A Phase II Study of Epacadostat and Pembrolizumab in Patients With Imatinib Refractory Advanced Gastrointestinal Stromal Tumors
Phase: PHASE2
Conditions: Gastrointestinal Stromal Tumors
Sponsor: Columbia University

Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date:  11/09/2017 
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Herbert Irving Comprehensive Cancer Center
Protocol
NCT03291054

Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date:  11/09/2017 
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TITLE: A Phase II Study of Epacadostat and Pembrolizumab in Patients with Imatinib-Refractory 
Advanced Gastrointestinal Stromal Tumors 
Coordinating Center: 
Columbia University Medical Center 
Principal Investigator: 
Richard D. Carvajal, MD 
177 Fort Washington Avenue, MHB 6GN-435 
New York, NY 10032 
Telephone: 646-317-6354 
Fax: 212-305-3035 
Email address: rdc2150@cumc.columbia.edu 
Co-Investigators: 
Gary K. Schwartz, MD 
177 Fort Washington Avenue, MHB 6GN-435 
New York, NY  10032 
Telephone: 212-305-2055 
Fax: 212-305-3035 
Email address: schwartzg@columbia.edu 
Kimberly M. Komatsubara, MD 
177 Fort Washington Avenue, MHB 6GN-435 
New York, NY 10032 
Telephone: 212-305-2637 
Fax: 212-305-3035 
Email address: kmk2213@cumc.columbia.edu 
Matthew Ingham, MD 
177 Fort Washington Avenue, MHB 6GN-435 
New York, NY 10032 
Telephone: 212-305-2637 
Fax: 212-305-3035 
Email address: mi2337@cumc.columbia.edu 
Yvonne Saenger, MD 
161 Fort Washington Avenue, HIP 10 
New York, NY 10032 
Telephone: 646-317-6313 
Fax: 212-305-3035 
Email address: yms4@cumc.columbia.edu 

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Gulam Manji, MD 
 
161 Fort Washington Avenue, HIP 9-907 
 
New York, NY 10032 
 
Telephone: 212-305-0592 
 
Fax: 212-305-3035 
 
Email address: gam2140@cumc.columbia.edu 
 
 
 
Prabhjot Mundi, MD 
 
161 Fort Washington Avenue, HIP 9 
 
New York, NY 10032 
 
Telephone: 646-317-6041 
 
Fax: 212-305-3035 
 
Email address: psm2134@ columbia.edu 
 
 
Statistician: 
Shing M. Lee, PhD 
 
722 West 168th Street, 
 
6th Floor, Room 645 
 
New York, NY 10032  
 
Telephone: 212-342-1266 
 
Email address: sml2114@columbia.edu 
 
 
 
 
 
 
 

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Regulatory Sponsor: 
Richard Carvajal, MD 
Columbia University Medical Center 
Funding Source: 
Incyte (study reference # I-24360-16-13) 
and  
Merck (study reference # MISP 55691) 
 
Study Agent: 
Epacadostat (INCB024360) (Incyte) 
 
 
Other Agent: 
Pembrolizumab (Merck) 
 
IND Status: 
IND # 
 
 
     
Affiliate Institutions: 
Site Principal Investigator and Contact Information: 
 
Site: University of Michigan 
 
Principal Investigator: 
Rashmi Chugh, MD  
1500 East Medical Center Drive SPC5912 
Ann Arbor, MI  48109 
Telephone: 734-647-8902 
Fax: 734-647-8672 
rashmim@med.umich.edu 
 
 
 
 
 
 
 
 
 
 

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Protocol Signature Page 
 
I confirm that I have read this protocol, I understand it, and I will work according to this protocol 
and to the ethical principles stated in the latest version of the Declaration of Helsinki, the 
applicable ICH guidelines for good clinical practices, and the applicable federal, state, and local 
laws, rules, and regulations relating to the conduct of the protocol. I have read and understand 
the information in the Investigators’ Brochure (or Manufacturer’s Brochure) regarding the risks 
and potential benefits. I will promptly submit the protocol to the applicable IRB for review and 
approval. Once the protocol has been approved by the IRB, I understand that any modification 
made during the course of the study must first be approved by the IRB, prior to implementation 
except when such modification is made to remove an immediate hazard to the subject. I certify 
that I, and the study staff, have received the requisite training to conduct this research protocol. I 
agree to maintain adequate and accurate records in accordance with Columbia University and 
Herbert Irving Comprehensive Cancer Center policies, Federal, state and local laws and 
regulations. I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol. 
 
 
_________________________________                _______________ 
Signature of Principal Investigator  
               Date 
 
 
 
_________________________________                 
Principal Investigator Name (Print) 
 
 
 
 
_________________________________                 
NAME OF INSTITUTION 
 
 
 
Instructions to Principal Investigator: Sign and Date this signature page and print your name. 
Return the original, completed and signed to the Clinical Protocol & Data Management Office. 
Retain a copy in the regulatory binder.  

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PROTOCOL SYNOPSIS 
 
Title 
A Phase II Study of Epacadostat and Pembrolizumab in Patients 
with Imatinib-Refractory Advanced Gastrointestinal Stromal 
Tumors 
Short Title 
IDO and PD-1 inhibition in imatinib-refractory GIST 
Phase 
Phase II 
Methodology 
This is a multi-center, single-arm phase II study of combined IDO 
and PD-1 inhibition with epacadostat and pembrolizumab in 
imatinib-refractory advanced GIST patients. This study will use a 
primary endpoint of overall response rate.   
Study Duration 
24 months 
Study Center(s) 
Multicenter: 2 sites 
 
Columbia University Medical Center  
University of Michigan 
Objectives 
Primary Objective:  
a.   To assess the efficacy of combined IDO and PD-1 inhibition 
in a single arm phase II trial of epacadostat and pembrolizumab in 
patients with advanced imatinib-refractory GIST, using a primary 
endpoint of overall response rate using RECIST v1.1 criteria. 
 
Secondary Objectives:  
a.   To evaluate the progression free survival (PFS) of patients 
with advanced GIST treated with epacadostat and pembrolizumab 
using RECIST v1.1 criteria.  
b.   To evaluate the overall survival (OS) of patients with 
advanced GIST treated with epacadostat and pembrolizumab. 
c.   To evaluate response rate using Choi criteria.  
d.  To evaluate the safety and tolerability of combined 
epacadostat and pembrolizumab treatment in the advanced GIST 
population. 
 
Exploratory Objectives: 
a.   To correlate the effect of IDO inhibition with response to 
therapy by evaluating baseline and on-treatment serum samples 
for tryptophan metabolite levels.  
b.   To characterize the effect of combined therapy with IDO and 
PD-1 inhibition on T-cell subsets by evaluating baseline and on-
treatment tumor samples for changes in the T-effector to T-
regulator cell ratio using immunohistochemistry.  
c.   To characterize the relationship between PD-L1 status and 
response to combined IDO and PD-1 inhibition.  

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Number of Subjects 
 
Total maximum accrual of subjects: 23 patients 
 
Diagnosis and Main 
Inclusion Criteria 
Study Population:  
Subjects with unresectable or metastatic GIST who have 
progressed on imatinib.  
 
Key Inclusion Criteria: 
 Age 18 years or older. 
 Histologically confirmed unresectable or metastatic GIST. 
 Clinical or radiographic progression on first-line imatinib. 
Those who were taken off of imatinib for intolerance must 
have progressed on at least one other TKI. 
 Subjects must have received ≥1 prior systemic therapy 
(including imatinib). A maximum of 4 prior therapies for 
metastatic disease are allowed.  
 ECOG performance status ≤1.   
 Estimated life expectance of ≥ 3 months. 
 Laboratory parameters within the following Protocol-
defined range. All screening laboratory tests should be 
performed within 28 days of treatment initiation and must 
be independent of hematopoietic growth factor support.  
 Absolute neutrophil count ≥ 1.5 x 109/L. 
 Platelets ≥ 100 x 109/L. 
 Hemoglobin ≥ 9 g/dL (transfusion is acceptable to 
meet this criteria). 
 Serum creatinine ≤ 1.5 x institutional upper limit of 
normal (ULN) OR calculated creatinine clearance ≥ 
50 mL/min for subjects with creatinine levels > 1.5 
x institutional ULN. 
 Aspartate aminotransferase, alanine 
aminotransferase, alkaline phosphatase ≤ 2.5 x 
ULN, or in subjects with liver metastases ≤ 5 x 
ULN.  
 Total bilirubin ≤ 1.5 x ULN 
 Subjects with hyperbilirubinemia clinically 
consistent with an inherited disorder of 
bilirubin metabolism (e.g., Gilbert Syndrome) 
will be eligible at the discretion of the 
principal investigator.  
 International normalized ratio (INR) or prothrombin 
time (PT) < 1.5x ULN unless subject is receiving 
anticoagulation therapy as long as PT or INR is 

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within therapeutic range of intended use of 
anticoagulant. 
 Activated partial thromboplastin time (aPTT) < 1.5 
x ULN unless subject is receiving anticoagulant 
therapy, as long as PTT is within therapeutic range 
of intended use of anticoagulants. 
 Presence of baseline measureable disease by RECIST 
v1.1 for solid tumors. 
 Subjects must agree to pre- and on-treatment tumor 
biopsies. Use of outside archived tumor tissue for a 
baseline biopsy is not permitted. An optional research 
biopsy at the time of progression will also be discussed 
with these patients, however, is not mandatory. Subjects in 
whom biopsy is technically not feasible or in whom would 
result in unacceptable risk, in the opinion of the 
investigator, may be exempted from the biopsy 
requirement with approval by the principal investigator.  
Key Exclusion Criteria:  
 Treatment with chemotherapy (not including Tyrosine 
Kinase Inhibitors) or radiotherapy within 4 weeks (6 
weeks from nitrosoureas or mitomycin C), or treatment 
with monoclonal antibody therapy within 4 weeks prior to 
start of study treatment.  
Note: No minimum washout period is required for 
tyrosine kinase inhibitor therapy (eg, imatinib or 
sunitinib). 
 Patients must have recovered from adverse events (greater 
than grade 1) due to prior anticancer therapy, except for 
stable chronic toxicities such as alopecia. 
 Participation in any other clinical study with 
investigational drug received within 28 days or 5 half 
lives (whichever is longer) before first dose.  
 Subjects who have received prior anti-PD-1 or anti-PD-L1 
antibody therapy, or an IDO inhibitor. Subjects who have 
received experimental vaccines or other immune therapies 
should be discussed with the principal investigator to 
confirm eligibility.  
 Subjects receiving immunosuppressive treatment, 
including chronic steroids (at a dose equivalent to > 10 
mg/day of prednisone) within 14 days prior to first study 
treatment. Inhaled or topical steroids or systemic steroids 
(at dose ≤10 mg/day of prednisone) is permitted. 

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 Subjects with any active or inactive autoimmune process 
(eg, rheumatoid arthritis, moderate or severe psoriasis, 
multiple sclerosis, inflammatory bowel disease). 
Exceptions include vitiligo, hypothyroidism controlled on 
hormone replacement, type I diabetes, grave’s disease, 
adrenal insufficiency on stable replacement doses of 
steroids (prednisone ≤10 mg/day or equivalent), or with 
principal investigator approval. 
 Subjects with known active hepatitis B (HBV) or hepatitis 
C (HCV) infection as defined by the following: (Hepatitis 
screening studies are required (see section 13)) 
 Positive test for hepatitis B surface antigen 
 Positive test for hepatitis C antibody and/ or 
hepatitis C quantitative viral load (Note: Subjects 
with a positive hepatitis C antibody and negative 
quantitative hepatitis C PCR viral load are eligible) 
 Subjects with a known history of HIV, including patients 
with controlled disease on anti-retroviral therapy. HIV 
testing is not required as part of screening for this study. 
 Subjects receiving MAO inhibitors within 21 days prior to 
study enrollment (epacadostat increases serotonin levels, 
theoretically increasing the risk of serotonin syndrome, 
although this has not been reported in any ongoing clinical 
studies to date).  
 Any history of serotonin syndrome (SS) after receiving 1 
or more serotonergic drugs.   
 Current pregnancy or breast-feeding. 
 A diagnosis of another active malignancy with the 
following exceptions: basal or squamous cell carcinoma 
of the skin, in-situ carcinoma of the cervix, isolated 
elevation of prostate-specific antigen, indolent secondary 
malignancies not requiring active therapy, or with the 
approval of the principal investigator. Subjects with a 
completely treated prior malignancy and no evidence of 
disease for ≥ 2 years are eligible. 
Study Product, Dose, 
Route, Regimen 
 
 Pembrolizumab 200 mg (flat dose) intravenously on day 1 
of a 21 day cycle.  
 Epacadostat 100 mg orally BID continuously. 
Study schedule/ 
Procedures:  
Subjects will have regularly scheduled study visits at the clinical 
site on Day 1 of every cycle (CXD1), where safety assessments, 
including laboratory assessments, vital signs, and physical 
examinations will be performed.  

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Response to treatment will be determined by CT scans of the 
chest, abdomen, and pelvis with contrast. The response rate 
evaluation for the primary endpoint will be determined using 
RECIST v1.1 criteria; however, clinical decision making may be 
made based on irRECIST criteria to allow treatment beyond 
initial progression (see section 15). Imaging will be performed at 
the following time points: 
 
Baseline scan 
Baseline scan within 4 weeks 
prior to first treatment 
Weeks 1 – 24  
Every 6 weeks +/- 1 week (at 
weeks 6, 12, 18, 24) 
Weeks 25 – until disease 
progression 
Every 12 weeks +/- 1 week (at 
weeks 36, 48, 60, 72, 84, 96, 
108) 
2 years 
If subjects achieve ongoing 
disease control at 2 years, 
patients will be taken off 
study treatment and observed 
with imaging every 12 weeks 
+/- 2 weeks. If the patient 
develops disease progression, 
the option of reinitiating study 
therapy may be considered. 
 
Subjects will continue treatment until confirmed radiographic 
disease progression, intolerable toxicity or side effects or ongoing 
disease control at 2 years. In the latter case, imaging will be 
performed every 12 weeks, and should the patient develop 
evidence of disease progression, the option to reinitiate therapy 
may be discussed with the principal investigator. 
 
All patients must undergo paired biopsies for correlative studies. 
Biopsies will be collected at baseline and between C2D1 and 
C3D1 of therapy for correlative studies. An optional research 
biopsy at the time of progression will also be discussed with these 
patients, however, is not mandatory. Subjects in whom biopsy is 
technically not feasible or in whom would result in unacceptable 
risk, in the opinion of the investigator, may be exempted from the 
biopsy requirement with discussion with the principal 
investigator.  
 
Adverse events and laboratory tests will be graded using the NCI 
CTCAE v4.0 scoring system. Adverse events will be assessed 

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continuously during the study and for 90 days after the last dose 
of treatment. Subjects will be followed until all treatment related 
adverse events have recovered to baseline or are deemed 
irreversible by the investigator. Subjects who are removed from 
study for reasons other than progression of disease will be 
followed every 3 months with imaging to evaluate disease status 
and survival analysis while the study remains open. 
 
Duration of 
administration 
Continuous treatment, on 21 day cycles. 
 
Treatment will be continued until confirmed radiographic disease 
progression, intolerable side effects, or ongoing response at 2 
years of therapy.  
 
Reference therapy 
The reference therapy is salvage TKI therapy (sunitinib or 
regorafenib) in imatinib-refractory GIST patients, which has 
previously shown response rates of 7% and 5%, respectively. 
 
Statistical Methodology 
Definition of primary outcome/endpoint: 
The primary endpoint is the overall response rate as defined as 
the best response, confirmed at ≥4 weeks, within the first 24 
weeks of the start of study therapy, using RECIST v1.1 criteria.  
 
Definition of secondary outcomes/endpoints: 
PFS is defined as time from registration to time of clinical or 
radiographic disease progression as defined by RECIST v1.1 
criteria, or death. OS is defined as time from registration to time 
of death from any cause. 
 
Analytic plan for primary objective: 
We will estimate the response rate to combination therapy with 
epacadostat and pembrolizumab using the exact 95% confidence 
interval based on the binomial distribution. 
 
Analytic plan for secondary and exploratory objectives: 
 We will estimate the survival distribution for both PFS 
and OS endpoints using the Kaplan Meier method. 
The log rank test will be used to examine differences 
between survival curves. 
 For correlative studies we will apply either the 
Fisher’s exact test or Wilcoxon rank sum test to 
examine the correlation between response status and 
markers for categorical and continuous variables, 
respectively.  
 

