptoms are very minor and 
stable. 
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Table 14: 
Recommended Approach for Handling Neuropathies (Continued) 
Toxicity 
Grade 
Withhold/Discontinue 
Epacadostat and 
Durvalumab 
Guidance for Restarting Study 
Treatment 
Supportive Care 
Grade 2 
Withhold epacadostat 
and durvalumab. 
• Hold study treatment until 
resolution to ≤ Grade 1. 
• Permanently discontinue study 
treatment if it does not resolve to 
≤ Grade 1 within 30 days or if 
there are signs of respiratory 
insufficiency or autonomic 
instability. 
• Discuss with the study physician. 
• Care should be taken to monitor 
subjects for sentinel symptoms of a 
potential decompensation as 
described below. 
• Obtain a neurology consult. 
• Sensory neuropathy/neuropathic 
pain may be managed by 
appropriate medications 
(eg, gabapentin, duloxetine). 
Myasthenia Gravis: 
• Steroids may be successfully used 
to treat myasthenia gravis.  
Important to consider that steroid 
therapy (especially with high 
doses) may result in transient 
worsening of myasthenia and 
should typically be administered in 
a monitored setting under 
supervision of a consulting 
neurologist. 
• Subjects unable to tolerate steroids 
may be candidates for treatment 
with plasmapheresis or IVIG.  
Such decisions are best made in 
consultation with a neurologist, 
taking into account the unique 
needs of each subject. 
• If myasthenia gravis−like 
neurotoxicity is present, consider 
starting acetylcholine esterase 
inhibitor therapy in addition to 
steroids.  Such therapy, if 
successful, can also serve to 
reinforce the diagnosis. 
Guillain-Barré Syndrome: 
• Important to consider that the use 
of steroids as the primary treatment 
is not typically considered 
effective.  Subjects requiring 
treatment should be started with 
IVIG, followed by plasmapheresis 
if not responsive to IVIG. 
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Table 14: 
Recommended Approach for Handling Neuropathies (Continued) 
Toxicity 
Grade 
Withhold/Discontinue 
Epacadostat and 
Durvalumab 
Guidance for Restarting Study 
Treatment 
Supportive Care 
Grade 3 or 
Grade 4 
Withhold epacadostat 
and durvalumab 
(Grade 3). 
Discontinue epacadostat 
and durvalumab 
(Grade 4). 
• Hold study treatment until 
resolution to ≤ Grade 1. 
• Permanently discontinue study 
treatment if Grade 3 irAE does 
not resolve to ≤ Grade 1 within 
30 days or if there are signs of 
respiratory insufficiency or 
autonomic instability. 
• For severe or life-threatening 
(Grade 3 or 4) events:  
• Discuss with study physician. 
• Recommend hospitalization. 
• Monitor symptoms and obtain 
neurological consult. 
Myasthenia Gravis: 
• Steroids may be successfully used.  
They should typically be 
administered in a monitored setting 
under supervision of a consulting 
neurologist. 
• Subjects unable to tolerate steroids 
may be candidates for treatment 
with plasmapheresis or IVIG. 
• If myasthenia gravis−like 
neurotoxicity is present, consider 
starting acetylcholine esterase 
inhibitor therapy in addition to 
steroids.  Such therapy, if 
successful, can also serve to 
reinforce the diagnosis. 
• Guillain-Barré Syndrome: 
• Important to consider that the use 
of steroids as the primary treatment 
is not typically considered 
effective.  Subjects requiring 
treatment should be started with 
IVIG, followed by plasmapheresis 
if not responsive to IVIG. 
IVIG = intravenous immunoglobulin. 
5.6.3.6. 
Procedures for Immune-Mediated Endocrinopathies 
Subjects should be monitored for clinical signs and symptoms of hypophysitis, adrenal 
insufficiency (including adrenal crisis), and hyper- or hypothyroidism.  Subjects may present 
with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and 
hypotension, or nonspecific symptoms that may resemble other causes such as brain metastasis 
or underlying disease.  Unless an alternate etiology has been identified, signs or symptoms of 
endocrinopathies should be considered immune-mediated.  Consult an endocrinologist. 
Monitor subjects' thyroid function tests and other relevant clinical chemistries at the start of 
treatment, every 6 cycles, and as clinically indicated based on symptoms.  In a limited number of 
subjects, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary 
gland.  If a subject experiences an AE that is thought to be possibly of an autoimmune nature 
(eg, thyroiditis, pancreatitis, hypophysitis, diabetes insipidus), the investigator should send a 
blood sample for appropriate autoimmune antibody testing. 
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Treatment may be withheld for ≥ Grade 2 events and treatment may be restarted after the 
initiation of appropriate hormone-replacement therapy.  Recommendations are shown in 
Table 15. 
Table 15: 
Recommended Approach for Handling Endocrinopathies 
Toxicity 
Grade 
Withhold/Discontinue 
Epacadostat and 
Durvalumab 
Guidance for Restarting 
Study Treatment 
Supportive Care 
Grade 1 
No action. 
Not applicable. 
• Provide symptomatic treatment. 
• Monitor patient with appropriate 
endocrine function tests. 
• If TSH < 0.5 × LLN, or TSH > 2 × 
ULN or consistently out of range in 
2 subsequent measurements, include 
FT4 at subsequent cycles as clinically 
indicated and consider endocrinology 
consult (includes those with 
asymptomatic TSH elevation). 
• For suspected 
hypophysitis/hypopituitarism, consider 
consultation of an endocrinologist to 
guide assessment of early-morning 
ACTH, cortisol, TSH and free T4; also 
consider gonadotropins, sex hormones, 
and prolactin levels, as well as 
cosyntropin stimulation test (though it 
may not be useful in diagnosing early 
secondary adrenal insufficiency). 
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Table 15: 
Recommended Approach for Handling Endocrinopathies (Continued) 
Toxicity 
Grade 
Withhold/Discontinue 
Epacadostat and 
Durvalumab 
Guidance for Restarting 
Study Treatment 
Supportive Care 
Grade 2 
For endocrinopathy other 
than hypothyroidism, 
withhold epacadostat and 
durvalumab. 
If study treatment is held, 
resume study treatment at 
same dose/schedule until 
subject is clinically stable. 
• If toxicity worsens, then 
treat as Grade 3 or Grade 4. 
• Study treatment can be 
resumed once the event 
stabilizes and after 
completion of steroid taper. 
• Subjects with 
endocrinopathies who may 
require prolonged or 
continued steroid 
replacement can be 
re-treated with study 
treatment on the following 
conditions:  1) the event 
stabilizes and is controlled, 
2) the subject is clinically 
stable as per investigator or 
treating physician's clinical 
judgement, and 3) doses of 
prednisone are at 
≤ 10 mg/day or equivalent. 
• Consult endocrinologist to guide 
evaluation of endocrine function, and as 
indicated by suspected endocrinopathy 
and as clinically indicated, consider 
pituitary scan. 
• Isolated hypothyroidism may be treated 
with replacement therapy without 
treatment interruption and without 
corticosteroids. 
• Isolated Type 1 DM may be treated 
with appropriate diabetic therapy, 
without study drug interruption, and 
without corticosteroids. 
• For subjects with abnormal endocrine 
work-up, except for those with isolated 
hypothyroidism, consider short-term, 
high-dose corticosteroids 
(eg, methylprednisolone 1-2 mg/kg per 
day or IV equivalent) and initiate 
appropriate hormone replacement 
therapy. 
• Once improving, gradually taper 
steroids over ≥ 28 days and consider 
prophylactic antibiotics, antifungals, 
and anti-PCP treatment (refer to current 
NCCN Guidelines for treatment of 
cancer-related infections [Category 2B 
recommendation]). 
• For subjects with normal endocrine 
work-up (labs or MRI), repeat labs/MRI 
as clinically indicated. 
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Table 15: 
Recommended Approach for Handling Endocrinopathies (Continued) 
Toxicity 
Grade 
Withhold/Discontinue 
Epacadostat and 
Durvalumab 
Guidance for Restarting 
Study Treatment 
Supportive Care 
Grade 3 
and 
Grade 4 
For endocrinopathy other 
than hypothyroidism, 
withhold epacadostat and 
durvalumab until 
endocrinopathy 
symptom(s) are 
controlled. 
• Study treatment can be 
resumed once event 
stabilizes and after 
completion of steroid taper. 
• Consult endocrinologist to guide 
evaluation of endocrine function, and as 
indicated by suspected endocrinopathy 
and as clinically indicated, consider 
pituitary scan. 
• Discuss with medical monitor. 
• Isolated hypothyroidism may be treated 
with replacement therapy without 
treatment interruption and without 
corticosteroids. 
• Isolated Type 1 DM may be treated 
with appropriate diabetic therapy, 
without study drug interruption, and 
without corticosteroids. 
• For all patients with abnormal 
endocrine work-up, except those with 
isolated hypothyroidism or Type 1 DM, 
and as guided by an endocrinologist, 
promptly initiate empiric IV 
methylprednisolone 1-2 mg/kg per day 
or equivalent. 
• For adrenal crisis, severe dehydration, 
hypotension, or shock:  immediately 
initiate intravenous corticosteroids with 
mineralocorticoid activity. 
• Once improving, gradually taper 
immunosuppressive steroids over 
≥ 28 days and consider prophylactic 
antibiotics, antifungals, and anti-PCP 
treatment (refer to current 
NCCN Guidelines for treatment of 
cancer- related infections [Category 2B 
recommendation]) 
FT4 = free thyroxine; LLN = lower limit of normal; MRI = magnetic resonance imaging; TSH = thyroid-stimulating hormone. 
5.6.3.7. 
Procedures for Immune-Mediated Nephritis or Renal Dysfunction 
Subjects should be monitored for signs and symptoms that may be related to changes in renal 
function (eg, routine urinalysis, elevated serum blood urea nitrogen and creatinine, decreased 
creatinine clearance, electrolyte imbalance, decrease in urine output, proteinuria).  Consult with a 
nephrologist.  Subjects should be thoroughly evaluated to rule out any alternative etiology 
(eg, disease progression, infections).  Steroids should be considered in the absence of clear 
alternative etiology even for low-grade events (Grade 2) in order to prevent potential progression 
to higher grade event.  Recommendations are shown in Table 16. 
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Table 16: 
Recommended Approach for Handling Nephritis or Renal Dysfunction 
Toxicity 
Grade 
Withhold/Discontinue 
Epacadostat and 
Durvalumab 
Guidance for 
Restarting Study 
Treatment 
Supportive Care 
Grade 1 
No action. 
Not applicable. 
For Grade 1 elevated creatinine: 
• Monitor serum creatinine weekly and any 
accompanying symptom 
− If creatinine returns to baseline, resume 
its regular monitoring per study Protocol. 
− If it worsens, depending on the severity, 
treat as Grade 2 or Grade 3 or Grade 4. 
• Consider symptomatic treatment, including 
hydration, electrolyte replacement, diuretics, 
etc. 
Grade 2 
Withhold epacadostat and 
durvalumab. 
Resume study treatment 
at same dose/schedule 
when nephritis is 
controlled. 
Hold study treatment 
until resolution to 
≤ Grade 1 or baseline. 
• If toxicity worsens, 
then treat as Grade 3 or 
Grade 4. 
• If toxicity improves to 
≤ Grade 1 or baseline, 
then resume study 
treatment after 
completion of steroid 
taper. 
Study treatment can be 
resumed at the next 
scheduled dose once 
event stabilizes to 
≤ Grade 1 and 5-7 days 
have passed after 
completion of steroid 
taper. 
For Grade 2 elevated creatinine: 
• Consider symptomatic treatment, including 
hydration, electrolyte replacement, diuretics, 
etc. 
• Carefully monitor serum creatinine as 
clinically warranted. 
• Consult nephrologist and consider renal 
biopsy if clinically indicated. 
• If event is persistent (> 3-5 days) or 
worsens, promptly start prednisone 
1-2 mg/kg per day PO or IV equivalent. 
• If event is not responsive within 3-5 days or 
worsens despite prednisone 1-2 mg/kg per 
day PO or IV equivalent, additional 
work-up should be considered and prompt 
treatment with IV methylprednisolone 
2-4 mg/kg per day started. 
• Once improving, gradually taper steroids 
over ≥ 28 days and consider prophylactic 
antibiotics, antifungals, and anti-PCP 
treatment (refer to current NCCN 
Guidelines for treatment of cancer-related 
infections [Category 2B recommendation]). 
• When event returns to baseline, resume 
study treatment and routine serum creatinine 
monitoring per study Protocol. 
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Table 16: 
Recommended Approach for Handling Nephritis or Renal Dysfunction 
(Continued) 
Toxicity 
Grade 
Withhold/Discontinue 
Epacadostat and 
Durvalumab 
Guidance for 
Restarting Study 
Treatment 
Supportive Care 
Grade 3 
or 
Grade 4 
Discontinue epacadostat 
and durvalumab. 
Not applicable. 
• Carefully monitor serum creatinine on daily 
basis. 
• Consult nephrologist and consider renal 
biopsy if clinically indicated. 
• Promptly start prednisone 1-2 mg/kg per 
day PO or IV equivalent. 
• If event is not responsive within 3-5 days or 
worsens despite prednisone 1-2 mg/kg per 
day PO or IV equivalent, additional 
work-up should be considered, and prompt 
treatment with IV methylprednisolone 
2-4 mg/kg per day started. 
• Once improving, gradually taper steroids 
over ≥ 28 days and consider prophylactic 
antibiotics, antifungals, and anti-PCP 
treatment (refer to current NCCN 
Guidelines for treatment of cancer-related 
infections [Category 2B recommendation]). 
5.6.3.8. 
Procedures and Guidelines for Lipase or Amylase Elevations 
Subjects should be carefully monitored for signs and symptoms of pancreatitis, including upper 
abdominal pain, abdominal pain that radiates to the back, abdominal pain that feels worse after 
eating, fever, rapid pulse, nausea, vomiting, and tenderness when touching the abdomen.  If any 
symptoms occur, dosing should be held, and, if severe, abdominal imaging should be considered 
and treatment should be permanently discontinued.  Recommendations for the management of 
lipase or amylase elevations are provided in Table 17. 
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Table 17: 
Recommended Approach to Handling Lipase or Amylase Elevations 
Toxicity 
Grade 
Withhold/Discontinue 
Epacadostat and Durvalumab 
Guidance for Restarting Study 
Treatment 
Supportive Care 
Grade 1 
No action. 
Not applicable. 
Not applicable. 
Grade 2 
Subjects with intolerable or 
persistent Grade 2 toxicity may 
hold study treatment per 
investigator discretion. 
If held, study treatment may 
resume when toxicity resolves to 
≤ Grade 1. 
Not applicable. 
Grade 3 
• If asymptomatic, may 
continue study treatment with 
medical monitor approval. 
• Permanently discontinue 
study treatment if clinical 
signs and symptoms of 
pancreatitis develop 
(eg, abdominal pain, nausea, 
vomiting). 
• If toxicity does not resolve to 
≤ Grade 1 within 12 weeks of 
last dose after interruption, 
study treatment must be 
permanently discontinued 
unless approved by the 
medical monitor. 
If held, study treatment may 
resume when toxicity resolves to 
≤ Grade 1. 
Not applicable unless 
symptomatic; then treat with 
systemic corticosteroids at a 
dose of 1-2 mg/kg per day 
prednisone or equivalent. 
Grade 4 
• Withhold epacadostat and 
durvalumab. 
• If lipase/amylase elevation is 
asymptomatic and abdominal 
imaging suggests no 
pathology, study treatment 
may continue with medical 
monitor approval. 
• Permanently discontinue if 
clinical signs and symptoms 
of pancreatitis develop 
(eg, abdominal pain, nausea, 
vomiting). 
• If toxicity does not resolve to 
≤ Grade 1 within 12 weeks of 
last dose after interruption, 
study treatment must be 
permanently discontinued 
unless approved by the 
medical monitor. 
If held, study treatment may 
resume when toxicity resolves to 
≤ Grade 1. 
May consider treatment with 
systemic corticosteroids at a 
dose of 1-2 mg/kg per day 
prednisone or equivalent. 
5.6.3.9. 
Procedures for Ocular Manifestations 
An ophthalmology consult should be considered.  Administer corticosteroid eye drops to subjects 
who develop uveitis, iritis, or episcleritis.  Permanently discontinue epacadostat and durvalumab 
for immune-mediated ocular disease that is unresponsive to local immunosuppressive therapy.  
The use of systemic immunosuppressive therapy may be appropriate for worsening ocular 
disease. 
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5.6.3.10. Procedures and Guidelines for Myocarditis 
Table 18 provides recommendations for the management of suspected and confirmed 
myocarditis. 
Table 18: 
Recommended Approach to Handling Myocarditis 
Toxicity 
Grade 
Withhold/Discontinue 
Epacadostat and Durvalumab 
Guidance for 
Restarting Study 
Treatment 
Supportive Care 
Any 
Discontinue study treatment 
permanently if biopsy-proven 
immune-mediated myocarditis. 
Not applicable. 
• The prompt diagnosis of 
immune-mediated myocarditis is 
important, particularly in patients with 
baseline cardiopulmonary disease and 
reduced cardiac function.  
• Consider, as necessary, discussing with 
the medical monitor. 
• Monitor patients for signs and 
symptoms of myocarditis (new onset or 
worsening chest pain, arrhythmia, 
shortness of breath, peripheral edema).  
As some symptoms can overlap with 
lung toxicities, simultaneously evaluate 
for and rule out pulmonary toxicity as 
well as other causes (eg, pulmonary 
embolism, congestive heart failure, 
malignant pericardial effusion). 
• A cardiology consultation should be 
obtained early, with prompt assessment 
of whether and when to complete a 
cardiac biopsy, including any other 
diagnostic procedures. 
• Initial work-up should include clinical 
evaluation, BNP, cardiac enzymes, 
ECG, ECHO, monitoring of 
oxygenation via pulse oximetry (resting 
and exertion), and additional laboratory 
work-up as indicated.  Spiral CT or 
cardiac MRI can complement ECHO to 
assess wall motion abnormalities when 
needed. 
• Patients should be thoroughly evaluated 
to rule out any alternative etiology 
(eg, disease progression, other 
medications, or infections). 
Grade 1 
No dose modifications required 
unless clinical suspicion is 
high, in which case hold study 
treatment during diagnostic 
work-up for other etiologies. 
If study treatment is 
held, resume after 
complete resolution to 
Grade 0. 
• Monitor and closely follow up in 
2-4 days for clinical symptoms, BNP, 
cardiac enzymes, ECG, ECHO, pulse 
oximetry (resting and exertion), and 
laboratory work-up as clinically 
indicated. 
• Consider using steroids if clinical 
suspicion is high. 
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Table 18: 
Recommended Approach to Handling Myocarditis (Continued) 
Toxicity 
Grade 
Withhold/Discontinue 
Epacadostat and Durvalumab 
Guidance for 
Restarting Study 
Treatment 
Supportive Care 
Grade 2 
or greater 
• Grade 2:  Hold study 
drug/study regimen dose 
until resolution to Grade 0.  
If toxicity rapidly improves 
to Grade 0, then the decision 
to reinitiate study drug/study 
regimen will be based upon 
treating physician’s clinical 
judgment and after 
completion of steroid taper.  
If toxicity does not rapidly 
improve, permanently 
discontinue study drug/study 
regimen. 
• Grade 3-4:  Permanently 
discontinue study treatment 
• Grade 2 only: 
− If toxicity rapidly 
improves to Grade 0, 
then the decision to 
reinitiate study 
treatment after 
steroid taper will be 
up to investigator’s 
clinical judgment.  
− If toxicity does not 
rapidly improve, 
permanently 
discontinue study 
treatment 
• Monitor symptoms daily, hospitalize. 
• Promptly start IV methylprednisolone 
2-4 mg/kg per day or equivalent after 
cardiology consultation has determined 
whether and when to complete 
diagnostic procedures including a 
cardiac biopsy. 
• Supportive care (eg, oxygen). 
• If no improvement within 3-5 days 
despite IV methylprednisolone at 
2-4 mg/kg per day, promptly start 
immunosuppressive therapy such as 
TNF inhibitors (eg, infliximab at 
5 mg/kg every 2 weeks).  Caution:  It is 
important to rule out sepsis and refer to 
infliximab label for general guidance 
before using infliximab. 
• Once the patient is improving, 
gradually taper steroids over ≥ 28 days 
and consider prophylactic antibiotics, 
antifungals, or anti-PJP treatment (refer 
to current NCCN Guidelines for 
treatment of cancer-related infections 
[Category 2B recommendation]) 
5.6.3.11. Procedures and Guidelines for Myositis/Polymyositis 
Table 19 provides recommendations for the management of myositis/polymyositis. 
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Table 19: 
Recommended Approach to Handling Myositis/Polymyositis 
Toxicity 
Grade 
Withhold/Discontinue 
Epacadostat and Durvalumab 
Guidance for 
Restarting Study 
Treatment 
Supportive Care 
Any 
Refer to guidance for specific 
grades below. 
Not applicable. 
• Monitor patients for signs and symptoms of 
myositis/polymyositis (poly/myositis).  
Typically, muscle weakness/pain occurs in 
proximal muscles, including upper arms, 
thighs, shoulders, hips, neck, and back but 
rarely affects the extremities, including 
hands and fingers; also difficulty breathing 
and/or trouble swallowing can occur and 
progress rapidly.  Increased general feelings 
of tiredness and fatigue may occur, and there 
can be new-onset falling, difficulty getting 
up from a fall, and trouble climbing stairs, 
standing up from a seated position, and/or 
reaching up. 
• Consider, as necessary, discussing with the 
medical monitor, 
• If poly/myositis is suspected, a neurology 
consultation should be obtained early, with 
prompt guidance on diagnostic procedures.  
− Myocarditis may co-occur with 
poly/myositis; refer to guidance under 
Section 5.6.3.10. 
− Given breathing complications, refer to 
guidance under Section 5.6.3.1. 
− Given possibility of an existent (but 
previously unknown) autoimmune 
disorder, consider rheumatology 
consultation. 
• Initial work-up should include clinical 
evaluation, creatine kinase, aldolase, LDH, 
BUN/creatinine, erythrocyte sedimentation 
rate or C-reactive protein level, urine 
myoglobin, and additional laboratory 
work-up as indicated, including a number of 
possible rheumatological/antibody tests 
(ie, consider whether a rheumatologist 
consultation is indicated and could guide the 
need for rheumatoid factor, antinuclear 
antibody, anti-smooth muscle, antisynthetase 
[such as anti-Jo-1], and/or signal-recognition 
particle antibodies).  Confirmatory testing 
may include electromyography, nerve 
conduction studies, an MRI of the muscles, 
and/or a muscle biopsy.  Consider barium 
swallow for evaluation of dysphagia or 
dysphonia. 
• Patients should be thoroughly evaluated to 
rule out any alternative etiology (eg, disease 
progression, other medications, or 
infections). 
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Table 19: 
Recommended Approach to Handling Myositis/Polymyositis (Continued) 
Toxicity 
Grade 
Withhold/Discontinue 
Epacadostat and Durvalumab 
Guidance for 
Restarting Study 
Treatment 
Supportive Care 
Grade 1 
No dose modifications 
Not applicable. 
• Monitor and closely follow up in 2-4 days 
for clinical symptoms and initiate evaluation 
as clinically indicated. 
• Consider a neurology consult. 
• Consider, as necessary, discussing with the 
medical monitor. 
Grade 2 
Hold study treatment 
• Restart study 
treatment when 
resolved to 
≤ Grade 1. 
• Permanently 
discontinue 
study treatment 
if it does not 
resolve to 
≤ Grade 1 
within 30 days 
or if there are 
signs of 
respiratory 
insufficiency. 
• Monitor symptoms daily and consider 
hospitalization. 
• Obtain a neurology consult, and initiate 
evaluation. 
• Consider, as necessary, discussing with the 
medical monitor. 
• If clinical course is rapidly progressive 
(particularly if difficulty breathing and/or 
trouble swallowing), promptly start IV 
methylprednisolone 2-4 mg/kg per day 
systemic steroids along with receiving input 
from the neurology consultant. 
• If clinical course is not rapidly progressive, 
start systemic steroids (eg, prednisone 
1-2 mg/kg per day PO or IV equivalent); if 
no improvement within 3-5 days, continue 
additional work-up and start treatment with 
IV methylprednisolone 2-4 mg/kg per day. 
• If after start of IV methylprednisolone at 
2-4 mg/kg per day there is no improvement 
within 3-5 days, consider start of 
immunosuppressive therapy such as TNF 
inhibitors (eg, infliximab at 5 mg/kg every 
2 weeks).  Caution:  It is important to rule 
out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
• Once the patient is improving, gradually 
taper steroids over ≥ 28 days and consider 
prophylactic antibiotics, antifungals, or 
anti-PJP treatment (refer to current NCCN 
Guidelines for treatment of cancer-related 
infections [Category 2B recommendation]). 
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Table 19: 
Recommended Approach to Handling Myositis/Polymyositis (Continued) 
Toxicity 
Grade 
Withhold/Discontinue 
Epacadostat and Durvalumab 
Guidance for 
Restarting Study 
Treatment 
Supportive Care 
Grade 3 
or 
Grade 4 
• Grade 3: Hold study 
treatment  
• Grade 4:  Permanently 
discontinue study treatment 
• Grade 3 only: 
− Restart study 
treatment when 
resolved to 
≤ Grade 1. 
− Permanently 
discontinue 
study treatment 
if it does not 
resolve to 
≤ Grade 1 
within 30 days 
or if there are 
signs of 
respiratory 
insufficiency. 
• Monitor symptoms closely; recommend 
hospitalization. 
• Obtain a neurology consult, and complete 
full evaluation. 
• Consider, as necessary, discussing with the 
medical monitor. 
• Promptly start IV methylprednisolone 
2-4 mg/kg per day systemic steroids along 
with receiving input from the neurology 
consultant. 
• If after start of IV methylprednisolone at 
2-4 mg/kg per day there is no improvement 
within 3-5 days, consider start of 
immunosuppressive therapy such as TNF 
inhibitors (eg, infliximab at 5 mg/kg every 
2 weeks).  Caution:  It is important to rule 
out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
• Consider whether patient may require IVIG, 
plasmapheresis. 
• Once the patient is improving, gradually 
taper steroids over ≥ 28 days and consider 
prophylactic antibiotics, antifungals, or 
anti-PJP treatment (refer to current NCCN 
Guidelines for treatment of cancer-related 
infections [Category 2B recommendation]). 
5.6.3.12. Procedures for Immune-Related Adverse Events Not Specifically Described 
Above 
Table 20 provides information on the diagnosis and treatment of potential irAEs. 
Table 20: 
General Guidance for Diagnosis and Treatment of Immune-Related Adverse 
Events (Not Described in Previous Sections) 
Subject evaluation to identify any alternative etiology 
In the absence of a clear alternative etiology, all events of inflammatory nature should be considered to be 
immune-related 
Symptomatic and topical therapy should be considered for low-grade events 
Systemic corticosteroids should be considered for a persistent low-grade event or for a severe event 
More potent immunosuppressives should be considered for events not responding to systemic steroids 
In general, both study drugs should be permanently discontinued for clinically significant or 
severe irAEs or for events where the steroid course cannot be tapered below 10 mg/day 
prednisone equivalent to manage symptoms.  Following an irAE where treatment was withheld, 
study treatment may resume when the following conditions are met:  steroid taper has reached 
≤ 10 mg/day prednisone or equivalent, symptoms have improved to ≤ Grade 1 within 4 weeks of 
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onset (or longer with medical monitor approval), and, as appropriate, physiologic replacement of 
hormones has been instituted.  Additional treatment regarding modifications to study drug 
administration for irAEs is detailed in Table 21. 
Table 21: 
Recommended Approach for Handling Immune-Related Adverse Events 
(Not Described in Previous Sections) 
Toxicity 
Grade 
Withhold/Discontinue 
Epacadostat and Durvalumab 
Guidance for Restarting 
Study Treatment 
Grade 1 
No action. 
Not applicable. 
Grade 2 
Withhold epacadostat and durvalumab.  If 
toxicity worsens, treat as Grade 3 or Grade 4. 
Subjects with endocrinopathies who may 
require prolonged or continued steroid 
replacement can be re-treated with study 
treatment on the following conditions:  1) the 
event stabilizes and is controlled, 2) the subject 
is clinically stable as per investigator or 
treating physician’s clinical judgement, and 
3) doses of prednisone are at ≥ 10 mg/day or 
equivalent. 
Consider whether study drug/study regimen 
should be permanently discontinued in Grade 2 
events with high likelihood for morbidity 
and/or mortality (eg, myocarditis, or other 
similar events even if they are not currently 
noted in the guidelines) when they do not 
rapidly improve to < Grade 1 upon treatment 
with systemic steroids and following full taper. 
Resume study treatment at same dose/schedule 
when AE resolves to ≤ Grade 1 or baseline. 
Grade 3 
Discontinue epacadostat and durvalumab 
(exceptions to this approach allowing study 
treatment to continue after resolution of the AE 
may be granted only with medical monitor 
approval). 
Not applicable (unless approved by the medical 
monitor). 
Grade 4 
Discontinue epacadostat and durvalumab. 
Note: There are some exceptions to permanent 
discontinuation of study drug for Grade 4 
events (ie, hyperthyroidism, hypothyroidism, 
Type 1 DM). 
Not applicable (unless approved by the medical 
monitor). 
5.6.4. 
Procedures for Subjects Exhibiting Serotonin Syndrome 
As noted in Section 1.3.1, there is a rare chance that epacadostat could cause an increase in 
serotonin levels in the brain that might trigger SS (Boyer and Shannon 2005) when administered 
in combination with other serotonergic agents.  This syndrome has been most closely associated 
with use of MAOIs, meperidine, linezolid, or methylene blue; all of these agents are prohibited 
during the study (see Section 5.10.2).  Selective serotonin reuptake inhibitors and SNRIs are 
permitted during the study.  Serotonin syndrome usually manifests with autonomic changes, 
mental status changes, and neurological findings.  These mild, moderate, and severe signs and 
symptoms of SS (summarized in Table 22) should be evaluated in the context of possible 
comorbid conditions as well. 
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The following procedures will be implemented if subjects exhibit the signs/symptoms of SS 
described in Table 22, including tremor, hyperreflexia, and spontaneous ocular or inducible 
clonus together with agitation, fever, diaphoresis, or muscle rigidity: 
• Immediately interrupt study treatment administration. 
• Immediately interrupt any SSRI or SNRI administration. 
• Provide appropriate medical management of the subject until all signs/symptoms are 
resolved (eg, IV fluids and/or sympathomimetic amines for hypotension, 
benzodiazepines for agitation, administration of 5-hydroxytryptamine antagonists 
such as cyproheptadine). 
• If etiologies other than SS are excluded, durvalumab administration may be resumed 
once all signs and symptoms have resolved unless other AE management guidelines 
apply for the specific event (eg, immune-mediated neurotoxicities). 
• If the subject chooses to remain in the study, restart dosing with epacadostat after the 
SSRI or SNRI has been discontinued, no sooner than 5 half-lives have elapsed for the 
specific SSRI or SNRI in question, and after resolution of signs/symptoms of SS.  
The SSRI or SNRI dosing MAY NOT be restarted. 
• If the subject chooses to discontinue the study, or must restart treatment with SSRI or 
SNRI, subject should be scheduled for a follow-up visit.  SSRI or SNRI treatment 
may be initiated 2 weeks after resolution of signs and symptoms of SS. 
• If a subject has experienced moderate or severe unconfounded SS in the opinion of 
the investigator, without concomitant SSRI or SNRI usage or serotonergic 
concomitant medications, epacadostat treatment should be permanently discontinued.  
Durvalumab administration may be resumed with medical monitor approval once all 
signs and symptoms have resolved. 
Table 22: 
Signs and Symptoms of Serotonin Syndrome 
Seriousness 
Autonomic Signs 
Neurological Signs 
Mental Status 
Other 
Mild 
Afebrile or low-grade fever 
Tachycardia 
Mydriasis 
Diaphoresis or shivering 
Intermittent tremor 
Akathisia 
Myoclonus 
Mild hyperreflexia 
Restlessness 
Anxiety 
 