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Sample size justification: 
We will use a Simon mini-max two-stage design with a target 
objective response rate of 20%, compared to a historical response 
rate of 5% with salvage tyrosine kinase inhibitor monotherapy, 
and the probabilities of type I and type II error set at 0.1 and 0.2 
respectively. In the first stage, 12 patients will be accrued. If less 
than 1 patient achieves a response among the initial 12 patients, 
the study will be declared negative and terminated. If at least 1 
patient achieves a response, an additional 9 patients will be 
accrued to the second stage for a total of 21 evaluable patients. If 
at least 3 total patients achieve a response, that treatment will be 
declared positive for attaining the primary endpoint. This study 
design yields at least 80% power to detect a 20% response rate 
(compared to the null hypothesis of 5%) at a significance level of 
10%. There is a 54% chance of stopping at Stage 1 if the true 
confirmed response rate is at most 5% (null hypothesis). 
Accounting for 10% dropout, we will plan to enroll a total of 23 
patients. 
 
 
 
 
 
 
 

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Protocol Schema: 
 

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Table of Contents 
Protocol Signature Page ...................................................................................................................... 5 
Name of Institution ............................................................................................................................... 5 
Protocol Synopsis .................................................................................................................................. 6 
 Introduction .................................................................................................................................. 18 
 Study Objectives .......................................................................................................................... 18 
2.1 
Primary Objective(s): ........................................................................................................................ 18 
2.2 
Secondary Objective(s): .................................................................................................................... 18 
2.3 
Exploratory Objectives: .................................................................................................................... 19 
 Background ................................................................................................................................... 19 
3.1 
Gastrointestinal Stromal Tumors (GIST) ................................................................................... 19 
3.2 
The immune system is an important anti-tumor mechanism in GIST ............................. 20 
3.3 
Indoleamine 2,3-dioxygenase (IDO) as a target for cancer therapy ................................ 20 
3.4 
Rationale for combined IDO and PD-1 inhibition in GIST. ................................................... 21 
 Investigational Agent: Epacadostat (INCB24360) ........................................................... 24 
4.1 
Preclinical Data ................................................................................................................................... 24 
4.2 
Clinical Data to Date ........................................................................................................................... 25 
4.3 
Other Agent(s): Pembrolizumab ................................................................................................... 26 
 Study Design .................................................................................................................................. 29 
5.1 
General study design ......................................................................................................................... 29 
5.2. 
Number of subjects ............................................................................................................................ 30 
6. Subjects Selection and Withdrawal ...................................................................................... 30 
6.1.    Inclusion Criteria ................................................................................................................................ 30 
6.2. 
Exclusion Criteria .............................................................................................................................. 32 
6.3. 
Pregnancy ............................................................................................................................................. 34 
6.4. 
Inclusion of Women and Minorities ............................................................................................ 35 
6.5. 
Subject Recruitment ......................................................................................................................... 35 
6.6. 
Early Withdrawal of Subjects ........................................................................................................ 35 
7. Registration Procedures ........................................................................................................... 36 
7.1. 
CUMC Research Participant Registration .................................................................................. 36 
7.2. 
Informed Consent Procedures ...................................................................................................... 38 
8. Treatment Plan ............................................................................................................................ 39 
8.1. 
Pembrolizumab Administration .................................................................................................. 39 
8.2. 
Epacadostat Administration .......................................................................................................... 41 
8.3. 
General Concomitant Medication and Supportive Care Guidelines ................................ 41 
8.3.1. 
Restricted Medications and Measures ............................................................................................... 41 
8.3.2. 
Prohibited Medications and Measures .............................................................................................. 42 
8.4. 
Treatment Compliance .................................................................................................................... 43 
8.5. 
Randomization and Blinding ......................................................................................................... 43 

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8.6. 
Duration of Treatment ..................................................................................................................... 43 
8.7. 
Treatment After Initial Evidence of Radiographic Disease Progression ....................... 43 
9. Dose Delays/ Modifications ..................................................................................................... 44 
9.1. 
Criteria and Procedures for Dose Modifications and Interruption ................................. 44 
9.2. 
Procedures for Subjects Exhibiting Immune-Related Adverse Events ........................... 47 
9.2.1. 
Procedures and Guidelines for Pneumonitis ................................................................................... 47 
9.2.2. 
Procedures and Guidelines for Enterocolitis .................................................................................. 48 
9.2.3. 
Procedures and Guidelines for Hepatitis .......................................................................................... 49 
9.2.4. 
Procedures for Immune-Mediated Dermatitis ............................................................................... 50 
9.2.5. 
Procedures for Immune-Mediated Neuropathies ......................................................................... 51 
9.2.6. 
Procedures for Immune-Mediated Endocrinopathies ................................................................. 52 
9.2.7. 
Procedures for Other Immune-Mediated Adverse Reactions, Including Ocular 
Manifestations .............................................................................................................................................................. 53 
9.3. 
Procedures for Subjects Exhibiting Serotonin Syndrome ................................................... 54 
10. Adverse Events:  List and Reporting Requirements ..................................................... 54 
10.1. 
Adverse  events ................................................................................................................................ 54 
10.2. 
Definitions ......................................................................................................................................... 54 
10.3. 
Recording of Adverse Events ...................................................................................................... 57 
10.4. 
Reporting of Serious Adverse Events ....................................................................................... 57 
11. Pharmaceutical Information ................................................................................................ 60 
11.1. 
Pembrolizumab ............................................................................................................................... 60 
11.1.1. 
Dispensing of Pembrolizumab ............................................................................................................ 60 
11.1.2. 
Packaging and Formulation ................................................................................................................. 60 
11.1.3. 
Storage .......................................................................................................................................................... 61 
11.1.4. 
Administration .......................................................................................................................................... 61 
11.1.5. 
Disposal ........................................................................................................................................................ 61 
11.1.6. 
Drug interactions and Concomitant therapy ................................................................................ 61 
11.1.7. 
Adverse Events .......................................................................................................................................... 61 
11.2. 
Epacadostat ....................................................................................................................................... 62 
11.2.1. 
Dispensing of Epacadostat ................................................................................................................... 62 
11.2.2. 
Packaging and Formulation ................................................................................................................. 62 
11.2.3. 
Storage .......................................................................................................................................................... 63 
11.2.4. 
Administration .......................................................................................................................................... 63 
11.2.5. 
Disposal ........................................................................................................................................................ 63 
11.2.6. 
Drug interactions and Concomitant therapy ................................................................................ 63 
11.2.7. 
Adverse Events .......................................................................................................................................... 63 
12. Study Evaluations ..................................................................................................................... 64 
12.1. 
Screening Phase ............................................................................................................................... 64 
12.2. 
Treatment Phase ............................................................................................................................. 64 
12.2.1. 
Clinic Visits.................................................................................................................................................. 65 
12.2.2. 
Assessment for Serotonin syndrome ............................................................................................... 65 
12.2.3. 
General laboratory assessment. ......................................................................................................... 65 
12.2.4. 
Schedule of Disease monitoring. ........................................................................................................ 65 
12.2.5. 
Collection of Tumor Biopsies and Blood for Correlative Studies ......................................... 66 
12.2.6. 
Adverse Events Monitoring ................................................................................................................. 66 
12.3. 
End of Treatment ............................................................................................................................. 66 

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12.4. 
Follow-up Phase............................................................................................................................... 66 
12.4.1. 
Safety Follow-up ....................................................................................................................................... 66 
12.4.2. 
Follow-up (patients taken off treatment for reasons other than POD) ............................. 67 
12.4.3. 
Survival Follow-up .................................................................................................................................. 67 
12.5. 
Unscheduled Visits .......................................................................................................................... 67 
13. Study Calendar ........................................................................................................................... 67 
14. Biomarker, Correlative, and Special Studies .................................................................. 74 
14.1. 
Collection of samples for correlative studies ........................................................................ 74 
14.1.1. 
Tumor biopsy samples ........................................................................................................................... 74 
14.1.2. 
Peripheral blood samples ..................................................................................................................... 75 
14.1.3 Blood samples for Phamacodynamic (PD)/ IDO analysis ............................................................ 75 
14.2. 
Correlative Studies ......................................................................................................................... 76 
14.2.1. 
IDO activity and expression ................................................................................................................. 76 
14.2.2. 
Tumor Infiltrating Lymphocytes ....................................................................................................... 76 
14.2.3. 
PD-L1 expression ..................................................................................................................................... 76 
14.2.4. 
Whole exome sequencing ..................................................................................................................... 76 
14.2.5 
Cell-free DNA .............................................................................................................................................. 76 
15. Measurement of Effect ............................................................................................................ 77 
15.1. 
Antitumor Effect – Solid Tumors ............................................................................................... 77 
15.2. 
Definitions ......................................................................................................................................... 77 
15.3. 
Disease Parameters ........................................................................................................................ 77 
15.4. 
Methods for Evaluation of Measurable Disease ................................................................... 78 
15.5. 
Response Criteria ............................................................................................................................ 80 
15.5.1. Evaluation of Target Lesions by irRECIST ......................................................................................... 81 
15.5.2. 
Evaluation by Choi Criteria .................................................................................................................. 81 
15.6. 
Duration of Response .................................................................................................................... 82 
15.7. 
Progression-Free Survival (PFS)................................................................................................ 82 
15.8. 
Response Review ............................................................................................................................. 82 
15.9. 
Unblinding Procedures ................................................................................................................. 82 
15.10. 
Stopping Rules ............................................................................................................................... 83 
15.11. 
Other Response Parameters ..................................................................................................... 83 
16. Data Reporting/ Regulatory Requirements .................................................................... 83 
16.1. 
Data Collection ................................................................................................................................. 83 
16.2. 
Data Reporting ................................................................................................................................. 83 
16.3. 
Data and Safety Monitoring Committee .................................................................................. 84 
16.4. 
Quality Control and Quality Assurance ................................................................................... 84 
16.5. 
Confidentiality .................................................................................................................................. 85 
16.6. 
Source Documents .......................................................................................................................... 86 
16.7. 
Case Report Forms .......................................................................................................................... 86 
16.8. 
Records Retention........................................................................................................................... 86 
17. Statistical Considerations ...................................................................................................... 86 
17.1. 
Study Endpoints and Analysis Plan ........................................................................................... 86 
17.2. 
Stratification Factors ..................................................................................................................... 87 
17.3. 
Reporting and Exclusions ............................................................................................................. 88 
18. Protection of Human Subjects .............................................................................................. 88 

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19. Study Finances ........................................................................................................................... 89 
19.1. 
Conflict of interest ........................................................................................................................... 89 
19.2. 
Subject Stipends or Payments .................................................................................................... 89 
20. Publication Plan ........................................................................................................................ 89 
21. Guidelines for Affiliate Institutions in Multicenter Studies....................................... 89 
21.1. 
Multi-site Communication ........................................................................................................... 89 
21.2. 
New Protocol Distribution, IRB Submission, Modifications, and Annual Renewals 89 
21.3. 
Regulatory Documents .................................................................................................................. 90 
21.4. 
Site activation ................................................................................................................................... 90 
21.5. 
Central Registration Procedures- Affiliate Institution Research Participant 
Registration Process ..................................................................................................................................... 91 
21.6. 
Protocol Deviation/Subject Waiver request for Affiliate Sites: ...................................... 92 
21.7. 
Guidelines for Affiliate Site Monitoring .................................................................................. 93 
21.8. 
Adverse event reporting ............................................................................................................... 94 
21.9. 
Efficacy analysis/ correlative analysis .................................................................................... 96 
21.10. 
Confidentiality ............................................................................................................................... 96 
21.11. 
Data Reporting Plan ..................................................................................................................... 97 
21.12. 
Data Acquisition and Submission ........................................................................................... 97 
21.13. 
Record Keeping and Record Retention ................................................................................. 97 
22. References ................................................................................................................................... 99 
23. Appendix ................................................................................................................................... 103 
23.1. 
Appendix A: ECOG Performance Status Criteria. .................................................................... 103 
23.2. 
Appendix B: Appropriate contraceptive methods for study subjects. ............................... 104 
23.3. 
Appendix C: Prohibited Monoamine Oxidase Inhibitors (MAOi) and Drugs Associated 
with Significant MAOi Activity. ................................................................................................................... 105 
23.4. 
Appendix D: Pill Diary ................................................................................................................... 106 
 
  
 
 
 
 
 
 
 
 

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 INTRODUCTION  
 
While targeted therapy with imatinib has significantly improved survival for patients with 
inoperable and metastatic gastrointestinal stromal tumors (GIST), the majority will eventually 
progress after a median of 20-26 months. Standard second-line treatment with sunitinib has a 
response rate of 7%, and third-line treatment with regorafenib has a response rate of only 5%. 
More effective treatments for imatinib-refractory GIST are needed. There is pre-clinical and 
clinical evidence that the anti-tumor mechanism of KIT inhibition in GIST is partially mediated 
by effects on the immune system. Indoleamine 2,3-dioxygenase (IDO) is an enzyme that 
metabolizes tryptophan to immunosuppressive metabolites that suppress cytotoxic T effector cells 
and activate inhibitory T regulatory cells. In a GIST mouse model, KIT inhibition with imatinib 
alters the tumor immune microenvironment by inhibiting IDO. Further, imatinib enhances the 
effect of anti-CTLA-4 and anti-PD-1 therapy in mice. We have also observed clinical benefit in 
refractory GIST patients treated on our ongoing phase I trial of dasatinib and ipilimumab. This 
data suggests that inhibition of IDO may be an important anti-tumor mechanism in GIST and can 
be combined with checkpoint inhibition to potentiate tumor control.  
 
This is a single-arm Phase II study to assess the efficacy of combined IDO and PD-1 inhibition 
with epacadostat (IDO inhibitor) and pembrolizumab (anti-PD-1 antibody) in patients with 
imatinib-refractory GIST (target enrollment of 23 subjects), with a primary endpoint of overall 
response rate using RECIST v1.1 criteria. We hypothesize that treatment with epacadostat and 
pembrolizumab will increase the response rate compared to what has been historically achieved 
with salvage tyrosine kinase inhibitors. Baseline and on-treatment biopsies will be obtained in a 
total of 10 subjects, with the goal of characterizing the effects of combined IDO and PD-1 
inhibition on the tumor immune microenvironment.  
 
 
 STUDY OBJECTIVES 
 
 
2.1 
 Primary Objective(s): 
 To assess the efficacy of combined IDO and PD-1 inhibition in a single arm phase II trial 
of epacadostat and pembrolizumab in patients with advanced imatinib-refractory GIST, 
using a primary endpoint of overall response rate using RECIST v1.1 criteria. 
 
2.2 
Secondary Objective(s): 
 To evaluate the progression free survival (PFS) of patients with advanced GIST treated 
with epacadostat and pembrolizumab using RECIST v1.1 criteria.  
 To evaluate the overall survival (OS) of patients with advanced GIST treated with 
epacadostat and pembrolizumab.  
  To evaluate response rate using Choi criteria.  
 To evaluate the safety and tolerability of combined epacadostat and pembrolizumab 
treatment in the advanced GIST population. 

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2.3 
Exploratory Objectives: 
 
 To correlate the effect of IDO inhibition with response to therapy by evaluating baseline 
and on-treatment serum samples for tryptophan metabolite levels. We predict that greater 
inhibition of IDO activity with epacadostat, as measured by a decrease in the serum 
kynurenine to tryptophan ratio, will correlate with treatment response. 
 To characterize the effect of combined therapy with IDO and PD-1 inhibition on T-cell 
subsets by evaluating baseline and on-treatment tumor samples for changes in the T-
effector to T-regulator cell ratio using immunohistochemistry. We predict that treatment 
with epacadostat and pembrolizumab will result in a higher ratio of T effector to T 
regulatory cells. 
 To characterize the relationship between PD-L1 status and response to combined IDO and 
PD-1 inhibition.  
 