Moderate 
Increased tachycardia 
Fever (up to 41°C) 
Diarrhea with hyperactive 
bowel sounds 
Diaphoresis with normal skin 
color 
Hyperreflexia 
Inducible clonus 
Ocular clonus (slow 
continuous lateral eye 
movements) 
Myoclonus 
Easily startled 
Increased 
confusion 
Agitation and 
hypervigilance 
Rhabdomyolysis 
Metabolic acidosis 
Renal failure 
Disseminated 
intravascular 
coagulopathy 
(secondary to 
hyperthermia) 
Severe 
Temperature often more than 
41°C (Secondary to 
increased tone) 
Increased muscle tone 
(lower limb > upper) 
Spontaneous clonus 
Substantial myoclonus 
or hyperreflexia 
Delirium 
Coma 
As above 
Source:  Boyer and Shannon 2005. 
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5.7. 
Withdrawal of Subjects From Study Treatment 
5.7.1. 
Withdrawal Criteria 
Subjects must be withdrawn from study treatment for the following reasons: 
• The subject completes 12 months of study treatment with epacadostat and 
durvalumab, or had completed 12 months of combination treatment (prior to 
Amendment 6 [28 JUN 2017]), and has taken epacadostat monotherapy for an 
additional 12 months (for a total of 24 months of study treatment). 
− Note:  A subject may be granted an exception by the medical monitor to continue 
on epacadostat monotherapy beyond 24 months of overall treatment duration if 
they are clinically stable or clinically improved.  Approvals to remain on 
epacadostat monotherapy will require continuing review every 3 months. 
• In the investigator's medical judgment, further participation would be injurious to the 
subject's health or well-being. 
• The subject becomes pregnant. 
• Consent is withdrawn by subject or legal representative (such as legal guardian). 
• The subject has experienced an unacceptable toxicity as described in Section 5.6 or a 
toxicity that does not recover in 4 weeks.  Investigators who wish to continue 
treatment after a treatment delay of 4 weeks should consult with the sponsor's medical 
monitor for approval. 
• Confirmed radiographic progression of disease per modified RECIST v1.1.  
See Section 7.4 for details on subjects with unconfirmed radiographic progression.  
An exception to continue on treatment with confirmed radiographic progression may 
be granted to clinically stable subjects.  See Section 7.4 for additional details. 
• The study is terminated by the sponsor. 
• The study is terminated by the local health authority or IRB or IEC. 
• ≥ Grade 3 infusion reaction. 
• Initiation of alternative anticancer therapy including another investigational agent. 
A subject may be withdrawn from the study treatment as follows: 
• If subject attains a CR (see Section 7.4.3), and the decision is made to discontinue 
durvalumab. 
• 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 study treatment.  See Section 11.3, 
Protocol Adherence. 
• If a subject is noncompliant with study procedures or study drug administration in the 
opinion of the investigator, the sponsor should be consulted for instruction on 
handling the subject. 
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5.7.2. 
Withdrawal Procedures 
Discontinuation of study treatment does not constitute study withdrawal or completion.  The 
subject will proceed to the safety follow-up period when both study drugs are permanently 
discontinued.  In the event that any subject discontinues study drug and subsequently withdraws 
from the study before completion, regardless of reason, reasonable efforts should be made to 
have the subject return for the EOT procedures to be completed as described in Section 6.3. 
If the subject discontinues study treatment and actively withdraws consent for collection of 
safety follow-up data, then no additional data collection should occur; however, subjects will 
have the option of withdrawing consent for study treatment but continuing in the follow-up 
period of the study for safety assessments.  The date the subject was withdrawn from the study 
and the specific reason for withdrawal will be recorded in the CRF. 
If a subject is withdrawn from study treatment: 
• The study monitor or sponsor must be notified. 
• The reason(s) for withdrawal must be documented in the subject's medical record and 
in the CRF. 
• The EOT visit should be performed. 
• Subjects must be followed for safety until the time of the safety follow-up visits or 
until study drug–related toxicities resolve, return to baseline, or are deemed 
irreversible, whichever is longer. 
5.8. 
Study Completion 
5.8.1. 
Study Completion Criteria 
Subjects will be considered completing the study if they met any of the following criteria: 
• Subject dies and a date of death is available. 
• Subject is known to have died; however, the date of death cannot be obtained 
(NOTE:  Every effort must be made to obtain the date of death). 
• Subject completes the 90-day safety follow-up period. 
• Consent is withdrawn for any further contact related to this study. 
− Subjects may choose to withdraw from the study at any time without penalty of 
jeopardizing their health care or loss of benefits to which the subject is otherwise 
entitled.  Every reasonable effort should be made to determine the reason a 
subject withdraws prematurely, and this information should be recorded in the 
CRF. 
• The study is terminated by the sponsor. 
• The study is terminated by the local health authority or IRB or IEC. 
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5.9. 
Beginning and End of the Study 
The study begins when the first subject signs the informed consent.  The end of the study may be 
designated as the timepoint when all subjects have discontinued the study drug and have 
completed applicable safety follow-up assessments. 
If there are ≤ 5 subjects on study for more than 6 months, a database lock of the study may occur 
to allow the analysis of the study data.  Any remaining subjects may continue to receive study 
treatment and be seen by the investigator per Protocol.  The remaining subjects are considered to 
be on study until a study completion criterion is met and/or written notification is provided to the 
sponsor. 
In addition, the investigator will be expected to monitor for and report any SAEs, as detailed in 
Section 8.3 (Serious Adverse Events).  The subject is considered on study until such time that he 
or she meets any of the discontinuation criteria and written notification is given to the sponsor. 
5.10. 
Concomitant Medications and Measures 
All concomitant medications and treatments must be recorded in the CRF.  Any prior medication 
received up to 28 days prior to enrollment will be recorded in the CRF.  Concomitant 
treatments/procedures that are required to manage a subject's medical condition during the study 
will also be recorded in the CRF.  Concomitant medications administered as treatment 
prophylaxis (eg, for the management of infusion reactions) should also be recorded in the CRF. 
5.10.1. 
Restricted Medications and Measures 
• Systemic steroids may be used at doses ≤ 10 mg/day prednisone or equivalent with 
medical monitor approval. 
• Use of coumarin-based anticoagulants (eg, warfarin) is discouraged.  Low-dose 
warfarin (1 mg) is acceptable; however, doses that increase the INR are discouraged 
and will require a dose modification.  If an alternative to coumarin-based 
anticoagulants cannot be used, investigators should follow the guidelines in Table 23 
and either closely monitor or closely monitor and reduce the subject's dose of 
coumarin-based anticoagulant upon initiating therapy with epacadostat. 
Table 23: 
Warfarin Dose Modification 
Stable Baseline INR 
Epacadostat Dose 
≤ 100 mg BID 
200 mg BID 
300 mg BID 
INR  ≤ 2.5 
Close INR monitoring 
Close INR monitoring 
Reduce warfarin by ~33% 
and monitor INR 
INR  > 2.5 
Close INR monitoring 
Reduce warfarin by 
20%-25% 
Reduce warfarin by ~33% 
and monitor INR 
• Use of the anticonvulsant carbamazepine (a UGT1A9 inducer) is discouraged.  
Because there is a potential interaction that could result in lower epacadostat 
exposures, an alternative to carbamazepine should be used if possible. 
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5.10.2. 
Prohibited Medications and Measures 
Subjects are prohibited from receiving the following therapies during the screening and treatment 
periods of this study unless otherwise noted below: 
• Any investigational medication other than the study drugs. 
• Use of any anticancer medications including chemotherapy or biologic therapy other 
than the study medications. 
• Use of any immunological-based treatment for any reason is prohibited.  
(NOTE:  Inhaled or topical steroids are allowed, and systemic steroids at doses 
≥ 10 mg/day prednisone or equivalent and immune suppressants are allowed with 
medical monitor approval for treatment of immune-related toxicities.)  Temporary 
courses of corticosteroids for treatment of underlying or concurrent illness may be 
permitted upon discussion with the medical monitor. 
• Radiation therapy. 
− Note:  Local treatment of isolated lesions for palliative intent is acceptable 
(eg, by local surgery or radiotherapy). 
• Use of any MAOI or drug associated with significant MAO inhibitory activity is 
prohibited from 21 days before Day 1 through 2 weeks after the final dose of 
epacadostat has been taken (see Appendix C). 
• Use of any UGT1A9 inhibitor (see Appendix D). 
− Note:  Administration of epacadostat on the morning of a procedure where 
propofol may be administered is permitted; however, the evening dose after the 
procedure should be held, and subjects may resume regular dosing the following 
day. 
• Administration of live attenuated vaccines is prohibited from 30 days prior to the first 
dose of study treatment through 30 days after the final dose of durvalumab.  
Examples of live vaccines include, but are not limited to, the following:  measles, 
mumps, rubella, chicken pox, yellow fever, rabies, Bacillus Calmette–Guérin, typhoid 
vaccine, and intranasal influenza vaccines. 
• Administration of inactivated vaccines (including the injectable influenza vaccine) is 
prohibited during the DLT observation period (ie, 42 days after Cycle 1 Day 1). 
6. 
STUDY ASSESSMENTS 
All study assessments will be performed as indicated in the schedule of assessments 
(see Table 24) and laboratory assessments (see Table 25).  The required analytes for each 
laboratory test are shown in Table 26.  The order of assessments is suggested by the order of 
mention within the schedule of assessments. 
 
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h Optional and can be obtained anytime for safety or with confirmed response or progression.  If a subject consents to an on-treatment biopsy, the sample must be collected at peak 
exposure after the morning epacadostat dose (approximately 2-3 hours after dosing) and a peripheral whole blood sample should be collected at the same time as the biopsy.  
Additionally, one of the subject’s target lesions may be used to collect this sample if it is the most accessible for biopsy (see Section 7.6.3.2.1). 
i Imaging will be performed every 12 weeks scheduled from C1D1. 
j If a scan was obtained within 4 weeks before the date of discontinuation, then a scan at treatment discontinuation isn't mandatory.  In subjects who discontinue study therapy 
without confirmed disease progression, a radiologic evaluation should be repeated at the time of treatment discontinuation (ie, date of discontinuation ± 4 week window). 
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results to be in error.  Additionally, a subject who fails screening may repeat the screening 
process 1 time if the investigator believes there has been a change in eligibility status 
(eg, following recovery from an infection). 
6.2. 
Treatment Period 
The treatment period with the combination therapy will continue every 14 days for up to 
12 months.  Once subjects complete 12 months of study treatment or permanently discontinue 
study treatment for any other reason, the EOT visit should be conducted, and they should enter 
the follow-up period of the study.  Subjects enrolled prior to Protocol Amendment 6 
(28 JUN 2017) who were on epacadostat monotherapy and allowed to continue taking it will be 
allowed to continue epacadostat monotherapy for up to an additional 12 months.  The overall 
treatment duration for these subjects should not exceed 24 months.  Exceptions to continue on 
epacadostat monotherapy will require medical monitor review and approval every 3 months. 
6.3. 
End of Treatment 
If a decision is made that the subject will permanently discontinue study drug, the EOT visit 
should be conducted.  If the EOT visit coincides with a regular study visit, the EOT evaluations 
will supersede those of that scheduled visit, and the data should be entered in the EOT page in 
the CRF.  The EOT visit should be performed within 7 days of the last dose of either epacadostat 
or durvalumab (whichever comes later).  The subject should be encouraged to return for the 
safety follow-up visits. 
6.4. 
Follow-Up Period 
6.4.1. 
Safety Follow-Up 
The safety follow-up period is the interval between the EOT visit and the last scheduled safety 
follow-up visit, which should occur 90 days after the EOT visit (or after the last dose of study 
drug if the EOT visit was not performed).  Safety follow-up visit 1 will be performed 42 days 
(± 7 days) after the EOT visit or the last dose of study treatment (if the EOT visit was not 
performed).  Safety follow-up visit 2 will be performed 90 days (± 7 days) after the EOT visit or 
last dose of study treatment (if the EOT visit was not performed).  Adverse events and SAEs 
must be reported up until at least 90 days after the last dose of study treatment or until study 
drug-related toxicities resolve, return to baseline, or are deemed irreversible, whichever is longer.  
Reasonable efforts should be made to have the subject return for the safety follow-up visits and 
report any AEs that may occur during this phase. 
If a subject initiates a new anticancer therapy within 90 days after the last dose of study 
treatment, reasonable efforts should be made to conduct the next scheduled safety follow-up 
(42-day or 90-day) visit before the first dose of the new therapy. 
6.5. 
Unscheduled Visits 
Unscheduled study visits may occur at any time if medically warranted.  Any assessments 
performed at those visits should be recorded in the CRF. 
6.6. 
Early Termination 
Not applicable. 
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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.  The granting of informed consent for study participation must be 
documented in writing using an ICF that contains all of the elements required by ICH E6, and 
describes the nature, scope, and possible consequences of the study in a form understandable to 
the study subject.  Local and institutional guidelines for ICF content and administration must be 
followed; a copy of the signed ICF must be provided to the study subject.  Subjects of 
childbearing potential must agree to take appropriate measures to avoid pregnancy in order to 
participate in the study (see Appendix A). 
7.2. 
Demography and History 
7.2.1. 
Demographics and Medical History 
Demographic data and a complete medical and medication history will be collected at screening 
by the investigator or qualified designee and will include date of birth, race, ethnicity, medical 
and surgical history, and concurrent illnesses assessed using the NCI CTCAE v4.0 (NCI 2010).  
Documentation of disease history, including details of malignancy (date of diagnosis, primary 
tumor histology, prior systemic anticancer therapies, surgeries, radiation therapy, and stage of 
cancer) will also be collected at screening. 
7.2.2. 
Prior and Concomitant Medications 
Prior and ongoing medications will be reviewed to determine study eligibility.  All prior 
treatments for the subject's advanced cancer will be recorded in the CRF. 
The medication record will be maintained after enrollment as documentation of concomitant 
medications, including any changes to the dose or regimen.  Concomitant medications include 
any prescription, over-the-counter, or natural/herbal preparations taken or administered during 
the study period. 
7.3. 
Safety Assessments 
7.3.1. 
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 CRFs regardless of the assumption of a causal 
relationship with the study drug.  The definition, reporting, and recording requirements for AEs 
are described in Section 8. 
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7.3.2. 
Comprehensive Physical Examination 
Physical examinations must be performed by a medically qualified individual such as a licensed 
physician, Physician's Assistant, or an advanced Registered Nurse Practitioner, as local law 
permits. 
The comprehensive physical examination will include the following organ or body system 
assessments:  skin; head, eyes, ears, nose, and throat; thyroid; lungs; cardiovascular system; 
abdomen (liver, spleen); extremities; lymph nodes; and a brief neurological examination. 
7.3.3. 
Targeted Physical Examination 
A targeted physical examination will be a symptom-directed evaluation.  The targeted physical 
examination will include assessment(s) of the body systems or organs indicated by subject 
symptoms, AEs, or other findings as determined by the investigator or designee. 
7.3.4. 
Vital Signs 
Vital sign measurements (blood pressure, pulse, respiratory rate, body temperature) will be taken 
with the subject in the recumbent, semirecumbent, or sitting position after 5 minutes of rest for 
the baseline measurements.  Weight will be measured at each visit where vital signs are assessed, 
and height will be measured at screening only. 
Vital sign measurements will also be performed at the following times in regard to infusion of 
durvalumab: 
• At the beginning of the infusion (at 0 minutes ± 5 minutes). 
• Every 15 minutes during the infusion (at 15, 30, and 45 minutes; all ± 5 minutes). 
• At the end of the infusion (at 60 minutes ± 5 minutes). 
• 30 and 60 minutes after the infusion (ie, 90 and 120 minutes from the start of the 
infusion; ± 5 minutes). 
• Followed by a 3-hour period of observation (± 15 minutes) after the first infusion. 
7.3.5. 
Twelve-Lead Electrocardiograms 
All 12-lead ECGs will be performed with the subject in a recumbent position after 5 minutes of 
rest for the baseline ECG.  Electrocardiograms will be obtained as outlined in Table 27 (unless 
emerging PK data suggest alternate timing).  Electrocardiograms should be performed before the 
PK blood draw when collected at the same visit. 
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Table 27: 
Schedule and Timing of ECG Assessments  
Study Visit 
Timing of ECG Relative to 
Epacadostat Administration 
ECG Frequency 
Screening 
NA 
Singlet
a 
Cycle 1 Day 1 
Predose
b,c 
1 hour postdose (± 10 min)b 
2 hours postdose (± 30 min)b 
Singlet 
Cycle 2 Day 1 
Predoseb,c 
1 hour postdose (± 10 min)b 
2 hours postdose (± 30 min)b 
Singlet 
EOT 
Any time during visitb 
Singlet 
Safety Follow-Up 1  
Any time during visit 
Singlet 
Safety Follow-Up 2 
Any time during visit 
Singlet 
a At screening, in the event that a single QTc is > 480 msec, the subject may be enrolled if the average QTc for the 3 ECGs is 
< 480 msec.  For subjects with an intraventricular conduction delay (eg, right bundle branch block), JTc < 340 msec is 
acceptable; however, subjects with a left bundle branch block would be excluded. 
b ECGs must be performed before PK draws. 
c ECGs should be performed before durvalumab and epacadostat administration. 
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. 
7.3.6. 
Laboratory Assessments 
A laboratory local to the study site may perform all clinical laboratory assessments for safety 
(including comprehensive chemistry, hematology assessments, and urinalysis).  A central 
laboratory will perform PK, immunogenicity, 
 assessments. 
7.3.6.1. 
Chemistry 
A comprehensive chemistry panel will be performed as indicated in Table 25; required analytes 
for this panel are listed in Table 26. 
7.3.6.1.1. Liver Chemistry Monitoring 
If analytes are found to be abnormal (Grade 1 or higher), frequency of monitoring should be 
increased to twice weekly until they have resolved to baseline or corticosteroid treatment has 
begun, at which time monitoring will be performed according to institutional standards or 
approximately weekly, whichever is shorter.  Liver chemistry monitoring for persistent 
low-grade abnormalities does not need to be monitored twice weekly indefinitely.  Appropriate 
liver chemistry monitoring intervals should be discussed with the medical monitor for these 
circumstances.  Required analytes for liver chemistry monitoring are listed in Table 26. 
7.3.6.2. 
Hematology 
Hematology assessments will be performed as indicated in Table 25.  Required analytes for this 
panel are listed in Table 26. 
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7.3.6.3. 
Coagulation Panel 
A coagulation panel including PT and INR will be measured at screening.  Subjects who are 
taking anticoagulant therapy should be monitored per local institutional guidelines.  
See Section 5.10.1 for use of coumarin-based anticoagulant guidelines and warfarin dose 
modification. 
7.3.6.4. 
Endocrine Function Testing 
Endocrine function testing will be performed as indicated in Table 25; required analytes for this 
panel are listed in Table 26. 
7.3.6.5. 
Serology 
Serology will be performed at screening to rule out hepatitis infection; required analytes are 
shown in Table 26. 
7.3.6.6. 
Pregnancy Testing 
A serum pregnancy test will be required for all female subjects of childbearing potential during 
screening.  Subsequent pregnancy tests (either serum or urine) may be conducted as medically 
necessary or as required per local guidelines. 
7.3.6.7. 
Urinalysis 
Urinalysis will be analyzed as indicated in Table 25; required analytes for this panel are listed in 
Table 26. 
7.3.7. 
Chest Radiograph 
A chest radiograph is required at screening.  Subsequent chest radiographs will be conducted 
only as clinically indicated. 
7.4. 
Efficacy Assessments 
7.4.1. 
Initial Tumor Imaging 
Initial tumor imaging must be performed within 28 days before the first dose of study treatment.  
The site study team must review prestudy images to confirm the subject has measurable disease 
per RECIST v1.1.  Images of the chest and abdomen are required for all subjects.  In addition, 
neck imaging is also required for subjects with SCCHN.  Imaging of the pelvis is only required 
for subjects with TCC of the GU tract but is strongly encouraged for all subjects.  Computed 
tomography or MRI scan of the brain will be performed at screening if there are signs or 
symptoms suggesting that the subject has disease involvement in the central nervous system. 
Scans performed as part of routine clinical management are acceptable for use as the screening 
scan if they are of diagnostic quality and performed within 28 days before the first dose of study 
treatment.  The preferred method of disease assessment is CT with contrast.  If CT with contrast 
is contraindicated, CT without contrast is preferred over MRI.  The same imaging technique 
should be used in a subject throughout the study. 
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7.4.2. 
Tumor Imaging During the Study 
Tumor assessments will be based on RECIST v1.1 guidelines (Eisenhauer et al 2009) with 
modifications for all subjects and will be performed every 12 weeks from the first dose of study 
treatment (see Table 24).  This assessment schedule also applies to those subjects who continue 
to receive study treatment beyond confirmed PD (see Section 7.4.3.3.4).  Scheduled disease 
assessments should always be calculated from the first dose of study treatment.  Imaging should 
not be delayed for delays in cycle starts.  For those subjects who discontinue study treatment as a 
result of confirmed PD, disease evaluation will be performed at the EOT visit if clinically 
appropriate (ie, in the absence of rapidly deteriorating clinical status).  Additional disease 
assessments may be performed as clinically indicated.  Images of the chest and abdomen are 
required for all subjects, and neck imaging is also required for subjects with SCCHN.  Imaging 
of the pelvis is only required for subjects with TCC of the GU tract but is strongly encouraged 
for all subjects. 
7.4.3. 
RECIST v1.1 
Tumor lesions that are located in a previously irradiated area, or in an area subjected to other 
locoregional therapy, should not be selected as target lesions.  Additionally, tumor lesions that 
will be biopsied should not be selected as target lesions. 
7.4.3.1. 
Tumor Assessments 
• Physical examination: 
− Lesions detected by physical examination will only be considered measurable if 
superficial, eg, skin nodules and palpable lymph nodes.  Documentation by color 
photography including ruler is recommended for estimating the size of skin 
lesions. 
• CT scan with contrast of the chest, abdomen, and pelvis (plus head and neck if 
applicable): 
− CT scans should be performed with contiguous cuts in slice thickness of 5 mm or 
less.  Spiral CT should be performed using a 5-mm contiguous reconstruction 
algorithm. 
• MRI scans: 
− MRI of the abdomen and pelvis (plus head and neck if applicable) is acceptable 
for measurement of lesions provided that the same anatomical plane is used for 
serial assessments.  If possible, the same imaging device should be used for serial 
evaluations.  In case of MRI, measurements will be preferably performed in the 
axial (transverse) plane on contrast-enhanced T1 weighted images.  However, 
there are no specific sequence recommendations. 
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7.4.3.2. 
Measurability of Tumor Lesions 
Tumor lesions will be categorized as follows: 
• Measurable Lesions:  Must be accurately measured in at least 1 dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 
− 10 mm by CT scan (irrespective of scanner type) and MRI (no less than double 
the slice thickness and a minimum of 10 mm). 
− 10 mm caliper measurement by clinical examination (when superficial). 
− Malignant lymph nodes are considered pathologically enlarged and measurable, a 
lymph node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm). 
• Nonmeasurable Lesions:  Nonmeasurable lesions are defined as all other lesions 
(or sites of disease), including small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis).  Lesions considered truly 
nonmeasurable include the following:  leptomeningeal disease, ascites, 
pleural/pericardial effusion, inflammatory breast disease, lymphangitic involvement 
of skin or lung, and abdominal masses/abdominal organomegaly identified by 
physical examination that is not measurable by reproducible imaging techniques. 
• Target Lesions:  All lesions up to a maximum of 5 lesions total (and a maximum of 
2 lesions per organ) representative of all involved organs should be identified as 
target lesions.  It may be the case that, on occasion, the largest lesion does not lend 
itself to reproducible measurement in which circumstance the next largest lesion 
which can be measured reproducibly should be selected. 
• Nontarget Lesions:  It is possible to record multiple nontarget lesions involving the 
same organ as a single item on the case record form (eg, "multiple enlarged pelvic 
lymph nodes" or "multiple liver metastases"). 
7.4.3.3. 
Response Criteria 
7.4.3.3.1. Evaluation of Target Lesions 
• Complete Response:  Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or nontarget) must have reduction in short axis to < 10 mm 
(the sum may not be "0" if there are target nodes). 
• Partial Response:  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
• Progressive Disease:  At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum 
if that is the smallest on study).  In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm.  (Note:  The appearance 
of 1 or more new lesions is also considered progression.) 
• Stable Disease:  Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum of diameters while on study. 
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7.4.3.3.2. Evaluation of Nontarget Lesions 
• Complete Response:  Disappearance of all nontarget lesions 
 
  All lymph nodes must be nonpathological in size (< 10 mm short 
axis). 
• Non−Complete Response/Non−Progressive Disease:  Persistence of 1 or more 
nontarget lesion(s) 
 
 
• Progressive Disease:  Unequivocal progression of existing nontarget lesions will be 
defined as the overall level of substantial worsening in nontarget disease such that, 
even in presence of SD or PR in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy.  In the absence of 
measurable disease, change in nonmeasurable disease comparable in magnitude to the 
increase that would be required to declare PD for measurable disease.  Examples 
include an increase in a pleural effusion from "trace" to "large," an increase in 
lymphangitic disease from localized to widespread. 
7.4.3.3.3. Appearance of New Lesions 
The appearance of new lesions is considered PD according to RECIST v1.1 guidelines.  
Considering the unique response kinetics that have been observed with immunotherapy, new 
lesions may not represent true disease progression.  In the absence of rapid clinical deterioration, 
subjects may continue to receive study treatment if investigators consider that subjects continue 
to benefit from treatment. 
7.4.3.3.4. Evaluation of Overall Response With Modifications 
Confirmation of PD should be assessed by a repeat, consecutive assessment no less than 4 weeks 
from the date of first documentation.  Treatment with study treatment will continue between the 
initial assessment of PD and confirmation for PD if they are considered clinically stable as 
defined by the following criteria: 
• Absence of signs and symptoms indicating disease progression. 
• No decline in ECOG performance status. 
• Absence of rapid progression of disease. 
• Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention. 
In addition, subjects may continue to receive study treatment beyond confirmed PD in the 
absence of clinical deterioration and if investigators consider that subjects continue to receive 
benefit from treatment after consultation with the medical monitor.  For example, subjects who 
are clinically stable with no further tumor increase after the initial scan demonstrating PD may 
be allowed to continue study treatment.  In the absence of clinical deterioration, such 
modifications to the RECIST criteria may discourage the early discontinuation of study treatment 
and provide a more complete evaluation of its antitumor activity than would be seen with 
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conventional response criteria.  Table 28 provides overall responses for all possible combinations 
of tumor responses in target and nontarget lesions with or without the appearance of new lesions. 
Table 28: 
Evaluation of Overall Response 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
Complete response 
Complete response 
(or no nontarget lesion) 
No 
Complete response 
Complete response 
Not evaluable
a 
No 
Partial response 
Complete response 
Non−complete response / 
non−progressive disease 
No 
Partial response 
Partial response 
Non−progressive disease and 
not evaluablea  
(or no nontarget lesion) 
No 
Partial response 
Stable disease 
Non-progressive disease and 
not evaluablea 
(or no non-target lesion) 
No 
Stable disease 
Not all evaluated 
Non−progressive disease 
No 
Not evaluable 
No target lesion
b 
Not all evaluated 
No 
Not evaluable 
No target lesionb 
Non−complete response / 
non−progressive disease 
No 
Non−complete response / 
non−progressive disease 
Progressive disease 
Any 
Yes/No 
Progressive disease 
Any 
Progressive disease 
Yes/No 
Progressive disease 
Any 
Any 
Yes 
Progressive disease 
No target lesionb 
Unequivocal progressive disease 
Yes/No 
Progressive disease 
No target lesionb 
Any 
Yes 
Progressive disease 
a Not evaluable is defined as either when no or only a subset of lesion measurements are made at an assessment. 
b Defined as no target lesion at baseline. 
7.5. 
Performance and Quality of Life Assessments 
Not applicable. 
7.6. 
Pharmacokinetic, Immunogenicity, 
 