 BACKGROUND 
 
3.1 Gastrointestinal Stromal Tumors (GIST) 
 
Background on GIST: 
Gastrointestinal stromal tumors (GIST) are the most common sarcomas of the digestive tract, with 
approximately 4,000 to 6,000 new cases diagnosed each year in the United States.1 The majority 
of these tumors harbor activating KIT or PDGFR-alpha mutations, making them sensitive to 
targeted treatment with the tyrosine kinase inhibitor imatinib mesylate.2 Imatinib has activity 
against KIT and PDGFR, and is considered first line therapy for non-operable and metastatic 
GIST. Treatment with imatinib in GIST leads to disease control in 70-85% of patients (overall 
response rate of 68.1%, and stable disease in 15.6%), with a median progression free survival 
(PFS) of 20-26 months.3-6 While targeted therapy with imatinib has significantly improved survival 
for patients with advanced GIST, about 14% of patients exhibit primary resistance to imatinib.4 In 
addition, the majority of patients will eventually acquire mutations in KIT or PDGFR leading to 
secondary resistance after an average of 2 years of initial imatinib therapy.7-9  
 
Treatment for imatinib-refractory advanced GIST: 
Effective treatment options for patients with imatinib-refractory GIST are limited. Sunitinib, an 
oral receptor tyrosine kinase inhibitor with activity against KIT, PDGFR, as well as VEGF 
receptors, FLT3, and RET, has been shown to improve progression free survival in patients with 
inoperable GIST who have failed imatinib therapy, and is now considered standard second-line 
treatment for advanced GIST. In a phase III randomized placebo-controlled study of sunitinib 
versus placebo in patients with imatinib-resistant advanced GIST, the sunitinib group had an 
overall median progression free survival of 27.3 weeks compared to 6.4 weeks in the placebo 
group.10 However, the overall response rate was only 7 percent in the sunitinib treated group, 
compared with 0 percent in the placebo group.10 Regorafenib, an oral multikinase inhibitor of KIT, 
PDGFR, VEGFR, RET, BRAF, and FGFR, has been studied as third line treatment in imatinib 
and sunitinib refractory patients, and has been shown to improve progression free survival from 

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0.9 months to 4.8 months (p < 0.0001), with an overall response rate of 4.5 percent.11 Given the 
overall low response rates to TKI therapy in the second-line setting and beyond, more effective 
therapies for imatinib-refractory GIST patients are needed. 
 
Other TKIs with preclinical activity against KIT and PDGFR have been examined as potential 
therapeutic options both in front-line and refractory GIST. Dasatinib is a TKI with a spectrum of 
activity including the SRC family of kinases in addition to KIT and PDGFR that has been evaluated 
as a treatment option for GIST. Preclinical data has described activity of dasatinib toward mutant 
KIT,12 as well as anti-tumor efficacy in imatinib-resistant GIST cell lines.13 Trent and colleagues 
presented the results of a phase II study of dasatinib as third-line therapy for GIST at ASCO 2011.14  
Results included a Choi partial response rate of 32%, a median PFS of 2 months and median OS 
of 19 months, and a PFS rate of 21% at 6 months.   
 
In summary, although treatment of GIST with tyrosine kinase inhibitors results in demonstrated 
clinical benefit, this efficacy is not sustained and treatment with KIT inhibition does not result in 
the cure of patients with advanced disease. Given the overall low response rates to TKI therapy in 
the second-line setting and beyond, novel and more effective therapies for imatinib-refractory 
GIST are needed. 
 
3.2 The immune system is an important anti-tumor mechanism in GIST 
 
Anti-tumor effects of imatinib are mediated by the immune system: 
While current treatment for imatinib-refractory GIST has focused on targeted therapy with newer 
generation TKIs, there is pre-clinical and clinical evidence that the anti-tumor effects of KIT 
inhibition in GIST are also mediated by effects on the immune system. In a mouse model of KIT 
mutant (KITV558/+) GIST, the response to imatinib was dependent upon the presence of intact CD8+ 
T cells—depletion of CD8+ T cells with a monoclonal antibody inhibited the response to imatinib, 
and GIST Rag1-/- mice, which lack mature T and B cells, had larger tumors than age matched 
controls or GIST-μMT-/- mice, which lack only B cells.15 Imatinib treatment also increased the 
number and activation of intratumoral CD8+ Teff cells and induced apoptosis of Treg cells in these 
mice.15 In human GIST tumors, the ratio of Teff cells to Treg cells was also shown to correlate with 
imatinib sensitivity.15 
 
3.3 Indoleamine 2,3-dioxygenase (IDO) as a target for cancer therapy 
 
Indoleamine 2,3-dioxygenase (IDO) in cancer: 
Indoleamine 2,3-dioxygenase (IDO) is a heme-containing, monomeric oxidoreductase  
produced in tumor cells, macrophages, and dendritic cells, that metabolizes tryptophan to N-
formyl-kynurenine metabolites.16-19 IDO 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.20 IDO activity also promotes the differentiation of naive T cells to 
T regulatory cells (Treg cells), which has been shown to promote tumor growth.19  
 
A critical role for IDO in immunomodulation has been confirmed in animal models, including 
models of allograft tolerance, inflammation, and cancer.21 While IDO inhibition can exacerbate 

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disease in models of autoimmune disorders, IDO null mice show no evidence of susceptibility to 
developing spontaneous autoimmunity or alterations in immune system development, suggesting 
the therapeutic potential of IDO inhibition.21 Within the context of cancer, several groups have 
demonstrated that blockade of IDO activity can directly influence the ability of tumor-bearing 
animals to reject tumors. Studies with the IDO inhibitor, 1-methyl-tryptophan, demonstrate that 
IDO inhibition can increase the efficacy of various chemotherapeutic agents without increased 
toxicity.18,22 In addition, IDO activity, as measured by levels of serum tryptophan and kynurenine, 
appears to be chronically activated in subjects with cancer and correlates with more extensive 
disease. IDO has been found to be overexpressed by a wide variety of human tumor cell types as 
well as by the DCs that localize to the tumor-draining lymph nodes.18 Increased expression of IDO 
in tumor cells has been shown to be an independent prognostic variable for reduced overall survival 
in various tumors including melanoma, ovarian cancer, and colorectal.17,23,24  
 
Together, these results suggest that the IDO pathway is a key regulatory element responsible for 
the induction and maintenance of tumor immune tolerance. Small molecule inhibitors of IDO may 
provide an innovative method to treat advanced malignancies either alone or in combination with 
immunotherapy-based strategies. 
 
Rationale for combined IDO and PD-1 inhibition in cancer:  
Blockade of immune inhibitory pathways with CTLA-4 or PD-1/PD-L1 blockade is emerging as 
an important therapeutic modality for the treatment of cancer. Although these single agents have 
antitumor activity, multiple immune inhibitory mechanisms are present concurrently within the 
tumor microenvironment, suggesting that combination therapies may be required for optimal 
therapeutic effect. As IDO is another negative regulatory mechanism that contributes to tumor-
derived immune suppression, targeting of both IDO and immune checkpoints may lead to 
enhanced efficacy. In preclinical models, IDO 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 
overall survival. In a mouse model of melanoma, combined IDO and CTLA-4 and PD-1 inhibition 
resulted in synergistic anti-tumor effect.25 Currently there is an ongoing phase 1/2 clinical trial of 
epacadostat in combination with pembrolizumab in advanced solid tumors (NCT 02178722). The 
Phase 1 portion of the study has been completed and the recommended phase II dose of 
pembrolizumab has been determined. 
 
3.4 Rationale for combined IDO and PD-1 inhibition in GIST.  
 
KIT inhibition alters the tumor immune microenvironment via IDO inhibition in GIST: Studies 
in a GIST mouse model found that imatinib altered intratumoral T cells through inhibition of IDO. 
In this GIST mouse model, KIT induced expression of the transcription factor ETV4 that 
transactivated IDO. Treatment with imatinib was able to inhibit this interaction.15 Treatment with 
the IDO specific inhibitor 1-methyl-D-tryptophan (1-MT) lead to a decrease in tumor size 
accompanied by an increase in intratumoral Teff cells in mice. Evaluation of human GIST tumor 
specimens was consistent with the findings in the GIST mouse model and demonstrated IDO 
suppression and a higher ratio of intratumoral Teff to Treg cells in imatinib-sensitive compared with 
imatinib-resistant tumors.15  
 

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PD-L1 is expressed in GIST:  
It has been previously demonstrated that GIST tumors express PD-L1. 29% of GIST tumors 
expressed PD-L1 by immunohistochemistry, which was the highest prevalence observed amongst 
all sarcoma pathologies evaluated in one study.26 Tumor lymphocyte and macrophage infiltration 
was present in 100% of these specimens, and PD-L1 was expressed in 50% of tumor infiltrating 
lymphocytes and macrophages.26 Other studies have shown that CD3+ tumor infiltrating 
lymphocytes are present in GIST and predict improved progression free survival.27 Given the high 
rate of PD-L1 expression, evaluation of anti-PD1/PD-L1 agents in GIST tumors is of high priority. 
 
KIT inhibition combined with immunotherapy enhances anti-tumor effect in pre-clinical studies 
and a Phase I study:  
 
a. KIT + CTLA-4 inhibition: In a GIST mouse model, CTLA-4 blockade synergized with imatinib 
to reduce tumor growth (Figure 2).15 We have also previously demonstrated clinical benefit with 
the combination of dasatinib and ipilimumab in a heavily pretreated GIST population (mean of 4.5 
prior treatments) enrolled on a phase I trial of dasatinib and ipilimumab. In the interim analysis, 
of 8 GIST patients enrolled, 3 achieved disease stability following initial tumor progression by 
RECIST criteria, with response kinetics similar to that described with ipilimumab immunotherapy 
in melanoma. One patient had a durable response with stable disease for over 1 year (Figure 3).28 
The full results of this study were recently reported, with a total of 28 patients enrolled, including 
20 patients with a diagnosis of GIST and 8 patients with other sarcomas. Dose limiting toxicities 
observed in this Phase I study included grade 3 gastric hemorrhage in 1 patient and grade 3 anemia 
in 2 patients. The final MTD was established as dasatinib at 140 mg daily and ipilimumab at 3 
mg/kg. There were no partial or complete responses observed by RECIST or irRC; however, there 
were 7 patients (out of 13 evaluable GIST patients) with partial responses by Choi criteria. In 
addition, 3 (out of 13 evaluable GIST patients) achieved stable disease.29 

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b. KIT + PD-1/PD-L1 inhibition: In a GIST mouse model, combined PD-1 or PD-L1 blockade 
with imatinib was more effective than imatinib therapy alone. Mice treated with either PD-1 or 
PD-L1 antibodies in combination with imatinib had an additional 25% or 30% decrease in tumor 
weight respectively.30,31 This combination resulted in decreased phosphorylated KIT, 
phosphorylated STAT1, TGF-β, and IDO protein expression (Figure 4), as well as decreased IDO 
mRNA expression. The anti-tumor effect of combined imatinib and anti-PD-1 therapy was durable 
at 3 months in this GIST mouse model.30 
 
 
 

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IDO inhibition combined with PD-1/PD-L1 blockade enhances anti-tumor effect in a GIST 
mouse model:  
IDO inhibition with 1-MT was combined with PD-1/PD-L1 axis blockade in a GIST KITV558Δ/+ 
mouse model. After 1 week of combined treatment, additional decrease in tumor weight was 
observed compared to IDO inhibition alone or controls (Figure 5).30  
 
Rationale and Hypothesis: 
New approaches to the treatment of imatinib-refractory GIST are needed. Investigation of the 
combination of IDO and PD-1 inhibition in GIST patients is warranted for the following reasons:  
 Pre-clinical evidence has shown that KIT inhibition alters the tumor immune 
microenvironment by increasing Teff  cells and decreasing Treg cells via suppression of the 
IDO enzyme.  
 PD-L1 is expressed in a high proportion of GIST tumors compared with other sarcoma 
sub-types, making investigation of anti-PD-1/PD-L1 agents a high priority in GIST. 
 Combined KIT and PD-1 or CTLA-4 inhibition was synergistic in a GIST mouse model, 
and we have observed clinical benefit in our phase I trial of dasatinib and ipilimumab in 
GIST.  
We propose a phase II trial of epacadostat and pembrolizumab to evaluate the efficacy of combined 
IDO and PD-1 inhibition in imatinib-refractory advanced GIST patients. We hypothesize that 
patients treated with IDO and PD-1 inhibition will have improved objective response rates 
compared to historical controls treated with salvage TKI therapy.  
 
 
 INVESTIGATIONAL AGENT: EPACADOSTAT (INCB24360) 
 
4.1 Preclinical Data  
 
Epacadostat is a novel selective inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1) manufactured 
by Incyte corporation. In cell-based assays, epacadostat potently inhibits IDO in both human tumor 
cells and human dendritic cells resulting in reduced tryptophan to kynurenin conversion (IC50 
values = 7.1-12.7 nM), and does not significantly inhibit other proteins that could impact 

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tryptophan catabolism. 
 
To test whether epacadostat could reverse the inhibitory effect of IDO1 on T cells, IDO1+ DCs 
were cocultured with either CD4+ or CD8+ T cells in the presence of a soluble anti-CD3 antibody 
to promote T-cell activation and growth. Compared with the T cells cocultured with immature 
DCs, which do not express IDO1, 3H-thymidine incorporation in CD4+ or CD8+ T cells was 
significantly suppressed when they were cocultured with DCs, which express high levels of IDO1. 
Addition of epacadostat to the cocultures protected CD4+ or CD8+ T cells from this inhibitory 
effect. The effects of epacadostat in this system were dose-dependent and were consistent with the 
potency of the compound in blocking Trp conversion, with an EC50 value of 17.7 ± 4.7 nM (n = 
3). In these same cultures, the effect of INCB24360 on cytokine levels was examined. Epacadostat 
treatment led to a 5-fold increase in the IFN-γ levels produced by CD4+ and CD8+ T cells when 
compared with vehicle control. Like T cells, NK cell proliferation was also inhibited by IDO1-
mediated Trp catabolism, and epacadostat treatment reversed this, resulting in a 4- to 5-fold 
increase in 3H-thymidine uptake by NK cells.  
 
Recent studies have also shown the potential for IDO1 activity to promote the differentiation of 
naïve T cells to cells with a regulatory T phenotype (Treg). The ability of IDO1+ DCs to promote 
differentiation to Treg cells as well as the ability of epacadostat to reverse this effect was therefore 
examined in an in vitro culture system similar to those previously reported. In these studies, co-
culture of naïve CD4+CD25- T cells with IDO1+ DCs resulted in a 2-fold increase in Treg cells 
as defined by Foxp3 staining when the cells were cultured with interleukin (IL)-2. Inclusion of 
epacadostat in the cultures reversed this effect. 
 
In Vitro Activity of Epacadostat on Human Immune Cells 
Cell Type 
Effects of IDO1 
Epacadostat Effects 
T cells 
Decreased proliferation 
Enhanced proliferation; enhanced IFN-
gamma production 
NK cells 
Decreased proliferation 
Enhanced proliferation 
Treg 
Increased cell numbers 
Decreased cell numbers 
DC 
Increased apoptosis 
Decreased apoptosis; increased DC 
activation markers 
 
 
4.2 Clinical Data to Date 
 
As of October 2016, a 12 Incyte-sponsored clinical studies have been completed or are ongoing. 
Epacadostat was evaluated in a multi-center, dose-escalation Phase 1 study (INCB 24360-101) in 
subjects with refractory solid tumors using a 3 + 3 design to determine the safety and tolerability, 
PK, and pharmacodynamics of escalating oral doses of epacadostat. Epacadostat was well tolerated 
at doses up to 700 mg BID. Fatigue and nausea were the most frequently reported treatment-related 
treatment-emergent adverse event (48.1%, 25 subjects). Two DLTs occurred, including 1 DLT for 
radiation pneumonitis and 1 DLT for fatigue. An MTD was not determined.. 
 
There is an ongoing Phase I/II study of the safety, tolerability, and efficacy of pembrolizumab in 

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combination with epacadostat in subjects with selected solid tumors, followed by an open-label 
expansion in subjects with select tumors (INCB 24360-202). This study enrolled 22 subjects with 
advanced melanoma on the Phase I portion of the study, of which 19 were treatment naïve. The 
overall response rate was 58% (11 of 19 patients), with 26% achieving a complete response and 
32% achieving a partial response. 3 patients (16%) had stable disease and 14 patients (74%) 
achieved disease control.32 Responses were observed in all epacadostat dose cohorts greater than 
or equal to 50 mg BID and at all sites of target lesions. Responses were also observed in patients 
with previously treated advanced melanoma (1 complete response, 1 stable disease, n=3), non-
small cell lung cancer (5 partial responses, 2 stable disease, n=12), renal cell carcinoma (3 partial 
responses, 5 stable disease, n=11), endometrial adenocarcinoma (1 complete response, 1 partial 
response, n=7), transitional cell carcinoma (3 partial responses, n=5), triple negative breast cancer 
(2 stable disease, n=3), and head and neck squamous cell carcinoma (1 partial response, 1 stable 
disease, n=2).32  
 
The safety profile for the 300mg BID dose of epacadostat in combination with pembrolizumab in 
the Phase I/II study (INCB24360-202) did not exceed the MTD in that study.  While there was a 
higher incidence of grade 3 rash in the 300mg BID cohort compared to the 100mg BID cohort, 
these did not qualify as protocol-specified DLTs. The dose combination of 100mg BID of 
epacadostat plus pembrolizumab is currently being evaluated in a Phase III melanoma study 
(INCB24360-301). The epacadostat 100mg BID dose combination is being moved forward as the 
recommended dose in combination with pembrolizumab because of the lower incidence of dose 
interruptions and dose reductions compared to the 300mg BID dose.  
 
 
 
4.3 Other Agent(s): Pembrolizumab 
 
Pharmaceutical and Therapeutic Background 
 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation between 
tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in various 
malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-cells / 
FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-term survival in 
many solid tumors. 
 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.  The normal function of PD-1, expressed on the cell surface of activated T-cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related to 
CD28 and CTLA-4 which has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or PD-L2). The structure of murine PD-1 has been resolved.  
PD-1 and family members are type I transmembrane glycoproteins containing an Ig Variable-type 
(V-type) domain responsible for ligand binding and a cytoplasmic tail which is responsible for the 
binding of signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling 

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motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor 
tyrosine-based switch motif (ITSM). Following T-cell stimulation, PD-1 recruits the tyrosine 
phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in 
the CD3 T-cell signaling cascade.  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.  PD-1 was shown to be expressed on activated lymphocytes including 
peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells.  Expression has also 
been shown during thymic development on CD4-CD8- (double negative) T-cells as well as subsets 
of macrophages and dendritic cells.  The ligands for PD-1 (PD-L1 and PD-L2) are constitutively 
expressed or can be induced in a variety of cell types, including non-hematopoietic tissues as well 
as in various tumors.  Both ligands are type I transmembrane receptors containing both IgV- and 
IgC-like domains in the extracellular region and contain short cytoplasmic regions with no known 
signaling motifs.  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 non-hematopoietic 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.  Although healthy organs express little (if any) 
PD-L1, a variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor.  
PD-1 has been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma 
(MEL).  This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion 
and should be considered as an attractive target for therapeutic intervention. 
 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-
L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the United Stated for 
the treatment of patients with unresectable or metastatic melanoma, patients with metastatic 
NSCLC whose tumors have high PD-L1 expression [(Tumor Proportion Score (TPS) ≥50%)] as 
determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and no 
prior systemic chemotherapy treatment for metastatic NSCLC, patients with metastatic NSCLC 
whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease 
progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic 
tumor aberrations should have disease progression on FDA-approved therapy for these aberrations 
prior to receiving. Approval was also received for patients with recurrent or metastatic HNSCC 
with disease progression on or after platinum-containing chemotherapy. 
 
Recently, pembrolizumab received accelerated approval for treatment of adult and pediatric 
patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch 
repair deficient (dMMR) solid tumors that have progressed following prior treatment and who 
have no satisfactory alternative treatment options, as well as patients with MSI-H or dMMR 
colorectal cancer following progression on a fluoropyrimidine, oxaliplatin, and irinotecan. 
 
 
Preclinical and Clinical Trial Data 

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Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
 
 
Rationale for Dose Selection/ Regimen/ Modification 
 
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and clinical 
activity of single agent MK-3475.  The dose escalation portion of this trial evaluated three dose 
levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with 
advanced solid tumors.  All three dose levels were well tolerated and no dose-limiting toxicities 
were observed.  This first in human study of MK-3475 showed evidence of target engagement and 
objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg 
Q2W).  No MTD has been identified to date. Recent data from other clinical studies within the 
MK-3475 program has shown that a lower dose of MK-3475 and a less frequent schedule may be 
sufficient for target engagement and clinical activity. 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic data (IL-2 
release assay) suggested that peripheral target engagement is durable (>21 days).  This early PK 
and pharmacodynamic data provides scientific rationale for testing a Q2W and Q3W dosing 
schedule.   
 
A population pharmacokinetic analysis has been performed using serum concentration time data 
from 476 patients. Within the resulting population PK model, clearance and volume parameters of 
MK-3475 were found to be dependent on body weight. The relationship between clearance and 
body weight, with an allometric exponent of 0.59, is within the range observed for other antibodies 
and would support both body weight normalized dosing or a fixed dose across all body weights.  
MK-3475 has been found to have a wide therapeutic range based on the melanoma indication.  The 
differences in exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body weight 
based regimen are anticipated to remain well within the established exposure margins of 0.5 – 5.0 
for MK-3475 in the melanoma indication. The exposure margins are based on the notion of similar 
efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg 
Q3W (i.e. 5-fold higher dose and exposure). The population PK evaluation revealed that there was 
no significant impact of tumor burden on exposure. In addition, exposure was similar between the 
NSCLC and melanoma indications. Therefore, there are no anticipated changes in exposure 
between different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in solid 
tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 2 mg/kg 
or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships of 
pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg Q3W, 
3) the lack of effect of tumor burden or indication on distribution behavior of pembrolizumab (as 
assessed by the population PK model) and 4) the assumption that the dynamics of pembrolizumab 
target engagement will not vary meaningfully with tumor type. 
 

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The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on 
simulations performed using the population PK model of pembrolizumab showing that the fixed 
dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent with those 
obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient exposures in the 
exposure range established in melanoma as associated with maximal efficacy response and 3) will 
maintain individual patients exposure in the exposure range established in melanoma that are well 
tolerated and safe.  
 
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and 
to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity in the 
logistical chain at treatment facilities and reduce wastage. 
 
 
 STUDY DESIGN 
 
5.1 
General study design 
 
This is a single-arm Phase 2 study to evaluate the efficacy of combined epacadostat and 
pembrolizumab in advanced imatinib-refractory GIST patients.  
 
Study Intervention: All subjects will receive pembrolizumab 200 mg IV every 3 weeks and 
epacadostat 100 mg PO BID continuously.  
 
Schedule of Evaluations: Subjects will have regularly scheduled study visits at the clinical site 
on Day 1 of every cycle (CXD1), where safety assessments, including laboratory assessments, 
vital signs, and physical examinations will be performed (see Section 12 for detailed study 
evaluations, and Section 13 for study calendar). 
 
Response to treatment will be determined by CT scans of the chest, abdomen, and pelvis with 
contrast. The overall response rate for the primary endpoint evaluation will be determined by 
RECIST v1.1 criteria; however, clinical decision making may be made based on immune related 
RECIST (irRECIST) criteria to allow treatment beyond initial progression (see section 15). In 
patients who are unable to get a CT scan w/ contrast due to renal function (or any other reason), 
an MRI with and without contrast may be used instead. Imaging will be performed at the following 
time points: 
 
Baseline scan 
Baseline scan within 4 weeks prior to first treatment 
Weeks 1 – 24  
Every 6 weeks +/- 1 week (at weeks 6, 12, 18, 24) 
Weeks 25 – until disease 
progression 
Every 12 weeks +/- 1 week (at weeks 36, 48, 60, 72, 84, 96, 108) 
2 years 
If subjects achieve ongoing disease control at 2 years, patients 
will be taken off study treatment and observed with imaging 
every 12 weeks +/- 2 weeks. If the patient develops disease 
progression, the option of reinitiating study therapy may be 
considered. 

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Duration of treatment: Subjects will continue treatment until confirmed radiographic disease 
progression, intolerable toxicity or side effects (see Section 6.6 for Criteria for Withdrawal) or 
ongoing disease control at 2 years. In the latter case, imaging will be performed every 12 weeks, 
and should the patient develop evidence of disease progression, the option of reinitiating study 
therapy may be considered based upon discussion with the study principal investigator.  
 
Biopsies for correlative studies: All enrolled subjects must undergo paired biopsies for 
correlative studies. CT-guided biopsies will be collected at baseline and between C2D1 and C3D1 
of therapy for correlative studies. An optional biopsy for research purposes at the time of 
progression will also be discussed with these patients, however, is not mandatory. Subjects in 
whom biopsy is technically not feasible or in whom would result in unacceptable risk, in the 
opinion of the investigator, may be exempted from the biopsy requirement with discussion with 
the principal investigator.  
 
Duration of follow-up: Adverse events and laboratory tests will be graded using the NCI CTCAE 
v4.0 scoring system. Adverse events will be assessed continuously during the study and for 90 
days after the last dose of treatment. Subjects will be followed for at least 90 days post-study, or 
until all treatment related adverse events have recovered to baseline or are deemed irreversible by 
the investigator. Subjects who are removed from study for reasons other than progression of 
disease will be followed every 3 months with imaging to evaluate disease status and survival 
analysis while the study remains open.  
 
 
5.2. 
Number of subjects 
 
Using a Simon two-stage design, 12 patients will be treated initially. If an objective response is 
observed in at least 1 patient, we will proceed with enrollment of an additional 9 patients for a total 
of 21 evaluable patients. Assuming a 10% drop-out rate, we anticipate a total maximal accrual of 
23 patients. 
 
 
 
6.  SUBJECTS SELECTION AND WITHDRAWAL 
 
6.1.    Inclusion Criteria 
 
The following criteria are required for inclusion in the study:  
 
1. Histologically confirmed diagnosis of GIST. 
 
2. Unresectable or metastatic GIST.  
 
3. Allowable prior therapies:  

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a. Subjects must have had clinical or radiographic progression on imatinib. Those who 
were taken off of imatinib for intolerance must have progressed on at least one other 
TKI. 
b. Subjects must have received ≥ 1 prior systemic therapy (including imatinib). A 
maximum of 4 prior therapies for metastatic disease are allowed. 
 
 
4. Male or female subjects, age 18 years or older. 
 
5. ECOG performance status ≤ 1 (Appendix A) 
 
6. Life expectance of  ≥ 3 months. 
 
7. Laboratory parameters within the following Protocol-defined range. All screening 
laboratory tests should be performed within 28 days of treatment initiation and must be 
independent of hematopoietic growth factor support.  
 Absolute neutrophil count ≥ 1.5 x 109/L. 
 Platelets ≥ 100 x 109/L. 
 Hemoglobin ≥ 9 g/dL (transfusion is acceptable to meet this criteria) 
 Serum creatinine ≤ 1.5 x institutional upper limit of normal (ULN) OR calculated 
creatinine clearance ≥ 50 mL/min for subjects with creatinine levels > 1.5 x institutional 
ULN. 
 Aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase ≤ 2.5 x 
ULN, or  ≤ 5 x ULN in subjects with liver metastases. 
 Total bilirubin ≤ 1.5 x ULN 
o Note: patients with hyperbilirubinemia clinically consistent with an inherited 
disorder of bilirubin metabolism (eg, Gilbert syndrome) will be eligible at the 
discretion of the principal investigator.  
 International normalized ratio (INR) or prothrombin time (PT) < 1.5x ULN unless 
subject is receiving anticoagulation therapy as long as PT or INR is within therapeutic 
range of intended use of anticoagulant. 
 Activated partial thromboplastin time (aPTT) < 1.5 x ULN unless subject is receiving 
anticoagulant therapy, as long as PTT is within therapeutic range of intended use of 
anticoagulants.  
 
8. Presence of baseline measureable disease by RECIST v1.1 for solid tumors, defined as at 
least one lesion that can be accurately measured in at least one dimension (longest diameter 
to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥ 20 mm with 
conventional techniques or as ≥ 10 mm with spiral CT scan, MRI, or calipers by clinical 
exam. (See Section 15.4 for the evaluation of measurable disease). 
 
9. The effects of pembrolizumab and epacadostat on the developing human fetus are 
unknown, and thus 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 
pregnancy test at screening and must agree to use adequate contraception (complete 

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abstinence, or two methods of birth control (Appendix B)) prior to study entry and until at 
least 4 months after the last dose of study treatment. Should a woman become pregnant or 
suspect she is pregnant while she or her partner is participating in this study, she should 
inform her treating physician immediately.   
 
10.  Fertile men must also agree to use adequate contraception (2 barrier methods or 
abstinence) during the study and for up to 4 months after the last dose of study drug.  
 
11. All subjects must agree to pre- and on-treatment tumor biopsies. Subjects in whom biopsy 
is technically not feasible or in whom would result in unacceptable risk, in the opinion of 
the investigator, may be exempted from the biopsy requirement with discussion with the 
principal investigator. Use of outside archived tumor tissue for a baseline biopsy is not 
permitted.  
 
12. Willingness and ability to provide written informed consent prior to any study-related 
procedures and to comply with all study requirements. 
 
6.2. Exclusion Criteria 
 
1. Treatment with chemotherapy (not including Tyrosine Kinase Inhibitors) or radiotherapy 
within 4 weeks (6 weeks from nitrosoureas or mitomycin C), or treatment with monoclonal 
antibody therapy within 4 weeks prior to start of study treatment.  
Note: No minimum washout period is required for tyrosine kinase inhibitor therapy 
(eg, imatinib or sunitinib). 
 
2. Patients must have recovered from adverse events (greater than grade 1) due to prior 
anticancer therapy, except for stable chronic toxicities such as alopecia. 
 
3. Participation in any other clinical study with investigational drug received within 28 days 
or 5 half lives (whichever is longer) before first dose. 
  
4. Subjects who have received prior anti-PD-1 or anti-PD-L1 antibody, or an IDO inhibitor. 
Subjects who have received experimental vaccines or other immune therapies should be 
discussed with the principal investigator to confirm eligibility.  
 
5. Any prior ≥ Grade 3 immune-related adverse event (irAE) while receiving immunotherapy, 
or any unresolved irAE > grade 1. 
 
6. Subjects receiving immunologically based treatment for any reason, including chronic 
steroids or prednisone (at dose >10 mg/day of prednisone) within 14 day prior to first study 
treatment. Inhaled or topical steroids or systemic steroids (at dose ≤10 mg/day of 
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7. Subjects with any active or inactive autoimmune process (eg, rheumatoid arthritis, 
moderate or severe psoriasis, multiple sclerosis, inflammatory bowel disease) or who are 
receiving systemic therapy for an autoimmune disease. Exceptions include vitiligo, 
hypothyroidism controlled on hormone replacement, type I diabetes, Grave’s disease, 
adrenal insufficiency on stable replacement doses of steroids (prednisone ≤10 mg/day or 
equivalent), or with principal investigator approval. 
 
8. No prior organ allograft or allogenic bone marrow transplantation.   
 
9. History of (noninfectious) pneumonitis that require steroids or current pneumonitis.  
 
10. A diagnosis of another active malignancy with the following exceptions: basal or squamous 
cell carcinoma of the skin, in-situ carcinoma of the cervix, isolated elevation of prostate-
specific antigen, indolent secondary malignancies not requiring active therapy, or with the 
approval of the principal investigator. Subjects with a completely treated prior malignancy 
and no evidence of disease for ≥ 2 years are eligible. 
 
11. Subjects with known active hepatitis B (HBV) or hepatitis C (HCV) infection as defined 
by the following (Hepatitis screening studies are required (see section 13)): 
 Positive test for hepatitis B surface antigen 
 Positive test for hepatitis C antibody and/ or hepatitis C quantitative viral load 
(Note: Subjects with a positive hepatitis C antibody and negative quantitative 
hepatitis C PCR viral load are eligible) 
 
12. Subjects with a known history of HIV, including patients with controlled disease on anti-
retroviral therapy. HIV testing is not required as part of screening for this study.  
 
13. Subjects receiving MAO inhibitors within 21 days of study enrollment (epacadostat 
increases serotonin levels, theoretically increasing the risk of serotonin syndrome, although 
this has not been reported in any ongoing clinical studies to date). 
 
14. Any history of serotonin syndrome (SS) after receiving 1 or more serotonergic drugs. 
 
15. Current pregnancy or breast feeding. Pregnant women are excluded from this study because 
the teratogenicity of epacadostat and pembrolizumab are unknown. Because there is an 
unknown but potential risk for adverse events in nursing infants secondary to treatment of 
the mother with pembrolizumab and/or epacadostat, breastfeeding should be discontinued 
in all female subjects. 
 
16. Receipt of live attenuated vaccines (including, but not limited to: intranasal influenza 
vaccine (FluMist), measles, mumps, rubella, chicken pox, yellow fever, rabies, Bacillus 

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Calmette-Guerin (BCG), and typhoid vaccine) within 30 days before the first dose of study 
treatment.  
 
17. Concurrent use of any medication that is an inhibitor of UGT1A9 (section 8.3.2) during 
the screening or treatment period.  
 
18. Major surgical procedure or significant traumatic injury within 14 days of initiating study 
drug or anticipation of the need for major surgery during the study. 
 
19. Inability to swallow capsules, or refractory nausea and vomiting, malabsorption, an 
external biliary shunt, or significant bowel resection that would preclude adequate 
absorption. 
 
20. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
active liver disease, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with study 
requirements. 
 
21. History of current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the study, or interfere with the subject’s participation for the full 
duration of the study. 
 
22. Known allergy or reaction to any component of either study drug formulation. 
 
6.3. 
Pregnancy 
 
The effects of pembrolizumab and epacadostat on the developing human fetus are unknown. For 
this reason, women of child-bearing potential and men must agree to use adequate contraception 
(Appendix B) prior to study entry and for the duration of study participation. Should a woman 
become pregnant or suspect she is pregnant while she or her partner is participating in this study, 
she should inform her treating physician immediately. Men treated or enrolled on this protocol 
must also agree to use adequate contraception prior to the study, for the duration of study 
participation, and 4 months after completion of pembrolizumab and/or epacadostat administration.  
 