Assessments 
Instructions for sample preparation and shipping will be provided in the Laboratory Manual.  
Sample collection visits are outlined in Table 25. 
7.6.1. 
Pharmacokinetics 
7.6.1.1. 
Pharmacokinetic Assessment for Epacadostat 
Subject will withhold morning dose of drug during PK days.  The time of last dose of study 
medication and prior meal will be recorded in the CRF.  Pharmacokinetic samples will be 
obtained at the visits indicated in Table 25 and Table 29.  After the predose PK sample is drawn 
(predose is defined as within 24 hours before dosing of durvalumab and before dosing 
epacadostat), subjects will take epacadostat and then begin infusion of durvalumab.  The exact 
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date and time of the PK blood draws will be recorded in the CRF along with the date and time of 
the last dose of study drug and last meal preceding the blood draw.  Sample collection times for 
epacadostat are shown in Table 29. 
Table 29: 
Sample Collection Windows for Pharmacokinetic Assessments for 
Epacadostat 
Study Visit 
Timing of Sample Relative to Epacadostat Administration 
Cycle 1 Day 1
a 
Predose
b 
0.5 h  
± 10 min 
1 h 
± 10 min 
2 h 
± 30 min 
4 h 
± 30 min 
6 h 
± 60 min 
OPTIONAL 
8 to 10 h 
± 60 min 
Cycle 1 Day 8
c  
Predoseb 
0.5 h  
± 10 min 
1 h 
± 10 min 
2 h 
± 30 min 
4 h 
± 30 min 
6 h 
± 60 min 
OPTIONAL 
8 to 10 h 
± 60 min 
Cycle 2 Day 1a 
Predoseb 
0.5 h 
± 10 min 
1 h 
± 10 min 
2 h 
± 30 min 
4 h 
± 30 min 
6 h 
± 60 min 
OPTIONAL 
8 to 10 h 
± 60 min 
a ECGs are also required.  See Table 27 for timing of ECGs relative to PK sampling.  ECGs should be performed before a PK 
draw. 
b Predose samples should be collected before durvalumab infusions as well. 
c Only subjects in Phase 1 should have epacadostat PK performed on Cycle 1 Day 8. 
7.6.1.2. 
Pharmacokinetic Assessment for Durvalumab 
Subjects will withhold morning dose of epacadostat on Cycle 1 Day 1 and Cycle 2 Day 1 before 
PK sample collection.  Pharmacokinetic samples will be obtained in Phase 1 and Phase 2 of the 
study at the visits indicated in Table 30.  After the predose PK sample is drawn, subjects will 
take epacadostat and then begin infusion of durvalumab.  The exact date and time of the PK 
blood draws will be recorded in the CRF along with the date and time of the last dose of study 
drug and last meal preceding the blood draw. 
Measurement of durvalumab concentrations in serum will be performed using validated 
immunoassays.  Only subjects who receive at least 1 dose of durvalumab and provide at least 
1 post-treatment sample will be evaluated.  Individual durvalumab will be tabulated by dose 
cohort along with descriptive statistics.  The following PK parameters after the first and 
steady-state dose will be estimated (as data allow):  Cmax, Cmin, tmax, and AUC.  Accumulation to 
steady state will be assessed as the ratio of Cmax,ss:Cmax and Cmin,ss:Cmin.  All PK parameters will 
be estimated by noncompartmental analysis.  Descriptive statistics of noncompartmental PK 
parameters will be provided. 
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The instructions for preparing and administering durvalumab are described in a separate 
pharmacy manual. 
7.7.3. 
Distribution of Subject Reminder Cards and Diaries 
Subjects will be provided with reminder cards at each visit.  The subject reminder cards will 
indicate the date/time of the next visit, and will also remind the subject when they should not 
take their morning dose of study drug and when they should arrive for the visit after an overnight 
fast of at least 8 hours or since midnight.  On Day 1 only, subjects will also be given 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. 
8. 
SAFETY MONITORING AND REPORTING 
8.1. 
Adverse Events 
8.1.1. 
Definitions and Reporting 
For the purposes of this Protocol, an AE is defined as the appearance of (or worsening of any 
pre-existing) undesirable sign(s), symptom(s), or medical condition(s) that occur after a subject 
provides informed consent.  Abnormal laboratory values or test results occurring after informed 
consent constitute AEs only if they induce clinical signs or symptoms, are considered clinically 
meaningful, require therapy (eg, hematologic abnormality that requires transfusion), or require 
changes in the study drug(s). 
Adverse events that begin or worsen after informed consent should be recorded on the Adverse 
Events page of the CRF.  Conditions that were already present at the time of informed consent 
should be recorded on the Medical History page of the CRF.  Adverse event monitoring should 
be continued for at least 90 days after the last dose of study treatment.  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. 
Adverse events will be assessed according to the CTCAE version 4.0.  The CTCAE severity 
Grade 5 (death) will not be used in this study; rather, information about deaths will be collected 
as an outcome of the event.  The occurrence of AEs should be sought by nondirective 
questioning of the subject during the screening process after signing the ICF and at each visit 
during the study.  Adverse events may also be detected when they are volunteered by the subject 
during the screening process or between visits, or through physical examination, laboratory test, 
or other assessments.  As far as possible, each AE should be evaluated to determine: 
• The severity grade (CTCAE Grade 1 to 4). 
• Reasonable possibility that the AE is related to the study treatment:  unrelated (no) or 
related (yes). 
NOTE:  Since this is a combination study of epacadostat with durvalumab, the 
relationship to study drug can be assessed for epacadostat alone, durvalumab alone, 
the combination of epacadostat with durvalumab, or not related to either epacadostat 
or durvalumab. 
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• Start and end dates, unless unresolved at final examination. 
• Action taken with respect to study drug (eg, none, dose adjusted, temporarily 
interrupted, permanently discontinued, unknown, not applicable). 
• Outcome (eg, not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown). 
• Whether it is serious, as per SAE definition provided in Section 8.3.1. 
Unlike routine safety assessments, SAEs are monitored continuously and have special reporting 
requirements, see Section 8.3.2. 
All AEs should be treated appropriately.  If a concomitant medication or nondrug therapy is 
given, this action should be recorded on the AE and Prior/Concomitant medications pages of the 
CRF. 
Once an AE is detected, it should be followed until it has resolved or until it is judged to be 
permanent; assessment should be made at each visit (or more frequently if necessary) of any 
changes in severity, the suspected relationship to the study drug, the interventions required to 
treat it, and the outcome. 
Disease progression should not be regarded or reported as an AE itself, unless it is associated 
with a separate AE. 
8.2. 
Laboratory Test Abnormalities 
8.2.1. 
Definitions and Reporting 
Laboratory abnormalities that constitute an AE in their own right (are considered clinically 
meaningful, induce clinical signs or symptoms, require concomitant therapy, or require changes 
in study drug), should be recorded on the AE page of the CRF.  Whenever possible, a diagnosis 
rather than a symptom should be provided (eg, anemia instead of low hemoglobin).  Laboratory 
abnormalities that meet the criteria for AEs should be followed until they have returned to 
normal or an adequate explanation of the abnormality is found.  When an abnormal laboratory 
test result corresponds to a sign or symptom of a previously reported AE, it is not necessary to 
separately record the laboratory test result as an additional event. 
Laboratory abnormalities that do not meet the definition of an AE should not be reported as AEs.  
A Grade 3 or 4 (severe) AE, as per CTCAE, does not automatically indicate an SAE unless it 
meets the definition of serious, as defined in Section 8.3.1, and/or per the investigator's 
discretion.  A dose interruption or adjustment for the laboratory abnormality may be required 
(see Section 5.6) and should not contribute to the designation of a laboratory test abnormality as 
an SAE. 
8.2.2. 
Potential Drug-Induced Liver Injury (or Hy’s Law) 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to 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). 
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Potential drug induced liver injury is defined as: 
1. AT (ALT or AST) elevation > 3 times ULN 
AND 
2. Total bilirubin > 2 times ULN, without initial findings of cholestatis (elevated serum 
alkaline phosphatase), 
AND 
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or 
the administration of other drug(s) known to be hepatotoxic. 
8.3. 
Serious Adverse Events 
8.3.1. 
Definitions 
A SAE is defined as an event that meets 1 of the following criteria: 
• Is fatal or life-threatening (ie, immediate risk of dying). 
• Results in persistent or significant disability or incapacity. 
• Constitutes a congenital anomaly or birth defect. 
• Is clinically meaningful (ie, defined as an event that jeopardizes the subject or 
requires potential medical or surgical intervention to prevent 1 of the outcomes listed 
above).  Considered meaningful by the investigator as an important medical event 
that may not result in death, be life-threatening, or require hospitalization, but may be 
considered a SAE when, based upon appropriate medical judgment, it may jeopardize 
the subject or may require medical or surgical intervention to prevent 1 of the 
outcomes listed in this definition. 
• Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is a result of: 
− Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition.  Elective or preplanned treatment for a pre-existing 
condition that is unrelated to the indication under study and has not worsened 
since signing the ICF. 
− Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission. 
− Social reasons and respite care, in the absence of any deterioration in the subject's 
general condition. 
− Any SAEs that are expected due to the condition being treated, including if the 
SAE is a primary outcome measure, or where there has been a clear agreement 
with regulators not to consider these as SAEs, provided the information is 
collected elsewhere. 
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8.3.2. 
Reporting 
To ensure subject safety, every SAE, regardless of suspected causality, occurring after the 
subject has signed the ICF and up to the last study visit, or up to 90 days after the last dose of 
study treatment, must be reported to the sponsor (or designee) within 24 hours of learning of its 
occurrence.  Any SAEs experienced after this period should be reported to the sponsor 
(or designee) only if the investigator suspects a causal relationship to the study drug.  Recurrent 
episodes, complications, or progression of the initial SAE must be reported as the follow-up to 
the original episode within 24 hours of the investigator receiving the follow-up information.  An 
SAE occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event.  Previously planned 
(before providing informed consent) surgeries should not be reported as SAEs unless the 
underlying medical condition worsens over the course of the study. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form.  The investigator must assess and record the relationship of each SAE to each specific 
study drug (if there is more than 1), complete the SAE Report Form in English, and send the 
completed, signed form by fax within 24 hours to the sponsor or its designee.  The investigator 
must assess if there is a reasonable possibility that the SAE is related to the study treatment:  
unrelated (no) or related (yes). 
Serious AEs related to unblinded comparator drugs or concomitant medications/drug delivery 
systems are reported directly to the manufacturers of those drugs/devices in accordance with the 
package insert. 
The telephone and facsimile number of the sponsor's contact persons, specific to the study, are 
listed in the investigator folder provided to each site.  The original copy of the SAE Report Form 
and the fax confirmation sheet must be kept with the CRF documentation at the study site. 
Follow-up information is sent to the same person to whom the original SAE Report Form was 
sent, using a new SAE Report Form stating that this is a follow-up to the previously reported 
SAE and giving the date of the original report.  Each recurrence, complication, or progression of 
the original event should be reported as a follow-up to that event regardless of when it occurs.  
The follow-up information should describe whether the event has resolved or continues, if and 
how it was treated, and whether the subject continued or withdrew from study participation, or if 
study drug was interrupted or discontinued. 
If the SAE is not previously documented in the IBs for the study drugs (new occurrence) and is 
thought to be related to the sponsor's study drug, a sponsor's associate may urgently require 
further information from the investigator for reporting to health authorities. 
The sponsor or its designee may need to issue an IN to inform all investigators involved in any 
study with the same drug that this SAE has been reported.  Suspected Unexpected Serious 
Adverse Reactions will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with Directive 2001/20/EC, or as per national regulatory requirements 
in participating countries. 
8.3.2.1. 
Hepatic Function Abnormalities (Hepatotoxicity) 
As defined in Section 8.2.2, Hy's law cases must be reported as SAEs.  Additional information 
regarding hepatic function abnormalities is provided in Section 8.8. 
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8.4. 
Emergency Unblinding of Treatment Assignment 
Not applicable. 
8.5. 
Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that study drug may 
have interfered with the effectiveness of a contraceptive medication or method.  When a 
pregnancy has been confirmed, the following procedures should occur: 
• The investigator must notify the sponsor or its designee immediately. 
• The study drug must be discontinued immediately. 
• The subject must be withdrawn from the study. 
• The EOT visit evaluations must be performed. 
• The investigator must complete and submit the Pregnancy Initial and Follow-Up 
Report forms to the sponsor or its designee. 
• A serum pregnancy test must be performed to confirm the urine pregnancy test result.  
(The serum test should be performed at the investigative site to ensure the test will be 
performed promptly and the result available immediately for review.) 
If a negative serum test does not confirm the urine pregnancy test result, then: 
• The investigator will use his or her expert judgment, based on an assessment of the 
potential benefit/risk to the subject, to determine if it is in the subject's best interest to 
resume study drug and continue participation in the study. 
To ensure subject safety, each pregnancy in a subject during maternal or paternal 
exposures to study drug must be reported within 24 hours of learning of its occurrence.  
Data on fetal outcome and breastfeeding are collected for regulatory reporting and drug safety 
evaluation.  Follow-up to each pregnancy should be conducted to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence of any 
birth defects, congenital abnormalities, or maternal and/or newborn complications, by following 
until the first well-baby visit.  Pregnancy should be recorded on a Clinical Study Pregnancy 
Form and reported by the investigator to the sponsor or its designee.  Pregnancy follow-up 
should be recorded on the same form and should include an assessment of the possible 
relationship to the sponsor's study drug of any pregnancy outcome and follow-up to the first 
well-baby visit.  Any SAE experienced during pregnancy must be reported on the SAE 
Report Form and to the sponsor or its designee. 
8.6. 
Warnings and Precautions 
No evidence available at the time of the approval of this study Protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided IBs.  Additional 
safety information collected between IB updates will be communicated in the form of INs.  Any 
important new safety information should be discussed with the subject during the study as 
needed.  If new, significant risks are identified, they will be added to the ICF. 
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8.7. 
Data Monitoring Committee 
There will be no formal external Data Monitoring Committee for this open-label study.  
Approximately weekly the sponsor will conduct telephone conferences with investigators in 
order to review cohort-specific data, overall safety data from prior cohorts (if applicable), and to 
agree on dose escalation, de-escalation, and cohort expansion decisions. 
8.8. 
Adverse Events of Special Interest 
Adverse events of special interest include irAEs that are seen with immunotherapy and any other 
observed autoimmune phenomenon.  Guidance for the assessment, diagnosis, and management 
of irAEs is provided in Section 5.6.3.  Immune-related AEs will be monitored carefully at each 
cycle and during the safety follow-up period. 
Adverse events of special interest for durvalumab are events of scientific and medical interest 
specific to the further understanding of the durvalumab safety profile and require close 
monitoring and rapid communication by the investigator to the sponsor.  Durvalumab AEs of 
special interest may be serious or nonserious.  The rapid reporting of these AEs of special 
interest allows ongoing analysis of these events in order to characterize and understand them in 
association with the use of this investigational product.  Durvalumab, an anti−PD-L1 antibody, 
binds with high affinity and specificity to PD-L1 and blocks its binding to PD-1 and CD80, thus 
promoting antitumor immunity and tumor cell killing.  Potential risks based on this mechanism 
of action of durvalumab and related molecules include immune-mediated reactions such as 
enterocolitis, dermatitis, hepatotoxicity or hepatitis, endocrinopathy, neuropathy, and 
pneumonitis.  The class including anti−PD-L1 drugs and other immune checkpoint antibodies 
such as anti−PD-1 or anti−CTLA-4, have a wide spectrum of immune-mediated reactions that 
have been considered inflammatory in nature and can affect any organs of the body. 
8.8.1. 
Pneumonitis 
Pneumonitis has been reported in association with use of anti−PD-L1/anti−PD-1 antibodies 
(Brahmer et al 2012).  Initial work-up should include a high-resolution CT scan, ruling out 
infection, and pulse oximetry.  Pulmonary consultation is recommended.  Guidelines for the 
management of subjects with immune-mediated events including pneumonitis are outlined in 
Section 5.6.3.1. 
8.8.2. 
Hypersensitivity Reactions 
Hypersensitivity reactions as well as infusion-related reactions have been reported with 
anti−PD-L1 and anti−PD-1 therapy (Brahmer et al 2012).  As with the administration of any 
foreign protein and/or other biologic agents, reactions following the infusion of monoclonal 
antibodies can be caused by various mechanisms, including acute anaphylactic (IgE-mediated) 
and anaphylactoid reactions against the monoclonal antibody, and serum sickness.  Acute 
allergic reactions may occur, may be severe, and may result in death.  Acute allergic reactions 
may include hypotension, dyspnea, cyanosis, respiratory failure, urticaria, pruritus, angioedema, 
hypotonia, urticaria, arthralgia, bronchospasm, wheeze, cough, dizziness, fatigue, headache, 
hypertension, myalgia, vomiting, and unresponsiveness. 
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Guidelines for management of subjects with hypersensitivity (including anaphylactic reaction) 
and infusion-related reactions are outlined in Section 5.1.2.2. 
8.8.3. 
Hepatic Function Abnormalities (Hepatotoxicity) 
Increased transaminases have been reported during treatment with anti−PD-L1 (Brahmer 
et al 2012).  Inflammatory hepatitis has been reported in 3% to 9% of subjects treated with 
anti−CTLA-4 monoclonal antibodies (eg, ipilimumab).  The clinical manifestations of 
ipilimumab-treated subjects included general weakness, fatigue, nausea and/or mild fever, and 
increased liver chemistry tests such as AST, ALT, alkaline phosphatase, and/or total bilirubin.  
Hepatic function abnormality is defined as any increase in ALT or AST to > 3 × ULN and 
concurrent increase in bilirubin to > 2 × ULN (ie, Hy's law cases).  Concurrent findings are those 
that derive from a single blood draw or from separate blood draws taken within 8 days of each 
other.  Follow-up investigations and inquiries will be initiated promptly by the investigational 
site to determine whether the findings are reproducible and/or whether there is objective 
evidence that clearly supports causation by a disease (eg, cholelithiasis and bile duct obstruction 
with distended gallbladder) or an agent other than the investigational product.  If the underlying 
diagnosis for the hepatic function abnormality is known (including progression of pre-existing 
disease such as primary or metastatic malignancy), the diagnosis should be recorded as an 
AE/SAE.  If the underlying diagnosis for the hepatic function abnormality remains unknown, the 
term "hepatic function abnormal" should be used to report the AE/SAE.  Hepatic function 
abnormality of unknown etiology, or which is considered attributable to investigational product, 
is required to be reported as "hepatic function abnormal" within 24 hours of knowledge of the 
event to the sponsor using the SAE Report Form, even if the event is considered to be 
nonserious. 
The investigator will review the data with the medical monitor.  The investigator should then use 
clinical judgment to establish the cause based on local standard of care and follow the subject by 
conducting testing as clinically indicated. 
8.8.4. 
Serotonin Syndrome 
As noted in Section 1.3.1, there is a theoretical chance that epacadostat could cause an increase 
in serotonin levels in the brain that might trigger SS (Boyer and Shannon 2005) when 
administered in combination with other serotonergic agents.  This syndrome has been most 
closely associated with use of MAOIs, meperidine, linezolid, or methylene blue; all of these 
agents are prohibited during the study.  Selective serotonin reuptake inhibitors and SNRIs are 
permitted in the study.  Procedures listed in Section 5.6.4 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. 
8.9. 
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. 
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The investigator or his/her designee is responsible for reporting a complete description of the 
product complaint and any associated AEs via email or other written communication to the 
Incyte contact. 
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint communication with the product. 
9. 
STATISTICS 
9.1. 
Study Populations 
Safety Evaluable:  All subjects enrolled who take at least 1 dose of study drug. 
Pharmacokinetic
 Evaluable:  Includes subjects who received at least 
1 dose of study drug(s) and provided at least 1 postdose blood sample for PK 
 
 assessmen
.  The study pharmacokineticist will review data listings of 
subject dosing and sample records to identify subjects to be excluded from the analysis. 
Phase 1 Population:  All subjects enrolled in the Phase 1 portion of the study taking at least 
1 dose of study drug. 
9.2. 
Selection of Sample Size 
9.2.1. 
Cohort Size in Phase 1 
The primary objective of the open-label Phase 1 portion of the study is to determine the MTD or 
PAD and DLT of epacadostat in combination with durvalumab.  The total number of subjects 
will depend on the number of dose levels tested before the MTD or PAD is established.  Up to 
36 subjects (6 subjects per dose level for 6 dose levels) will be included based on the dose 
escalation.  Dose escalation will follow the 3 + 3 design algorithm as defined in Section 4.1.1.  
Based on this algorithm, which enrolls 3 evaluable subjects in each cohort with a maximum of 
6 subjects at any dose level, the probabilities of dose de-escalation from a given dose level for 
the various DLT rates are provided in Table 32. 
Table 32: 
Probability of Dose De-Escalation for Various DLT Rates 
True DLT Rate 
Probability of Dose De-Escalation 
20% 
23.6% 
30% 
47.2% 
40% 
68.3% 
50% 
83.4% 
60% 
92.4% 
For example, if the true DLT rate is 50% at a given dose level, there is a 17% chance that the 
dose would be escalated.  Further, if the true DLT rate is 20%, there is a 76% chance that the 
dose would be escalated. 
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9.2.2. 
Sample Size for Phase 2 
The sample size for the melanoma, TNBC, and gastric and GE junction cohorts will be guided by 
the Simon 2-stage design (Simon 1989).  Let P0 denote a clinically uninteresting response rate 
(eg, for melanoma P0 = 30%).  In order to determine whether a target response rate (eg, 55%) is 
likely, an initial number of subjects (eg, 15) will be treated at first in a cohort (Stage 1).  For 
example, in a group in which ≤ 5 subjects have responses, it will be concluded that the true 
response rate is unlikely to be greater than or equal to the target rate and no more subjects will be 
enrolled in that group in Stage 2.  Otherwise, in the groups in which at least 6 responses among 
the Stage 1 subjects is observed, 25 additional subjects will be treated in Stage 2 to estimate the 
response rate.  At the end of Stage 2, if ≤ 16 subjects have responded among a total of 
40 subjects, the drug will be declared nonpromising.  In other words, after the study is finished, 
if there is a sufficient number of responses in the 2 stages combined, the study compound is 
considered promising; otherwise it is considered nonpromising.  The detail is displayed in 
Table 33 using a Type I error of 0.05 and power of 90% for estimation. 
Table 33: 
Details of Simon 2-Stage Design (Melanoma, TNBC, and Gastric and 
Gastroesophageal Junction Cancer) 
 
Melanoma 
(P0 = 30%, 
Target RR = 55%) 
TNBC 
(P0 = 15%, 
Target RR = 40%) 
Gastric and GE 
Junction 
(P0 = 10%, 
Target RR = 40%) 
Drug is not promising if Stage 1 
responder number ≤  
5 
2 
1 
Sample size for Stage 1 
15 
13 
9 
Drug is not promising if total 
responder number ≤ 
16 
7 
4 
Sample size total 
40 
29 
20 
Under Amendment 6, enrollment of the NSCLC, SCCHN, and TCC of the GU tract cohorts will 
be completed as expansion cohorts at the 300 mg BID dose level.  The sample size for each 
cohort will be increased to account for the heterogeneity of PD-1 pathway–treated and PD-1 
pathway–naive subjects within the selected tumor types.  The approximate number of subjects 
per tumor type is listed in Table 34, and the number of PD-1 pathway–treated subjects in each 
cohort will be limited to 10 in order to reduce the risk of any cohort having a significant 
imbalance between PD-1 pathway–treated and PD-1 pathway–naive subjects, thereby preserving 
the predicted levels of baseline efficacy observed with PD-1 pathway monotherapy.  Subjects 
enrolled at the 100 mg BID will be analyzed independently.  The sample size for each cohort 
expansion is based on a power of 90% to detect a target ORR of about 20% increase with a 
1-sided alpha of 10% and 10% lost to follow-up. 
Table 34: 
Sample Size Details (NSCLC, SCCHN, and TCC of the GU Tract) 
Tumor Type 
ORR 
Sample Size 
H0 
Ha 
NSCLC 
10% 
30% 
28 
SCCHN 
10% 
30% 
28 
TCC of the GU Tract 
10% 
30% 
28 
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9.3. 
Level of Significance 
No formal efficacy hypotheses will be tested.  All CIs will be 95%. 
9.4. 
Statistical Analyses 
9.4.1. 
Primary Analyses 
Phase 1:  The safety and tolerability of epacadostat in combination with durvalumab will be 
evaluated.  See Section 9.4.3 for more details.  Descriptive statistics (eg, mean, standard 
deviation, range) will be derived where appropriate.  Subject enrollment, disposition, 
demographics, and medical history will be summarized at baseline.  The rate of DLTs will be 
summarized for each cohort.  Dose exposure and density will be calculated for each cohort.  
Safety and disease response data will be compared over time to assess change from baseline, 
during treatment, and follow-up.  Pharmacokinetic 
 data will be analyzed 
with appropriate standard nonlinear analytic software. 
Phases 1 and 2:  The proportion of subjects with objective response by mRECIST v1.1 will be 
summarized.  A subject is considered an objective responder as assessed by mRECIST v1.1 if he 
or she has an overall response of CR or PR at any postbaseline visit.  The proportion of 
responders within each treatment group will be estimated with 95% CIs by treatment group.  
Confidence intervals will be calculated based on the exact method for binomial distributions. 
9.4.2. 
Secondary Analyses 
For objective responders, the duration of response is the time from the first overall response 
contributing to an objective response, to the first overall response of PD (by mRECIST v1.1) 
occurring after the first overall response contributing to the objective response.  Median duration 
of response and time to disease progression will be estimated using the Kaplan-Meier method.  
Confidence intervals for median survival time will be calculated using the method of 
Brookmeyer and Crawley (1982), which is the default method within SAS v9.1. 
Progression-free survival data will be analyzed by the Kaplan-Meier method, treating subjects 
with no observed death or progression censored at their last date known to be alive and 
progression-free. 
9.4.3. 
Safety Analyses 
The principal analysis will be based on the safety evaluable population, according to treatment 
assignment. 
Adverse events will be coded by the MedDRA, and incidences will be tabulated by preferred 
term and system organ class for all events, related events, and events ≥ Grade 3.  Severity of AEs 
will be based on the CTCAE scale as indicated in Section 8.1.1.  Quantitative safety variables 
and their changes from baseline (laboratory, vital signs) will be summarized with descriptive 
statistics.  Clinically significant abnormal values will be flagged and tabulated based on 
predefined criteria. 
Exposure will be analyzed by describing dose intensity, which is defined as the dose received, 
divided by the dose planned, over a given time interval.  This will be done by cycle as well as 
overall cycles received for durvalumab + epacadostat and durvalumab alone.  For each cycle, 
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incidences of dose reductions and cycle delays will also be tabulated by reason for the reduction 
or delay.  The percentage of subjects with any delay and/or reduction will also be calculated. 
9.4.4. 
Clinical Laboratory Tests 
The clinical laboratory data will be analyzed using summary statistics (eg, means and 
frequencies).  In addition, distributions of key laboratory parameters (including hemoglobin, 
neutrophils, and platelets) will be plotted over time; these values will also be classified into 
CTCAE toxicity grades and tabulated.  Descriptive statistics and mean change from baseline will 
be determined for vital signs at each assessment time.  Vital sign results will be reviewed for 
clinically notable abnormalities. 
9.5. 
Data Monitoring Committee 
Not applicable. 
9.6. 
Interim Analysis 
An interim safety analysis is planned for Phase 2 after 16 subjects have been enrolled and treated 
for 8 weeks, and then approximately every 3 months thereafter.  If the following is reported 
during these reviews, enrollment of subjects would be suspended until the sponsor determined 
the appropriate course of action and notified IRBs and regulatory authorities: 
• ≥ 40% of subjects have experienced an AE ≥ Grade 3 that was attributable to the 
investigational agents. 
No formal interim analysis for futility or efficacy is planned for this study. 
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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Investigational Product Description 
10.1.1. 
Packaging, Labeling, and Preparation of Study Drug 
10.1.1.1. Epacadostat 
The study drug will be available as 25 mg and 100 mg tablets packaged in HDPE bottles. 
All Incyte investigational product labels will be in the local language and will comply with the 
legal requirements of each country. 
10.1.1.2. Durvalumab 
Durvalumab will be provided as a vialed liquid solution containing 500 mg (nominal) 
durvalumab.  The solution contains 50 mg/mL durvalumab, 26 mM histidine/histidine-HCl, 
275 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, at pH 6.0.  The investigator shall take 
responsibility for and shall take all steps to maintain appropriate records and ensure appropriate 
supply, storage, handling, distribution, and use of investigational product in accordance with the 
Protocol and any applicable laws and regulations. 
10.1.2. 
Storage and Stability of Study Drug 
10.1.2.1. Epacadostat 
Clinical supplies must be stored as described in the iIB. 
10.1.2.2. Durvalumab 
Unopened vials of durvalumab liquid Drug Product must be stored at 2°C to 8°C (36°F to 46°F). 
10.2. 
Accountability, Handling, and Disposal of Study Drug 
Responsibility for drug accountability at the study site rests with the investigator; however, the 
investigator may assign some of the drug accountability duties to an appropriate pharmacist or 
other designee.  Inventory and accountability records must be maintained and readily available 
for inspection by the study monitor and are open to inspection at any time by any applicable 
regulatory authorities. 
The investigator or designee will be expected to collect and retain all used, unused, and partially 
used containers of study drug until the end of the study.  The investigator or designee must 
maintain records that document: 
• Delivery of study drug to the study site. 
• Inventory of study drug at the site. 
• Subject use of the study drug including pill or unit counts from each supply 
dispensed. 
• Return of study drug to the investigator or designee by subjects. 
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These records should include dates, quantities, batch or serial numbers (if available), and the 
unique code numbers (if available) assigned to the investigational product and study subjects. 
The investigational product must be used only in accordance with the Protocol.  The investigator 
will also maintain records adequately documenting that the subjects were provided the correct 
study drug specified. 
Completed accountability records will be archived by the site.  At the completion of the study, 
the investigator or designee will oversee shipment of any remaining study drug back to the 
sponsor or its designee for destruction according to institutional standard operating procedures.  
If local procedures mandate site destruction of investigational supply, prior written approval 
must be obtained from Incyte. 
11. 
STUDY ADMINISTRATION 
11.1. 
Data Management 
11.1.1. 
Data Collection 
The investigator will be provided with a CRF for each subject.  Entries made in the CRF must be 
verifiable against source documents; any discrepancies should be explained and documented.  
The investigator will be responsible for reviewing all data and CRF entries and will sign and date 
the designated pages in each subject's CRF, verifying that the information is true and correct.  
The investigator is responsible for the review and approval of all responses. 
11.1.2. 
Data Management 
Data management will be performed from CRFs.  All CRF data will be entered into a validated 
database.  All data entry, verification, and validation will be performed in accordance with the 
current standard operating procedures of the Data Management Department at the sponsor or its 
designee.  The database will be authorized for lock once all defined procedures are completed. 
11.2. 
Study Monitoring 
Qualified representatives of the sponsor or its designee, "study monitors," will monitor the study 
according to a predetermined monitoring plan.  Monitoring visits provide the sponsor with the 
opportunity to: 
• Evaluate the progress of the study. 
• Verify the accuracy and completeness of CRFs. 
• Assure that all Protocol requirements, applicable laws and/or regulations, and 
investigator's obligations are being fulfilled. 
• Resolve any inconsistencies in the study records. 
The investigator must allow the study monitors to periodically review, at mutually convenient 
times during the study and after the study has been completed, all CRFs and office, hospital, and 
laboratory records supporting the participation of each subject in the study.  The CRFs and other 
documentation supporting the study must be kept up-to-date by the investigator and the research 
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staff at the investigative site.  These study materials must be available for review by the study 
monitor, and/or other qualified representatives of the sponsor or its designee, at each monitoring 
visit. 
The study monitor will review the various records of the study (CRFs, subject medical and 
laboratory records, and other pertinent data).  The study monitor will verify the CRF data against 
original source documentation for accuracy and completeness.  The study monitor will identify 
data discrepancies and collaborate with the investigator and research staff to resolve the 
discrepancies in a timely manner.  Protocol deviations will also be identified and recorded on a 
"Protocol Deviation Log."  The study monitor will follow an "Issue Escalation" plan in order to 
ensure that each issue identified during a monitoring visit is appropriately documented, reported, 
and resolved in a timely manner in accordance with the plan's requirements. 
11.3. 
Protocol Adherence 
The principal investigator must obtain IRB or IEC approval for the investigation.  Initial IRB or 
IEC approval and all materials approved by the IRB or IEC for this study including the subject 
ICF and recruitment materials must be maintained by the investigator and made available for 
inspection. 
Each investigator must adhere to the Protocol as described in this document and agree that 
changes to the Protocol, with the exception of medical emergencies, must be discussed and 
approved, firstly, by the sponsor or its designee and, secondly, by the IRB or IEC.  Each 
investigator is responsible for enrolling subjects who have met the Protocol inclusion and 
exclusion criteria.  The IRB or IEC that granted original approval, or the IRB or IEC currently 
responsible for overseeing the conduct of the study, must be notified of all changes in and 
deviations from the Protocol that may increase risk to the subject, and/or that may adversely 
affect the rights of the subject or validity of the investigation.  The investigator must send a copy 
of the approval letter from the IRB or IEC to the sponsor or its designee and retain the original in 
the site study regulatory file. 
Major eligibility deviations must be reported to the IRB or IEC in accordance with the IRB or 
IEC requirements.  During the course of the study, the monitor must notify the sponsor or its 
designee of subjects found not to have met eligibility criteria.  The medical monitor, in 
collaboration with the investigator, will determine if the subject should be withdrawn from the 
study. 
11.4. 
Financial Disclosure 
All clinical investigators participating in clinical studies subject to FDA Regulation Title 21 CFR 
Part 54 – Financial Disclosure by Clinical Investigators, are required before study initiation to 
submit a completed Clinical Investigator Financial Disclosure Request Form that sufficiently 
details any financial interests and arrangements that apply.  For the purpose of this regulation, 
clinical investigator is defined as any investigator or subinvestigator who is directly involved in 
the treatment or evaluation of research subjects, including the spouse and each dependent child 
of the clinical investigator.  These requirements apply to both US and foreign clinical 
investigators conducting covered clinical studies. 
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Any new investigators or subinvestigators added to the covered clinical study during its conduct 
must also submit a completed Clinical Investigator Financial Disclosure Request Form.  During a 
covered clinical study, any changes to the financial information previously reported by a clinical 
investigator must be reported to the sponsor or its designee.  At the conclusion of the covered 
clinical study, the clinical investigators will be reminded of their obligation to report to the 
sponsor or its designee any changes to the financial information previously reported.  The 
clinical investigators will also be reminded that they must report any changes in their financial 
information for a period of 1 year after completion of the covered clinical study. 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
12.1. 
Sponsor Audits 
At some point during the study, individuals from the sponsor's Quality Assurance department 
and/or their authorized representative may visit the investigator's site to conduct an audit of the 
study.  The purpose of this visit will be to determine the investigator's adherence to the Protocol, 
applicable regulations, and the sponsor's procedures, in addition to assessing the accuracy of the 
study data.  Before initiating this audit, the investigator will be contacted by the sponsor to 
arrange a convenient time for this visit.  The investigator and staff are expected to cooperate with 
the auditors and allow access to all subject records supporting the CRFs and other study-related 
documents. 
12.2. 
Inspection by Regulatory Authorities 
At some point during the investigational product's development program, a regulatory authority 
may visit the investigator to conduct an inspection of the study and the site.  The investigator and 
staff are expected to cooperate with the inspectors and allow access to all source documents 
supporting the CRFs and other study-related documents.  The investigator must immediately 
notify the sponsor when contacted by any regulatory authority for purposes of conducting an 
inspection. 
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13. 
ETHICS 
13.1. 
Ethical Conduct of the Study 
This study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and conducted in adherence to the study Protocol, GCPs as defined in 
Title 21 of the US CFR Parts 50, 54 56, 312, and Part 11, as well as ICH GCP consolidated 
guidelines (E6) and applicable regulatory requirements. 
13.2. 
Written Informed Consent 
Informed consent documentation that includes both information about the study and the ICF will 
be prepared and given to the subject.  This document will contain all elements required by the 
ICH E6 Guideline for GCP and any additional elements required by local regulations.  The 
document must be in a language understandable to the subject and must specify who informed 
the subject.  Where required by local law, the person who informs the subject must be a 
physician. 
The principal investigator at each center will ensure that the subject is given full and adequate 
verbal and written information about the nature, purpose, and the possible risk and benefit of the 
study.  Subjects must also be notified that they are free to discontinue study drug and withdraw 
from the study at any time.  The subject should be given the opportunity to ask questions and 
allowed time to consider the information provided. 
The subject's signed and dated ICF must be obtained before conducting any study procedures.  
The principal investigator must maintain the original, signed ICF.  A copy of the signed ICF 
must be given to the subject.  The investigator should inform the subject's primary physician 
about the subject's participation in the study if the subject has a primary physician and if the 
subject agrees to the primary physician being informed. 
Preparation of the ICF is the responsibility of the investigator and must include all elements 
required by the ICH GCP, and applicable regulatory requirements, and must adhere to the ethical 
principles that have their origin in the Declaration of Helsinki.  A template will be provided by 
the sponsor or its designee.  The sponsor or its designee must review and approve all changes to 
site-specific ICFs.  The ICF must include a statement that the sponsor or its designee and 
regulatory authorities have direct access to subject records.  Before the beginning of the study, 
the IRB or IEC must provide the investigator with written approval/favorable opinion of the 
written ICF and any other information to be provided to the subjects. 
13.3. 
Ethics Review 
It is the responsibility of the investigator to assure that all aspects of the ethics review are 
conducted in accordance with the Declaration of Helsinki as described in the ICH E6:  Guideline 
for GCP, and/or local laws, whichever provides the greatest level of protection for the study 
participants.  The Protocol and any information supplied to the subject to obtain informed 
consent, including written ICFs, subject recruitment procedures (eg, advertisements), and written 
information to be provided to subjects (information leaflets), must be reviewed and approved by 
a qualified IRB/IEC before enrollment of participants in the study.  Before initiation of the study, 
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the sponsor or its designee must receive documentation of the IRB or IEC approval, which 
specifically identifies the study/protocol, and a list of the committee members. 
The principal investigator is responsible for informing the IRB or IEC of any amendment to the 
Protocol in accordance with local requirements.  Protocol amendments and revisions to the ICF 
must be submitted to and approved by the IRB or IEC. 
Investigators must submit progress reports to the IRB or IEC in accordance with the IRB or IEC 
requirements and local regulations.  Annual re-approval of the study must be obtained.  Copies 
of progress reports and annual re-approvals must be sent to the sponsor or its designee. 
The principal investigator is also responsible for providing the IRB or IEC with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product.  The sponsor or its designee will provide this information to the principal investigator. 
When the sponsor or its designee provides the investigator with a safety report, the investigator 
must promptly forward a copy to the IRB or IEC. 
After completion or termination of the study, the investigator must submit a final report to the 
IRB or IEC and to the sponsor or its designee. 
The investigator, as part of the records retention requirements for the study, must maintain 
documentation of all submissions, correspondence, and approvals to and from the IRB or IEC. 
Each clinical investigator is responsible to conduct the study in accordance with the Protocol, all 
applicable laws, regulations, and GCP according to ICH guidelines. 
13.4. 
Data Privacy 
The investigator and the sponsor or its designee must adhere to applicable data privacy laws and 
regulations.  The investigator and the sponsor (or its designee) are responsible for ensuring that 
sensitive information is handled in accordance with local requirements (eg, HIPAA).  
Appropriate consent and authorizations for use and disclosure and/or transfer (if applicable) of 
protected information must be obtained. 
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14. 
DATA HANDLING AND RECORDKEEPING 
14.1. 
Inspection of Records 
The sponsor or its designee will be allowed to conduct site visits to the investigation facilities for 
the purpose of monitoring any aspect of the study.  The investigator agrees to allow the monitor 
to inspect the drug storage area, study drug stocks, drug accountability records, subject charts 
and study source documents, and other records relative to study conduct. 
The investigator must ensure that all records pertaining to the conduct of the clinical study 
(as listed above) are adequately maintained for a period of 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region, or at least 2 years have elapsed since the formal termination of 
clinical development of the investigational product. 
14.2. 
Retention of Records 
The principal investigator must maintain all documentation relating to the study for a period of 
2 years after the last marketing application approval, or if not approved, 2 years following the 
termination of the test article for investigation.  If it becomes necessary for the sponsor or the 
regulatory authority to review any documentation relating to the study, the investigator must 
permit access to such records. 
The investigator must not destroy any records associated with the study without receiving 
approval from Incyte.  The investigator must notify the sponsor or its designee in the event of 
accidental loss or destruction of any study records.  If the investigator leaves the institution 
where the study was conducted, the sponsor or its designee must be contacted to arrange 
alternative record storage options. 
Whenever possible, an original recording of an observation must be retained as the source 
document.  However, a photocopy of a record is acceptable, provided it is legible and is a 
verified copy of the original document. 
All CRF 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 CRF data and 
audit trail. 
14.3. 
Confidentiality 
Subject names will not be supplied to the sponsor or its designee if applicable.  Only the subject 
number and subject's initials will be recorded in the CRF, where permitted; if the subject's name 
appears on any other document (eg, laboratory report), it must be obliterated on the copy of the 
document to be supplied to the sponsor or its designee.  Study findings stored on a computer will 
be stored in accordance with local data protection laws.  The subjects will be informed that 
representatives of the sponsor or its designee, IRB or IEC, or regulatory authorities may inspect 
their medical records to verify the information collected, and that all personal information made 
available for inspection will be handled in strictest confidence and in accordance with local data 
protection laws. 
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15. 
PUBLICATION POLICY 
By signing the study Protocol, the investigator and his or her institution agree that the results of 
the study may be used by the sponsor, Incyte Corporation (Incyte), for the purposes of national 
and international registration, publication, and information for medical and pharmaceutical 
professionals.  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.  The signed agreement is 
retained by the sponsor or its designee. 
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dendritic cell subsets suppresses T cell clonal expansion. J Immunol 2003;171:1652-1655. 
Mellor AL, Munn DH. IDO expression by dendritic cells: tolerance and tryptophan catabolism. 
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Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine 
alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer 
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Moran T, Sequist LV. Timing of epidermal growth factor receptor tyrosine kinase inhibitor 
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Muller AJ, DuHadaway JB, Donover PS, Sutanto-Ward E, Prendergast GC. Inhibition of 
indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, 
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Munn DH, Mellor AL. Indoleamine 2,3-dioxygenase and tumor- induced tolerance. J Clin Invest 
2007;117:1147-1154. 
Munn DH, Sharma MD, Hou D, et al. Expression of indoleamine 2,3-dioxygenase by 
plasmacytoid dendritic cells in tumor-draining lymph nodes. J Clin Invest 2004;114:280-290. 
Muro K, Bang YJ, Shankaran V, et al. Relationship between PD-L1 expression and clinical 
outcomes in patients (Pts) with advanced gastric cancer treated with the anti-PD-1 monoclonal 
antibody pembrolizumab (Pembro; MK-3475) in KEYNOTE-012. J Clin Oncol 
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Nakamura T, Shima T, Saeki A, et al. Expression of indoleamine 2,3-dioxygenase and the 
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Swain S. Triple-negative breast cancer: metastatic risk and role of platinum agents. ASCO 
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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  Vasectomized partner is a highly effective method provided of avoiding pregnancy that partner is the sole sexual 
partner of the WOCBP trial participant and that the vasectomized partner has received medical assessment of the 
surgical success.  
4  In the context of this guidance, sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments.  The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the subject. 
Source:  CTFG 2014. 
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APPENDIX B. EASTERN COOPERATIVE ONCOLOGY GROUP 
(ECOG) PERFORMANCE STATUS 
Grade 
Performance Status 
0  
Fully active, able to carry on all pre-disease performance without restriction  
1  
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, eg, light house work, office work  
2  
Ambulatory and capable of all selfcare but unable to carry out any work activities.  Up and 
about more than 50% of waking hours  
3  
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours  
4  
Completely disabled.  Cannot carry on any selfcare.  Totally confined to bed or chair  
5  
Dead 
Source:  Oken et al 1982. 
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APPENDIX C. PROHIBITED MONOAMINE OXIDASE INHIBITORS 
AND DRUGS ASSOCIATED WITH SIGNIFICANT 
MONOAMINE OXIDASE INHIBITORY ACTIVITY 
Monoamine Oxidase Inhibitors 
Drugs Associated With Significant Monoamine 
Oxidase Inhibitory Activity 
Hydrazine (example phenelzine) 
Meperidine 
Caroxazone 
Linezolid 
Echinopsidine 
Methylene blue 
Furazolidone 
 