Sexually active women of child-bearing potential (WOCBP) must use an effective method of birth 
control during the course of the study, in a manner such that risk of failure is minimized (Appendix 
B).  
 
Before study enrollment, WOCBP must be advised of the importance of avoiding pregnancy 
during study participation and the potential risk factors for an unintentional pregnancy. The subject 
must sign an informed consent form documenting this discussion. 
 
All WOCBP MUST have a negative pregnancy test at the time of study screening. The minimum 

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sensitivity of the pregnancy test must be 25 IU/L or equivalent units of HCG. If the pregnancy test 
is positive, the subject must not receive treatment and must not be enrolled in the study. 
 
In addition, all WOCBP should be instructed to contact the investigator immediately if they suspect 
they might be pregnant (e.g., missed or late menstrual period) at any time during study 
participation. 
 
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 6 half-lives after product administration, the investigational product will 
be permanently discontinued in an appropriate manner (e.g., dose tapering if necessary for subject 
safety). The investigator must immediately notify the sponsor of this event and record the 
pregnancy on the Pregnancy Surveillance Form (not an SAE form). Initial information on a 
pregnancy must be reported immediately to the sponsor, and the outcome information provided 
once the outcome is known. Completed Pregnancy Surveillance Forms must be forwarded to 
Incyte and Merck according to SAE reporting procedures (See Section 10.4.4). 
 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
the sponsor. Information on this pregnancy will be collected on the Pregnancy Surveillance Form. 
 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (e.g., X-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated. In addition, the investigator must report 
and follow-up on information regarding the course of the pregnancy, including perinatal and 
neonatal outcome. Infants should be followed for a minimum of 8 weeks. 
 
6.4. 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
6.5. 
Subject Recruitment 
 
Patients will be recruited for the study from investigator or co-investigator clinical practices and 
referring physicians.  
 
6.6. 
Early Withdrawal of Subjects     
 
6.6.1.  When and How to Withdraw Subjects 
 
Patients may withdraw from study at any time. Patients who discontinue early should return within 
30 days of the last dose of the study drugs for a follow up evaluation. Any assessments listed for 
the final visit should be performed at that time. 
 
In addition, any of the following conditions require withdrawal of the subject from study treatment: 
 

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 Disease progression defined by irRECIST criteria 
 Lost to follow up or non-compliance with the protocol schedule 
 
An AE or concurrent illness that in the opinion of the investigator or sponsor warrants 
the subject’s withdrawal from treatment. 
 Necessary treatment with other investigational drug or other anticancer medications 
prohibited by protocol 
 Participation in another clinical study using anti-cancer agents 
 Request by regulatory agencies for termination of treatment of an individual subject or 
all subjects under this protocol 
 Sexually active subjects who refuse to use medically accepted barrier methods of 
contraception during the course of the study and for 4 months following discontinuation 
of study treatment 
 Women who are pregnant or are breast feeding 
 If the patient withdraws consent for continued participation, he/she will be removed 
from study. 
 
The reason for study treatment discontinuation will be documented. For subjects who discontinue 
or are withdrawn from study treatment, every effort must be made to undertake protocol specified 
follow up procedures and end of treatment assessments, if possible unless consent to participate in 
the study is also withdrawn.  
 
If a subject is discontinued from study treatment because of an AE considered to be related to 
study treatment and the event is ongoing 90 days after the last dose of study treatment, the event 
must be followed until resolution or determination by the investigator that the event has become 
stable or irreversible. 
 
If a subject withdraws consent to participate in the study the reason for withdrawal will be 
documented, no further study procedures or assessments will be performed, and no further study 
data will be collected for this subject other than the determination of survival status from public 
records such as governmental vital statistics or obituaries. 
 
 
6.6.2     Data Collection and Follow-up for Withdrawn Subjects 
 
Patients will do off-study visit as long as all toxicity is resolved. The reason for study removal 
and date the patient was removed must be documented.  
 
 
 
7. 
REGISTRATION PROCEDURES 
 
 
7.1.   CUMC Research Participant Registration 
 

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Confirm eligibility as defined in the section entitled Criteria for Subject Eligibility. 
 
 
Obtain informed consent, by following procedures defined in section entitled Informed Consent 
Procedures, along with applicable institutional policies and federal regulations. 
 
Only Investigators/Research personnel properly trained and delegated to consent subjects for this 
protocol will participate in the consenting process. Furthermore, properly delegated/trained 
Physician Investigators (e.g., MD, MD/PhD) are required to sign/verify a protocol specific 
Eligibility Checklist for each subject enrolled on the study, in addition to providing the relevant 
source documentation confirmation subject eligibility. 
 
All participants must be centrally registered through the Central Registration Office within 
Herbert Irving Comprehensive Cancer Center at CUMC prior to initiation of study 
treatment. 
 
Registration hours are available Monday through Friday from 9:00am – 5:00pm EST (excluding 
holidays and weekends). Same day patient registrations (and after hour registrations) will be 
accommodated on a case by case basis provided that the study team has expressed all time sensitive 
registration concerns/cases in a timely manner to the Central Registration Office.  
 
CPDM Central Registration Procedures: 
Within 48 hours of obtaining consent (excluding holidays and weekends), a completed/signed IRB 
approved informed consent HIPAA form, and demographics forms must be submitted to the 
CPDM Central Registration Office via an email to CPDMRegistration@cumc.columbia.edu or fax 
to 212.305.5292, with the subject line “AAAR1581 Pending Subject Registration Request (PHI)”.  
Upon receipt, applicable subject information as well as a “pending eligibility” status will be 
entered into HICCC’s institutional database.  This status will remain until further source 
documentation is made available to confirm overall patient eligibility. Required materials for all 
pending registration submissions are as follows: 
 
 
Completed/signed IRB approved/stamped Informed Consent Forms, including additional 
study ICFs for tissue. 
 
The completed/signed IRB approved HIPAA Authorization form 
 
Completed/signed CPDM ICF checklist 
 
Completed/signed HICCC personal census form 
 
Completed/signed CPDM Demographics Note to File 
In order to confirm eligibility status, Investigators/designees (e.g., study specific Clinical Research 
Coordinator/Research Nurse, etc.) must submit the following documentation to the Central 
Registration Office via email or fax: 
 

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 
The completed/signed study specific Eligibility Checklist  (signed by an Physician level 
Investigator) 
 
Copies of source documentation necessary for each item to be verified on the CPDM specific 
Eligibility Checklist, including but not limited to: 
o Copy of required laboratory test and procedure reports (e.g., complete blood count, 
complete metabolic panel, cholesterol and triglycerides pregnancy test when 
applicable, MRI reports, CT/bone scans, etc.) 
o Copy of pathology and surgical reports 
o List of all prior malignancy-directed treatments 
o Copy of clinic note(s) or other appropriate medical records capturing the consent 
process information, along with providing source documentation of any other items 
needed for screening/eligibility that are not captured in other source document forms 
(e.g., positive investigator statements of unique eligibility items not captured via other 
direct source documentation, concomitant medication lists, etc.). 
o Protocol deviation/waiver approvals (if applicable) 
o Please note: subject line of email or fax should include the following: “Complete 
Subject Registration Request (PHI)”. 
Upon receipt of the above mentioned documentation, participant eligibility information will be 
verified by a qualified Central Registration Registrar. If any questions arise during the review 
process, queries in the form of emails will be addressed to the applicable study team personnel for 
clarification prior to enrollment. All applicable finalized registration/eligibility information will 
then be entered into HICCC’s institutional CTMS database by the Central Registration Registrar.  
Upon completion, an official subject registration notification email will be sent to the PI/research 
team which will include eligibility/enrollment status, as well as subject ID information.  Protocol 
therapy may not be initiated prior to receipt of this notification from the Central Registration 
Office. 
 
All screen fail/ineligible subjects, as well as subject’s who withdraw consent prior to 
enrollment/initiation of protocol therapy must be submitted to the Central Registration office in a 
manner analogous to the procedures noted above. Applicable source documentation will be 
required within the corresponding submissions. 
 
7.2. Informed Consent Procedures 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior to 
their inclusion in the study. Participants will also be informed that they are free to withdraw from 
the study at any time. All participants must sign an IRB/PB-approved consent form indicating their 
consent to participate. This consent form meets the requirements of the Code of Federal 

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Regulations and the Institutional Review Board/Privacy Board of this Center. The consent form 
will include the following:  
 
1. The nature and objectives, potential risks and benefits of the intended study.  
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time.  
 
Before any protocol-specific procedures can be carried out, the consenting professional will fully 
explain the aspects of patient privacy concerning research specific information.  In addition to 
signing the IRB Informed Consent, all patients must agree to the Research Authorization 
component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
 
 
8. 
TREATMENT PLAN 
 
 
Treatment will be administered on an outpatient basis. Reported adverse events and potential risks 
for pembrolizumab and epacadostat are described in Section 8. Appropriate dose modifications for 
pembrolizumab and epacadostat are described in Section 9. No investigational or commercial 
agents or therapies other than those described below may be administered with the intent to treat 
the patient's malignancy. 
 
8.1. Pembrolizumab Administration 
 
Pembrolizumab is approved by the US Food and Drug Administration for the treatment of 
metastatic melanoma, non-small cell lung cancer, head and neck cancer, and unresectable or 
metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid 
tumors that have progressed following prior treatment and who have no satisfactory alternative 
treatment options. Subjects will receive pembrolizumab 200 mg (flat dose) IV every 3 weeks on 
day 1 of a 21 day cycle.   
 
Study treatment should be administered after all procedures/ assessments have been completed as 
detailed in the schedule of assessments (Section 12 & 13). All study treatments will be 
administered on an outpatient basis. Pembrolizumab will be administered as a 30 minute IV 
infusion. At the end of the infusion, the line should be flushed with a sufficient quantity of normal 
saline.  

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8.1.1. Management of Pembrolizumab Infusion Reactions 
 
Signs and symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion.  
The table below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475). 
 
Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption not 
indicated; intervention not indicated 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(e.g., from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until 
symptoms resolve and the subject should be 
premedicated for the next scheduled dose. 
Subjects who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further 
trial treatment administration. 
Subject may be premedicated 1.5h (± 
30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
 
Acetaminophen 500-1000 mg po (or 
equivalent dose of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial 
improvement; hospitalization indicated 
for other clinical sequelae (e.g., renal 
impairment, pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator. 
Hospitalization may be indicated. 
No subsequent dosing 

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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Subject is permanently discontinued from 
further trial treatment administration. 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
 
 
 
8.2. Epacadostat Administration 
 
Epacadostat will be dosed at 100 mg PO BID daily. Doses should be taken twice daily, in the 
morning and evening, approximately 12 hours apart, without regard to food. If a dose is late but 
within 4 hours of its scheduled administration time it should be taken; if more than 4 hours have 
passed, the dose should be omitted and the patient should continue treatment with the next 
scheduled dose. If vomiting occurs while taking epacadostat, no redosing is allowed before the 
next rescheduled dose. 
 
For epacadostat, patients will not require any premedications, however supportive medications to 
control symptoms such as nausea, emesis, diarrhea, and pain will be provided for symptom control 
(Section 9.2 for management of immune related adverse effects). 
 
Doses will be self-administered, except on Cycle 2 Day 1, when the morning dose will be given at 
the study site clinic. Subjects will be required to keep a pill diary (Appendix D). Each cycle of 
treatment will last 21 days.  
 
 
8.3. General Concomitant Medication and Supportive Care Guidelines  
 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during 
the ongoing study. If there is a clinical indication for 1 of these or other medications or vaccinations 
specifically prohibited during the study, discontinuation from study therapy may be required.  
 
8.3.1. Restricted Medications and Measures 
 
 Systemic steroids may be used at doses of prednisone ≤ 10 mg/day, or equivalent.  
 
 Use of coumarin-based anticoagulants (eg, Coumadin) is discouraged. Low-dose 
Coumadin® (1 mg) is acceptable; however, doses that increase the INR are discouraged 
and will require dose modification. If an alternative to coumarin-based anticoagulants 
cannot be used, dose modifications of the Coumadin® may be needed.  Based on the 
observed magnitude of epacadostat/warfarin PK interaction and PK/PD modeling results, 
for an epacadostat dose of 300 mg BID, the dose of warfarin should be reduced by 
approximately one-third after initiation of epacadostat administration based on 
approximately 30% to 40% reduction in S- and R-warfarin oral clearance values.  Close 

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INR monitoring is recommended for subjects on a stable dose of warfarin who are starting 
treatment with epacadostat.  Based on PK/PD modeling, recommendations for warfarin 
dose modifications for subjects receiving other epacadostat doses are summarized in Table  
below based on the INR prior to starting epacadostat.  
 
Warfarin Dose Adjustment Recommendation when Initiating Concurrent Epacadostat Treatment 
Stable Baseline INR 
Epacadostat  Dose 
≤ 100 mg BID 
200 mg BID 
300 mg BID 
INR  ≤ 2.5 
Close INR 
monitoring 
Close INR monitoring 
Reduce warfarin by 
~33% and monitor INR 
INR  > 2.5 
Close INR 
monitoring 
Reduce warfarin by 
20%-25% and monitor 
INR 
Reduce warfarin by 
~33% and monitor INR 
 
 Use of the anticonvulsant carbamazepine (a UGT1A9 inducer) is discouraged. Because 
there is a potential interaction that could result in lower epacadostat exposures, an 
alternative to carbamazepine should be used, if possible.  
 
8.3.2. Prohibited Medications and Measures 
 
Subjects are prohibited from receiving the following therapies during the screening and treatment 
phase of this study unless otherwise noted below:  
 Any investigational medication other than the study drugs.  
 Any anticancer medications, including chemotherapy or biologic therapy other than the 
study medications.  
 Any immunological-based treatment for any reason.  
o Note: Inhaled or topical steroids are allowed, and systemic steroids at doses ≤ 10 
mg/day prednisone or equivalents are allowed, and immune suppressants are 
allowed for treatment for immune toxicities.  
 Radiation therapy  
o Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed after consultation with the principal investigator.  
 Live Administration of live attenuated vaccines within 30 days before the first dose of 
study treatment and while participating in the study is prohibited. Examples of live 
vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken 
pox, yellow fever, rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines for 
injection are generally killed virus vaccines and are allowed; however, intranasal influenza 
vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed. 
 Any melatonin supplements.  
 Any MAOI or drug associated with significant MAO inhibitory activity agents is 
prohibited from 21 days before Day 1 through 2 weeks after the final dose of epacadostat 
has been taken (see Appendix C).  

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 Any UGT1A9 inhibitor, including acitretin, amitriptyline, androsterone, cyclosporine, 
dasatinib, diclofenac, diflunisal, efavirenz, erlotinib, estradiol (17-beta), flutamide, 
gefitinib, 
gemfibrozil, 
glycyrrhetinic 
acid 
glycyrrhizin, 
imatinib, 
imipramine, 
ketoconazole, linoleic acid supplements, mefenamic acid, mycophenolic acid, niflumic 
acid, nilotinib, phenobarbital, phenylbutazone, phenytoin, probenecid propofol*, 
quinidine, ritonavir, sorafenib, sulfinpyrazone, valproic acid, and verapamil. 
 *Note – Propofol, when used for short-term sedation during surgical/biopsy 
procedures, is allowed after consultation with the principal investigator. The 
epacadostat dose may be taken on the morning of the procedure, and the 
evening dose held following the procedure.  Epacadostat may be resumed the 
next day. 
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the study. Subjects may receive other 
medications that the investigator deems to be medically necessary.  
 
The exclusion criteria describe other medications that are prohibited during this study. There are 
no prohibited therapies during the post-treatment follow-up phase. 
 
8.4. Treatment Compliance 
 
Treatment compliance with all study-related medications should be emphasized to the subject by 
the site personnel. Subjects will bring all bottles of unopened, empty, and unused study drug with 
them to each study visit. The appropriate study personnel will maintain records of study drug 
receipt and dispensing. Any discrepancy regarding the dose administered and the reason for the 
discrepancy will be recorded in the electronic case report form (eCRF). At each clinic visit, patients 
will be questioned about their compliance with study drug administration, and their dosing diary 
should be reviewed. Bottles of study drug, including all bottles of unopened, partially opened, or 
empty bottles cannot be destroyed or returned to the depot until a monitor reviews and verifies all 
tablet counts for compliance. Compliance with pembrolizumab will also be documented in the 
medical record and monitored by the principal investigator of its designee.  
 
8.5. Randomization and Blinding 
 
Not applicable. 
 