Tranylcypromine 
 
Brofaromine 
 
Metralindole 
 
Minaprine 
 
Moclobemide 
 
Pirlindole 
 
Toloxatone 
 
Lazbemide 
 
Pargyline 
 
Rasagiline 
 
Selegiline 
 
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APPENDIX D. PROHIBITED UGT1A9 INHIBITORS 
Acitretin 
Linoleic acid 
Amitriptyline 
Mefenamic acid 
Andosterone 
Mycophenolic acid 
Cyclosporine 
Niflumic acid 
Dasatinib 
Nilotinib 
Diclofenac 
Phenobarbital 
Diflunisal 
Phenylbutazone 
Efavirenz 
Phenytoin 
Estradiol (17-beta-) 
Probenecid 
Flutamide 
Propofol 
Gefitinib 
Quinidine 
Gemfibrozil 
Ritonavir 
Glycyrrhetinic acid 
Sorafenib 
Glycyrrhizin 
Sulfinpyrazone 
Imatinib 
Valproic acid 
Imipramine 
Verapamil 
Ketoconazole 
 
 
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APPENDIX E. PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document 
Date 
Amendment (Version) 1: 
29 SEP 2014 
Amendment (Version) 2: 
20 FEB 2015 
Amendment (Version) 3: 
10 JUL 2015 
Amendment (Version) 4: 
12 JAN 2016 
Amendment (Version) 5: 
25 MAY 2016 
Amendment (Version) 6: 
28 JUN 2017 
Amendment (Version) 7: 
21 SEP 2018 
Amendment 7 (21 SEP 2018) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to reduce required study procedures and update 
guidelines on the management of legacy subjects who remained on epacadostat monotherapy. 
This amendment includes the changes to INCB 24360-203 Protocol Amendment 6 
(28 JUN 2017) summarized below. 
1. Synopsis; Section 5.4, Duration of Treatment and Subject Participation; 
Section 5.7.1, Withdrawal Criteria; Section 6.2, Treatment Period; Section 6.2.1, 
Restarting Treatment With Study Therapy After Treatment Withdrawal; 
Section 7.3.6, Laboratory Assessments; Section 7.3.7, Chest Radiograph; Section 
7.4.2, Tumor Imaging During the Study; Appendix F, Re-Treatment 
Description of change:  The duration of epacadostat monotherapy treatment for any 
subject taking epacadostat monotherapy at the time of Amendment 6 and allowed to 
remain on the monotherapy regimen was capped at 12 months, thereby also capping 
overall treatment duration maximum for these subjects at 24 months.  Exceptions will 
require medical monitor review and approval every 3 months.  The option for subjects 
who completed 12 months of combination therapy with SD or better, to restart study 
therapy post-progression was removed. 
Rationale for change:  The sponsor has decided to cap the duration of epacadostat 
monotherapy and remove the option to restart combination therapy post-progression 
based on emerging data, from the Phase 3 KEYNOTE-252/ECHO-301 study in advanced 
or metastatic melanoma. 
2. Section 1.2, Study Rationale 
Description of change:  Language regarding the results of the ECHO-
301/KEYNOTE-252 study eDMC review was added. 
Rationale for change:  To provide updated data regarding the rationale of epacadostat 
and anti–PD-(L)-1 combination therapy. 
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3. Section 1.3.1, Risks from Epacadostat; Section 5.6.4, Procedures for Subjects 
Exhibiting Serotonin Syndrome; Section 5.10.2, Prohibited Medications and 
Measures; Appendix C, Publication on Serotonin Syndrome 
Description of changes: Protocol text relevant to serotonin syndrome was updated.  
Prohibition of concomitant melatonin supplements was lifted.  Appendix C was removed. 
Rationale for changes:  To make language consistent with epacadostat program-wide 
standards. 
4. Synopsis; Section 4.1, Overall Study Design; Section 5.4, Duration of Treatment and 
Subject Participation; Section 5.6.3.6, Procedures for Immune-Mediated 
Endocrinopathies; Section 5.7.2, Withdrawal Procedures; Section 5.8.1, Study 
Completion Criteria; Section 5.9, Beginning and End of the Study; Section 6, Study 
Assessments (Table 22:  Schedule of Assessments; Table 23:  Laboratory 
Assessments); Section 6.3, End of Treatment; Section 6.4, Follow-Up Period; Section 
7.4.2, Tumor Imaging During the Study; Section 7.4.3.3.4, Evaluation of Overall 
Response With Modifications; Section 7.5.1 Eastern Cooperative Oncology Group 
Performance Status; Section 7.6.1.2, Pharmacokinetic Assessment for Durvalumab 
(Table 28:  Sample Collection Windows for Pharmacokinetic Assessments for 
Durvalumab [Phase 1 and Phase 2]); 
 
Description of change:  Follow-up phases (disease and survival follow-up) beyond the 
90-day safety follow-up visit have been removed from the protocol.  The frequency of 
required endocrine function testing and disease imaging studies has changed from every 
8 weeks (4 cycles) to every 12 weeks (6 cycles).  Study completion criteria have been 
revised to include completion of the 90-day safety follow-up period.  ECOG performance 
status, durvalumab pharmacokinetic sample collection beyond Cycle 2, soluble PD-1 
concentration, 
, and whole blood correlative 
assessment have all been removed from the protocol.  The language regarding collection 
of optional on-treatment biopsies was modified.  The requirement to submit copies of 
tumor imaging data to a central vendor was removed.  The requirement to confirm 
radiographic responses was removed. 
Rationale for change:  The frequency and necessity of study procedures were modified 
based on emerging data from the Phase 3 KEYNOTE-252/ECHO-301 study in advanced 
or metastatic melanoma. 
5. Section 5.6.2, Criteria and Procedures for Interruption or Dose Reduction (Table 8:  
Dose Modification Guidelines of Epacadostat and Durvalumab for Non−Immune-
Related Adverse Events); Section 5.6.3, Criteria for Subjects Exhibiting Immune-
Related Adverse Events 
Description of change:  Protocol language and recommendations for managing on-study 
toxicities were updated. 
Rationale for change:  To align with current durvalumab toxicity management 
guidelines. 
6. 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 (28 JUN 2017) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to revise the design and composition of the NSCLC, 
SCCHN, and TCC of the GU tract Phase 2 expansion cohorts.  Additional changes include 
removal of the optional epacadostat monotherapy treatment period of the study updating 
inclusion/exclusion criteria and including updated safety information for epacadostat and 
durvalumab. 
This amendment includes the changes to INCB 24360-203 Protocol Amendment 5 
(25 MAY 2016) summarized below. 
1. Synopsis; Section 4.1.2, Phase 2; Section 4.4, Number of Subjects; Section 9.2.2, 
Sample Size for Phase 2 
Description of change:  The Phase 2 expansion cohorts for the NSCLC, SCCHN, and 
TCC tumors were revised from a Simon 2-stage design to single expansion cohorts 
treated at the epacadostat 300 mg BID dose level.  The approximate sample size for each 
cohort was increased, as was the approximate total number of subjects expected to be 
enrolled into the study and the estimated last subject completion date.  The number of 
prior PD-1 pathway–treated subjects in each cohort was restricted to 10.  Table 6 and 
Table 31 were added to depict the new expansion cohort composition and statistical basis 
for the sample size. 
Rationale for change:  The design and composition of the NSCLC, SCCHN, and TCC 
cohorts were revised to allow for the full complement of Phase 2 subjects enrolled with 
these tumor types to be analyzed at the epacadostat 300 mg BID dose level.  The sample 
size for these tumor types, and subsequently the estimated planned number of total 
subjects enrolled and estimated last subject completed date, were modified to account for 
the heterogeneity of PD-1 pathway–treated and PD-1 pathway–naive subjects within the 
respective tumor types.  Restricting the number of prior PD-1 pathway–treated subjects 
within each cohort was instituted to preserve the predicted levels of baseline efficacy 
observed with PD-1 pathway monotherapy. 
2. Synopsis; Section 4.1, Overall Study Design; Section 5.1.1, Epacadostat; Section 5.4, 
Duration of Treatment and Subject Participation; Section 5.6.2, Criteria and 
Procedures for Interruption or Dose Reduction; Section 5.7, Withdrawal of Subjects 
from Study Treatment; Section 6, Study Assessments (Table 21:  Schedule of 
Assessments); Section 6.2, Treatment Period; Section 6.2.1, Restarting Treatment 
With Study Therapy After Treatment Withdrawal; Section 6.4.2, Follow-Up; 
Section 7.3.6, Laboratory Assessments; Section 7.3.7, Chest Radiograph; Section 
7.4.2, Tumor Imaging During the Study; Appendix F:  Re-Treatment 
Description of change:  The epacadostat monotherapy treatment option was removed 
from the Protocol.  Relevant sections were modified to allow for restarting combination 
therapy upon evidence of disease progression under certain conditions and to allow for 
subjects to be re-treated with durvalumab monotherapy upon evidence of disease 
progression if the combination therapy was not tolerated in the initial treatment period 
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due to a toxicity attributed to epacadostat, but they completed 12 months of durvalumab 
and had a status of stable disease or better when they discontinued treatment. 
Rationale for change:  Based on emerging data with regard to epacadostat monotherapy 
as well as monotherapy data from other agents targeting the IDO pathway, there is no 
clear evidence of antitumor activity with IDO inhibitors as monotherapy in the tumors 
being evaluated in this study.  IDO1 is an interferon response gene and a resistance 
mechanism to PD-1 pathway targeting agents.  Based on Phase 2 studies, augmenting 
activity of PD-1 pathway−targeting agents has been reported in tumor types where PD-1 
pathway−targeting agents have been approved by regulatory authorities.  Thus, 
responders who complete 12 months of treatment and discontinue study treatment may 
resume combination therapy. 
3. Synopsis; Section 3.3, Subject Exclusion Criteria 
Description of changes: 
a. Exclusion criteria 1e and 1f were revised to remove alkaline phosphatase and update 
requirements for aspartate aminotransferase, alanine aminotransferase, and total 
bilirubin. 
b. Criterion 7 was revised to exclude subjects with major surgical procedure within 
28 days of starting study treatment OR inadequate recovery from toxicity and/or 
complications from major surgery before starting study treatment. 
c. Criterion 9 was revised to include carcinomatous meningitis and define CNS 
metastases. 
d. Criterion 10 was revised to include additional autoimmune and inflammatory 
disorders and updated exceptions. 
e. Criterion 23 was revised to include additional requirements for subjects who have 
received prior immunotherapy. 
f. New criteria 26 and 27 added to exclude subjects with a history of primary 
immunodeficiency or leptomeningeal carcinomatosis.  
Rationale for changes:  To make criteria consistent with current epacadostat and/or 
durvalumab development program standard protocol language. 
4. Synopsis; Section 1.3, Potential Risks and Benefits of the Treatment Regimen; 
Section 5.6.2, Criteria and Procedures for Interruption or Dose Reduction (Table 8); 
Section 5.6.3, Criteria for Subjects Exhibiting Immune-Related Adverse Events 
(including Tables 10-17 and 19)  Section 5.6.4, Procedures for Subjects Exhibiting 
Serotonin Syndrome 
Description of change:  Safety language with regard to epacadostat and durvalumab, 
including updated guidelines for the management of certain immune-related adverse 
events, were revised or added. 
Rationale for change:  To align the Protocol with the current safety-related information 
and strategies pertinent to the epacadostat and durvalumab clinical development 
programs. 
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Amendment 5 (25 MAY 2016) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to provide additional guidance for subjects continuing 
on monotherapy epacadostat and provide guidance for subjects who restart treatment with 
combination therapy after durvalumab has been stopped. 
This amendment includes the changes to the INCB 24360-203 Protocol Amendment 4 
(12 JAN 2016) summarized below. 
1. Synopsis; Section 3.3, Subject Exclusion Criteria (Criterion #5); Section 5.6.3.9, 
Procedures for Immune-Related Adverse Events Not Specifically Described 
Above; Section 5.10, Concomitant Medications and Measures 
Description of change:  The threshold for systemic steroids was changed from 
≥ 7.5 mg/day to ≥ 10 mg/day prednisone equivalent. 
Rationale for change:  Several recent studies evaluating immune-related adverse 
events (irAEs) and the need for systemic immunosuppression indicate that low doses 
of systemic steroids for the management of irAEs do not impact survival or time to 
treatment failure.  Although the threshold for the study was increased, a maximum 
dose of 10 mg/day prednisone equivalent is still considered a low dose. 
2. Section 1.1.6, Melanoma; Section 1.1.7, Non–Small Cell Lung Cancer; 
Section 1.1.9, Squamous Cell Carcinoma of the Head and Neck; Section 1.1.11, 
Gastric and Gastroesophageal Junction Cancer 
Description of change:  Updated background information on therapies approved for 
the treatment of melanoma, non-small cell lung cancer, squamous cell carcinoma of 
the head and neck, and gastric and gastroesophageal junction cancer. 
Rationale for change:  To provide up-to-date information. 
3. Section 3.2, Subject Inclusion Criteria 
Description of change:  Inclusion criterion #16 was updated to note that male 
subjects should refrain from sperm donation from screening through 90 days after the 
last dose of study drug. 
Rationale for change:  Male subjects were required to take appropriate precautions 
throughout the study not to father a child, which was inclusive of sperm donation.  
The language seeks to clarify the subject's responsibilities while participating in the 
study. 
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4. Section 3.3, Subject Exclusion Criteria; Section 6, Study Assessments (Table 21) 
Description of change:  Exclusion criterion #16 and Table 21 were updated to 
specify that subjects with hepatitis B no longer are required to have Hepatitis B 
surface antigen antibody testing.  Subjects with hepatitis C antibody positivity may 
also enroll if they have completed treatment for hepatitis C intended to eradicate to 
the virus and hepatitis C RNA levels are undetectable. 
Rationale for change:  The availability of highly active treatments for HCV has 
transformed hepatitis C into a curable illness.  Subjects who have undergone antiviral 
therapy and have an undetectable viral load are an important population to consider 
for immunotherapy studies.  In the dose-escalation phase of the study, subjects 
underwent increased monitoring of liver chemistry tests weekly for the first 8 weeks 
on study.  There were no cases of hepatitis reported, and no subjects experienced 
drug-induced liver injury while on study.  A recent case study of 2 HCV+ subjects 
treated with pembrolizumab alone and pembrolizumab + ipilumumab demonstrated 
that no significant toxicities and no increases in viral load occurred during the course 
of immunotherapy treatment.1  The safety expansion portion of this 1b study includes 
interim safety analyses approximately every 3 months and offers a unique opportunity 
to study this population in the clinical trial setting.  For this reason, we plan to allow 
subjects with previously treated and controlled hepatitis C infections to participate in 
the safety expansion. 
With respect to hepatitis B, the Protocol excluded subjects with prior HBV exposure, 
regardless of whether they are immune or have chronic active disease.  The Protocol 
is modified to allow subjects who by definition of the CDC Guidelines are immune to 
HBV, and those with chronic active HBV are still excluded 
(http://www.cdc.gov/hepatitis/hbv/hbvfaq.htm#general). 
5. Section 3.3, Subject Exclusion Criteria 
Description of change:  Exclusion criterion #22 was updated to note that a subject 
with an arrhythmia may enroll if the subject is on anti-arrhythmic medication and is 
in sinus rhythm on the screening ECG. 
Rationale for change:  More than 250 subjects have been administered epacadostat 
monotherapy or epacadostat in combination with other immune-checkpoint inhibitors, 
and no clinically meaningful changes or cardiac trends have been noted. 
1 Davar D, Wilson M, Pruckner C, Kirkwood JM. PD-1 blockade in advanced melanoma in patients with hepatitis C 
and/or HIV. Case Rep Oncol Med 2015; Article ID 737389, 5 pages. http://dx.doi.org/10.1155/2015/737389. 
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6. Section 4.1.2, Phase 2 
Description of change:  Revised to indicate that if more than 1 PAD is evaluated, the 
cohort may or may not be repeated for the specified tumor type. 
Rationale for change:  A higher dose level may be explored based on PK/PD data 
from the Phase 1 portion of the study.  If target inhibition at the 300 mg BID dose 
level is greater than the 100 mg BID dose level, subjects may be enrolled at the 
higher dose level.  If the lower dose level does not meet the threshold for the number 
of responses required to expand the cohort, the cohort may be enrolled at the higher 
dose level. 
7. Section 5.6.2, Criteria and Procedures for Interruption or Dose Reduction  
Description of change:  In Table 7 (Dose Modification Guidelines of Epacadostat 
and Durvalumab for Non−Immune-Related Adverse Events), "Action with Respect to 
Durvalumab" was revised for infusion-related reactions:  For Grade 1 or 2,  the time 
limit of "up to 4 hours" for temporary interruption of durvalumab was deleted; for 
Grade ≥ 3, a note was added that severe infusion-related reactions should be managed 
per institutional standards (eg, IM epinephrine, followed by IV diphenhydramine and 
ranitidine, and IV glucocorticoid). 
Rationale for change:  To provide additional guidance to investigators regarding the 
management of irAEs. 
8. Section 5.6.3, Criteria for Subjects Exhibiting Immune-Related Adverse Events  
Description of change:  Tables 9 through 15 (Recommended Approach for Handling 
Noninfectious Pneumonitis, Enterocolitis, Hepatitis, Dermatitis, Neuropathies, 
Endocrinopathies, and Nephritis or Renal Dysfunction, respectively) were updated, 
and precautions were added for any grade immune-mediated peripheral neuromotor 
syndromes, such as Guillain-Barré syndrome and myasthenia gravis. 
Rationale for change:  To provide additional guidance to investigators regarding the 
management of irAEs. 
9. Section 5.9, Beginning and End of Study 
Description of change:  Revised to define end of study as when all subjects have 
discontinued the study drug and have completed applicable follow-up assessments, 
and to indicate that if ≤ 5 subjects are on study for more than 6 months, a database 
lock of the study may occur to allow the analysis of the study data.  Any remaining 
subjects may continue on study until a discontinuation criterion is met and/or written 
notification is provided to the sponsor. 
Rationale for change:  To clarify that the end of study will be declared when all 
subjects have been discontinued the study drug and completed all applicable 
follow-up visits. 
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14. Section 7.6.1.1, Pharmacokinetic Assessment for Epacadostat 
Description of change:  In Table 24 (Sample Collection Windows for 
Pharmacokinetic Assessments for Epacadostat), the window for the 6-hour and 
optional 8- to 10-hour samples was changed to ± 60 minutes (instead of 
± 30 minutes). 
Rationale for change:  Visit windows were lengthened to allow greater flexibility. 
15. Section 9.6, Interim Analysis 
Description of change: The interim analysis was modified to evaluate all ≥ Grade 3 
adverse events attributable to the investigational agents in Phase 2 of the study. 
Rationale for change:  The revised criteria for evaluation allows for efficient 
monitoring of safety in a larger sample size. 
16. Section 10.1.1.1, Epacadostat 
Description of change:  The packaging/labeling statement was revised to:  All Incyte 
investigational product labels will be in the local language and will comply with the 
legal requirements of each country. 
Rationale for change:  The study will now include ex-US centers; therefore, the 
language was updated for global compliance. 
17. Appendix A, Information Regarding Effectiveness of Contraceptive Methods 
Description of change:  Appendix A was updated with Clinical Trial Facilitation 
Group's recommendations related to contraception in clinical studies. 
Rationale for change: The study will now include ex-US centers; therefore, the 
language was updated for global compliance. 
18. Incorporation of administrative changes.  Other minor, administrative changes 
have been incorporated throughout the Protocol and are noted in the redline version 
of the amendment. 
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4. Synopsis; Section 3.2, Subject Inclusion Criteria 
Description of change:  Inclusion criterion #6 was updated to indicate that subjects with 
NSCLC may have received prior treatment with an anti–PD-1 targeted agent. 
Rationale for change:  The PD-1 targeted agents nivolumab and pembrolizumab were 
recently approved for the treatment of subjects with metastatic NSCLC who have disease 
progression on or after platinum-containing chemotherapy.  Therefore, subjects may have 
received prior therapy with either of these agents. 
5. Synopsis; Section 3.3, Subject Exclusion Criteria 
Description of change:  Exclusion criterion #21 was revised to indicate that subjects 
with a screening QTc interval > 480 msec (instead of > 470 msec) are excluded. 
Rationale for change:  An analysis of QTc interval prolongation and the relationship 
between epacadostat plasma concentration and QTc intervals in Phase 1 and 2 
epacadostat studies was conducted, and no clinically meaningful changes or trends were 
noted. 
6. Section 1.1.5, Combined Immune Checkpoint Inhibition; Section 1.1.6, Melanoma; 
Section 1.1.7, Non−Small Cell Lung Cancer, Section 1.1.13, Preclinical and Clinical 
Study Data; Section 1.3, Potential Risks and Benefits of the Treatment Regimen; 
Section 1.4, Justification for Treatment Regimen 
Description of change:  In Section 1.1.5, additional background information was added 
from a study of nivolumab in combination with ipilimumab versus ipilimumab alone, and 
updated data were added from the ongoing Phase 1/2 study of epacadostat in combination 
with ipilimumab.  In Sections 1.1.6 and 1.1.7, information regarding recent approvals for 
the treatment of melanoma and NSCLC was added.  Preclinical and clinical study data 
were updated in Section 1.1.13.  Safety data were updated in Sections 1.3 and 1.4. 
Rationale for change:  To provide up-to-date information. 
7. Section 1.3.1, Risks from Epacadostat; Section 6, Study Assessments, Section 7.3.4, 
Assessment of Serotonin Syndrome Symptoms 
Description of change:  Serotonin syndrome assessment was deleted from the schedule 
of assessments (Table 19) and corresponding sections. 
Rationale for change:  Of the 253 subjects administered INCB24360 to date, no subjects 
have exhibited serotonin syndrome.  Subjects and sites are informed of the signs and 
symptoms associated with serotonin syndrome; however, the separate serotonin 
syndrome assessment has been removed from the Protocol. 
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8. Section 5.6.3.3, Procedures and Guidance for Hepatitis; Section 6, Study 
Assessments, Section 7.3.6.1.1, Liver Chemistry Monitoring 
Description of change:  The requirement to conduct liver chemistry tests weekly for the 
first 8 weeks on study treatment was deleted. 
Rationale for change:  Because of the low incidence of Grade 3 or greater ALT and 
AST elevations seen on study, weekly monitoring of liver chemistry tests are not 
required.  Additional monitoring of liver chemistries will occur every cycle while 
epacadostat is administered as combination therapy. 
9. Section 5.10, Concomitant Medications and Measures 
Description of change:  Text updated to indicate that concomitant medications 
administered as treatment prophylaxis (eg, for the management of infusion reactions) 
should be recorded in the CRF.  A new table was added (Table 18) to provide warfarin 
dose modification guidance. 
Rationale for change:  In the INCB 24360-102 study, PK
 modeling 
showed that the observed extent of epacadostat interaction on multiple-dose warfarin PK 
is expected to cause greater INR increases in subjects on warfarin therapy; therefore, 
detailed coadministration guidance has been provided. 
10. Section 6, Study Assessments, Section 7.3.7, Pulmonary Function Tests 
Description of change:  The requirement for pulmonary function testing was deleted 
from Tables 20 and 21. 
Rationale for change:  Because of the low incidence of Grade 3 or greater pulmonary 
events, the requirement for pulmonary function testing has been removed. 
11. Section 6, Study Assessments; Section 7.3.5, Twelve-Lead Electrocardiograms 
Description of change:  Timing of ECGs was clarified in Table 19 (footnote c) and a 
new table was added to Section 7.3.5 (Table 22) providing the schedule and timing of 
ECG assessments. 
Rationale for change:  ECGs will be taken in conjunction with the updated timepoints 
for PK assessments. 
12. Section 6, Study Assessments; Section 7.6.1, Pharmacokinetics 
Description of change:  The PK sample collection timing for epacadostat and 
durvalumab PK was updated, and a new table was added (Table 25) providing sample 
collection windows for durvalumab PK assessments. 
Rationale for change:  Pharmacokinetic assessments for the INCB24360 program were 
aligned to collect additional information at predose, Cmax, and steady state. 
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13. Section 7.4, Efficacy Assessments 
Description of change:  The tumor imaging sections were updated to indicate that 
imaging of the pelvis is only required for subjects with TCC of the GU tract but is 
strongly encouraged for all subjects. 
Rationale for change:  Pelvic imaging is considered standard of care for TCC of the GU 
tract. 
14. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the red-line version of the 
amendment. 
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3. Synopsis, Key Inclusion Criteria and Key Exclusion Criteria; Section 3.2, Subject 
Inclusion Criteria; Section 3.3, Subject Exclusion Criteria 
Description of change:  Inclusion criterion 5b and exclusion criterion 4 have been 
updated to allow prior anti–PD-1 therapy for melanoma as well as any tumor type in 
which a PD-1 pathway targeted agent is approved. 
Rationale for change:  PD-1 targeted agents have been approved for use in subjects with 
melanoma and have also been incorporated into the NCCN guidelines as an option for 
first-line treatment in melanoma.  Incyte anticipates additional approvals for anti–PD-1 
and anti–PD-L1 targeted agents in other tumor types during the conduct of this study. 
4. Synopsis, Key Inclusion Criteria; Section 3.2, Subject Inclusion Criteria 
Description of change:  Inclusion criterion 7 has been updated to allow subjects with 
exocrine pancreatic neoplasms to enroll in Part 1.  Part 2 subjects must have 
adenocarcinoma of the pancreas. 
Rationale for change:  The change was updated to allow for a broader population of 
pancreatic subjects to enroll in the study. 
5. Synopsis, Key Inclusion Criteria; Section 3.2, Subject Inclusion Criteria; 
Section 7.6.3.5, Analysis of Tumor Samples 
Description of change:  Fresh tumor biopsies are still required for all subjects at 
screening; however, subjects may now be enrolled if the tumor tissue is deemed 
inaccessible by the local interventional radiologist in consultation with the subject's 
treating physician.  This exception requires medical monitor approval.  Archival tumor 
tissue should be submitted if available; however, if archival tumor tissue is not available 
and the subject is able to undergo a fresh biopsy, the subject will be considered eligible. 
Rationale for change:  Subjects with late-stage disease may have had any diagnostic 
archival specimens exhausted or have had their initial diagnosis made by fine-needle 
aspirate that would not be adequate for correlative studies.  Therefore, if these subjects 
are willing and able to submit fresh biopsy samples they will not be excluded from the 
study (Administrative Change 2 dated 31 MAR 2015). 
6. Synopsis, Key Inclusion Criteria; Section 3.3, Subject Exclusion Criteria; 
Section 7.3.6, Twelve-Lead Electrocardiograms 
Description of change:  The average QTc of the 3 ECGs may be used for enrollment if a 
single QTc is > 470 milliseconds.  In addition, subjects with an intraventricular 
conduction delay (eg, right bundle branch block), JTc < 340 milliseconds is acceptable; 
however, subjects with a left bundle branch block would be excluded. 
Rationale for change:  Additional guidance was requested for situations when one of the 
3 QTc measurements obtained at baseline exceeds > 470 milliseconds and for subjects 
with an intraventricular conduction delay. 
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7. Synopsis, Study Drugs, Dosages, and Modes of Administration; Section 5.1.1, 
Epacadostat 
Description of change:  Instructions for epacadostat administration have been updated to 
specify that an additional dose should not be taken if a subject vomits. 
Rationale for change:  Language was added to inform sites how to manage dosing if this 
event occurs in subjects dosed with epacadostat. 
8. Section 1.1, Pharmaceutical and Therapeutic Background 
Description of change:  New subsections containing background information for 
epacadostat (Section 1.1.3) and durvalumab (Section 1.1.4) have been added.  
Section 1.1.6 (Melanoma) was updated to include NCCN guidance and CHMP approval 
of PD-1 inhibitors for the treatment of melanoma.  Section 1.1.10 (Preclinical and 
Clinical Trial Data) was updated to include a summary of epacadostat pharmacokinetic 
(PK) 
 data and durvalumab PK data in humans. 
Rational for change:  Therapeutic background section was updated for consistency with 
the most recent information from the Investigator Brochures (IBs) for epacadostat and 
durvalumab. 
9. Section 1.3.1, Risks From Epacadostat 
Description of change:  Updated to report that in Study INCB 24360-201, 12 of the 
48 subjects enrolled as of 29 OCT 2014 received concomitant treatment with an MAOI 
and epacadostat, and that 0 of the 12 subjects exhibited serotonin syndrome. 
Rationale for change:  Theoretically, inhibition of IDO1 could cause an increase in 
serotonin levels that could precipitate a cluster of AEs termed serotonin syndrome (SS) 
when administered alone or in combination with other serotonergic agents.  This rare 
syndrome has been associated with some monoamine oxidase inhibitors (MAOIs) and 
combinations of serotonergic drugs.  MAOIs and serotonergic drugs are prohibited while 
on study however, data from the INCB 24360-201 study indicate that SS was not 
observed in 0 of 12 subjects who received concomitant treatment with an MAOI and 
epacadostat. 
10. Section 5.6.2, Criteria and Procedures for Interruption or Dose Reduction 
Description of change:  The infusion of durvalumab may be interrupted for up to 
4 hours if an infusion reaction occurs. 
Rationale for change:  Instructions in Table 7 were updated to make consistent with 
Section 5.1.2.2. 
11. Section 5.6.3, Criteria for Subjects Exhibiting Immune-Related Adverse Events 
Description of change:  The recommended approach to managing immune-related 
adverse events was updated. 
Rationale for change:  The update provides additional guidance for supportive care 
measures for pneumonitis, enterocolitis, hepatitis, dermatitis, neuropathies, 
endocrinopathies other than hypothyroidism, and nephritis or renal dysfunction. 
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12. Section 7.4.3, RECIST v1.1 
Description of change:  Updated to indicate that tumor lesions located in a previously 
irradiated area or in an area subjected to other locoregional therapy should not be selected 
as target lesions.  In addition, tumor lesions that will be biopsied should not be selected as 
target lesions. 
Rationale for change:  Lesions located in a previously irradiated area or in an area 
subjected to other locoregional therapy may confound the results of the overall response 
assessment for the subject. 
13. Incorporation of administrative changes and adoption and use of INN generic 
names for INCB024360 and MEDI4736 have been replaced throughout.  Other 
minor, administrative changes have been incorporated throughout the Protocol and are 
noted in the attached red-line/strike-out version of the amendment. 
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Amendment 2 (20 FEB 2015) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to allow for the option of intrasubject dose escalation 
to 10 mg/kg for subjects who enroll in the initial dose cohort at MEDI4736 3 mg/kg in 
combination with INCB024360.  This option will only be available when MEDI4736 10 mg/kg 
has been shown to be tolerable in combination with INCB024360 25 mg BID based on DLT 
rules. 
This amendment includes the changes to INCB 24360-203 Protocol Amendment 1 
(29 SEP 2014) summarized below. 
1. Synopsis, Study Drugs, Dosages, and Modes of Administration; Section 5.1.2, 
MEDI4736; Section 5.6.1, Planned Dose Increases  
Description:  Allow the option for subjects enrolled into the initial dose cohort of 
INCB024360 25 mg BID and MEDI4736 3 mg/kg to dose escalate to MEDI4736 
10 mg/kg in combination with INCB024360 25 mg BID if a number of conditions are 
met. 
Rationale:  MEDI4736 at a dose of 10 mg/kg has been shown to be well tolerated and is 
being carried forward as the dose in Phase 3 studies.  If 10 mg/kg is found to be tolerable 
in combination with INCB024360 25 mg BID based on DLT rules, subjects who start at a 
dose of 3 mg/kg will be given the opportunity to escalate the dose to 10 mg/kg at the 
discretion of the investigator. 
2. Synopsis, Key Inclusion Criteria; Section 3.2, Subject Inclusion Criteria 
Description of change to inclusion criterion #4:  Added language to allow 
investigational agents in combination with standard therapies to be considered a line of 
therapy and also allow adjuvant, neoadjuvant, or chemoradiation regimens given within 
6 months of screening to be considered a line of therapy. 
Rationale:  Reorganization of inclusion criteria already present in the Protocol to clarify 
that these situations may apply to subjects of any disease indication. 
Description of change to inclusion criterion #5:  Clarified that melanoma subjects may 
be treatment-naïve or have received prior anti–CTLA-4 therapy with the exception that in 
Phase 1, subjects with BRAF mutations must have received prior treatment with a 
BRAF inhibitor. 
Rationale:  A recent update to the NCCN guidelines for melanoma has listed anti–PD-1 
therapy as an option for first-line treatment.  MEDI4736 is an anti-PD-L1 antibody and 
the mechanism of action is similar; therefore, it is reasonable to allow subjects to 
consider treatment in this study as appropriate first-line treatment. 
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Description of change to inclusion criterion #6:  Removed the requirement for prior 
treatment with a platinum-based therapy.  Clarified the requirement for subjects with 
driver mutations to have received and progressed or be intolerant to a targeted agent, if 
one is available. 
Rationale:  To allow NSCLC subjects who are not eligible for treatment with a 
platinum-based therapy the opportunity to enroll in the study and to clarify that subjects 
who have tumors with driver mutations should receive appropriate targeted therapy if one 
is available. 
3. Synopsis, Key Exclusion Criteria; Section 3.3, Subject Exclusion Criteria 
Description of change to exclusion criterion #1b:  Platelet count of < 75 × 109/L at 
baseline is now considered exclusionary. 
Rationale:  Heavily pretreated subjects may have persistent low-grade 
thrombocytopenia.  As the risk of myelosuppression with the combination treatment 
given in this study is low, it is reasonable to allow subjects with Grade 1 
thrombocytopenia to enroll. 
Description of change to exclusion criterion #21:  Subjects with a QTc interval of 
> 470 ms are excluded. 
Rationale:  Based on preclinical testing, there is no QTc liability for either INCB024360 
or MEDI4736.  The original QTc interval criterion was too strict in error and has been 
corrected to allow enrollment with a QTc interval of up to 470 msec. 
Description of change to exclusion criterion #25:  Addition of an exclusion criterion 
that would require a conversation with the medical monitor to determine eligibility for a 
subject requiring ongoing thorocentesis or paracentesis for palliation. 
Rationale:  Requirements for recurrent thorocentesis or paracentesis may be indicative of 
aggressive end-stage disease, and cases should be reviewed with the medical monitor to 
determine if the subject is an appropriate candidate for the study. 
4. Section 1.1.4, Melanoma; Section 1.3.2.2, Possible Risks Based on Clinical Data 
Description:  Added information on the recent FDA approval of anti–PD-1 antibodies 
for use in a subset of patients with metastatic melanoma and updated clinical data for 
MEDI4736 to reflect an IB update. 
Rationale:  To provide investigators with the most updated information. 
5. Section 4.1.2, Phase 2 
Description:  Requirement for at least 5 subjects with PD-L1–positive tumors in each 
expansion cohort has been removed from the Protocol. 
Rationale:  This requirement and the caveat to enroll additional subjects that express 
PD-L1 would have compromised the integrity of the Simon 2-stage design planned for 
Phase 2 of the study.  Therefore, the requirement was removed. 
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12. Appendix F, Prohibited UGT-1A9 Inhibitors 
Description:  A new appendix was added listing prohibited UGT-1A9 inhibitors.   
Rationale:  The use of UGT-1A9 inhibitors is prohibited while subjects are on study 
treatment per Section 5.10.2.  A list of these agents was added as a reference for 
investigators. 
13. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the red-line/strike-out version 
of the amendment. 
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Amendment 1 (29 SEP 2014) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to address FDA's 25 SEP 2014 clinical comments, 
including clarification and requested changes to the inclusion criteria, updates to the definition of 
dose-limiting toxicities, addition of dose levels to the dose-escalation portion of the study, and 
revision of the observation period for dose-limiting toxicities.  
This amendment includes the changes to the INCB 24360-203 Protocol (dated 18 AUG 2014) 
summarized below. 
1. Synopsis; Section 1.4, Justification for Treatment Regimen; Section 4.1.1 Phase 1 
Dose Escalation; Section 4.4 Number of Subjects; Section 5.1.2 MEDI4736; 
Section 5.6.2, Criteria and Procedures for Interruption; Section 9.2.1 Cohort Size in 
Phase 1 
Description of change:  The starting dose of MEDI4736 was adjusted in the 
dose-escalation portion of the study to 3 mg/kg.  Additional dose-escalation cohorts of 
INCB024360 75 mg BID and 200 mg BID in combination with MEDI4736 were added 
to Phase 1 of the study. 
Rationale for change:  FDA requested changes to the dose-escalation phase of the study. 
2. Synopsis; Section 3.2, Subject Inclusion Criteria 
Description of change:  The inclusion criteria for melanoma have been revised to 
require subjects with a BRAF-mutation to have received prior treatment with a BRAF 
inhibitor with or without a MEK inhibitor.  The inclusion criteria have also been updated 
to clarify that subjects may not refuse standard treatment in Phase 1 of the study. 
Rationale for change:  FDA requested changes to the inclusion criteria. 
3. Section 5.5.1, Definition of Dose-Limiting Toxicities 
Description of change:  The following have been added to the definition of DLT:  Grade 
4 thrombocytopenia related to either drug, ≥ Grade 3 neutropenia lasting > 5 days related 
to either drug, Grade 4 anemia related to either drug, thrombotic thrombocytopenic 
purpura, hemolytic uremic syndrome, disseminated intravascular coagulation, idiopathic 
thrombocytopenic purpura, ≥ Grade 3 hemolysis, and any drug-related toxicity that left 
the subject unable to receive 75% of INCB024360 or 3 doses of MEDI4736 during the 
DLT observation period.   
Rationale for change: The FDA requested modification of the criteria defining DLTs. 
4. Synopsis; Section 4.1.1, Phase 1 Dose Escalation; Section 5.5, Rationale for Dose 
Modification; Section 5.5.1, Definition of Dose-Limiting Toxicities 
Description of change:  The DLT observation period has been changed to 42 days 
(6 weeks) in the Phase 1 dose-escalation portion of the study.  Text has also been added 
to limit enrollment to 2 subjects per week in Phase 1 of the study.  Additionally, a 1-week 
interval will be required between subjects in successive weeks. 
Rationale for change: FDA requested change. 
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5. Section 6, Study Assessments 
Description of change:  Table 14 and Table 15 were edited to clarify that liver function 
tests should be performed on a weekly basis for the first 8 weeks on study treatment.  The 
chemistry panel and hematology panel are required to be performed at the start of every 
cycle. 
Rationale for change:  FDA requested clarification of safety laboratory testing. 
6. Section 6, Study Assessments; Section 7.3.6, Twelve-Lead Electrocardiograms 
Description of change:  An electrocardiogram (ECG) was added at Cycle 2 Day 1 prior 
to administration of INCB024360 or infusion of MEDI4736 in addition to the scheduled 
assessment at 60 to 90 minutes after administration of INCB024360. 
Rationale for change:  An additional time point was added to monitor the ECG at the 
anticipated steady state of INCB024360. 
7. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the protocol and are noted in the attached red-line/strike-
out version of the amendment. 
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SAP_001.pdf: 
Incyte Corporation 
Page 1 of 68 
INCB 24360-203 Statistical Analysis Plan 
26 NOV 2014 
CONFIDENTIAL 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
INCB 24360-203 
 
A Phase 1/2 Study Exploring the Safety, Tolerability, and Efficacy 
of INCB024360 in Combination With MEDI4736 in Subjects With 
Selected Advanced Solid Tumors 
 
 
IND Number: 
 
Date of Plan: 
26 NOV 2014 
Based on: 
Protocol Amendment 1 dated 29 SEP 2014 
 
CRF version approved 08 SEP 2014 
 
 
SPONSOR: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
 
 
 
This study is being conducted in compliance with good clinical practice, 
including the archiving of essential documents. 




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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN APPROVAL ..........................................................................2 
LIST OF ABBREVIATIONS ..........................................................................................................7 
1. 
INTRODUCTION ........................................................................................................9 
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 .................................................................................................10 
 
 
2.3. 
Study Endpoints ..........................................................................................................10 
2.3.1. 
Primary Endpoints ......................................................................................................10 
2.3.2. 
Secondary Endpoints ..................................................................................................11 
3. 
STUDY DESIGN .......................................................................................................11 
3.1. 
Phase 1 Dose-Escalation Design ................................................................................11 
3.1.1. 
Phase 2 ........................................................................................................................12 
3.2. 
Control of Type I Error ...............................................................................................13 
3.3. 
Sample Size Considerations .......................................................................................13 
3.3.1. 
Sample Size in Phase 1 ...............................................................................................13 
3.3.2. 
Sample Size in Phase 2 ...............................................................................................13 
3.4. 
Schedule of Assessments ............................................................................................14 
4. 
DATA HANDLING DEFINITIONS AND CONVENTIONS ..................................19 
4.1. 
Scheduled Study Evaluations and Study Periods .......................................................19 
4.1.1. 
Day 1 ...........................................................................................................................19 
4.1.2. 
Study Day ...................................................................................................................19 
4.1.3. 
Scheduled Visits .........................................................................................................19 
4.1.4. 
Baseline Assessments .................................................................................................19 
4.1.5. 
Last Available Value ..................................................................................................19 
4.1.6. 
Cycle Length and Duration .........................................................................................19 
4.2. 
Variable Definitions ....................................................................................................19 
4.2.1. 
Age ..............................................................................................................................19 
4.2.2. 
Prior and Concomitant Medication .............................................................................20 


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5. 
STATISTICAL METHODOLOGY ...........................................................................21 
5.1. 
General Methodology .................................................................................................21 
5.2. 
Treatment Groups .......................................................................................................21 
5.3. 
Analysis Populations ..................................................................................................22 
5.3.1. 
Phase 1 Intent-to-Treat Population .............................................................................22 
5.3.2. 
Phase 1 Safety Population ..........................................................................................22 
5.3.3. 
Phase 2 ITT Population ..............................................................................................22 
5.3.4. 
Phase 2 Safety Population ..........................................................................................22 
5.3.5. 
Pharmacokinetic/Pharmacodynamic Evaluable Population .......................................22 
6. 
BASELINE, EXPOSURE, AND DISPOSITION VARIABLES AND 
ANALYSES ...............................................................................................................23 
6.1. 
Baseline and Demographics, Physical Characteristics, and Disease History .............23 
6.2. 
Disposition of Subjects ...............................................................................................23 
6.3. 
Protocol Deviations ....................................................................................................23 
6.4. 
Exposure .....................................................................................................................23 
6.5. 
Study Drug Compliance .............................................................................................24 
6.6. 
Medical History ..........................................................................................................24 
6.7. 
Prior and Concomitant Medication .............................................................................24 
7. 
EFFICACY .................................................................................................................25 
7.1. 
General Considerations ...............................................................................................25 
7.2. 
Efficacy Hypotheses ...................................................................................................25 
7.3. 
Analysis of the Primary Efficacy Parameter ..............................................................25 
7.3.1. 
Objective Response Rate ............................................................................................25 
7.4. 
Analysis of Secondary Efficacy Parameters ...............................................................26 
7.4.1. 
Objective Response Rate ............................................................................................26 
7.4.2. 
Durability of Response ...............................................................................................26 
7.4.3. 
Progression-Free Survival ..........................................................................................26 
7.4.4. 
Largest Percent Reduction in Sum of Diameters of Target Lesions ..........................27 
7.4.5. 
Other Efficacy Analyses .............................................................................................27 
7.4.5.1. 
Eastern Cooperative Oncology Group Performance Status ........................................27 
7.4.5.2. 
Weight .........................................................................................................................28 
7.5. 
Pharmacokinetic Analyses ..........................................................................................28 
7.5.1. 
Pharmacokinetic Data .................................................................................................28 


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7.5.2. 
Subject Demographic, Clinical Laboratory, Disease-Related, and 
Pharmacogenomic Variables and Concomitant Medications .....................................28 
7.5.3. 
INCB024360 Pharmacokinetic Analyses ...................................................................29 
7.5.4. 
Immunogenicity for MEDI4736 .................................................................................29 
7.5.5. 
Report .........................................................................................................................30 
 
 
8. 
SAFETY AND TOLERABILITY ..............................................................................30 
8.1. 
General Considerations ...............................................................................................30 
8.2. 
Adverse Events ...........................................................................................................30 
8.2.1. 
Adverse Event Definitions ..........................................................................................30 
8.2.2. 
Adverse Event Summaries ..........................................................................................31 
8.3. 
Clinical Laboratory Tests ...........................................................................................34 
8.3.1. 
Laboratory Value Definitions .....................................................................................34 
8.3.2. 
Laboratory Value Summaries .....................................................................................34 
8.4. 
Vital Signs ..................................................................................................................35 
8.5. 
Electrocardiograms .....................................................................................................36 
9. 
INTERIM ANALYSES ..............................................................................................36 
9.1. 
Overview of Interim Analysis ....................................................................................36 
9.2. 
Guidelines for Decision Rules ....................................................................................36 
10. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN ........................37 
10.1. 
Changes to Protocol-Defined Analyses ......................................................................37 
10.2. 
Changes to the Statistical Analysis Plan .....................................................................37 
11. 
REFERENCES ...........................................................................................................38 
APPENDIX A. LABORATORY TESTS:  REQUIRED ANALYTES AND 
PULMONARY FUNCTION TESTS .........................................................................39 
APPENDIX B. LABORATORY GRADING .............................................................................40 
APPENDIX C. PLANNED TABLES, FIGURES, AND LISTINGS.........................................42 
 


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LIST OF TABLES 
Table 1: 
Treatment Cohorts ......................................................................................................12 
Table 2: 
Approximate Number of Subjects by Tumor Type and Stage of Study .....................13 
Table 3: 
Probability of Dose De-Escalation for Various Dose-Limiting Toxicity Rates .........13 
Table 4: 
Details of Simon 2-Stage Optimal Design by Tumor Type .......................................14 
Table 5: 
Schedule of Assessments ............................................................................................15 
Table 6: 
Laboratory Assessments .............................................................................................17 
Table 7: 
RECIST Evaluation Criteria for Objective Response:  Measurable Disease at 
Baseline .......................................................................................................................25 
Table 8: 
Evaluation and Censoring of Progression-Free Survival ............................................27 
Table 9: 
Sample Collection Windows for Pharmacokinetic Assessments for 
INCB024360 ...............................................................................................................28 
Table 10: Immune-Related Adverse Events (Preferred Terms) .................................................33 
Table 11: Identification of Records for By-Visit Summaries .....................................................34 
Table 12: Criteria for Clinically Notable Vital Sign Abnormalities ...........................................36 
Table 13: Criteria for Clinically Notable ECG Abnormalities ...................................................36 
Table 14: Probability of Early Termination for Various Safety Event Rates .............................37 
Table 15: Dates for SAP Amendments .......................................................................................37 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
adverse event 
ADA 
antidrug antibody 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-12h 
AUC from hour 0 to 12 
AUC0-τ 
AUC from time zero (predose) to time of last observed quantifiable concentration 
within a subject across all treatments 
BID 
twice daily 
CI 
confidence intervals 
CL/F 
apparent oral dose clearance 
Cmax 
maximum observed concentration 
CR 
complete response 
CRF 
case report form 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLCO 
diffusing capacity of the lung for carbon monoxide 
DLT 
dose-limiting toxicity 
DoR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
FEF 
forced expiratory flow 
FEV1 
forced expiratory volume in 1 second 
FVC 
forced vital capacity 
GGT 
gamma-glutamyl transferase 
HBV-DNA 
hepatitis B virus deoxyribonucleic acid 
HCV-RNA 
hepatitis C virus ribonucleic acid 
IDO 
indoleamine 2,3–dioxygenase 
IgG1κ 
human immunoglobulin G1 kappa 
INR 
international normalized ratio 
ITT 
intent to treat  
IV 
intravenously 
LFT 
liver function tests 
LLN 
lower limit of normal 
MedDRA 
Medical Dictionary for Regulatory Activities 


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Abbreviation 
Term 
mRECIST v1.1 
modified Response Evaluation Criteria in Solid Tumors version 1.1 
MTD 
maximum tolerated dose 
NE 
not evaluable 
NSCLC 
non–small cell lung cancer 
ORR 
objective response rate 
PAD 
pharmacologically active dose 
PD 
 progressive disease 
PD-L1 
programmed cell-death ligand 1 
PFS 
progression-free survival 
PK 
pharmacokinetics 
PR 
partial response 
PT 
prothrombin time 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RR 
ribonucleotide reductase 
SCCHN 
squamous cell carcinoma of the head and neck 
SD 
stable disease 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SI 
International System of Units 
t½ 
terminal phase half-life 
Tmax 
time of occurrence of Cmax 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
VA 
alveolar volume 
WHO 
World Health Organization  
 


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1. 
INTRODUCTION 
INCB 24360-203 is a Phase 1/2 study of INCB024360 administered in combination with 
MEDI4736 in subjects with advanced melanoma, non–small cell lung cancer (NSCLC), 
pancreatic cancer, or squamous cell carcinoma of the head and neck (SCCHN).  Phase 1 will be 
an open-label dose escalation to identify the maximum tolerated dose (MTD) or 
pharmacologically active dose (PAD) of INCB024360 in combination with MEDI4736.  Phase 2 
will further explore the safety and efficacy of the MTD or PAD of INCB024360 in combination 
with MEDI4736 determined in Phase 1.  INCB024360 represents a novel, potent, and selective 
inhibitor of the enzyme indoleamine 2,3–dioxygenase 1 (IDO1) in both human tumor cells and 
human dendritic cells. 
MEDI4736 is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody directed against 
human programmed cell-death ligand 1 (PD-L1).  The antibody is composed of 2 identical heavy 
chains of approximately 49,670 Da each and 2 identical light chains of approximately 23,390 Da 
each.  The fragment crystallizable domain of MEDI4736 contains a triple mutation in the 
constant domain of the IgG1 heavy chain that reduces binding to the complement component 
C1q and the fragment crystallizable gamma receptors responsible for mediating 
antibody-dependent cell-mediated cytotoxicity. 
A detailed description of the investigational product, target patient population, rationale for doses 
to be examined, and potential risks and benefits of treatment with INCB024360 and MEDI4736 
is provided in the Protocol, Section 1.  The purpose of this Statistical Analysis Plan (SAP) is to 
define the methodology for analyzing and summarizing the data collected during the conduct of 
Study INCB 24360-203. 
2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS 
2.1. 
Protocol and Case Report Form Version 
This SAP is based on INCB 24360-203 Protocol Amendment 1 dated 29 SEP 2014 and case 
report form (CRF) approved on 08 SEP 2014.  Unless superseded by an amendment, this SAP 
will be effective for all subsequent Protocol amendments and CRF versions. 
2.2. 
Study Objectives 
2.2.1. 
Primary Objectives 
The primary objectives of the study are: 
• Phase 1:  To evaluate the safety and tolerability, and define the MTD or a PAD of 
INCB024360 administered in combination with MEDI4736 in subjects with select 
advanced solid tumors. 
• Phase 2:  To evaluate the efficacy of INCB024360 administered in combination with 
MEDI4736 in subjects with select advanced solid tumors by assessing the objective 
response rate (ORR) per modified RECIST version 1.1 (mRECIST v1.1) at the MTD 
or PAD. 




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2.3.2. 
Secondary Endpoints 
• Phase 1:  ORR determined by radiographic disease assessments per mRECIST v1.1. 
• Phase 2:  Safety and tolerability of the combination as assessed by monitoring the 
frequency, duration, and severity of AEs, through physical examinations, by 
evaluating changes in vital signs and ECGs, and through clinical laboratory blood and 
urine sample evaluations. 
• Phases 1 and 2:  Durability of response determined by radiographic disease 
assessment defined as the time from earliest date of disease response until earliest 
date of disease progression. 
• Phases 1 and 2:  PFS determined from the date of randomization until disease 
progression or death. 
• Phases 1 and 2:  The endpoints for assessment of PK of MEDI4736 and INCB024360 
include individual MEDI4736 and INCB024360 concentrations and PK parameters. 
• Phases 1 and 2:  The endpoints for assessment of immunogenicity of MEDI4736 
include the number and percentage of subjects who develop detectable antidrug 
antibodies (ADAs). 
3. 
STUDY DESIGN 
This is a Phase 1/2 open-label study of INCB024360 administered in combination with 
MEDI4736 in subjects with advanced melanoma, NSCLC, pancreatic cancer or SCCHN.  The 
dose-escalation part of the study (Phase 1) uses a 3 + 3 design to identify the MTD or PAD of 
INCB024360 in combination with MEDI4736.  Phase 2 will further explore the safety and 
efficacy of the MTD or PAD of INCB024360 in combination with MEDI4736 determined in 
Phase 1. 
3.1. 
Phase 1 Dose-Escalation Design 
Phase 1 is the dose-escalation phase, which will include up to 7 cohorts of subjects treated with 
INCB024360 at doses of 25 mg twice daily (BID), 50 mg BID, 75 mg BID, 100 mg BID, 
200 mg BID, and 300 mg BID in combination with MEDI4736 3mg/kg or 10 mg/kg given on 
Day 1 of each 14-day cycle. 
A minimum of 3 subjects will be enrolled and treated in each cohort, and all 3 subjects will be 
observed for a minimum of 42 days before the subsequent cohort begins enrollment.  In Phase 1, 
only 2 subjects may be enrolled within a week.  A 1-week interval will be required between 
subjects in successive weeks. 
Subjects must have received the cohort-specific dose of INCB024360 for at least 75% of the 
doses (63 doses) and have received at least 3 doses of MEDI4736 during the 42-day DLT 
observation period, or have reported a DLT to be evaluable for dose tolerability.  Additional 
subjects will be enrolled in a cohort to achieve the minimum of 3 evaluable subjects if dropouts 
or dose interruptions/reductions occur that result in a subject being nonevaluable for DLTs. 
Alternative intermediate doses (eg, 75 mg once daily) or schedules (eg, 1 week on, 1 week off) 


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of INCB024360 may be evaluated based on emerging safety, PK, and PD observations.  If an 
alternate schedule is tested and determined to be safe, re-escalation of INCB024360 according to 
Table 1 will proceed. 
The dose of INCB024360 will be escalated if 0 of the first 3 evaluable subjects enrolled report a 
DLT.  If 1 of the first 3 evaluable subjects enrolled report a DLT, the cohort will be expanded to 
include 3 additional evaluable subjects.  If 2 or more of either 3 or 6 subjects enrolled report a 
DLT, the prior dose level will be considered the MTD.  If only 3 subjects were treated at this 
dose level, the dose will be confirmed as the MTD by evaluation of an additional 3 subjects 
before this dose is recommended for Phase 2 testing. 
Alternative schedules of INCB024360 (ie, 25 mg BID 1 week on/1 week off) may be evaluated 
if 25 mg BID continuous treatment cannot be safely combined with MEDI4736 3 mg/kg.  The 
cohorts and dose levels are shown in Table 1.  If cohort de-escalation is required and Cohort -1 is 
tested and determined to be safe, re-escalation of INCB024360 according to Table 1 will proceed 
with the alternative treatment schedule of INCB024360.  Intrasubject dose escalation is not 
permitted. 
Table 1: 
Treatment Cohorts 
Cohort 
Maximum Daily Dose of INCB024360  
Dose of MEDI4736 (Once Every 14 Days) 
-1 
Alternative treatment schedule of 25 mg BID orallya 
3 mg/kg IV 
1 
25 mg BID orally 
3 mg/kg IV 
2 
25 mg BID orally 
10 mg/kg IV 
3 
50 mg BID orally 
10 mg/kg IV 
4 
75 mg BID orally 
10 mg/kg IV 
5 
100 mg BID orally 
10 mg/kg IV 
6 
200 mg BID orally 
10 mg/kg IV 
7 
300 mg BID orally 
10 mg/kg IV 
IV = intravenously. 
a An alternative treatment schedule (ie, 25 mg BID 1 week on/1 week off) may be evaluated if 25 mg BID continuous treatment 
cannot be safely combined with MEDI4736. 
3.1.1. 
Phase 2 
Approximately 68 to 157 subjects with advanced melanoma, NSCLC, pancreatic cancer, or 
SCCHN will be enrolled at the MTD or PAD of INCB024360 in combination with MEDI4736.  
The approximate number of subjects needed for each tumor type will be determined using the 
Simon 2-stage design:  Stage 1 will be the initial number of subjects per tumor type, and the 
decision to proceed with Stage 2 will be determined by the response rate observed in Stage 1 
(further described in Section 3.3.2).  To allow the combination therapy to be explored in subjects 
with PD-L1–positive tumors, at least 5 subjects with PD-L1–positive tumor samples may be 
required in each stage of the tumor-specific expansion cohorts.  If this is not met, additional 
subjects may be enrolled into these cohorts until 5 PD-L1–positive subjects are enrolled. 
The number of subjects to be enrolled in each stage per tumor type is detailed in Table 2. 