8.6. Duration of Treatment 
 
The subject will continue to receive study treatment as long as the subject is receiving benefit from 
treatment and has not met any criteria for study withdrawal (Section 6.6). If the subject 
discontinues study treatment, the treatment phase will end and the subject will enter the follow-up 
phase (Section 12).  
 
8.7. Treatment After Initial Evidence of Radiographic Disease Progression 
 

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Immunotherapeutic agents such as pembrolizumab and epacadostat may produce antitumor effects 
by potentiating endogenous cancer-specific immune responses. The response patterns seen with 
such an approach may extend beyond the typical time course of responses seen with cytotoxic 
agents and can manifest as a clinical response after an initial increase in tumor burden or even the 
appearance of new lesions.  
 
If radiologic imaging shows progressive disease (PD), tumor assessment should be repeated ≥ 4 
weeks later to confirm PD, with the option of continuing treatment for clinically stable subjects 
while awaiting radiologic confirmation of progression. Clinically stable may be 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 determining whether the tumor burden has increased or decreased, investigators should consider all 
target lesions as well as non-target lesions. Subjects who are deemed clinically unstable are not 
required to have repeat imaging for confirmation. If radiologic progression is confirmed, then the 
subject will be discontinued from study treatment as specified in the Protocol, and the first radiographic 
evidence of PD should be the date of progression. If radiologic progression is not confirmed, then the 
subject should resume/continue study treatment and have their next scan according to the Protocol-
specified schedule. 
 
 
 
9. DOSE DELAYS/ MODIFICATIONS 
 
 
9.1. Criteria and Procedures for Dose Modifications and Interruption 
 
In some circumstances, it may be necessary to temporarily interrupt study treatments as a result of 
AEs that may have an unclear relationship to the study drug(s). If an interruption is necessary both 
study treatments should be interrupted.  
 
Treatment with both study drugs should be withheld for drug-related Grade 4 hematologic 
toxicities, non-hematological toxicity ≥ Grade 3 (including laboratory abnormalities) or selected 
≥ grade 2 immune-related toxicities (see section 9.2), and severe or life-threatening AEs.  
 
Pembrolizumab must be permanently discontinued for Stevens Johnson Syndrome (SJS) or Toxic 
Epidermal Necrolysis (TEN) 
 
 
Table 1 summarizes the dose administration guidance for pembrolizumab and epacadostat that 
should be implemented with the indicated related AEs. Additional information related to dose 
changes for epacadostat and pembrolizumab for specific AEs can be found in Section 9.2. 

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Table 1: Dose Modification Guidelines for Drug-Related Adverse Events 
 
Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing of 
Treatment 
Restart 
Dose Schedule for Treatment Restart 
Discontinue Subject  
Epacadostat 
Pembrolizumab 
Hematologic 
Toxicity 
1, 2, 3 
No 
N/A 
N/A 
N/A 
N/A 
4 
Yes 
Toxicity 
resolves to  
≤ Grade 1 or 
baseline 
Reduce dose to 50 mg PO 
BID. If 50 mg PO BID is 
not tolerated, then 
epacadostat should be 
discontinued.  
Restart at same dose for the 
following events: Grade 4 
neutropenia lasting ≤ 7 
days, Grade 4 lymphopenia 
or leukopenia. For all other 
Grade 4 Hematologic 
toxicities treatment with 
pembrolizumab may not be 
restarted. 
 
Toxicity does not resolve within 
6 weeks of last infusion. 
Permanent discontinuation 
should be considered for any 
severe or life-threatening event. 
Non-Hematologic 
Toxicity 
Note: Exception to be 
treated similar to Grade 1 
toxicity:  
- Grade 2 alopecia 
- Grade 2 fatigue 
- Grade 3 rash in the 
absence of 
desquamation, without 
mucosal involvement, 
not requiring systemic 
steroids, and that 
resolves to Grade 1 
within 14 days 
* See section 9.2 for 
immune-related AE’s 
1 
No 
N/A 
N/A 
N/A 
N/A 
 
2 
Consider 
holding for 
persistent 
symptoms 
Toxicity 
resolves to  
≤ Grade 1 or 
baseline 
Restart at same dose for 
non-immune related AEs 
 
*See section 9.2 for 
management of immune-
related AE’s that may 
require dose reductions.  
If dose reduction is 
required: Reduce dose to 
50 mg PO BID. If 50 mg 
PO BID is not tolerated, 
then epacadostat should be 
discontinued. 
 
Restart at same dose 
 
*See section 9.2 for 
management of immune-
related AE’s that may 
require dose reductions.  
 
Toxicity does not resolve within 
6 weeks of last infusion. 
Permanent discontinuation 
should be considered for any 
severe or life-threatening event. 
 
3 
Yes 
Toxicity 
resolves to  
≤ Grade 1 or 
baseline 
Reduce dose to 50 mg PO 
BID. If 50 mg PO BID is 
not tolerated, then 
epacadostat should be 
discontinued. 
 
Restart at same dose 
Toxicity does not resolve within 
6 weeks of last infusion. 
Permanent discontinuation 
should be considered for any 
severe of life-threatening event.  
4 
Yes 
Discontinue 
treatment 
Treatment with 
epacadostat may not be 
restarted 
Treatment with 
pembrolizumab may not be 
restarted 
Toxicity does not resolve within 
6 weeks of last infusion. 
Permanent discontinuation 

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should be considered for any 
severe of life-threatening event. 
 
Note: Subjects who experience a recurrence of the same severe or life-threatening AE at the same grade or greater treatment should be discontinued from study treatment.  

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9.2. Procedures for Subjects Exhibiting Immune-Related Adverse Events 
 
This section is meant to apply to suspected immune-related adverse effects (irAEs) from 
epacadostat, pembrolizumab, or the combination. Immune-related AEs may be defined as an AE 
of unknown etiology, associated with drug exposure and consistent with an immune phenomenon. 
Immune-related AEs may be predicted based on the nature of the pembrolizumab 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.  
 
Recommendations for management of specific immune-mediated AEs such as pneumonitis, 
enterocolitis, hepatitis, dermatitis, neuropathies, endocrinopathies, and other immune-mediated 
AEs are detailed in the sections below. 
 
 
9.2.1. Procedures and Guidelines for Pneumonitis 
 
Subjects with symptomatic pneumonitis should immediately stop receiving pembrolizumab and 
epacadostat and have an evaluation. The evaluation may include bronchoscopy and pulmonary 
function tests 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 2. 
 
 
Table 2. Recommended Approach to Handling Noninfectious Pneumonitis.  
 
 
Withhold/ Discontinue 
Pembrolizumab and 
Epacadostat 
Guidance for Restarting 
Study Treatment 
Supportive Care 
Grade 1 
No action. 
N/A. 
Intervention not indicated. 
 
Grade 2 
Withhold pembrolizumab 
and epacadostat. 
First episode of pneumonitis:  
• If improves to near baseline:  
o Decrease the dose of 
epacadostat to 50 mg BID, 
and for pembrolizumab 
restart at same dose and 
schedule for subsequent 
cycles. 
• If not improved after 2 weeks 
or worsening permanently 
discontinue pembrolizumab.  
 
Second episode of 
pneumonitis:  
• Permanently discontinue 
pembrolizumab and epacadostat 
if upon rechallenge subject 
Systemic corticosteroids 
are indicated. Taper if 
necessary. 
 

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develops pneumonitis ≥ Grade 
2. 
 
Grade 3 and 4 
Discontinue pembrolizumab 
and epacadostat. 
  
 
Not applicable. Any exceptions 
require PI approval. 
Systemic corticosteroids 
are indicated. The use of 
infliximab may be 
indicated as appropriate.  
 
 
 
9.2.2. Procedures and Guidelines for Enterocolitis 
 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such 
as peritoneal signs and ileus). In symptomatic subjects, infectious etiologies should be ruled out 
and endoscopic evaluation should be considered for persistent or severe symptoms. 
Recommendations for management of enterocolitis are shown in Table 3. 
 
Table 3. Recommended Approach to Handling Enterocolitis.  
 
 
Withhold/ Discontinue 
Pembrolizumab and 
Epacadostat 
Guidance for Restarting 
Study Treatment 
Supportive Care 
Grade 1 
No action. 
N/A. 
All subjects who 
experience diarrhea 
should be advised to drink 
liberal quantities of clear 
fluids. If sufficient oral 
fluid intake is not 
feasible, fluid and 
electrolytes should be 
substituted via IV 
infusion. An antidiarrheal 
can be started.  
 
Grade 2 
Withhold pembrolizumab 
and epacadostat. 
May return to treatment if 
improves to Grade 1. If AE 
resolves ≤ Grade 1 or baseline 
within 4 weeks, subject may 
restart at the same dose and 
schedule for both 
pembrolizumab and epacadostat.  
 
For an AE that does not resolve 
≤ Grade 1 or baseline in 4 
weeks, epacadostat should be 
reduced as per Table 1, but 
pembrolizumab may be restarted 
at the same dose and schedule. 
If AE does not resolve within 6 
weeks, study treatment with 
An antidiarrheal should 
be started. If symptoms 
are persistent for > 1 
week, systemic 
corticosteroids should be 
initiated (eg, 0.5-1 mg/kg 
per day of prednisone or 
equivalent). When 
symptoms improve to ≤  
Grade 1, corticosteroid 
taper should be started 
and continued over at 
least 1 month.  
 

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both study drugs should be 
discontinued. 
 
Grade 3 and 4 
Discontinue pembrolizumab 
and epacadostat. 
  
 
Not applicable. Any exceptions 
require PI approval. 
 
Treatment with systemic 
corticosteroids should be 
initiated at a dose of 1 to 
2 mg/kg per day of 
prednisone or equivalent. 
Systemic corticosteroids 
are indicated. The use of 
infliximab may be 
indicated as appropriate. 
When symptoms improve 
to ≤  Grade 1, 
corticosteroid taper 
should be started and 
continued over at least 1 
month.  
 
 
 
9.2.3. Procedures and Guidelines for Hepatitis 
 
Liver function tests (hepatic transaminase and bilirubin levels) should be monitored and signs and 
symptoms of hepatotoxicity should be assessed before each dose of pembrolizumab and 
epacadostat. In subjects with hepatotoxicity, infectious or malignant causes should be ruled out 
and frequency of LFT monitoring increased until resolution. Recommendations for management 
of hepatitis are shown in Table 4. 
 
Table 4. Recommended Approach to Handling Hepatitis.  
 
 
Withhold/ Discontinue 
Pembrolizumab and 
Epacadostat 
Guidance for Restarting 
Study Treatment 
Supportive Care 
Grade 1 
No action. 
N/A. 
Increase frequency of 
LFT monitoring to twice 
per week until LFTs 
return to baseline.  
 
Grade 2 
Withhold pembrolizumab 
and epacadostat. 
If AE resolves to ≤ Grade 1 or 
baseline within 4 weeks, subject 
may restart at the same dose and 
schedule for both 
pembrolizumab and epacadostat.  
 
For an AE that does not resolve 
≤ Grade 1 or baseline within 4 
weeks, epacadostat should be 
reduced as per Table 1, but 
pembrolizumab may be restarted 
at the same dose and schedule. 
Increase frequency of 
LFT monitoring to twice 
per week until LFTs 
return to baseline. If 
elevation persists for > 1 
week, systemic 
corticosteroids should be 
initiated (eg, 0.5 mg/kg 
per day of prednisone or 
equivalent). When 
symptoms improve to ≤ 
Grade 1, corticosteroid 

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If AE does not resolve within 6 
weeks, study treatment with 
both study drugs should be 
discontinued. 
 
taper should be started 
and continued over at 
least 1 month.  
 
Grade 3 and 4 
Discontinue pembrolizumab 
and epacadostat.  
  
 
Not applicable. Any exceptions 
require PI approval. 
 
Increase frequency of 
LFT monitoring to every 
1-2 days. Treatment with 
systemic corticosteroids 
should be initiated at a 
dose of 1 to 2 mg/kg per 
day of prednisone or 
equivalent. When 
symptoms improve to  ≤ 
Grade 1, corticosteroid 
taper should be started 
and continued over at 
least 1 month.  
 
 
 
9.2.4. Procedures for Immune-Mediated Dermatitis 
 
Monitor subjects for signs and symptoms of dermatitis such as rash and pruritus. Unless an 
alternate etiology has been identified, signs or symptoms of dermatitis should be considered 
immune mediated. Recommendations for management of dermatitis are shown in Table 5. 
 
Table 5. Recommended Approach to Handling Dermatitis.  
 
 
Withhold/ Discontinue 
Pembrolizumab and 
Epacadostat 
Guidance for Restarting 
Study Treatment 
Supportive Care 
Grade 1 
No action. 
N/A. 
For mild to moderate 
dermatitis, such as 
localized rash and 
pruritus, treat 
symptomatically. 
Administer topical or 
systemic corticosteroids if 
there is no improvement 
of symptoms within 1 
week.  
 
Grade 2 
No action 
N/A. 
 
For mild to moderate 
dermatitis, such as 
localized rash and 
pruritus, treat 
symptomatically. 
Administer topical or 
systemic corticosteroids if 
there is no improvement 

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of symptoms within 1 
week.  
 
Grade 3 and 4 
Withhold epacadostat and 
pembrolizumab in subjects 
with moderate to severe 
signs and symptoms of rash.  
Permanently discontinue 
epacadostat and 
pembrolizumab in subjects 
with Stevens-Johnson 
syndrome, toxic epidermal 
necrosis, or rash complicated 
by full thickness dermal 
ulceration or by necrotic, 
bullous, or hemorrhagic 
manifestations.  
If AE resolves to ≤ Grade 1 or 
baseline within 4 weeks, subject 
may restart at the same dose and 
schedule for both 
pembrolizumab and epacadostat.  
 
If rash is mild and Grade 3 only 
based on BSA, and resolves 
without oral steroids, treatment 
may be restarted at the previous 
dose. 
 
For an AE that does not resolve 
to ≤ Grade 1 or baseline within 
4 weeks, epacadostat should be 
reduced as per Table 1, but 
pembrolizumab may be restarted 
at the same dose and schedule. 
If AE does not resolve within 6 
weeks, study treatment with 
both study drugs should be 
discontinued. 
 
Administer systemic 
corticosteroids at a dose 
of 1 to 2 mg/kg per day of 
prednisone or equivalent. 
When dermatitis is 
controlled, corticosteroid 
tapering should occur 
over a period of at least 1 
month.  
 
 
 
9.2.5. Procedures for Immune-Mediated Neuropathies 
 
Subjects should be monitored for symptoms of motor or sensory neuropathy such as unilateral or 
bilateral weakness, sensory alterations, or parenthesis. Recommendations for management of 
neuropathies are shown in Table 6. 
 
Table 6. Recommended Approach to Handling Neuropathies.  
 
 
Withhold/ Discontinue 
Pembrolizumab and 
Epacadostat 
Guidance for Restarting 
Study Treatment 
Supportive Care 
Grade 1 
No action. 
N/A. 
Provide symptomatic 
treatment.  
 
Grade 2 
May withhold 
pembrolizumab and 
epacadostat. 
May return to treatment if 
improves to Grade 1 or baseline. 
If AE resolves within 4 weeks, 
subject may restart at the same 
dose and schedule for both 
pembrolizumab and epacadostat.  
 
For an AE that does not resolve 
≤ Grade 1 or baseline within 4 
Consider systemic 
corticosteroids in addition 
to appropriate 
symptomatic treatment.  
 

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weeks, epacadostat should be 
reduced as per Table 1, but 
pembrolizumab may be restarted 
at the same dose and schedule. 
If AE does not resolve within 6 
weeks, study treatment with 
both study drugs should be 
discontinued. 
 
Grade 3 and 4 
Discontinue pembrolizumab 
and epacadostat. 
  
 
Not applicable.  Any exceptions 
require PI approval. 
 
Consider initiation of 
systemic corticosteroids at 
a dose of 1 to 2 mg/kg per 
day prednisone or 
equivalent for severe 
neuropathies.  
Institute medical 
intervention as 
appropriate for 
management of severe 
neuropathy.  
 
 
 
9.2.6. Procedures for Immune-Mediated Endocrinopathies 
 
Subjects should be monitored for clinical signs and symptoms of hypophysitis, adrenal 
insufficiency (including adrenal crisis), and hyper- or hypothyroidism. Subjects may present with 
fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension 
or with nonspecific symptoms which may resemble other causes such as brain metastasis or 
underlying disease. Unless an alternate etiology has been identified, signs or symptoms of 
endocrinopathies should be considered immune-mediated.  
 
Thyroid function tests and clinical chemistries should be monitored at the start of treatment, 
before each dose, and as clinically indicated based on symptoms. In a limited number of subjects, 
hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland. 
Recommendations for management of endocrinopathies are shown in Table 7.  
 
Table 7. Recommended Approach to Handling Endocrinopathies.  
 