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Table 2: 
Approximate Number of Subjects by Tumor Type and Stage of Study 
Tumor Type 
Number of Subjects Enrolled 
Stage 1  
Stage 2  
(If Study Proceeds to Stage 2) 
Total 
(Stage 1 + 2) 
Melanoma 
15 
25 
40 
NSCLC 
16 
22 
38 
Pancreatic cancer 
21 
20 
41 
SCCHN 
16 
22 
38 
3.2. 
Control of Type I Error 
Not applicable.  No formal efficacy hypotheses will be tested.  All confidence intervals (CIs) will 
be 95%. 
3.3. 
Sample Size Considerations 
3.3.1. 
Sample Size in Phase 1 
The primary objective of the open-label Phase 1 portion of the study is to determine the MTD or 
PAD and DLT of INCB024360 in combination with MEDI4736.  The total number of subjects 
will depend on the number of dose levels tested before the MTD or PAD is established.  Up to 
42 subjects (6 subjects per dose level for 7 dose levels) will be included based on the dose 
escalation.  Dose escalation will follow the 3 + 3 design algorithm as defined in Section 3.1.  
Based on this algorithm, which enrolls 3 evaluable subjects in each cohort with a maximum of 
6 subjects at any dose level, the probabilities of dose de-escalation from a given dose level for 
the various DLT rates are provided in Table 3. 
Table 3: 
Probability of Dose De-Escalation for Various Dose-Limiting Toxicity Rates 
True DLT Rate 
Probability of Dose De-Escalation 
20% 
23.6% 
30% 
47.2% 
40% 
68.3% 
50% 
83.4% 
60% 
92.4% 
For example, if the true DLT rate is 50% at a given dose level, there is a 17% chance that the 
dose would be escalated.  Further, if the true DLT rate is 20%, there is a 76% chance that the 
dose would be escalated. 
3.3.2. 
Sample Size in Phase 2 
The sample size for each group will be guided by the optimal Simon 2-stage design 
(Simon 1989).  Let P0 denote a clinically uninteresting response rate (eg, for melanoma P0 = 
30%).  In order to determine whether a target response rate (eg, 55%) is likely, an initial number 
of subjects (eg, 15 subjects) will be treated at first in a cohort (Stage 1).  In a group in which 
≤ 5 subjects have responses (suggest the first scheduled Week 8 visit be the tumor assessment), it 


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will be concluded that the true response rate is unlikely to be greater than or equal to the target 
rate and no more subjects will be enrolled in that group in Stage 2.  Otherwise, in the groups in 
which at least 6 responses among the Stage 1 subjects are observed, 25 additional subjects will 
be treated in Stage 2 to estimate the response rate.  At the end of Stage 2, if ≤ 16 subjects have 
responded (suggest the first scheduled Week 8 visit be the tumor assessment) among a total of 
40 subjects, the drug will be declared nonpromising.  The response does not need to be 
confirmed.  In other words, after the study is finished, if there is a sufficient number of responses 
in the 2 stages combined, the study compound is considered promising; otherwise it is 
considered nonpromising.  The detail is displayed in Table 4 using a Type I error of 0.05 and 
power of 90% for estimation. 
Table 4: 
Details of Simon 2-Stage Optimal Design by Tumor Type 
 
Pancreatic 
(P0 = 5%, Target 
RR = 20%) 
Melanoma 
(P0 = 30%, Target 
RR = 55%) 
NSCLC 
(P0 = 17%, Target 
RR = 40%) 
SCCHN 
(P0 = 17%, Target 
RR = 40%) 
Drug is not promising if 
Stage 1 responder number ≤  
1 
5 
3 
3 
Sample size for Stage 1 
21 
15 
16 
16 
Drug is not promising if 
total responder number ≤ 
4 
16 
10 
10 
Sample size total 
41 
40 
38 
38 
RR = ribonucleotide reductase. 
3.4. 
Schedule of Assessments 
All study assessments will be performed as indicated in the schedule of assessments (Table 5) 
and laboratory assessments (Table 6).  The required analytes for the each laboratory test as well 
as the assessments to be performed as part of the pulmonary function tests are shown in 
Appendix A.  The order of assessments is suggested by the order of mention within the schedule 
of assessments.


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Table 5: 
Schedule of Assessments 
Visit (Range) 
Screening 
Treatment Cycles 
EOT 
Follow-Up 
C1D1 
C1D8 
C2D1 
C2D8 
Day 1 All 
Subsequent 
Cycles 
Every 
8 
Weeks 
Discon 
Safety 
Follow-
Up 
Visit 1 
Safety 
Follow-
Up 
Visit 2 
Follow-
Up 
Survival 
Follow-
Up 
Day -28 
to -1 
± 3 
Days 
± 3 
Days 
± 3 
Days 
± 3 
Days 
± 3 Days 
± 5 
Days 
Time of 
Discon 
± 5 Days 
42 Days 
After 
EOT or 
Last Dose 
± 7 Days 
90 Days 
After 
EOT or 
Last Dose 
±7 Days 
Every 
8 Week
s After 
Discon 
Every 
3 Months 
After 
Discon 
Administrative procedures 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Medical and cancer history 
X 
 
 
 
 
 
 
 
 
 
 
 
Smoking history 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medications review 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
Administer INCB024360 at 
clinic 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Administer MEDI4736 
 
X 
 
X 
 
X 
 
 
 
 
 
 
Poststudy anticancer therapy 
status 
 
 
 
 
 
 
 
 
X 
X 
X 
 
Survival status 
 
 
 
 
 
 
 
 
 
 
X 
X 
Clinical procedures and 
assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Comprehensive physical 
examination 
X 
 
 
 
 
 
 
X 
X 
X 
 
 
Targeted physical 
examination 
 
X 
 
X 
 
X 
 
 
 
 
 
 
ECOG performance status 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
Assess for serotonin 
syndrome 
 
Xa 
 
X 
 
X 
 
X 
 
 
 
 
Vital signs and weight 
(height at screening only) 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 


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Table 5: 
Schedule of Assessments (Continued) 
Visit (Range) 
Screening 
Treatment Cycles 
EOT 
Follow-Up 
C1D1 
C1D8 
C2D1 
C2D8 
Day 1 All 
Subsequent 
Cycles 
Every 
8 
Weeks 
Discon 
Safety 
Follow-
Up 
Visit 1 
Safety 
Follow-
Up 
Visit 2 
Follow-
Up 
Survival 
Follow-
Up 
Day -28 
to -1 
± 3 
Days 
± 3 
Days 
± 3 
Days 
± 3 
Days 
± 3 Days 
± 5 
Days 
Time of 
Discon 
± 5 Days 
42 Days 
After 
EOT or 
Last Dose 
± 7 Days 
90 Days 
After 
EOT or 
Last Dose 
±7 Days 
Every 
8 Week
s After 
Discon 
Every 
3 Months 
After 
Discon 
Postinfusion observationb 
 
X 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
Xc 
 
Xc 
 
 
 
X 
X 
X 
 
 
Adverse event assessmentd 
X 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
Laboratory assessments 
X 
X 
Xe 
X 
Xf 
X 
X 
X 
X 
X 
 
 
Pulmonary function testing 
X 
 
 
 
 
 
 
 
 
 
 
 
Chest radiograph 
X 
 
 
 
 
 
 
 
 
 
 
 
Tumor tissue collectiong 
X 
Xh 
 
 
 
 
 
Tumor imaging 
X 
 
 
 
 
 
Xi 
Xj, k 
 
 
Xj 
 
C1D1 = Cycle 1 Day 1; C1D8 = Cycle 1 Day 8; C2D1 = Cycle 2 Day 1; C2D8 = Cycle 2 Day 8; Discon = discontinuation; EOT = end of treatment; LFT = liver function test; PD 
= progressive disease. 
a Assessment should occur approximately 6 hours postdose on Day 1.  An information sheet will also be provided to subjects describing the signs and symptoms of serotonin 
syndrome instructing them to seek immediate care if any of these symptoms are observed. 
b Subjects will be observed in clinic for 3 hours after the first infusion of MEDI4736 is administered. 
c ECG should be performed prior to INCBC024360 and MEDI4736 administration at Cycle 2 Day 1 and 60 to 90 minutes after administration of INCB024360 at Cycle 1 Day 1 
and Cycle 2 Day 1. 
d Subjects need to be followed for AEs for 90 days after the last dose of study treatment. 
e Liver function tests, PK, and 
 are performed on Cycle 1 Day 8 as described  in Table 6. 
f Liver function tests are performed weekly for the first 8 weeks on study treatment.  If LFTs are abnormal, then LFT monitoring should increase to twice per week until resolved 
to baseline. 
g If the subjects agrees to such in the informed consent form, any leftover tissue will be stored for future biomedical research. 
h Optional and can be obtained anytime for safety or with confirmed response or progression. 
i Imaging will be performed every 8 weeks for the first 12 months and then may be done every 12 weeks thereafter.  Per the mRECIST v1.1 criteria used in this Protocol, if 
imaging shows PD, the imaging assessment should be performed at a minimum of 4 weeks later in order to confirm PD as described in the Protocol. 
j Subjects who discontinue treatment for reasons other than disease progression, every effort should be made to continue monitoring their disease status by imaging every 8 weeks 
for 1 year and then every 12 weeks thereafter until the start of new anticancer therapy, documented disease progression, death, or the end of the study, whichever occurs first. 
k If a scan was obtained within 4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation isn't mandatory.  In subjects who discontinue study therapy 
without confirmed disease progression, a radiologic evaluation should be repeated at the time of treatment discontinuation (ie, date of discontinuation ± 4 week window). 


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Table 6: 
Laboratory Assessments 
Visit (Range) 
Screening 
Treatment Cyclesa 
EOT 
 
 
C1D1 
C1D8 
C2D1 
C2D8 
Day 1 All 
Subsequent 
Cycles 
Every 
8 Weeksb 
Discon 
Safety 
Follow-Up 
Visit 1 
Safety 
Follow-Up 
Visit 2 
Day -28 
to -1 
± 3 
Days 
± 3 
Days 
± 3 
Days 
± 3 
Days 
± 3 Days 
± 5 Days 
Time of 
Discon 
± 5 Days 
42 Days 
After EOT 
or Last Dose 
± 7 Days 
90 Days 
After EOT 
or Last Dose 
± 7 Days 
Safety and eligibilityc 
 
 
 
 
 
 
 
 
 
 
Chemistry panel 
X 
Xd 
 
X 
 
X 
 
X 
X 
X 
Liver function testse 
X 
X 
X 
X 
X 
Xe 
 
X 
X 
X 
Hematology with differential 
X 
Xd 
 
X 
 
X 
 
X 
X 
X 
Coagulation panel (PT, INR, aPTT)f 
X 
 
 
 
 
 
 
 
 
 
Endocrine function testing 
X 
Xd 
 
 
 
 
X 
X 
 
 
Urinalysis 
X 
 
 
 
 
 
X 
X 
 
 
Serum pregnancy or urineg 
X 
 
 
 
 
 
 
 
 
 
Hepatitis B and C 
X 
 
 
 
 
 
 
 
 
 
Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
Blood sample for INCB24360 PK 
 
Xh 
Xh 
Xh 
 
 
 
 
 
 
Blood sample for MEDI4736 PK 
 
Xi 
X 
X 
 
Xi 
X 
 
X 
Immunogenicity 
 
 
 
 
 
 
 
 
 
 
Immunogenicity assessment 
 
X 
 
 
 
Xj 
X 
 
X 
aPTT = activated partial thromboplastin time; C1D1 = Cycle 1 Day 1; C1D8 = Cycle 1 Day 8; C2D1 = Cycle 2 Day 1; C2D8 = Cycle 2 Day 8; Discon = discontinuation; 
EOT = end of treatment; INR = international normalized ratio; PT = prothrombin time. 




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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 of first dose of INCB024360 or MEDI4736. 
4.1.2. 
Study Day 
The study day at a visit or reporting date will be calculated by the visit or reporting date minus 
the Day 1 date plus 1 (visit date - Day 1 date + 1).  This study day will be subtracted by 1 if it is 
≤ 0, so that a study day of 0 will never occur.  A study day of -1 indicates 1 day before Day 1. 
4.1.3. 
Scheduled Visits 
Study evaluations in weeks or days from Day 1 are presented in the Schedule of Assessments 
(Table 5). 
4.1.4. 
Baseline Assessments 
Baseline is defined as the last nonmissing measurement obtained before the first dose of 
INCB024360 or MEDI4736 is administered. 
4.1.5. 
Last Available Value 
The last available value is the last nonmissing measurement obtained after starting INCB024360 
or MEDI4736 and within 90 days after the last dose of INCB024360 or MEDI4736. 
4.1.6. 
Cycle Length and Duration 
Cycle 1 Day 1 is defined as the day of the first dose of INCB024360 or MEDI4736.  One 
treatment cycle consists of 14 days.  The first cycle of therapy is defined as the period beginning 
with the first dose of INCB024360 or MEDI4736 and ending the earlier of:  (1) 14 calendar days 
(inclusive) later; or (2) permanent discontinuation of INCB024360.  Subsequent cycles have 
Day 1 as the corresponding visit date associated with the corresponding cycle. 
4.2. 
Variable Definitions 
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 informed consent form, using the following formula: 
Age = integer part of (date of informed consent - date of birth + 1)/365.25 
If date of birth is missing, then the age entered in the Demography section of the CRF will be 
used instead. 


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4.2.2. 
Prior and Concomitant Medication 
Prior medication is defined as any nonstudy drug started before the first dose of INCB024360 or 
MEDI4736. 
Concomitant medication is defined as any nonstudy drug that is taken as follows: 
• Started before the date of first administration of INCB024360 or MEDI4736 and is 
ongoing throughout the study or ends on/after the date of first study drug 
administration 
• Started on/after the date of first administration of INCB024360 or MEDI4736 and is 
ongoing or ends during the course of study drug administration 
Note:  A prior medication could also be classified as "both prior and concomitant medication" if 
the end date is on or after first dose of INCB024360 or MEDI4736.  In the listing, it will be 
indicated whether a medication is prior only, concomitant only, or both prior and concomitant 
medication. 
The start/stop dates recorded in the CRF by the investigator and his or her research staff will be 
used to identify when a concomitant medication was taken during the study.  Any missing start 
date must be queried for resolution.  Unresolved missing start dates will be handled as follows: 
• If the date is completely missing, the medication will be considered both prior and 
concomitant. 
• If only the day is missing, and the last day of the month is before the first dose date 
on Day 1, then the concomitant medication will be considered as starting before 
Day 1, and the incomplete date will be imputed as the last day of the month. 
• If only the day is missing, and the first day of the month is after the first dose date on 
Day 1, then the concomitant medication will be considered as starting after Day 1, 
and the incomplete date will be imputed as the first day of the month. 
• If only the day is missing, and the month is equal to the month of the first dose date 
on Day 1, then the incomplete date will be imputed as the first day of the month. 
• If both the month and day are missing, and the last day of the year is before the first 
dose date on Day 1, then the concomitant medication will be considered as starting 
before Day 1, and the incomplete date will be imputed as if it is the last day of the 
year.  Otherwise, the incomplete date will be imputed as if it is the first day of the 
year. 


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5. 
STATISTICAL METHODOLOGY 
5.1. 
General Methodology 
Unless otherwise noted, SAS software (SAS Institute Inc, Cary, NC; version 9.1 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. 
For the dose-escalation portion of the study, the Phase 1 safety population (defined in 
Section 5.3.2) will be used for all safety analyses, and the Phase 1 intent-to-treat (ITT) 
population will be used for all efficacy analyses.  For the expansion portion of the study, the 
Phase 2 safety population will be used for all safety analyses, and the Phase 2 ITT population 
will be used for all efficacy analyses.  Analyses of PK endpoints are described in Section 7.5 and 
will be performed by the Incyte and MedImmune pharmacokineticist, respectively. 
Interim safety analyses are planned for this study as defined in Section 9. 
5.2. 
Treatment Groups 
Subjects will be summarized overall and based on the dose regimen initially assigned: 
• 3 mg/kg IV MEDI4736 once every 14 days + 25 mg BID INCB024360 (Phase 1) 
• 10 mg/kg IV MEDI4736 once every 14 days + 25 mg BID INCB024360 (Phase 1) 
• 10 mg/kg IV MEDI4736 once every 14 days + 50 mg BID INCB024360 (Phase 1) 
• 10mg/kg IV MEDI4736 once every 14 days + 75 mg BID INCB024360 (Phase 1) 
• 10 mg/kg IV MEDI4736 once every 14 days + 100 mg BID INCB024360 (Phase 1) 
• 10 mg/kg IV MEDI4736 once every 14 days + 200 mg BID INCB024360 (Phase 1) 
• 10 mg/kg IV MEDI4736 once every 14 days + 300 mg BID INCB024360 (Phase 1) 
• 3 mg/kg or 10 mg/kg IV MEDI4736 once Every 14 Days + selected MTD/PAD of 
INCB024360 (Phase 2:  Melanoma) 
• 3 mg/kg or 10 mg/kg IV MEDI4736 once every 14 days + selected MTD/PAD of 
INCB024360 (Phase 2:  NSCLC) 
• 3 mg/kg or 10 mg/kg IV MEDI4736 once every 14 days + selected MTD/PAD of 
INCB024360 (Phase 2:  Pancreatic Cancer) 
• 3 mg/kg or 10 mg/kg IV MEDI4736 once every 14 days + selected MTD/PAD of 
INCB024360 (Phase 2:  SCCHN) 
Table summaries, unless otherwise indicated, will be provided by treatment group.  Note that 
separate summaries will be provided for the Phase 1 and Phase 2 portions of the study. 




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6. 
BASELINE, EXPOSURE, AND DISPOSITION VARIABLES AND 
ANALYSES 
Sample data displays are provided in Appendix C.  Data from Phase 1 and 2 portions will be 
summarized separately where appropriate. 
6.1. 
Baseline and Demographics, Physical Characteristics, and Disease 
History 
The following demographic and baseline characteristics will be summarized for the ITT 
population:  age, sex, race, ethnicity, weight, height, ECOG performance status, staging, prior 
radiation (yes/no), prior surgery (yes/no), prior systemic therapy other than radiation (yes/no), 
date of diagnosis, and primary tumor histology. 
6.2. 
Disposition of Subjects 
The number and percentage of subjects who were enrolled and who were withdrawn from the 
study (with a primary reason for withdrawal) will be summarized for the ITT and safety 
populations. 
6.3. 
Protocol Deviations 
Protocol deviations captured on the Protocol Deviation Log will be presented in the subject data 
listings. 
6.4. 
Exposure 
For subjects in the ITT and safety populations, descriptive statistics will be provided by cohort; 
number of cycles; duration of treatment; average daily dose (mg) and total dose (mg) of 
INCB024360; and number of doses, relative dose intensity (mg/kg), and average dose (mg/kg) of 
MEDI4736. 
• Number of Cycles:  Number of cycles for INCB024360 will be the number of cycles 
with a nonzero dose of INCB024360. 
• Duration of Treatment:  The number of study days between Day 1 and the last 
nonzero dose administration record of INCB024360 or MEDI4736 taken by the 
subject. 
• Number of Doses of MEDI4736:  Number of doses of MEDI4736 for a subject will 
be the number of administered, scheduled infusions of MEDI4736 recorded on the 
MEDI4736 Dosing CRF. 
• Average Doses of MEDI4736 (mg/kg):  The average dose of MEDI4736 (in mg/kg) 
will be the sum of the doses of MEDI4736 recorded on the MEDI4736 Dosing CRF 
divided by the number of doses of MEDI4736. 
Treatment with MEDI4736 will be discontinued after 12 months of treatment.  Discontinuation 
of MEDI4736 treatment may also be considered for subjects who have attained a confirmed 
complete response (CR).  Subjects may continue on INCB024360 monotherapy at this time.  


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Subjects who then report radiographic disease progression will be eligible for re-treatment with 
MEDI4736 at the discretion of the investigator if no cancer treatment was administered other 
than INCB024360 and the subject meets the safety parameters listed in the inclusion/exclusion 
criteria.  Subjects will resume therapy at the same dose and schedule at the time of initial 
discontinuation.  Number of does, average doses, and dose intensity for MEDI4736 in this 
re-treatment phase will be summarized separately and then combined with all previous doses. 
6.5. 
Study Drug Compliance 
For subjects in the ITT and safety populations, overall compliance (%) for INCB024360 will be 
calculated for all subjects as follows: 
Overall Compliance (%) = 100 × [total dose taken] / [intended dose] 
The intended dose will be determined up to the earliest study day of permanent discontinuation 
of INCB024360 (ie, AE discontinuation is the first AE with action taken being "drug 
withdrawn"), last study drug record in the database, or subject death.  Intended dose is defined as 
the sum of the doses prescribed by the investigator accounting both for planned dose reductions 
as well as those reductions or increases mandated by the investigator. 
6.6. 
Medical History 
For subjects in the ITT and safety population, medical history will be summarized by assigned 
treatment group.  This summation will include the number and percentage of subjects with 
significant medical history for each body system/organ class and documented on the Medical 
History CRF. 
6.7. 
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.  In the data listing, each medication will be recorded as prior, concomitant, or both prior 
and concomitant.  Results will be summarized as number and percentage of subjects with prior 
and concomitant medications by preferred term and WHO drug class. 
Prior medication information will also be used to identify anticancer medication received by 
subjects before enrollment into the study.  Prior anticancer medication data will be summarized 
and presented by treatment group as well as listed. 


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7. 
EFFICACY 
Sample data displays are provided in Appendix C. 
7.1. 
General Considerations 
Not applicable. 
7.2. 
Efficacy Hypotheses 
Not applicable. 
7.3. 
Analysis of the Primary Efficacy Parameter 
7.3.1. 
Objective Response Rate 
The primary variable for the Phase 2 portion of the study is ORR.  Objective disease status will 
be categorized using mRECIST v1.1.  Subjects' objective response will be evaluated as CR, 
partial response (PR), stable disease (SD), progressive disease (PD), or not evaluable (NE) at 
each postbaseline radiological assessment based on changes in target lesions, nontarget lesions, 
and appearance of new lesions. 
For subjects with measurable disease at baseline, the mRECIST v1.1 assessment criteria 
presented in Table 7 can be used to determine the overall response at a given timepoint based on 
the target lesion, nontarget lesion, and new lesion assessment. 
Table 7: 
RECIST Evaluation Criteria for Objective Response:  Measurable Disease at 
Baseline 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR  
(or no nontarget lesion) 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non-PD and NE  
(or no nontarget lesion) 
No 
PR 
SD 
Non-PD and NE  
(or no nontarget lesion) 
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 
PR = partial response. 


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A subject is considered an objective responder as assessed by mRECIST if they have an overall 
response of CR or PR at any postbaseline visit.  The proportion of responders within each 
treatment group will be estimated with 95% CIs by treatment group.  Confidence intervals will 
be calculated based on the exact method for binomial distributions. 
In general, best response is determined on subject level using the highest overall response 
achieved postbaseline.  In the case of SD, measurements must meet the SD criteria at least once 
after study entry at a minimum interval of 56 (± 7) days.  Subjects who fail to meet these criteria 
will have best response of PD if the next available RECIST evaluation after the initial scan 
indicates PD or NE if there are no additional RECIST evaluations are available. 
A sensitivity analysis for the primary endpoint will be performed in response evaluable 
population. 
7.4. 
Analysis of Secondary Efficacy Parameters 
7.4.1. 
Objective Response Rate 
One of the secondary variables for the Phase 1 portion of the study is ORR.  The definition and 
analysis for this variable is same as Section 7.3.1. 
7.4.2. 
Durability of Response 
For objective responders, the DoR is the time from the first overall response contributing to an 
objective response (CR or PR) to the earlier of the subject's death or first assessment of PD (for 
mRECIST v1.1) occurring after the first objective response contributing to the objective 
response.  Median DoR will be estimated using the Kaplan-Meier method.  Confidence intervals 
for median survival time will be calculated using the method of Brookmeyer and Crawley 
(1982), which is the default method within SAS v9.1.  Subjects who are still responding (no PD 
or death) at the time of database freeze or discontinuation will be right censored at the time of 
last valid RECIST assessment.  The DoR evaluation will be performed separately for each 
treatment arm and no statistical comparison will be made. 
7.4.3. 
Progression-Free Survival 
Progression-free survival is defined as the number of days from enrollment to the earlier of death 
or disease progression by mRECIST v1.1.  Date of death will be determined using the Death 
Report, the Survival Follow-Up, and the Subject Status CRFs. Censoring for PFS will follow the 
algorithm outlined in Table 8, which is based on FDA guidance (FDA 2007).  Of note, the 
Protocol mandates radiological evaluation of subjects every 8 weeks after the first dose of study 
treatment for 12 months (and then every 12 weeks thereafter until disease progression), and 
radiological evaluation should follow calendar days and not be adjusted for delays in cycle starts 
or extension of combination treatment cycle frequencies.  The analyses will be based on the ITT 
population, according to treatment group assignment.  Time-to-event data will be analyzed by 
the Kaplan-Meier method.  The Kaplan-Meier curve for PFS will be provided. 


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Table 8: 
Evaluation and Censoring of Progression-Free Survival 
Situation 
Outcome 
Date of Progression or Censoring 
No baseline tumor assessments 
Censored 
Date of randomization 
Progression documented between 
scheduled visits 
Progressed 
Earliest of: 
• Date of radiological assessment showing 
new lesion (if progression is based on new 
lesion); or  
• Date of last radiological assessment of 
measured lesions (if progression is based on 
increase in sum of measured lesions)  
No progression 
Censored 
Date of last valid radiologic assessment (not NE 
and not missing) 
Treatment discontinuation for 
undocumented progression 
Censored 
Date of last valid radiologic assessment (not NE 
and not missing) 
Treatment discontinuation for 
toxicity or other reason 
Censored 
Date of last valid radiologic assessment (not NE 
and not missing) 
New anticancer treatment started 
Censored 
Date of last valid radiologic assessment (not NE 
and not missing) 
Death before first PD assessment 
Progressed 
Date of death 
Death between adequate assessment 
visits 
Progressed 
Date of death 
Death or progression after more than 
1 missed consecutive assessment 
Censored 
Date of last valid radiologic assessment (not NE 
and not missing) 
7.4.4. 
Largest Percent Reduction in Sum of Diameters of Target Lesions 
For each subject, the percentage change from baseline in sum of the diameters (shortest diameter 
is used for lymph nodes, longest diameter for all other target lesions per RECIST v1.1) of target 
lesions will be derived for each postbaseline period at which a valid target lesion assessment is 
provided.  The best percentage change for each subject will be derived for waterfall plots
 
 
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, that is, assessment missing or NE, then 
the overall sum of target lesions will not be evaluable for that postbaseline timepoint. 
7.4.5. 
Other Efficacy Analyses 
7.4.5.1. 
Eastern Cooperative Oncology Group Performance Status 
Subjects' ECOG performance status at scheduled assessment times (see Table 5) will be 
summarized in the listings. 


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7.4.5.2. 
Weight 
Subjects' body weight at scheduled assessment times (see Table 5) will be summarized in the 
listings. 
7.5. 
Pharmacokinetic Analyses 
INCB024360 PK in this subject population will be evaluated using noncompartmental analysis 
and/or population PK modeling. 
7.5.1. 
Pharmacokinetic Data 
Subject will withhold morning dose of INCB024360 during INCB024360 PK days.  The time of 
last dose of INCB024360 and prior meal will be recorded in the CRF.  Pharmacokinetic samples 
will be obtained at the visits indicated in Table 6.  After the predose PK sample is drawn 
(predose is defined as within 24 hours before administration of MEDI4736 and before 
administration of INCB024360), subjects will take INCB024360 and then begin infusion of 
MEDI4736.  The exact date and time of the PK blood draws will be recorded in the CRF along 
with the date and time of the last dose of study drug preceding the blood draw.  Sample 
collection times for INCB024360 are shown in Table 9. 
Table 9: 
Sample Collection Windows for Pharmacokinetic Assessments for 
INCB024360 
Study Visit 
Timing of Sample Relative to INCB024360 Administration 
Cycle 1 Day 1 
Predose 
0.5 h  
± 10 min 
1 h 
± 10 min 
2 h 
± 30 min 
4 h 
± 30 min 
6 h 
± 30 min 
OPTIONAL 
8 to 10 h 
± 30 min 
Cycle 1 Day 8 
Predose 
0.5 h 
± 10 min 
1 h 
± 10 min 
2 h 
± 30 min 
4 h 
± 30 min 
6 h 
± 30 min 
OPTIONAL 
8 to 10 h 
± 30 min 
Cycle 2 Day 1 
Predose 
Anytime (required) 
Measurement of MEDI4736 concentrations in serum will be performed using validated 
immunoassays.  Only subjects who receive at least 1 dose of MEDI4736 and provide at least 
1 post-treatment sample will be evaluated.  Individual MEDI4736 will be tabulated by dose 
cohort along with descriptive statistics.  The following PK parameters after the first and 
steady-state dose will be estimated (as data allow):  peak concentration (Cmax), trough 
concentration (Cmin), time to maximum observed concentration (tmax), and AUC.  Accumulation 
to steady state will be assessed as the ratio of Cmax,ss:Cmax and Cmin,ss:Cmin.  All PK parameters 
will be estimated by noncompartmental analysis.  Descriptive statistics of noncompartmental PK 
parameters will be provided. 
7.5.2. 
Subject Demographic, Clinical Laboratory, Disease-Related, and 
Pharmacogenomic Variables and Concomitant Medications 
Subject demographic assessments (age, weight, BMI, gender, and race), clinical laboratory 
measurements (eg, creatinine clearance, serum albumin, total bilirubin, alkaline phosphatase, 
alanine aminotransferase, aspartate aminotransferase), and the baseline polymorphism of 






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an AE changes over time for a reporting period (eg, between visits), each change in intensity will 
be reported as an AE until the event resolves. 
The subset of AEs considered by the investigator to be related to INCB024360 or MEDI4736 
will be considered to be treatment-related AEs.  If the investigator does not specify the 
relationship of the AE to study drug, the AE will be considered to be treatment related.  The 
incidence of AEs and treatment-related AEs will be tabulated.  Serious adverse events (SAEs) 
will also be tabulated. 
Any missing onset date, causality, or severity must be queried for resolution.  Unsolved missing 
values will be handled according to the following rules: 
• An unsolved missing causality will be considered treatment related. 
• An unsolved 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.  Therefore, an unsolved missing onset date will be considered 
treatment emergent, with the following exceptions: 
• If the stop/resolution date is before the first dose administration date on Day 1, then 
the AE will be considered as not being treatment emergent. 
• If both the month and day are missing, and the last day of the year is before the first 
dose administration date on Day 1, then the AE will not be considered treatment 
emergent. 
• If only the day is missing, and the last day of the month is before the first dose 
administration date on Day 1, then the AE will not be considered treatment emergent. 
• If only the day is missing, and the first day of the month is after the first dose 
administration date on Day 1, then the AE will be considered treatment emergent. 
8.2.2. 
Adverse Event Summaries 
An overall summary of AEs by treatment group will include: 
• Number (%) of subjects reporting any TEAEs 
• Number (%) of subjects reporting any treatment-related TEAEs 
• Number (%) of subjects reporting any SAEs 
• Number (%) of subjects reporting any Grade 3 or 4 TEAEs 
• Number (%) of subjects who temporarily interrupted study drug because of TEAEs 
• Number (%) of subjects who permanently discontinued study drug because of TEAEs 
• Number (%) of subjects who withdrew from study because of a TEAE 
• Number (%) of subjects with INCB024360 dose reductions because of TEAEs  
• Number (%) of subjects who had a fatal TEAE 


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The following summaries will be produced by MedDRA term (if ≤ 10 subjects appear in a table, 
a listing may be appropriate): 
• Number (%) of subjects reporting TEAEs by system organ class and preferred term 
• Number (%) of subjects reporting TEAEs by preferred term in decreasing order of 
frequency 
• Number (%) of subjects reporting TEAEs by system organ class, preferred term, and 
highest CTCAE grade 
• Number (%) of subjects reporting any Grade 3 or 4 TEAEs by system organ class and 
preferred term 
• Number (%) of subjects reporting treatment-related AEs by system organ class and 
preferred term 
• Number (%) of subjects reporting treatment-related AEs by preferred term in 
decreasing order of frequency 
• Number (%) of subjects reporting treatment-related AEs by system organ class, 
preferred term, and highest CTCAE grade 
• Number (%) of subjects reporting any Grade 3 or 4 treatment-related AEs by system 
organ class and preferred term 
• Number (%) of subjects reporting TEAEs leading to death by system organ class and 
preferred term 
• Number (%) of subjects reporting treatment emergent SAEs by system organ class 
and preferred term 
• Number (%) of subjects reporting treatment-related SAEs by system organ class and 
preferred term 
• Number (%) of subjects reporting TEAEs leading to withdrawal from the study by 
system organ class and preferred term 
• Number (%) of subjects reporting TEAEs leading to dose reduction of INCB024360 
by system organ class and preferred term 
• Number (%) of subjects reporting TEAEs leading to discontinuation of medication by 
system organ class and preferred term 
• Number (%) of subjects reporting TEAEs requiring concomitant medications by 
system organ class and preferred term 
• Number (%) of subjects reporting treatment-emergent non-SAE by system organ 
class and preferred term 
• Number (%) of subjects reporting events of special interest by system organ class and 
preferred term 
• Number (%) of subjects reporting treatment-emergent immune-related AEs by system 
organ class and preferred term 
• Number (%) of subjects reporting Grade 3 or higher treatment-emergent 
immune-related AEs by system organ class and preferred term 




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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 using the last nonmissing values collected prior the first 
dose.  For baseline laboratory candidates with the same date and time, 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.  See 
Appendix B for laboratory grading criteria.  The incidence of abnormal laboratory values and 
shift tables relative to baseline will be tabulated. 
8.3.2. 
Laboratory Value Summaries 
Clinical laboratory tests, including hematology and serum chemistry (see Appendix A), will be 
performed for each subject during the study in accordance with Table 6.  
If specific safety issues arise, additional unscheduled laboratory tests/analyses may be performed 
at the discretion of the investigator. 
All test results and associated normal ranges from central laboratories will be reported in 
International System of Units (SI).  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, a set of standard normal ranges based 
on documented reference ranges will be applied to facilitate reporting the test results. 
When there are multiple nonmissing laboratory values for a subject's particular test within a visit 
window, the convention shown in Table 11 will be used to determine the record used for by-visit 
tabulations and summaries. 
Table 11: 
Identification of Records for By-Visit Summaries 
Priority 
Laboratory Visit 
Proximity to Visit Window 
Tiebreaker 
1 
Scheduled 
In-window 
Use smallest laboratory 
sequence number 
2 
Unscheduled 
In-window 
3 
Scheduled 
Out-of-window 
Laboratory parameters identified in Appendix A will be summarized.  Shift tables based on 
worst postbaseline value recorded will use all postbaseline values.  Other laboratory parameters 
collected will only be listed in an appendix to the Clinical Study Report (CSR) in their original 
units without SI conversions. 
Numeric laboratory values will be summarized descriptively, and non-numeric test values will be 
tabulated.  In addition, line graph and box-and-whisker plots will be provided for prespecified 
laboratory parameters. 


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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 as well as the subset 
of subjects treated at the MTD.  The denominator for the percentage calculation will use the 
number of subjects in the baseline category (ie, low, high, normal, missing) as the denominator 
for the percentage in each of the categories during the treatment period. 
For all gradable laboratory parameters identified in Appendix A, the values will be classified into 
grade levels corresponding to CTCAE v4.03 criteria.  For specific laboratory values requiring 
clinical intervention to grade, the classification according to the quantitative component will be 
provided.  See Appendix B for laboratory grading criteria. 
The number and percentage of subjects with the laboratory values of Grade 1, 2, 3, or 4 will be 
calculated for each treatment according to the largest treatment-emergent worsening of 
laboratory grade.  Separate summaries for abnormally high and abnormally low laboratory 
values will be provided when the laboratory in question has both high and low grading criteria.  
For instance, if a subject has a baseline fasting glucose of 210 mg/dL, maximum fasting glucose 
after starting treatment of 245 mg/dL, and minimum fasting glucose after starting treatment of 
52 mg/dL, then the subject should be reported as follows: 
• The subject will be counted as a Grade 2 "Glucose decreased" in summaries of 
hypoglycemia because the subject was not hypoglycemic at study entry but became 
hypoglycemic after treatment. 
• The subject will not count as a "Glucose increased" in summaries of hyperglycemia 
because the subject met the numeric requirements for Grade 2 hyperglycemia at 
baseline (fasting glucose value > 160 to 250 mg/dL) and did not increase in grade 
after starting treatment. 
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 
Vital signs, including systolic blood pressure, diastolic blood pressure, heart rate, respiration 
rate, and body temperature, will be taken with subjects in the seated position during the study in 
accordance with Table 5.  Change and percentage change from baseline will be calculated using 
the last nonmissing value before first dose of study drug (Day 1) as the baseline value. 
Incidences of clinically notable vital sign abnormalities are defined in Table 12.  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%. 


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Table 12: 
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 
Heart rate 
> 100 bpm 
< 45 bpm 
Temperature 
> 38ºC 
< 35.5ºC 
Respiratory rate 
> 24/min 
< 8/min 
8.5. 
Electrocardiograms 
Twelve-lead ECGs will be obtained for each subject during the study in accordance with Table 5.  
Electrocardiogram results will be reviewed for clinically notable abnormalities according to 
predefined criteria (see Table 13).  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. 
Table 13: 
Criteria for Clinically Notable ECG Abnormalities 
Parameter 
High Threshold 
Low Threshold 
QTcFa 
> 460 ms 
< 295 ms 
PR 
> 220 ms 
< 75 ms 
QRS 
> 120 ms 
< 50 ms 
QT 
> 500 ms 
< 300 ms 
RR 
> 1500 ms 
< 600 ms 
a QTcF (Fridericia correction). 
9. 
INTERIM ANALYSES 
9.1. 
Overview of Interim Analysis 
No interim analysis for efficacy or futility will be conducted in this study.  As this Phase 1/2 
study is intended to support a Phase 3 development decision, the selected Type I and Type II 
error rates lead to a relatively small sample size in this Protocol.  As such, the level of 
uncertainty for point estimates at an interim analysis limits the value of such an interim analysis.  
The safety of subject participants will be assessed through regular meetings between 
investigators and sponsors who will monitor for critical safety signals. 
9.2. 
Guidelines for Decision Rules 
An interim safety analysis is planned for Phase 2 after 16 subjects have been enrolled and treated 
for 8 weeks, and then every 3 months thereafter.  If either of the following is reported during 


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CONFIDENTIAL 
these reviews, enrollment of subjects would be suspended until the sponsor determined the 
appropriate course of action and notified IRBs and regulatory authorities: 
• ≥ 40% of subjects report a DLT or  
• ≥ 20% of subjects have had a nondermatologic immune-related AE ≥ Grade 3 that 
was attributable to the investigational agent. 
Based on these rules, the probabilities of stopping a treatment group for safety is provided in 
Table 14. 
Table 14: 
Probability of Early Termination for Various Safety Event Rates 
Proportion of Subjects 
Having DLT 
Probability of Early 
Termination Based 
Upon DLT Rulea 
Proportion of Subjects 
Having Immune Event 
Probability of Early 
Termination Based on 
Immune-Related 
Toxicitya 
5% 
0.0% 
5% 
6.4% 
10% 
0.5% 
10% 
24.6% 
15% 
2.3% 
15% 
50.4% 
20% 
7.0% 
20% 
74.4% 
25% 
16.4% 
25% 
89.8% 
30% 
32.0% 
30% 
97.1% 
40% 
72.5% 
40% 
99.9% 
a Assumes the interim safety analyses occur when enrollment in the active treatment arm are 8, 19, 30, and 41 subjects.  
Probability estimated via simulation with 100,000 replications. 
10. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN 
Dates for the SAP, including any amendments, are included in Table 15. 
Table 15: 
Dates for SAP Amendments 
SAP Version 
Date 
Original 
26 NOV 2014 
10.1. 
Changes to Protocol-Defined Analyses 
Not applicable. 
10.2. 
Changes to the Statistical Analysis Plan 
Not applicable. 


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CONFIDENTIAL 
11. 
REFERENCES 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 
1982;38:29-41. 
Food and Drug Administration (FDA). Guidance for Industry: Clinical trial endpoints for the 
approval of cancer drugs and biologics. 2007. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/u
cm071590.pdf. Accessed November 25, 2014. 
Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989;10:1-10. 




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APPENDIX B. LABORATORY GRADING 
Laboratory  
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Haptoglobin decreased 
< LLN 
– 
– 
– 
Hemoglobin decreased 
< LLN - 100 g/L 
< 100 – 80 g/L 
< 80 g/L 
– 
Hemoglobin increased 
Increase in > 0 – 2 g/dL 
above ULN or above 
baseline if baseline is 
above ULN 
Increase in > 2 – 4 g/dL 
above ULN or above 
baseline if baseline is 
above ULN 
Increase in > 4 g/dL 
above ULN or above 
baseline if baseline is 
above ULN 
– 
Lymphocyte count decreased 
< LLN – 0.8 × 109 /L 
< 0.8 - 0.5 × 109 /L 
< 0.5 - 0.2 × 109 /L 
< 0.2 × 109 /L 
Lymphocyte count increased 
- 
> 4000/mm3 - 20,000/mm3 
> 20,000/mm3 
– 
Neutrophil count decreased 
< LLN – 1.5 × 109 /L 
< 1.5 - 1.0 × 109 /L 
< 1.0 - 0.5 × 109 /L 
< 0.5 × 109 /L 
Platelet count decreased 
< LLN - 75.0 × 109 /L 
< 75.0 - 50.0 × 109 /L 
< 50.0 - 25.0 × 109 /L 
< 25.0 × 109/L 
White blood cell decreased 
< LLN – 3.0 × 109 /L 
< 3.0 - 2.0 × 109 /L 
< 2.0 - 1.0 × 109 /L 
< 1.0 × 109 /L 
Activated partial thromboplastin 
time prolonged 
> ULN – 1.5 × ULN 
> 1.5 - 2.5 × ULN 
> 2.5 × ULN 
– 
INR increased 
> 1 - 1.5 × ULN 
> 1.5 - 2.5 × ULN 
> 2.5 × ULN; 
– 
Alanine aminotransferase increased 
> ULN – 3.0 × ULN 
> 3.0 - 5.0 × ULN 
> 5.0 - 20.0 × ULN 
> 20.0 × ULN 
Alkaline phosphatase increased 
> ULN – 2.5 × ULN 
> 2.5 - 5.0 × ULN 
> 5.0 - 20.0 × ULN 
> 20.0 × ULN 
Aspartate aminotransferase 
increased 
> ULN – 3.0 × ULN 
> 3.0 - 5.0 × ULN 
> 5.0 - 20.0 × ULN 
> 20.0 × ULN 
Blood bilirubin increased 
> ULN - 1.5 × ULN 
> 1.5 - 3.0 × ULN 
> 3.0 - 10.0 × ULN 
> 10.0 × ULN 
CD4 lymphocytes decreased 
< LLN - 0.5 × 109 /L 
< 0.5 - 0.2 × 109 /L 
< 0.2 - 0.05 × 109 /L 
< 0.05 × 109 /L 
Cholesterol high 
> ULN - 7.75 mmol/L 
> 7.75 - 10.34 mmol/L 
> 10.34 - 12.92 mmol/L 
> 12.92 mmol/L 
CPK increased 
> ULN - 2.5 × ULN 
> 2.5 × ULN - 5 × ULN 
> 5 × ULN - 10 × ULN 
> 10 × ULN 
Creatinine increased 
> 1 - 1.5 × baseline; 
>ULN - 1.5 × ULN 
> 1.5 - 3.0 × baseline; 
>1.5 - 3.0 × ULN 
> 3.0 baseline; >3.0 - 6.0 
× ULN 
> 6.0 × ULN 


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Laboratory  
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Fibrinogen decreased 
< 1.0 - 0.75 × LLN or 
< 25% decrease from 
baseline 
< 0.75 - 0.5 × LLN or  
25 - < 50% decrease from 
baseline 
< 0.5 - 0.25 × LLN or 
50 - < 75% decrease 
from baseline 
< 0.25 × LLN or 75% 
decrease from baseline 
or absolute value 
< 50 mg/dL 
GGT increased 
> ULN - 2.5 × ULN 
> 2.5 - 5.0 × ULN 
> 5.0 - 20.0 × ULN 
> 20.0 × ULN 
Lipase increased 
> ULN - 1.5 × ULN 
> 1.5 - 2.0 × ULN 
> 2.0 - 5.0 × ULN 
> 5.0 × ULN 
Serum amylase increased 
> ULN - 1.5 × ULN 
> 1.5 - 2.0 × ULN 
> 2.0 - 5.0 × ULN 
> 5.0 × ULN 
Serum albumin decreased 
< LLN - 30 g/L 
< 30 - 20 g/L 
< 20 g/L 
− 
Serum calcium decreased 
< LLN - 2.0 mmol/L 
< 2.0 - 1.75 mmol/L 
< 1.75 - 1.5 mmol/L 
< 1.5 mmol/L 
Serum calcium increased 
> ULN - 2.9 mmol/L 
> 2.9 - 3.1 mmol/L 
> 3.1 - 3.4 mmol/L 
> 3.4 mmol/L 
Serum glucose decreased (fasting) 
< LLN - 3.0 mmol/L 
< 3.0 - 2.2 mmol/L 
< 2.2 - 1.7 mmol/L 
< 1.7 mmol/L 
Serum glucose increased (fasting) 
> ULN - 8.9 mmol/L 
> 8.9 - 13.9 mmol/L 
> 13.9 - 27.8 mmol/L 
> 27.8 mmol/L 
Serum magnesium decreased 
< LLN - 0.5 mmol/L 
< 0.5 - 0.4 mmol/L 
< 0.4 - 0.3 mmol/L 
< 0.3 mmol/L 
Serum magnesium increased 
> ULN - 1.23 mmol/L 
– 
> 1.23 - 3.30 mmol/L 
> 3.30 mmol/L 
Serum phosphate decreased 
< LLN - 0.8 mmol/L 
< 0.8 - 0.6 mmol/L 
< 0.6 - 0.3 mmol/L 
< 0.3 mmol/L 
Serum potassium decreased 
< LLN - 3.0 mmol/L 
– 
< 3.0 - 2.5 mmol/L 
< 2.5 mmol/L 
Serum potassium increased 
> ULN - 5.5 mmol/L 
> 5.5 - 6.0 mmol/L 
> 6.0 - 7.0 mmol/L 
> 7.0 mmol/L 
Serum sodium decreased 
< LLN - 130 mmol/L 
– 
< 130 - 120 mmol/L 
< 120 mmol/L 
Serum sodium increased 
> ULN - 150 mmol/L 
> 150 - 155 mmol/L 
> 155 - 160 mmol/L 
> 160 mmol/L 
Serum triglycerides increased 
1.71 - 3.42 mmol/L 
> 3.42 - 5.7 mmol/L 
> 5.7 - 11.4 mmol/L 
> 11.4 mmol/L 
Serum uric acid increased 
> ULN - 0.59 mmol/L 
– 
> ULN - 0.59 mmol/L 
> 0.59 mmol/L; 
 


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APPENDIX C. PLANNED TABLES, FIGURES, AND LISTINGS 
This appendix provides a list of the planned tables, figures, and listings for the CSR.  Standard 
tables will follow the conventions in the Standard Safety Tables initial version.  Shells are 
provided for nonstandard, in-text CSR tables.  In-text tables are identical in structure and content 
as appendix tables, but follow a Rich Text Format. 
Tables 
Table No. 
Title 
Population 
Standard 
In-
Text 
Baseline and Demographic Characteristics 
1.1.1 
Analysis Populations 
 
X 
X 
1.1.2.1 
Summary of Subject Disposition 
Phase 1 ITT 
X 
X 
1.1.2.2 
Summary of Subject Disposition 
Phase 2 ITT 
X 
X 
1.2.1.1 
Summary of Demographics 
Phase 1 ITT 
X 
X 
1.2.1.2 
Summary of Demographics 
Phase 2 ITT 
X 
X 
1.3.1.1 
Summary of Baseline Disease Characteristics 
Phase 1 ITT 
 
X 
1.3.1.2 
Summary of Baseline Disease Characteristics 
Phase 2 ITT 
 
X 
1.3.2.1 
Summary of General Medical History 
Phase 1 ITT 
 
 
1.3.2.2 
Summary of General Medical History 
Phase 2 ITT 
 
 
1.4.1.1 
Summary of Prior Medications 
Phase 1 ITT 
 
 
1.4.1.2 
Summary of Prior Medications 
Phase 2 ITT 
 
 
1.4.2.1 
Summary of Concomitant Medications 
Phase 1 ITT 
 
 
1.4.2.2 
Summary of Concomitant Medications 
Phase 2 ITT 
 
 
1.4.3.1 
Summary of Prior Medications for Cancer 
Phase 1 ITT 
 
X 
1.4.3.2 
Summary of Prior Medications for Cancer 
Phase 2 ITT 
 
X 
1.5.1 
Summary of Study Medication Compliance 
Phase 1 Safety 
 
X 
1.5.2 
Summary of Study Medication Compliance 
Phase 2 Safety 
 
X 
Efficacy 
2.1.1 
Kaplan-Meier Analysis of Progression-Free Survival by 
RECIST Criteria 
Phase 1 ITT 
 
X 
2.1.2 
Kaplan-Meier Analysis of Progression-Free Survival by 
RECIST Criteria 
Phase 2 ITT 
 
X 
2.2.1.1 
Summary of Best Response by RECIST Criteria 
Phase 1 ITT 
 
X 
2.2.1.2 
Summary of Best Response by RECIST Criteria 
Phase 2 ITT 
 
X 
2.2.4.1 
Summary of Duration of Response 
Phase 1 ITT 
 
X 
2.2.4.2 
Summary of Duration of Response 
Phase 2 ITT 
 
X 
Safety 
3.1.1.1 
Summary of Exposure and Duration of Exposure to 
INCB024360 and MEDI4736 
Phase 1 ITT 
 
X 
3.1.1.2 
Summary of Exposure and Duration of Exposure to 
INCB024360 and MEDI4736 
Phase 2 ITT 
 
X 
3.2.1.1 
Overall Summary of Treatment-Emergent Adverse Events 
Phase 1 Safety 
X 
X 
3.2.1.2 
Overall Summary of Treatment-Emergent Adverse Events 
Phase 2 Safety 
X 
X 
3.2.2.1 
Summary of Treatment-Emergent Adverse Events By 
MedDRA System Organ Class and Preferred Term 
Phase 1 Safety 
X 
 


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Table No. 
Title 
Population 
Standard 
In-
Text 
3.2.2.2 
Summary of Treatment-Emergent Adverse Events By 
MedDRA System Organ Class and Preferred Term 
Phase 2 Safety 
X 
 
3.2.3.1 
Summary of Treatment-Emergent Adverse Events By 
MedDRA Preferred Term in Decreasing Order of Frequency 
Phase 1 Safety 
X 
X 
3.2.3.2 
Summary of Treatment-Emergent Adverse Events By 
MedDRA Preferred Term in Decreasing Order of Frequency 
Phase 2 Safety 
X 
X 
3.2.4.1 
Summary of Treatment-Emergent Adverse Events By 
MedDRA System Organ Class, Preferred Term, and 
Maximum Severity 
Phase 1 Safety 
X 
 
3.2.4.2 
Summary of Treatment-Emergent Adverse Events By 
MedDRA System Organ Class, Preferred Term, and 
Maximum Severity 
Phase 2 Safety 
X 
 
3.2.7.1 
Summary of Grade 3 or Higher Treatment-Emergent 
Adverse Events By MedDRA System Organ Class and 
Preferred Term 
Phase 1 Safety 
X 
X 
3.2.7.2 
Summary of Grade 3 or Higher Treatment-Emergent 
Adverse Events By MedDRA System Organ Class and 
Preferred Term 
Phase 2 Safety 
X 
X 
3.2.11.1 
Summary of Treatment-Related Adverse Events By 
MedDRA System Organ Class and Preferred Term 
Phase 1 Safety 
X 
 
3.2.11.2 
Summary of Treatment-Related Adverse Events By 
MedDRA System Organ Class and Preferred Term 
Phase 2 Safety 
X 
 
3.2.12.1 
Summary of Treatment-Related Adverse Events By 
MedDRA Preferred Term in Decreasing Order of Frequency 
Phase 1 Safety 
X 
 
3.2.12.2 
Summary of Treatment-Related Adverse Events By 
MedDRA Preferred Term in Decreasing Order of Frequency 
Phase 2 Safety 
X 
 
3.2.13.1 
Summary of Treatment-Related Adverse Events By 
MedDRA System Organ Class, Preferred Term, and 
Maximum Severity 
Phase 1 Safety 
X 
 
3.2.13.2 
Summary of Treatment-Related Adverse Events By 
MedDRA System Organ Class, Preferred Term, and 
Maximum Severity 
Phase 2 Safety 
X 
 
3.2.16.1 
Summary of Grade 3 or Higher Treatment-Related Adverse 
Events By MedDRA System Organ Class and Preferred 
Term 
Phase 1 Safety 
X 
 
3.2.16.2 
Summary of Grade 3 or Higher Treatment-Related Adverse 
Events By MedDRA System Organ Class and Preferred 
Term 
Phase 2 Safety 
X 
 
3.2.17.1 
Summary of Treatment-Emergent Adverse Events Leading 
to Death By MedDRA System Organ Class and Preferred 
Term 
Phase 1 Safety 
X 
X 
3.2.17.2 
Summary of Treatment-Emergent Adverse Events Leading 
to Death By MedDRA System Organ Class and Preferred 
Term 
Phase 2 Safety 
X 
X 
3.2.18.1 
Summary of Serious Treatment-Emergent Adverse Events 
By MedDRA System Organ Class and Preferred Term 
Phase 1 Safety 
X 
X 
3.2.18.2 
Summary of Serious Treatment-Emergent Adverse Events 
By MedDRA System Organ Class and Preferred Term 
Phase 2 Safety 
X 
X 


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Table No. 
Title 
Population 
Standard 
In-
Text 
3.2.19.1 
Summary of Non-Serious Treatment-Emergent Adverse 
Events By MedDRA System Organ Class and Preferred 
Term 
Phase 1 Safety 
X 
 
3.2.19.2 
Summary of Non-Serious Treatment-Emergent Adverse 
Events By MedDRA System Organ Class and Preferred 
Term 
Phase 2 Safety 
X 
 
3.2.20.1 
Summary of Treatment-Related Serious Adverse Events By 
MedDRA System Organ Class and Preferred Term 
Phase 1 Safety 
X 
 
3.2.20.2 
Summary of Treatment-Related Serious Adverse Events By 
MedDRA System Organ Class and Preferred Term 
Phase 2 Safety 
X 
 
3.2.21.1 
Summary of Treatment-Emergent Adverse Events Leading 
to Withdrawal From the Study By MedDRA System Organ 
Class and Preferred Term 
Phase 1 Safety 
X 
X 
3.2.21.2 
Summary of Treatment-Emergent Adverse Events Leading 
to Withdrawal From the Study By MedDRA System Organ 
Class and Preferred Term 
Phase 2 Safety 
X 
X 
3.2.22.1 
Summary of Treatment-Emergent Adverse Events Leading 
to Dose Reduction By MedDRA System Organ Class and 
Preferred Term 
Phase 1 Safety 
X 
 
3.2.22.2 
Summary of Treatment-Emergent Adverse Events Leading 
to Dose Reduction By MedDRA System Organ Class and 
Preferred Term 
Phase 2 Safety 
X 
 
3.2.23.1 
Summary of Treatment-Emergent Adverse Events Leading 
to Discontinuation of Drug Medication By MedDRA System 
Organ Class and Preferred Term 
Phase 1 Safety 
X 
X 
3.2.23.2 
Summary of Treatment-Emergent Adverse Events Leading 
to Discontinuation of Drug Medication By MedDRA System 
Organ Class and Preferred Term 
Phase 2 Safety 
X 
X 
3.2.25.1 
Summary of Treatment-Emergent Immune-Related Adverse 
Events By MedDRA System Organ Class and Preferred 
Term (Investigator Determined) 
Phase 1 Safety 
X 
X 
3.2.25.2 
Summary of Treatment-Emergent Immune-Related Adverse 
Events By MedDRA System Organ Class and Preferred 
Term (Investigator Determined) 
Phase 2 Safety 
X 
X 
3.2.26.1 
 Summary of Grade 3 or Higher Treatment-Emergent 
Immune-Related Adverse Events By MedDRA System 
Organ Class and Preferred Term (Investigator Determined) 
Phase 1 Safety 
X 
X 
3.2.26.2 
 Summary of Grade 3 or Higher Treatment-Emergent 
Immune-Related Adverse Events By MedDRA System 
Organ Class and Preferred Term (Investigator Determined) 
Phase 2 Safety 
X 
X 
3.2.27.1 
Summary of Treatment-Emergent Immune-Related Adverse 
Events By MedDRA System Organ Class and Preferred 
Term (With Grade Specific) 
Phase 1 Safety 
X 
X 
3.2.27.2 
Summary of Treatment-Emergent Immune-Related Adverse 
Events By MedDRA System Organ Class and Preferred 
Term (With Grade Specific) 
Phase 2 Safety 
X 
X 
3.2.28.1 
Summary of Treatment-Emergent Immune-Related Adverse 
Events By MedDRA System Organ Class and Preferred 
Term (Regardless of Grade) 
Phase 1 Safety 
X 
X 


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Table No. 
Title 
Population 
Standard 
In-
Text 
3.2.28.2 
Summary of Treatment-Emergent Immune-Related Adverse 
Events By MedDRA System Organ Class and Preferred 
Term (Regardless of Grade) 
Phase 2 Safety 
X 
X 
3.2.29.1 
Summary of Grade 3 or Higher Treatment-Emergent 
Immune-Related Adverse Events By MedDRA System 
Organ Class and Preferred Term 
Phase 1 Safety 
X 
X 
3.2.29.2 
Summary of Grade 3 or Higher Treatment-Emergent 
Immune-Related Adverse Events By MedDRA System 
Organ Class and Preferred Term 
Phase 2 Safety 
X 
X 
3.2.30.1 
Summary of Adverse Events of Special Interest By 
MedDRA System Organ Class and Preferred Term 
Phase 1 Safety 
X 
X 
3.2.30.2 
Summary of Adverse Events of Special Interest By 
MedDRA System Organ Class and Preferred Term 
Phase 2 Safety 
X 
X 
Lab 
3.3.1 
Summary of Laboratory Values - Hematology 
Phase 1 Safety 
X 
 
3.3.2 
Summary of Laboratory Values - Hematology 
Phase 2 Safety 
X 
 
3.3.3 
Summary of Laboratory Values - Chemistry 
Phase 1 Safety 
X 
 
3.3.4 
Summary of Laboratory Values - Chemistry 
Phase 2 Safety 
X 
 
3.3.5.1  
Shift Summary of Laboratory Values in CTC Grade - To the 
Worst Abnormal Value (Tests with One Directional CTC 
Grade) 
Phase 1 Safety 
X 
X 
3.3.5.2  
Shift Summary of Laboratory Values in CTC Grade - To the 
Worst Abnormal Value (Tests with One Directional CTC 
Grade) 
Phase 2 Safety 
X 
X 
3.3.6.1  
Shift Summary of Laboratory Values in CTC Grade - To the 
Worst Abnormal Value (Tests with Two Directional CTC 
Grade) 
Phase 1 Safety 
X 
 
3.3.6.2  
Shift Summary of Laboratory Values in CTC Grade - To the 
Worst Abnormal Value (Tests with Two Directional CTC 
Grade) 
Phase 2 Safety 
X 
 
3.4.1.1 
Summary of Systolic Blood Pressure 
Phase 1 Safety 
X 
 
3.4.1.2 
Summary of Systolic Blood Pressure 
Phase 2 Safety 
X 
 
3.4.2.1 
Summary of Diastolic Blood Pressure  
Phase 1 Safety 
X 
 
3.4.2.2 
Summary of Diastolic Blood Pressure 
Phase 2 Safety 
X 
 
3.4.3.1 
Summary of Heart Rate  
Phase 1 Safety 
X 
 
3.4.3.2 
Summary of Heart Rate 
Phase 2 Safety 
X 
 
3.4.4.1 
Summary of Body Temperature 
Phase 1 Safety 
X 
 
3.4.4.2 
Summary of Body Temperature 
Phase 2 Safety 
X 
 
3.4.5.1 
Summary of Respiration Rate 
Phase 1 Safety 
X 
 
3.4.5.2 
Summary of Respiration Rate 
Phase 2 Safety 
X 
 
3.4.6.1 
Summary of Subjects with Clinically Notable Vital Signs 
Phase 1 Safety 
X 
 
3.4.6.2 
Summary of Subjects with Clinically Notable Vital Signs 
Phase 2 Safety 
X 
 
3.5.1.1 
Summary of 12-Lead ECG: PR Interval Values 
Phase 1 Safety 
X 
 
3.5.1.2 
Summary of 12-Lead ECG: PR Interval Values 
Phase 2 Safety 
X 
 
3.5.2.1 
Summary of 12-Lead ECG: QRS Interval Values 
Phase 1 Safety 
X 
 
3.5.2.2 
Summary of 12-Lead ECG: QRS Interval Values 
Phase 2 Safety 
X 
 


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Table No. 
Title 
Population 
Standard 
In-
Text 
3.5.3.1 
Summary of 12-Lead ECG: QT Interval Values 
Phase 1 Safety 
X 
 
3.5.3.2 
Summary of 12-Lead ECG: QT Interval Values 
Phase 2 Safety 
X 
 
3.5.4.1 
Summary of 12-Lead ECG: QTcB Interval Values 
Phase 1 Safety 
X 
 
3.5.4.2 
Summary of 12-Lead ECG: QTcB Interval Values 
Phase 2 Safety 
X 
 
3.5.5.1 
Summary of 12-Lead ECG: QTcF Interval Values 
Phase 1 Safety 
X 
 
3.5.5.2 
Summary of 12-Lead ECG: QTcF Interval Values 
Phase 2 Safety 
X 
 
3.5.6.1 
Summary of 12-Lead ECG: RR Interval Values 
Phase 1 Safety 
X 
 
3.5.6.2 
Summary of 12-Lead ECG: RR Interval Values 
Phase 2 Safety 
X 
 
3.5.7.1 
Summary of Treatment Emergent, Clinically Significant 
ECG Abnormality from Baseline 
Phase 1 Safety 
 
X 
3.5.7.2 
Summary of Clinically Notable ECG Abnormalities 
Phase 2 Safety 
 
X 
 
Figures 
Figure No. 
Title 
4.1 
Kaplan-Meier Plot of Progression-free Survival by Treatment Group 
4.2 
Waterfall plot of largest percent reduction in sum of target lesion lengths  
4.3 
Percent change from baseline over time in sum of target lesion lengths 
4.4 
Line Graph of Selected Laboratory Values by Study Day 
4.5 
Box-and-Whisker Plot of Selected Laboratory Values by Study Visit 
Listings 
Listing No. 
Title 
16.2.1.1 
Subject Enrollment and Disposition Status 
16.2.1.2 
Subject Inclusion and Exclusion Criteria 
16.2.1.3 
Medical History 
16.2.1.4 
Oncology Disease History 
16.2.1.5 
Systemic Cancer Medication History 
16.2.1.6 
Prior Surgery 
16.2.1.7 
Prior Radiotherapy 
16.2.2 
Protocol Deviations/Violations 
16.2.3.1 
Demographic and Baseline Characteristics 
16.2.3.2 
Baseline Disease Characteristics 
16.2.3.3 
Prior and Concomitant Drug Treatments 
16.2.4.1 
Study Drug Compliance 
16.2.5.1 
PFS Events and Assessments 
16.2.6.1 
Investigator Reported Assessment by RECIST Criteria  
16.2.6.2 
Target Lesions 
16.2.6.3 
Non-target Lesions 
16.2.6.4 
New Lesions 
16.2.6.5 
Percent Reduction in Sum of Target Lesion Lengths 
16.2.6.6 
Time to Disease Progression 
16.2.6.7 
ECOG Status 