 
Withhold/ Discontinue 
Pembrolizumab and 
Epacadostat 
Guidance for Restarting 
Study Treatment 
Supportive Care 
Grade 1 
No action. 
N/A. 
Provide symptomatic 
treatment.  
 
Grade 2 
May withhold 
pembrolizumab and 
epacadostat. 
May return to treatment if 
improves to Grade 1 or baseline. 
If AE resolves within 4 weeks ≤ 
Grade 1 or baseline, subject may 
restart at the same dose and 
Initiate systemic 
corticosteroids treatment 
at a dose of 1 to 2 mg/kg 
per day of prednisone or 
equivalent, and initiate 

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schedule for both 
pembrolizumab and epacadostat.  
 
For an AE that does not resolve 
≤ Grade 1 or baseline within 4 
weeks, epacadostat should be 
reduced as per Table 1, but 
pembrolizumab may be restarted 
at the same dose and schedule. 
If AE does not resolve within 6 
weeks, study treatment with 
both study drugs should be 
discontinued. 
 
appropriate hormone 
replacement therapy.  
 
Grade 3  
Withhold or discontinue 
pembrolizumab and 
epacadostat. 
  
 
May return to treatment if 
improves to Grade 1 or baseline. 
If AE resolves ≤ Grade 1 or 
baseline within 4 weeks, subject 
may restart at the same dose and 
schedule for both 
pembrolizumab and epacadostat.  
 
For an AE that does not resolve 
≤ Grade 1 or baseline within 4 
weeks, epacadostat should be 
reduced as per Table 1, but 
pembrolizumab may be restarted 
at the same dose and schedule. 
If AE does not resolve within 6 
weeks, study treatment with 
both study drugs should be 
discontinued. 
 
Consider initiating 
systemic corticosteroids 
treatment at a dose of 1 to 
2 mg/kg per day of 
prednisone or equivalent, 
and initiate appropriate 
hormone replacement 
therapy.  
 
Grade 4 
Discontinue both 
pembrolizumab and 
epacadostat.  
Not applicable. Any exceptions 
require PI approval. 
Consider initiation of 
systemic corticosteroids at 
a dose of 1 to 2 mg/kg per 
day of prednisone or 
equivalent, and initiate 
appropriate hormone 
replacement therapy.  
 
 
 
9.2.7. Procedures for Other Immune-Mediated Adverse Reactions, Including Ocular 
Manifestations 
 
Epacadostat and pembrolizumab should be permanently discontinued for severe immune-
mediated adverse reactions. Systemic corticosteroids treatment should be initiated at a dose of 1 
to 2 mg/kg per day of prednisone or equivalent for severe immune-mediated adverse reactions.  
 
Corticosteroid eye drops should be administered to subjects who develop uveitis, iritis, or 
episcleritis. Epacadostat and pembrolizumab should be permanently discontinued for immune-

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mediated ocular disease that is unresponsive to local immunosuppressive therapy. 
 
9.3. Procedures for Subjects Exhibiting Serotonin Syndrome 
 
There is a theoretical chance that epacadostat could cause an increase in serotonin levels in the 
brain that might trigger serotonin syndrome (SS) when administered in combination with other 
serotonergic agents. This syndrome has been most closely associated with use of MAOIs, 
Demerol®, linezolid, or methylene blue; all of these agents are prohibited during the study. 
Serotonin reuptake inhibitors (SSRIs) and serotonin/norepinephrine reuptake inhibitors (SNRIs) 
are permitted in the study. The following procedures will be implemented if subjects exhibit the 
signs/symptoms of SS, including tremor, hyperreflexia, spontaneous, ocular, or inducible clonus, 
together with agitation, fever, diaphoresis, or muscle rigidity:  
 Immediately interrupt epacadostat administration. Administration of pembrolizumab may 
continue. 
 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 subject chooses to remain in the study, restart treatment with epacadostat after the 
SSRI or SNRI has been discontinued, no sooner than 5 half-lives have elapsed for the 
specific SSRI or SNRI in question and after resolution of signs/symptoms of SS. The 
SSRI or SNRI treatment MAY NOT be restarted.  
 If subject chooses to withdraw from the study, or must restart treatment with SSRI or 
SNRI, the subject should be scheduled for a follow-up visit. Treatment with SSRI or 
SNRI may be initiated 2 weeks after resolution of signs and symptoms of SS.  
 
 
10. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
10.1. Adverse  events  
 
See sections 11.1.7 and 11.2.7 for a list of adverse events related to pembrolizumab and 
epacadostat, respectively. 
 
10.2. Definitions  
 
Adverse Event: 
An adverse event (AE) is any untoward or unfavorable medical occurrence in a human subject, 
including abnormal sign, symptom or disease, temporally associated with the subject’s 
participation in research, Please note: laboratory, vital signs or ECG abnormalities are to be 
recorded as Adverse Events only if they are medically relevant (clinically significant): 
symptomatic, requiring corrective treatment, leading to treatment discontinuation and/or fulfilling 
a seriousness criterion..  
 

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Therefore, abnormal results of diagnostic procedures are considered to be adverse events if the 
abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event 
 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
 
Serious Adverse Event: 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
 fatal 
 life-threatening 
 requires inpatient hospitalization/prolongation of existing hospitalation, unless:  
o routine treatment  or monitoring of the studied indication, not associated with any 
deterioration in condition (procedures such as central line placements, paracentesis, 
pain control) 
o elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the start of study drug 
o treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of an SAE given above/below and not resulting in hospital administrations 
o social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of 
major clinical significance.   They may jeopardize the subject, and may require intervention to 
prevent one of the other serious outcomes noted above.  For example, drug overdose or abuse, a 
seizure that did not result in in-patient hospitalization or intensive treatment of bronchospasm in 
an emergency department would typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious events should be regarded as 
non-serious adverse events.  
 
Unanticipated Problem: 
An unanticipated problem is any incident, experience or outcome involving risks to subjects or 
others in any human subjects research that meets all of the following criteria: 
 Unexpected (in terms of nature, severity or frequency) given (a) the research procedures 
that are described in the IRB-approval protocol and informed consent document, and (b) the 
characteristics of the subject population being studied; 

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 Related or possibly related to participation in such research (e.g., there is a reasonable 
possibility that the incident, experience or outcome may have been caused by the procedures 
involved in such research); and  
 Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic or social harm) than was previously known or recognized.  
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the period 
from the initiation of any study procedures (e.g., after the first dose of study treatment) to the end 
of the study treatment (e.g., last dose of study treatment) and/or follow-up.  For this study, the 
study treatment follow-up is defined as 90 days following the last administration of study 
treatment, or 90 days following the decision to remove the subject from study treatment, 
whichever is earliest. 
Baseline/Preexisting Condition 
A baseline/preexisting condition is one that is present at the start of the study. A preexisting 
condition should be recorded as an adverse event if the frequency, intensity, or if the character of 
the condition worsens during the study period. 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting condition.  
At the end of the study, any new clinically significant findings/abnormalities that meet the 
definition of an adverse event must also be recorded and documented as an adverse event.  
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are resolved, 
the subject is lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled 
visit, the investigator should instruct each subject to report any subsequent event(s) that the subject, 
or the subject’s personal physician, believes might reasonably be related to participation in this 
study.   
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the 
following conditions is met:  
 The laboratory abnormality is not otherwise refuted by a repeat test to confirm the abnormality 
 The abnormality suggests a disease and/or organ toxicity 
 The abnormality is of a degree that requires active management (e.g., change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic investigation, 
etc.). 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed otherwise in this 
protocol.  Any condition responsible for surgery should be documented as an adverse event if the 
condition meets the criteria for an adverse event.  
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
adverse event in the following circumstances: 

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 Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for 
a preexisting condition.  Surgery should not be reported as an outcome of an adverse event if the 
purpose of the surgery was elective or diagnostic and the outcome was uneventful. 
 Hospitalization or prolonged hospitalization required to allow efficacy measurement for the 
study. 
 Hospitalization or prolonged hospitalization for therapy of the target disease of the study, 
unless it is a worsening or increase in frequency of hospital admissions as judged by the clinical 
investigator. 
 
10.3. Recording of Adverse Events 
 
At each contact with the subject, the investigator must seek information on adverse events by 
specific questioning and, as appropriate, by examination.  Information on all adverse events should 
be recorded immediately in the source document, and also in the appropriate adverse event module 
of the case report form (CRF).  All clearly related signs, symptoms, and abnormal diagnostic 
procedures results should recorded in the source document, though should be grouped under one 
diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The clinical course of each 
event should be followed until resolution, stabilization, or until it has been determined that the 
study treatment or participation is not the cause.  Serious adverse events that are still ongoing at 
the end of the study period must be followed up to determine the final outcome.  Any serious 
adverse event that occurs after the study period and is considered to be possibly related to the study 
treatment or study participation should be recorded and reported immediately. 
 
10.4. 
Reporting of Serious Adverse Events 
 
10.4.1     IRB Notification by Sponsor-Investigator 
Reports of all events (including follow-up information) that meet the definition of an unanticipated 
problem posing risk to subjects or others must be submitted to the IRB within one week (5 business 
days) following the occurrence of the unanticipated problem or the principal investigator’s 
acquiring knowledge of the unanticipated problem  in accordance with IRB policy. Additionally, 
the sponsor-investigator will submit a summary of all Unanticipated problems that occurred since 
the beginning of the study at the time of continuing review. Copies of each report and 
documentation of IRB notification and receipt will be kept in the Regulatory binder. 
 
10.4.2    FDA Notification by Sponsor-Investigator 
The Columbia University Medical Center Sponsor-Investigator, as holder of the IND, will be 
responsible for all communication with the FDA. Columbia University Medical Center Principal 
Investigator will report to the FDA, regardless of the site of occurrence, any adverse event that is 
serious, unexpected and there is evidence to suggest a causal relationship between the drug and 
the adverse event. These must be reported to the FDA and any affiliate sites as soon as possible, 
but in no case later than 15 calendar days after the sponsor determines that the information 
qualifies for reporting.  The Sponsor-Investigator will also submit an IND annual report to the 

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FDA in accordance with 21.CFR 312.33. 
 
The Columbia University Medical Center Sponsor Investigator must report to the FDA and any 
affiliate site investigators as follows:  
 Any unexpected fatal or life-threatening event must be reported as soon as possible, but no 
later than 7 calendar days after the sponsor investigator initial receipt of the information 
 Any findings from epidemiological studies, pooled analysis of multiple studies, or clinical 
studies, whether or not conducted under an IND, and whether or not conducted by the sponsor-
investigator, that suggest a significant risk in humans exposed to the drug  must be reported 
as soon as possible but no later than 15 calendar days after the sponsor-investigator determines 
that the information qualifies for reporting 
 Any findings from animal or in vitro testing whether or not conducted under an IND, and 
whether or not conducted by the sponsor-investigator, that suggest a significant risk in humans 
exposed to the drug  must be reported as soon as possible but no later than 15 calendar days 
after the sponsor-investigator determines that the information qualifies for reporting 
 Any clinically important increase in the rate of a serious suspected adverse reactions  over that 
listed in the protocol or Investigator Brochure 
 Expected SAEs and AEs will be included in the IND Annual Reports. 
Follow-up information to a safety report should be submitted as soon as the relevant information 
is available.  However, if the results of a sponsor’s investigation show that an adverse drug 
experience not initially determined to be reportable are so reportable, the sponsor investigator 
must report such experience as soon as possible, but no later than 15 calendar days after the 
determination is made. 
 
All other serious unexpected experiences associated with the use of the study treatment will be 
reported to FDA as soon as possible but in no event later than 15 calendar days after initial receipt 
of the information. 
 
10.4.3  DSMC Reporting by the Sponsor Investigator 
Serious adverse events not constituting unanticipated problems are to be reported to the HICCC 
DSMC. Reporting should occur within 24 hours of knowledge of the SAE occurring at our 
institution or affiliate sites. CUMC will notify the HICCC DSMC within 24 hours of knowledge 
of the SAE once informed by the affiliate site. 
 
Participating investigators must report each serious adverse event to the Columbia University 
Medical Center Overall Principal Investigator within 24 hours of learning of the occurrence using 
the SAE Report Form. In the event that the participating investigator does not become aware of the 
serious adverse event immediately (e.g., participant sought treatment elsewhere), the participating 
investigator is to report the event within 24 hours after learning of it and document the time of his 
or her first awareness of the adverse event. Report serious adverse events by telephone, email or 
facsimile to: 
 
 
Richard D. Carvajal, MD 
 
177 Fort Washington Avenue, MHB 6GN-435 
 
New York, NY 10032 

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Telephone: 646-317-6354 
 
Fax: 212-305-3035 
 
Email address: CPDM_R1581@lists.cumc.columbia.edu 
 
Within the following 24-48 hours, the participating investigator must provide follow-up 
information on the serious adverse event. Follow-up information should describe whether the event 
has resolved or continues, if and how the event was treated, and whether the participant will 
continue or discontinue study participation. 
 
10.4.4  Reporting to Drug Manufacturer by Sponsor-Investigator (Incyte) 
 
All Serious Adverse Events (“SAE”), including pregnancy and lactation exposure, required to be 
reported pursuant to the Protocol shall be provided to Incyte and its representatives by Institution 
or Principal Investigator within twenty-four (24) hours of learning of the event as well as any 
additional reports agreed upon by Institution or Principal Investigator and Incyte.   
 
SAE Reports will be sent to: Incyte PhVOpsIST@incyte.com.   
 
By sending to this e-mail address, the Incyte Pharmacovigilance group will receive copies of the 
reports. This process will be tested and established before the first patient is enrolled in the Study. 
Notwithstanding anything to the contrary herein, Institution will have the primary responsibility 
of reporting adverse events (“AE”) to regulatory authorities. 
 
10.4.5  Reporting to Drug Manufacturer by Sponsor-Investigator (Merck) 
 
For the time period beginning after the first dose of study treatment, any serious adverse event, 
or follow up to a serious adverse event, including death due to any cause that occurs to any 
participant must be reported within 24 hours to the Sponsor and within 2 working days to Merck 
Global Safety if it causes the participant to be excluded from the trial, or is the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of usual therapy, 
diet, placebo treatment or a procedure.  
 
For the time period beginning after the first dose of study treatment through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the participant initiates new 
anticancer therapy, whichever is earlier, any serious adverse event, or follow up to a serious 
adverse event, including death due to any cause whether or not related to the Merck product, must 
be reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety. 
 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at any 
time following consent through the end of the specified safety follow-up period specified in the 
paragraph above, or at any time outside of the time period specified in the previous paragraph 
also must be reported immediately to Merck Global Safety. 
 
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SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-661-6229 
 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to the 
Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215-661-6229) at the time of submission to FDA. 
 
10.4.6. Reporting Process 
 
Adverse events may be submitted on FDA Form 3500A, the HICCC DSMC Serious Adverse 
Event Reporting Form, or in a narrative format. If supplied as in a narrative format, the minimum 
information to be supplied is noted above at the beginning of section 10.  
 
At the time of IRB renewal or at the request of the manufacturer, the Sponsor- Investigator will 
submit a summary of all Serious Adverse Events that have occurred inclusive of all sites to 
manufacturer. 
 
 
11. PHARMACEUTICAL INFORMATION  
 
11.1. Pembrolizumab 
 
11.1.1. Dispensing of Pembrolizumab 
 
An initial bulk supply of pembrolizumab will be provided to investigative sites prior to enrollment 
of the first subject. Thereafter, the site will contact the sponsor for re-supply of pembrolizumab. 
The investigator or designee will calculate the number of pembrolizumab vials needed, pull the 
appropriate number of vials to prepare the infusion solution, and enter the vials used into the eCRF 
and drug accountability log. The Principal Investigator must keep accurate and up-to-date 
dispensation records. Any discrepancies between the amounts of Study drug dispensed and 
returned must also be explained in writing. All such records of drug accountability must be entered 
on the corresponding Subject CRF’s. 
 
11.1.2. Packaging and Formulation 
 
Clinical Supplies will be provided by Merck as summarized in the table below 
 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 

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Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
 
11.1.3. Storage  
 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label.   
 
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial 
site. 
 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
 
11.1.4. Administration 
 
Administer intravenously over 30 minutes. Do not co-administer other drugs through the same 
infusion line. See section 8.1 for details on pembrolizumab and administration and Section 8.1.1 
for management of infusion reactions. 
 
11.1.5. Disposal 
 
The investigator is responsible for keeping accurate records of the clinical supplies received from 
Merck or designee, the amount dispensed to and returned by the subjects and the amount remaining 
at the conclusion of the trial.  
 
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s responsibility 
to arrange for disposal of all empty containers, provided that procedures for proper disposal 
have been established according to applicable federal, state, local and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept. 
 