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CONFIDENTIAL 
Listing No. 
Title 
16.2.7.1 
Study Drug Administration 
16.2.7.2 
Adverse Events  
16.2.7.3 
Dose-limiting Toxicities 
16.2.7.4 
Serious Adverse Events 
16.2.7.5 
Adverse Events Leading to Study Drug Discontinuation 
16.2.7.6 
Deaths 
16.2.8.1 
Clinical Laboratory Values (Hematology)  
16.2.8.2 
Clinical Laboratory Values (Chemistry) 
16.2.8.3 
Clinical Laboratory Values (Coagulation) 
16.2.8.4 
Clinical Laboratory Values (Endocrine and CRP) 
16.2.8.5 
Abnormal Clinical Laboratory Values (Hematology)  
16.2.8.6 
Abnormal Clinical Laboratory Values (Chemistry) 
16.2.8.7 
Abnormal Clinical Laboratory Values (Coagulation) 
16.2.8.8 
Abnormal Clinical Laboratory Values (Endocrine and CRP) 
16.2.9.6 
Urinalysis Values 
16.2.10.1 
Vital Signs 
16.2.10.2 
Abnormal Vital Sign Values 
16.2.11.1 
12-Lead ECG Values 
16.2.11.2 
Abnormal 12-Lead ECG Values 
16.2.12.2 
Body Weight 
16.2.13 
Symptoms of Serotonin Syndrome 
16.2.14 
CA19-9 


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PROTOCOL: INCB XXXXX-XXX                                                                              (Page 1 of YYYY) 
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                                                    Table 1.3.1.1 
  
                                      Summary of Baseline Disease Characteristics 
                                          (Population: Phase 1 Intent-to-Treat Subjects) 
  
______________________________________________________________________________________________________________________ 
                                                                          Treatment Group 
                                                             ____________________________________ 
                                                 
  Dose 1           Dose 2           Dose 3            Total  
    Variable                                      
  (N=xxx)          (N=xxx)          (N=xxx)          (N=xxx)           
______________________________________________________________________________________________________________________ 
This table follows the same shell as that  
for 14.1.3.1.2 
 
______________________________________________________________________________________________________________________ 
PROGRAM\OUTPUT: T_MHIST.SAS\T_MHIST1.LST                                                   DATE(TIME): DDMMMYY(HH:MM) 
  
Reference: Listing 16.x.x.x.x 


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PROTOCOL: INCB XXXXX-XXX                                                                              (Page 1 of YYYY) 
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                                                    Table 1.3.1.2 
  
                                      Summary of Baseline Disease Characteristics 
                                        (Population: Phase 2 Intent-to-Treat Subjects) 
  
______________________________________________________________________________________________________________________ 
                                                                          Treatment Group 
                                                                 ____________________________________ 
                                                                   Cancer Type 1   Cancer Type 2    Cancer Type 3            
Total  
    Variable                                                        (N=xxx)          (N=xxx)          (N=xxx) 
______________________________________________________________________________________________________________________ 
 
 
    Prior Systemic Therapy 
      Yes                                                          xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      No                                                           xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
 
    Stage at Initial Diagnosis 
      Stage 0                                                      xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      Stage 1A                                                     xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      Stage 2B                                                     xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      Stage 2A                                                     xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      Stage 2B                                                     xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      Stage 2C                                                     xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      Stage 3A                                                     xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      Stage 3B                                                     xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      Stage 3C                                                     xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      Stage 4                                                      xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
 
______________________________________________________________________________________________________________________ 
PROGRAM\OUTPUT: T_MHIST.SAS\T_MHIST1.LST                                                   DATE(TIME): DDMMMYY(HH:MM) 
  
Reference: Listing 16.x.x.x.x 


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PROTOCOL: INCB XXXXX-XXX                                                                              (Page 2 of YYYY) 
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                                                    Table 1.3.1.2 
  
                                      Summary of Baseline Disease Characteristics 
                                        (Population: Phase 2 Intent-to-Treat Subjects) 
  
______________________________________________________________________________________________________________________ 
                                                                          Treatment Group 
                                                             ______________________________________ 
                                                                  Cancer Type 1   Cancer Type 2    Cancer Type 3  
    Variable                                                        (N=xxx)          (N=xxx)          (N=xxx) 
______________________________________________________________________________________________________________________ 
 
    Current Staging 
      Stage 0                                                      xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      Stage 1A                                                     xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      Stage 2B                                                     xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      Stage 2A                                                     xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      Stage 2B                                                     xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      Stage 2C                                                     xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      Stage 3A                                                     xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      Stage 3B                                                     xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      Stage 3C                                                     xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      Stage 4                                                      xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
 
    Distant Metastasis 
      Yes                                                          xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      No                                                           xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
 
    Sites of Metastatic Disease 
      xxxxxxxxxxxxxxxxxxxxxxxxxx                                   xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      xxxxxxxxxxxxxxxxxxxxxxxxxx                                   xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      xxxxxxxxxxxxxxxxxxxxxxxxxx                                   xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
 
______________________________________________________________________________________________________________________ 
PROGRAM\OUTPUT: T_MHIST.SAS\T_MHIST1.LST                                                   DATE(TIME): DDMMMYY(HH:MM) 
  
Reference: Listing 16.x.x.x.x 
 
 


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PROTOCOL: INCB XXXXX-XXX                                                                              (Page 1 of YYYY) 
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                                                   Table 1.3.2.1 
  
                                          Summary of General Medical History 
                                          (Population: Phase 1 Intent-to-Treat Subjects) 
  
______________________________________________________________________________________________________________________ 
                                                                          Treatment Group 
                                                             ___________________________________ 
                                                 Dose 1           Dose 2           Dose 3            Total  
    Variable                                     (N=xxx)          (N=xxx)          (N=xxx)          (N=xxx)           
______________________________________________________________________________________________________________________ 
This table follows the same shell as  
that for 1.3.2.2 
 
______________________________________________________________________________________________________________________ 
PROGRAM\OUTPUT: T_MHIST.SAS\T_MHIST1.LST                                                   DATE(TIME): DDMMMYY(HH:MM) 
  
Reference: Listing 16.x.x.x.x 


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PROTOCOL: INCB XXXXX-XXX                                                                              (Page 1 of YYYY) 
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                                                   Table 1.3.2.2 
  
                                          Summary of General Medical History 
                                        (Population: Phase 2 Intent-to-Treat Subjects) 
  
______________________________________________________________________________________________________________________ 
                                                                          Treatment Group 
                                                             ______________________________________ 
    MedDRA Organ Class/                                          Cancer Type 1    Cancer Type 2    Cancer Type 3    
    MedDRA Preferred Term                                           (N=xxx)          (N=xxx)          (N=xxx) 
______________________________________________________________________________________________________________________ 
    Number (%) of Subjects with any General                        xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
       Medical History 
    xxxxxxxxxxxxxxxxxxxxxxxxxx                                     xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      xxxxxxxxxxxx                                                 xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      xxxxxxxxxxxx                                                 xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      xxxxxxxxxxxx                                                 xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      xxxxxxxxxxxx                                                 xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
 
    xxxxxxxxxxxxxxxxxxxxxxxxxx                                     xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      xxxxxxxxxxxx                                                 xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      xxxxxxxxxxxx                                                 xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      xxxxxxxxxxxx                                                 xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      xxxxxxxxxxxx                                                 xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
 
    xxxxxxxxxxxxxxxxxxxxxxxxxx                                     xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      xxxxxxxxxxxx                                                 xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      xxxxxxxxxxxx                                                 xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      xxxxxxxxxxxx                                                 xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      xxxxxxxxxxxx                                                 xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
  
______________________________________________________________________________________________________________________ 
PROGRAM\OUTPUT: T_MHIST.SAS\T_MHIST1.LST                                                   DATE(TIME): DDMMMYY(HH:MM) 
  
Reference: Listing 16.x.x.x.x 
 
 
 


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CONFIDENTIAL 
PROTOCOL: INCB XXXXX-XXX                                                                              (Page 1 of YYYY) 
DRUG/INDICATION: xxxxxxxxxxx/xxxxxxxxxxxxx                                                             VERSION: Final 
  
                                                    Table 1.4.1.1 
  
                                             Summary of Prior Medications 
                                          (Population: Phase 1 Intent-to-Treat Subjects) 
  
______________________________________________________________________________________________________________________ 
                                                                          Treatment Group 
                                                             _____________________________________ 
                                                 Dose 1           Dose 2           Dose 3            Total  
    Variable                                     (N=xxx)          (N=xxx)          (N=xxx)          (N=xxx)           
______________________________________________________________________________________________________________________ 
This table follows the same shell as  
that for 1.4.1.2 
 
______________________________________________________________________________________________________________________ 
PROGRAM\OUTPUT: T_MHIST.SAS\T_MHIST1.LST                                                   DATE(TIME): DDMMMYY(HH:MM) 
  
Reference: Listing 16.x.x.x.x 


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PROTOCOL: INCB XXXXX-XXX                                                                              (Page 1 of YYYY) 
DRUG/INDICATION: xxxxxxxxxxx/xxxxxxxxxxxxx                                                             VERSION: Final 
  
                                                    Table 1.4.1.2 
  
                                             Summary of Prior Medications 
                                        (Population: Phase 2 Intent-to-Treat Subjects) 
  
______________________________________________________________________________________________________________________ 
                                                                          Treatment Group 
                                                              _____________________________________ 
    MedDRA Organ Class/                                           Cancer Type 1   Cancer Type 2    Cancer Type 3    
    MedDRA Preferred Term                                           (N=xxx)          (N=xxx)          (N=xxx) 
______________________________________________________________________________________________________________________ 
    Subjects With Any Prior Medication                             xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
 
    WHO Drug Class 1                                               xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      WHO Preferred Term 1                                         xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      WHO Preferred Term 2                                         xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      WHO Preferred Term 3                                         xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      WHO Preferred Term 4                                         xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
 
    WHO Drug Class 2                                               xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      WHO Preferred Term 1                                         xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      WHO Preferred Term 2                                         xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      WHO Preferred Term 3                                         xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      WHO Preferred Term 4                                         xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
 
    WHO Drug Class 3                                               xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      WHO Preferred Term 1                                         xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      WHO Preferred Term 2                                         xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      WHO Preferred Term 3                                         xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      WHO Preferred Term 4                                         xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
  
______________________________________________________________________________________________________________________ 
PROGRAM\OUTPUT: T XXXXXX\XXXXXX.SAS\XXXXXX.LST                                            DATE(TIME): DDMMMYY(HH:MM) 
  
Reference: Listing 16.x.x.x.x 
 
 


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PROTOCOL: INCB XXXXX-XXX                                                                              (Page 1 of YYYY) 
DRUG/INDICATION: xxxxxxxxxxx/xxxxxxxxxxxxx                                                             VERSION: Final 
  
                                                    Table 1.4.2.1 
  
                                          Summary of Concomitant Medications 
                                          (Population: Phase 1 Intent-to-Treat Subjects) 
  
______________________________________________________________________________________________________________________ 
                                                                          Treatment Group 
                                                             ___________________________________ 
                                                 Dose 1            Dose 2           Dose 3           Total  
    Variable                                     (N=xxx)          (N=xxx)          (N=xxx)          (N=xxx)           
______________________________________________________________________________________________________________________ 
This table follows the same shell as  
that for 1.4.2.2 
 
______________________________________________________________________________________________________________________ 
PROGRAM\OUTPUT: T_MHIST.SAS\T_MHIST1.LST                                                   DATE(TIME): DDMMMYY(HH:MM) 
  
Reference: Listing 16.x.x.x.x 


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PROTOCOL: INCB XXXXX-XXX                                                                              (Page 1 of YYYY) 
DRUG/INDICATION: xxxxxxxxxxx/xxxxxxxxxxxxx                                                             VERSION: Final 
  
                                                    Table 1.4.2.2 
  
                                          Summary of Concomitant Medications 
                                        (Population: Phase 2 Intent-to-Treat Subjects) 
  
______________________________________________________________________________________________________________________ 
                                                                           Treatment Group 
                                                                    _______________________________ 
    MedDRA Organ Class/                                          Cancer Type 1   Cancer Type 2     Cancer Type 3  
    MedDRA Preferred Term                                           (N=xxx)          (N=xxx)          (N=xxx) 
______________________________________________________________________________________________________________________ 
This table follows the same shell as that for 1.4.1.2 
______________________________________________________________________________________________________________________ 
PROGRAM\OUTPUT: T XXXXXX\XXXXXX.SAS\XXXXXX.LST                                            DATE(TIME): DDMMMYY(HH:MM) 
  
Reference: Listing 16.x.x.x.x 
 
 
 


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PROTOCOL: INCB XXXXX-XXX                                                                              (Page 1 of YYYY) 
DRUG/INDICATION: xxxxxxxxxxx/xxxxxxxxxxxxx                                                             VERSION: Final 
  
                                                    Table 1.4.3.1 
  
                                        Summary of Prior Medications for Cancer 
                                          (Population: Phase 1 Intent-to-Treat Subjects) 
  
______________________________________________________________________________________________________________________ 
                                                                          Treatment Group 
                                                             ____________________________________ 
                                                  Dose 1           Dose 2           Dose 3           Total  
    Variable                                     (N=xxx)          (N=xxx)          (N=xxx)          (N=xxx)           
______________________________________________________________________________________________________________________ 
This table follows the same shell as  
that for 1.4.3.2 
 
______________________________________________________________________________________________________________________ 
PROGRAM\OUTPUT: T_MHIST.SAS\T_MHIST1.LST                                                   DATE(TIME): DDMMMYY(HH:MM) 
  
Reference: Listing 16.x.x.x.x 


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PROTOCOL: INCB XXXXX-XXX                                                                              (Page 1 of YYYY) 
DRUG/INDICATION: xxxxxxxxxxx/xxxxxxxxxxxxx                                                             VERSION: Final 
  
                                                    Table 1.4.3.2 
  
                                        Summary of Prior Medications for Cancer 
                                        (Population: Phase 2 Intent-to-Treat Subjects) 
  
______________________________________________________________________________________________________________________ 
                                                                           Treatment Group 
                                                                    _______________________________ 
    MedDRA Organ Class/                                          Cancer Type 1   Cancer Type 2     Cancer Type 3  
    MedDRA Preferred Term                                           (N=xxx)          (N=xxx)          (N=xxx) 
______________________________________________________________________________________________________________________ 
This table follows the same shell as that for 1.4.1.2 
______________________________________________________________________________________________________________________ 
PROGRAM\OUTPUT: T XXXXXX\XXXXXX.SAS\XXXXXX.LST                                            DATE(TIME): DDMMMYY(HH:MM) 
  
Reference: Listing 16.x.x.x.x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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PROTOCOL: INCB XXXXX-XXX                                                                              (Page 1 of YYYY) 
DRUG/INDICATION: xxxxxxxxxxx/xxxxxxxxxxxxx                                                             VERSION: Final 
  
                                                      Table 2.1.1 
  
                          Kaplan-Meier Analysis of Progression-Free Survival by RECIST Criteria 
                                        (Population: Phase 1 Intent-to-Treat Subjects) 
  
______________________________________________________________________________________________________________________ 
                                                                          Treatment Group 
                                                             ______________________________________ 
                                                              Cohort 1             Cohort 2            Cohort 3  
    Variable                                                   (N=xxx)              (N=xxx)             (N=xxx)         
______________________________________________________________________________________________________________________ 
    Number (%) of Subjects with Disease Progression or  
      Death [1] 
      Observed                                                xxx (xxx.x)           xxx (xxx.x)          xxx (xxx.x)           
        Deaths                                                xxx (xxx.x)           xxx (xxx.x)          xxx (xxx.x)       
        Disease Progression                                   xxx (xxx.x)           xxx (xxx.x)          xxx (xxx.x)       
      Censored                                                xxx (xxx.x)           xxx (xxx.x)          xxx (xxx.x)       
 
    Median Time to Event (95% CI) [3]                         ##.# (##.#,##.#)      ##.# (##.#,##.#)   ##.# (##.#,##.#) 
    Month  3 Survival Rate (95% CI)                           ##.# (##.#,##.#)      ##.# (##.#,##.#)   ##.# (##.#,##.#) 
    Month  6 Survival Rate (95% CI)                           ##.# (##.#,##.#)      ##.# (##.#,##.#)   ##.# (##.#,##.#) 
    Month  9 Survival Rate (95% CI)                           ##.# (##.#,##.#)      ##.# (##.#,##.#)   ##.# (##.#,##.#) 
    Month 12 Survival Rate (95% CI)                           ##.# (##.#,##.#)      ##.# (##.#,##.#)   ##.# (##.#,##.#) 
______________________________________________________________________________________________________________________ 
PROGRAM\OUTPUT: T XXXXXX\XXXXXX.SAS\XXXXXX.LST                                            DATE(TIME): DDMMMYY(HH:MM) 
  
Reference: Listing 16.x.x.x.x 
[1]  Progression free survival was the first occurrence of death or progressive disease by RECIST 1.1   
[2]  The median time and the 95% CI were estimated using Brookmeyer and Crowley. 
 
 
 
 
 
 
 
 
 
 
 
 


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PROTOCOL: INCB XXXXX-XXX                                                                              (Page 1 of YYYY) 
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                                                      Table 2.1.2 
  
                          Kaplan-Meier Analysis of Progression-Free Survival by RECIST Criteria 
                                        (Population: Phase 2 Intent-to-Treat Subjects) 
  
 
______________________________________________________________________________________________________________________ 
                                                                          Treatment Group 
                                                             ______________________________________ 
                                                             Cancer Type 1       Cancer Type 2        Cancer Type 3  
    Variable                                                   (N=xxx)              (N=xxx)             (N=xxx)         
______________________________________________________________________________________________________________________ 
    Number (%) of Subjects with Disease Progression or  
      Death [1] 
      Observed                                                xxx (xxx.x)           xxx (xxx.x)          xxx (xxx.x)           
        Deaths                                                xxx (xxx.x)           xxx (xxx.x)          xxx (xxx.x)       
        Disease Progression                                   xxx (xxx.x)           xxx (xxx.x)          xxx (xxx.x)       
      Censored                                                xxx (xxx.x)           xxx (xxx.x)          xxx (xxx.x)       
 
    Median Time to Event (95% CI) [3]                         ##.# (##.#,##.#)      ##.# (##.#,##.#)   ##.# (##.#,##.#) 
    Month  3 Survival Rate (95% CI)                           ##.# (##.#,##.#)      ##.# (##.#,##.#)   ##.# (##.#,##.#) 
    Month  6 Survival Rate (95% CI)                           ##.# (##.#,##.#)      ##.# (##.#,##.#)   ##.# (##.#,##.#) 
    Month  9 Survival Rate (95% CI)                           ##.# (##.#,##.#)      ##.# (##.#,##.#)   ##.# (##.#,##.#) 
    Month 12 Survival Rate (95% CI)                           ##.# (##.#,##.#)      ##.# (##.#,##.#)   ##.# (##.#,##.#) 
______________________________________________________________________________________________________________________ 
PROGRAM\OUTPUT: T XXXXXX\XXXXXX.SAS\XXXXXX.LST                                            DATE(TIME): DDMMMYY(HH:MM) 
  
Reference: Listing 16.x.x.x.x 
[1]  Progression free survival was the first occurrence of death or progressive disease by RECIST 1.1   
[2]  The median time and the 95% CI were estimated using Brookmeyer and Crowley. 
 
 


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PROTOCOL: INCB XXXXX-XXX                                                                              (Page 1 of YYYY) 
DRUG/INDICATION: xxxxxxxxxxx/xxxxxxxxxxxxx                                                             VERSION: Final 
  
                                                      Table 2.2.1.1 
  
                                       Summary of Best Response by RECIST Criteria 
                                          (Population: Phase 1 Intent-to-Treat Subjects) 
  
______________________________________________________________________________________________________________________ 
                                                              Treatment Group 
                                                             _________________________________________ 
                                                 Dose 1           Dose 2           Dose 3       
    Variable                                     (N=xxx)          (N=xxx)          (N=xxx)               
______________________________________________________________________________________________ 
    Overall Response                            xxx (xxx.x)       xxx (xxx.x)     xxx (xxx.x) 
      Complete Response                         xxx (xxx.x)       xxx (xxx.x)     xxx (xxx.x) 
      Partial Response                          xxx (xxx.x)       xxx (xxx.x)     xxx (xxx.x) 
    Stable Disease                              xxx (xxx.x)       xxx (xxx.x)     xxx (xxx.x) 
    Progressive Disease                         xxx (xxx.x)       xxx (xxx.x)     xxx (xxx.x) 
    Unable to Evaluate                          xxx (xxx.x)       xxx (xxx.x)     xxx (xxx.x) 
 
______________________________________________________________________________________________________________________ 
PROGRAM\OUTPUT: T_MHIST.SAS\T_MHIST1.LST                                                   DATE(TIME): DDMMMYY(HH:MM) 
  
Reference: Listing 16.x.x.x.x 


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PROTOCOL: INCB XXXXX-XXX                                                                              (Page 1 of YYYY) 
DRUG/INDICATION: xxxxxxxxxxx/xxxxxxxxxxxxx                                                             VERSION: Final 
  
                                                      Table 2.2.1.2 
  
                                       Summary of Best Response by RECIST Criteria 
                                        (Population: Phase 2 Intent-to-Treat Subjects) 
  
______________________________________________________________________________________________________________________ 
                                                                          Treatment Group 
                                                             ______________________________________ 
    Variable                                                Cancer Type 1        Cancer Type 2         Cancer Type 3  
                                                               (N=xxx)              (N=xxx)               (N=xxx)               
__________________________________________________________________________________________________________________ 
 
    Overall Response                                          xxx (xxx.x)           xxx (xxx.x)          xxx (xxx.x)           
      Complete Response                                       xxx (xxx.x)           xxx (xxx.x)          xxx (xxx.x)           
      Partial Response                                        xxx (xxx.x)           xxx (xxx.x)          xxx (xxx.x)           
    Stable Disease                                            xxx (xxx.x)           xxx (xxx.x)          xxx (xxx.x)                  
    Progressive Disease                                       xxx (xxx.x)           xxx (xxx.x)          xxx (xxx.x)                 
    Unable to Evaluate                                        xxx (xxx.x)           xxx (xxx.x)          xxx (xxx.x)                  
______________________________________________________________________________________________________________________ 
PROGRAM\OUTPUT: T XXXXXX\XXXXXX.SAS\XXXXXX.LST                                            DATE(TIME): DDMMMYY(HH:MM) 
  
Reference: Listing 16.x.x.x.x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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PROTOCOL: INCB XXXXX-XXX                                                                              (Page 1 of YYYY) 
DRUG/INDICATION: xxxxxxxxxxx/xxxxxxxxxxxxx                                                             VERSION: Final 
  
                                                      Table 2.2.4.1 
  
                                            Summary of Duration of Response  
                                            (Population: Phase 1 Intent-to-Treat Subjects) 
  
______________________________________________________________________________________________________________________ 
                                                                     Treatment Group 
                                                         ___________________________________ 
                                                         Dose 1                Dose 2                Dose 3  
    Variable                                             (N=xxx)               (N=xxx)               (N=xxx) 
______________________________________________________________________________________________________________________ 
 
This table follows the same shell as that for 2.2.5.2 
______________________________________________________________________________________________________________________ 
PROGRAM\OUTPUT: T XXXXXX\XXXXXX.SAS\XXXXXX.LST                                            DATE(TIME): DDMMMYY(HH:MM) 
  
Reference: Listing 16.x.x.x.x 
[1]  The median time and the 95% CI was estimated using Brookmeyer and Crowley. 


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PROTOCOL: INCB XXXXX-XXX                                                                              (Page 1 of YYYY) 
DRUG/INDICATION: xxxxxxxxxxx/xxxxxxxxxxxxx                                                             VERSION: Final 
  
                                                      Table 2.2.4.2 
  
                                            Summary of Duration of Response  
                                        (Population: Phase 2 Intent-to-Treat Subjects) 
  
______________________________________________________________________________________________________________________ 
                                                                     Treatment Group 
                                                         ___________________________________ 
                                                      Cancer Type 1          Cancer Type 2         Cancer Type 3  
    Variable                                             (N=xxx)               (N=xxx)               (N=xxx) 
______________________________________________________________________________________________________________________ 
 
    RECIST Criteria 
      Number of Responders (%)                           ### (xxx.x)           ### (xxx.x)           ### (xxx.x) 
      Median Duration of Response (Range) [1]            ##.# (##.#,##.#)      ##.# (##.#,##.#)      ##.# (##.#,##.#) 
 
______________________________________________________________________________________________________________________ 
PROGRAM\OUTPUT: T XXXXXX\XXXXXX.SAS\XXXXXX.LST                                            DATE(TIME): DDMMMYY(HH:MM) 
  
Reference: Listing 16.x.x.x.x 
[1]  The median time and the 95% CI was estimated using Brookmeyer and Crowley. 
 
 
 
 
 
 
 
 
 
 
 
PROTOCOL: INCB XXXXX-XXX                                                                              (Page 1 of YYYY) 
DRUG/INDICATION: xxxxxxxxxxx/xxxxxxxxxxxxx                                                             VERSION: Final 
  


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                                                   TABLE 3.1.1.1  
  
                            Summary of Exposure and Duration of Exposure to INCB024360 and MEDI4736 
                                              (Population: Phase 1 Intent-to-Treat Subjects) 
 
                                                                                                      
______________________________________________________________________________________________________________________ 
                                                                                     Treatment Group 
                                                                     ___________________________________ 
                                                                      Dose 1           Dose 2           Dose 3 
                                                                      (N=xxx)          (N=xxx)          (N=xxx) 
______________________________________________________________________________________________________________________ 
 
This table follows the same shell as that for 3.1.1.2 
__________________________________________________________________________________________________________________________________________________________ 
FOLDER\PROGRAM\OUTPUT: XXXXXX\XXXXXX.SAS\XXXXXX.LST                                                                           DATE(TIME): MMDDYYYY(hh:mm) 


Incyte Corporation 
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INCB 24360-203 Statistical Analysis Plan 
26 NOV 2014 
CONFIDENTIAL 
PROTOCOL: INCB XXXXX-XXX                                                                              (Page 1 of YYYY) 
DRUG/INDICATION: xxxxxxxxxxx/xxxxxxxxxxxxx                                                             VERSION: Final 
  
                                                   TABLE 3.1.1.2  
  
                           Summary of Exposure and Duration of Exposure to INCB024360 and MEDI4736 
                                           (Population: Phase 2 Intent-to-Treat Subjects) 
 
                                                                                                      
______________________________________________________________________________________________________________________ 
                                                                       Treatment Group 
                                                                     ________________________________ 
                                                                     Cancer Type 1  Cancer Type 2   Cancer Type 3  
                                                                      (N=xxx)          (N=xxx)          (N=xxx) 
______________________________________________________________________________________________________________________ 
 
    Days of Exposure to INCB024360 
      N                                                               ###              ###              ###               
      Mean (STD)                                                      ##.## (#.###)    ##.## (#.###)    ##.## (#.###)               
      Median                                                          ##.##            ##.##            ##.##         
      (Q1,Q3)                                                         (##.##,##.##)    (##.##,##.##)    (##.##,##.##) 
      (MIN,MAX)                                                       (##.##,##.##)    (##.##,##.##)    (##.##,##.##) 
                                                                                                                      
    Average Daily Dose (mg) of INCB024360                         
      N                                                               ###              ###              ###               
      Mean (STD)                                                      ##.## (#.###)    ##.## (#.###)    ##.## (#.###)               
      Median                                                          ##.##            ##.##            ##.##         
      (Q1,Q3)                                                         (##.##,##.##)    (##.##,##.##)    (##.##,##.##) 
      (MIN,MAX)                                                       (##.##,##.##)    (##.##,##.##)    (##.##,##.##) 
                                                                                                                                                       
    Dose Intensity (%) of INCB024360                               
      N                                                               ###              ###              ###               
      Mean (STD)                                                      ##.## (#.###)    ##.## (#.###)    ##.## (#.###)               
      Median                                                          ##.##            ##.##            ##.##         
      (Q1,Q3)                                                         (##.##,##.##)    (##.##,##.##)    (##.##,##.##) 
      (MIN,MAX)                                                       (##.##,##.##)    (##.##,##.##)    (##.##,##.##) 
                                                                                                                                                       
__________________________________________________________________________________________________________________________________________________________ 
FOLDER\PROGRAM\OUTPUT: XXXXXX\XXXXXX.SAS\XXXXXX.LST                                                                           DATE(TIME): MMDDYYYY(hh:mm) 
 


Incyte Corporation 
Page 67 of 68 
INCB 24360-203 Statistical Analysis Plan 
26 NOV 2014 
CONFIDENTIAL 
PROTOCOL: INCB XXXXX-XXX                                                                              (Page 2 of YYYY) 
DRUG/INDICATION: xxxxxxxxxxx/xxxxxxxxxxxxx                                                             VERSION: Final 
  
                                                    TABLE 3.1.1.2  
  
                           Summary of Exposure and Duration of Exposure to INCB024360 and MEDI4736 
                                           (Population: Phase 2 Intent-to-Treat Subjects) 
 
                                                                                                      
______________________________________________________________________________________________________________________ 
                                                                       Treatment Group 
                                                                     ________________________________ 
                                                                   Cancer Type 1    Cancer Type 2    Cancer Type 3    
                                                                      (N=xxx)          (N=xxx)          (N=xxx) 
______________________________________________________________________________________________________________________ 
 
    Days of Exposure to MEDI4736 
      N                                                               ###              ###              ###               
      Mean (STD)                                                      ##.## (#.###)    ##.## (#.###)    ##.## (#.###)               
      Median                                                          ##.##            ##.##            ##.##         
      (Q1,Q3)                                                         (##.##,##.##)    (##.##,##.##)    (##.##,##.##) 
      (MIN,MAX)                                                       (##.##,##.##)    (##.##,##.##)    (##.##,##.##) 
                                                                                                                      
    Number of Doses of MEDI4736 
      0                                                               xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      1                                                               xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      2                                                               xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      3                                                               xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
      4                                                               xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
                                                                                                                                                       
__________________________________________________________________________________________________________________________________________________________ 
FOLDER\PROGRAM\OUTPUT: XXXXXX\XXXXXX.SAS\XXXXXX.LST                                                                           DATE(TIME): MMDDYYYY(hh:mm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Incyte Corporation 
Page 68 of 68 
INCB 24360-203 Statistical Analysis Plan 
26 NOV 2014 
CONFIDENTIAL 
PROTOCOL: INCB XXXXX-XXX                                                                              (Page 1 of YYYY) 
DRUG/INDICATION: xxxxxxxxxxx/xxxxxxxxxxxxx                                                             VERSION: Final 
  
                                                    Table 3.5.7.1 
  
                     Summary of Treatment Emergent, Clinically Significant ECG Abnormality from Baseline 
                                        (Population: Phase 1 Safety Subjects) 
  
______________________________________________________________________________________________________________________ 
                                                                          Treatment Group 
                                                                  _________________________________ 
    MedDRA Organ Class/                                            Cohort 1         Cohort 2         Cohort 3  
    MedDRA Preferred Term                                           (N=xxx)          (N=xxx)          (N=xxx) 
______________________________________________________________________________________________________________________ 
 
    Number (%) of Subjects With a Postbaseline ECG Evaluation      xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
 
    Number (%) of Subjects With a Clinically Significant Post-     xxx (xxx.x)      xxx (xxx.x)      xxx (xxx.x) 
       Baseline ECG Abnormality 
______________________________________________________________________________________________________________________ 
PROGRAM\OUTPUT: T XXXXXX\XXXXXX.SAS\XXXXXX.LST                                            DATE(TIME): DDMMMYY(HH:MM) 
  
Reference: Listing 16.x.x.x.x 
 


Signature Manifest
Document Number: IC-STS-SAP-0048
Revision: 0
Title: INCB24360-203 Statistical Analysis Plan
All dates and times are in Eastern Standard Time.
INCB24360-203 SAP
Approval
Name/Signature
Title
Date
Meaning/Reason
26 Nov 2014, 03:08:47 PM
Approved
26 Nov 2014, 03:20:58 PM
Approved
04 Dec 2014, 02:11:35 PM
Approved
09 Dec 2014, 10:58:15 AM
Approved
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Signature Manifest
12/9/2014