11.1.6. Drug interactions and Concomitant therapy 
 
No formal pharmacokinetic drug interaction studies have been conducted with pembrolizumab. 
 
11.1.7. Adverse Events 
 
Common side effects (≥10% by frequency) seen with Pembrolizumab in patients with melanoma 
include the following:  
 
Most Common Adverse Events in Subjects Treated with Pembrolizumab 33 
 
Adverse Event 
N 
(Total = 2799) 
(%) 
Fatigue 
1044 
37.3% 

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Nausea 
685 
24.5% 
Decreased appetite 
630 
22.5% 
Diarrhea 
625 
22.3% 
Cough 
615 
22.0% 
Pruritus 
562 
20.1% 
Arthralgia 
504 
18.0% 
Rash 
499 
17.8% 
Asthenia 
362 
12.9% 
Pyrexia 
357 
12.8% 
 
Adverse Events of Special Interest In Subjects Treated with Pembrolizumab 33 
 
Adverse Event 
N 
(Total = 2799) 
(%) 
Hypothyroidism 
237 
8.5% 
Hyperthyroidism 
96 
3.4% 
Pneumonitis 
94 
3.4% 
Infusion reactions 
70 
2.5% 
Colitis 
49 
1.8% 
Severe skin reactions 
46 
1.6% 
Autoimmune hepatitis 
19 
0.7% 
Adrenal insufficiency 
22 
0.8% 
Hypophysitis 
17 
0.6% 
Uveitis 
14 
0.5% 
Myositis 
11 
0.4% 
Pancreatitis 
9 
0.3% 
Type 1 diabetes mellitus 
6 
0.2% 
Guillain-Barre Syndrome 
2 
0.1% 
 
Additional risks associated with pembrolizumab that have been identified are: Steven Johnson’s 
Syndrome (SJS), myocarditis, and Toxic Epidermal Necrolysis (TEN) 
 
11.2. Epacadostat 
 
11.2.1. Dispensing of Epacadostat 
 
 
An initial bulk supply of epacadostat will be provided to investigative sites prior to enrollment of 
the first subject. Thereafter, the site staff will contact the sponsor for re-supply of epacadostat. 
When dispensing to subjects, the investigator or designee will remove the appropriate quantity of 
epacadostat from their stock, dispense the medication, and enter the amount dispensed into the 
eCRF and drug accountability log.  
 
11.2.2. Packaging and Formulation 
 

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The drug is available at 25 mg, 100 mg, and 300 mg tablets. The drug will be packaged in high-
density polyethylene bottles. All bottles will be labeled with a statement such as: “Caution: New 
Drug—Limited by Federal Law to Investigational Use.”  
 
11.2.3. Storage  
 
Epacadostat should be stored at ambient conditions (15-30° C). The study drug provided in 
accordance with this Protocol will be kept in a secure place, and will only be supplied to subjects 
participating in this study.  
 
11.2.4. Administration 
 
Epacadostat should be taken twice daily, in the morning and evening, approximately 12 hours 
apart, without regard to food. If a dose is late but within 4 hours of its scheduled administration 
time it should be taken; if more than 4 hours have passed, the dose should be omitted and the 
patient should continue treatment with the next scheduled dose.  
 
11.2.5. Disposal 
 
The investigator is responsible for keeping accurate records of the clinical supplies received from 
Incyte or designee, the amount dispensed to and returned by the subjects and the amount remaining 
at the conclusion of the trial.  
 
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s responsibility 
to arrange for disposal of all empty containers, provided that procedures for proper disposal 
have been established according to applicable federal, state, local and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept. 
 
11.2.6. Drug interactions and Concomitant therapy 
 
See Section 8.3 for details of restricted concomitant therapy. 
 
11.2.7. Adverse Events 
 
Common side effects (≥10% by frequency) seen with epacadostat monotherapy in patients enrolled 
on a Phase 1 clinical trial:  
 
Adverse Reactions in ≥10% of Patients in Phase 1 trial of Epacadostat. 
 
Adverse Reaction 
All grades (%) 
General 
 
   Fatigue 
69.2% 
   Pyrexia 
15.4 
Gastrointestinal 
 

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   Nausea 
65.4 
   Diarrhea 
26.9 
   Constipation 
36.5 
   Abdominal Pain 
28.8 
Respiratory 
 
   Dyspnea 
25 
   Cough 
21.2 
Skin 
 
   Rash 
17.6 
Metabolism 
 
   Decreased appetite 
53.8 
Musculoskeletal 
 
   Back pain 
25 
Nervous System 
 
   Dizziness 
11.5 
 
 
 
12. STUDY EVALUATIONS  
 
 
12.1. Screening Phase 
 
The screening phase will be up to 28 days. Screening is the interval between the signing of the 
informed consent form (ICF) and the day the subject receives the first dose of treatment in the 
study (Cycle 1 Day 1). Informed consent must be obtained before performing any study-specific 
procedures not considered standard of care. Assessments that are required to demonstrate 
eligibility may be performed over the course of 1 or more days during this phase.  
 
Results from the screening visit evaluations will be reviewed to confirm subject eligibility before 
enrollment or the administration of study drug. Tests with results that fail eligibility requirements 
may be repeated during the screening phase if the investigator believes the 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, after recovery from an 
infection). 
 
See Section 13 (table 10-11) for detailed list of screening procedures.  
 
12.2. Treatment Phase 
 
The treatment period will continue every 21 days and may continue as long as subjects are 
receiving benefit from treatment and have not met any criteria for study withdrawal. 
 
See Section 13 (Table 10 and Table 11) for detailed list and schedule of procedures while on 

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treatment.  
 
12.2.1. Clinic Visits 
 
During Cycle 1, patients will be seen weekly for vitals, physical exam, assessment of adverse 
effects, and appropriate laboratory tests and procedures (Section 13, Table 10 and table 11).  
Starting Cycle 2 and onward, patients will be seen on Day 1 of each cycle for vitals, physical exam, 
assessment of adverse effects, and appropriate laboratory tests and procedures. Patients may be 
seen for additional unscheduled visits as needed at the discretion of the investigator.  
 
12.2.2. Assessment for Serotonin syndrome 
 
Subjects will be assessed for the presence of any of the following symptoms (Table 8) of serotonin 
syndrome at the time points indicated in the study calendar. 
 
Table 8: Symptoms of Serotonin Syndrome  
Tremor and hyper-reflexia 
Spontaneous clonus 
Muscle rigidity, temperature > 38 C, and either ocular clonus or inducible clonus 
Ocular clonus and either agitation or diaphoresis 
Inducible clonus and either agitation or diaphoresis 
 
12.2.3. General laboratory assessment.  
 
See Table 11 and 12 for detailed laboratory tests and timing of these tests. 
 
 
 
12.2.4. Schedule of Disease monitoring.  
 
A CT scan of the chest, abdomen, and pelvis with contrast will be obtained to evaluate disease 
status. A scan will be obtained at baseline (within 28 days of first study drug dose), then every 6 
weeks for the first 24 weeks (imaging of the area with known disease involvement only (ex: CT 
chest only or CT abdomen/ pelvis only) is allowed for week 6 and week 18 tumor assessments at 
the investigator’s discretion)). After week 24, a CT chest, abdomen, pelvis with contrast will be 
performed every 12 weeks until disease progression, withdrawal from study, or ongoing disease 
control at 2 years (defined as at least stable disease at this point). For patients who achieve ongoing 
disease control at 2 years, treatment will be stopped and subjects will be observed with a CT scan 
every 12 weeks. If the patient develops disease progression during this observation time, they will 
have the option of restarting study treatment at that time.  
 
Table 9: Schedule of Disease Monitoring. 
 
Baseline scan 
Baseline scan within 4 weeks prior to first treatment 
Weeks 1 – 24  
Every 6 weeks +/- 1 week (at weeks 6, 12, 18, 24) 
Weeks 25 – until disease 
progression 
Every 12 weeks +/- 1 week (at weeks 36, 48, 60, 72, 84, 96, 
108) 

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2 years 
If subjects achieve ongoing disease control at 2 years, patients 
will be taken off study treatment and observed with imaging 
every 12 weeks +/- 2 week. If the patient develops disease 
progression, the option of re-initiating study therapy may be 
considered. 
 
 
12.2.5. Collection of Tumor Biopsies and Blood for Correlative Studies 
 
All enrolled subjects must undergo pre- and on-treatment research tumor biopsies. Subjects in 
whom biopsy is technically not feasible or in whom would result in unacceptable risk, in the 
opinion of the investigator, may be exempted from the biopsy requirement with discussion with 
the principal investigator. Use of outside archived tumor tissue for a baseline biopsy is not 
permitted. Biopsies will be collected at baseline and between C2D1 and C3D1 of therapy for 
correlative studies. An optional research biopsy at the time of progression will also be discussed 
with these patients, however, is not mandatory.  
 
12.2.6. Adverse Events Monitoring 
 
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. All AEs (serious and nonserious) must be recorded on the source documents 
and eCRFs regardless of the assumption of a causal relationship with the study drug. The 
definition, reporting, and recording requirements for AEs are described in Section 10. 
 
All AEs of unknown etiology associated with pembrolizumab and epacadostat exposure should be 
evaluated to determine if it is possibly an irAE.  
 
 
12.3. End of Treatment 
 
If a decision is made that the subject will permanently discontinue study drug, the EOT visit should 
be conducted. If the EOT visit coincides with a regular study visit, the EOT evaluations will 
supersede those of that scheduled visit, and the data should be entered in the EOT page in the 
eCRF. The subject should be encouraged to return for the follow-up visits. 
 
 
12.4. Follow-up Phase  
 
12.4.1. Safety Follow-up 
 
The safety follow-up phase is the interval between the last dose of study treatment and the 
scheduled safety follow-up visits, which should occur on days 30 (+/- 7 days) after the EOT visit. 
Adverse events and SAEs must be reported up until at least 90 days after the last dose of study 
drug, or until study drug-related toxicities resolve, return to baseline, or are deemed irreversible, 

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whichever is longer. If a subject initiates a new anti-cancer therapy within 90 days after the last 
dose of study treatment, the next scheduled safety follow-up visit must occur before the first dose 
the new therapy. Once new anti-cancer therapy has been initiated, the subject will move into the 
survival follow-up phase.  
 
12.4.2. Follow-up (patients taken off treatment for reasons other than POD) 
 
Subjects who discontinue study treatment for a reason other than disease progression (including 
patients who achieve stable disease control at 2 years) will move into the follow-up phase and will 
be assessed every 12 weeks by radiologic imaging to monitor disease status.  
 
For patients who achieved stable disease at  2 years, re-treatment on study may be allowed at the 
time of disease recurrence or progression with permission of the study PI.  
 
Every effort should be made to collect information regarding disease status until the start of new 
anti-neoplastic therapy, disease progression, death, and end of the study.  
 
12.4.3. Survival Follow-up 
 
Once a subject has confirmed disease progression or starts a new anticancer therapy, the subject 
moves into the survival follow-up phase and should be contacted by telephone, email, or visit every 
12 weeks (+/- 2 weeks) to assess survival status. Clinical notes for patients currently being treated 
at Columbia University Medical Center (or collaborating medical center) will also suffice as follow 
up. Overall survival will be followed until death, withdrawal of consent, or the end of the study, 
whichever occurs first.  
 
12.5. Unscheduled Visits 
 
Unscheduled study visits may occur at any time if medically warranted. Any assessments 
performed at those visits should be recorded in the eCRF. 
 
 
 
13. STUDY CALENDAR 
 
All study assessments will be performed as indicated in the schedules of assessments in Table 10 
– Table 13 below.  

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Table 10. Schedule of Assessments for Screening Through Treatment Phase 
 
Procedure 
Screening 
Cycle 1  
Cycle 2 
All 
subsequent 
cycles 2, 16 
Day –28 
to –1 1 
C1D1 
C1D8 
± 3d 
C1D15 
± 3d 
C2D1 
± 3d 
Day 1 
± 3d 
Informed Consent  
X 
 
 
 
 
 
Inclusion/ Exclusion Criteria 
X 
 
 
 
 
 
Past Medical and Cancer History 
X 
 
 
 
 
 
GIST diagnosis confirmation by 
site pathologist 3 
X 
 
 
 
 
 
 
Concomitant medication review 4 
X 
X 
X 
X 
X 
X 
Physical examination, vital signs5 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
Weight 
X 
X 
 
 
X 
X 
ECOG Performance Status 
X 
X 
 
 
X 
X 
Laboratory assessments 6 
X 
X 
X 
X 
X 
X 
EKG 
X 
 
 
 
 
 
O2 saturation 7 
X 
X 
X 
X 
X 
X 
Serum pregnancy test8  
X 
 
 
 
 
 
Assess for Serotonin Syndrome9 
 
 
X 
X 
X 
X 
Adverse events 
 
X 
X 
X 
X 
X 
Study drug compliance (Pill diary) 
 
 
 
 
X 
X 
CT chest, abdomen, pelvis 10 
X 
 
 
 
X 10 
 
Fresh tumor biopsy  
X 11 
 
 
 
X 12 
 
Blood for correlative study 
analysis  
 
X 13 
 
 
X 13 
X 13 
Blood for PD analysis (fasting) 
 
X 14 
 
 
X 14 
 
Administer pembrolizumab 
 
X 
 
 
X 
X 
Administer/ dispense epacadostat 
15 
 
X 15 
 
 
X 15 
X 
 
1. Protocol-specified screening procedures that are performed as part of standard of care and 
within 28 days of Day 1 of Cycle 1 may be used for screening purposes. Clinical 
laboratory studies must be performed within 28 days before Cycle 1 Day 1, and baseline 
CT scan must be performed within the 28-day period before Day 1 of Cycle 1. 
2. If the study treatment is well tolerated, then the clinic visit, laboratory studies and other 
procedures indicated in the column (except CT chest/abdomen/pelvis – see footnote 10) 
will be performed every 3 weeks at the beginning of each subsequent cycle. 
3. Initial diagnostic slides (if archived slides are available) will be requested and reviewed 
by site pathologist to confirm diagnosis of GIST for the patient to be considered for the 
study. 
4. Concomitant medications will include non-prescribed medications and any 
complementary/herbal supplements. 
5. A complete physical examination will be performed at screening and each subsequent 

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visit. 
6. For complete list of laboratory assessments, see Table 11.  
7. Resting O2 saturation should be assessed at each visit. Ambulatory O2 saturation (after 
mild to moderate exertion) should be checked as clinically indicated.  
8. Only required in women of child-bearing potential. 
9. See section 12.2.2 for assessment of serotonin syndrome. 
10. CT chest, abdomen, and pelvis with contrast to assess tumor status will be performed at 
baseline (within 28 days prior to Cycle 1 Day 1 of treatment) and then every 6 weeks (+/- 
1 week) during the first 24 weeks of study treatment. Imaging of the area with known 
disease involvement only (ex: CT chest only or CT abdomen/ pelvis only) is allowed for 
week 6 and week 18 tumor assessments at the investigator’s discretion. After week 24, a 
CT chest, abdomen, pelvis with contrast will be performed every 12 weeks (+/- 1 week). 
In patients who are unable to get a CT scan with contrast due to renal function (or any 
other reason), a CT chest without contrast and MRI abdomen/ pelvis with and without 
contrast may be used instead. 
11. A fresh tumor biopsy will be performed at baseline within screening period, prior to 
C1D1 of treatment. Archived FFPE slides are not acceptable. This biopsy is mandatory. 
However, subjects in whom biopsy is technically not feasible or in whom would result in 
unacceptable risk, in the opinion of the investigator, may be exempted from the biopsy 
requirement with discussion with the principal investigator. 
12. On-treatment biopsy will be obtained anytime between C2D1 and C3D1 (prior to starting 
cycle 3). This biopsy is mandatory. However, subjects in whom biopsy is technically not 
feasible or in whom would result in unacceptable risk, in the opinion of the investigator, 
may be exempted from the biopsy requirement with discussion with the principal 
investigator. 
13. Blood for ctDNA will be collected on day 1 ±  3d for cycles 1-3, and then day 1 ± 3d  of 
every other cycle thereafter. In addition, blood for PBMC collection will be collected on 
cycle 1 day 1 and cycle 2 day 1 (±  3d). See section 14.1.2 for collection instructions.   
14. A fasting blood sample for PD analysis will be collected on Cycle 1, Day 1 (pre-dose) 
and Cycle 2, Day 1 ± 3d (pre-dose and +2 hours (+/- 30 minutes)), and at the end of 
treatment. See section 14.1.3 for collection instructions.   
15. One full cycle (21 days) supply of epacadostat will be dispensed at the beginning of each 
subsequent cycle. Cycle 2, Day 1 epacadostat dose will be administered in clinic (for PD 
blood sample studies). 
16. For subjects who restart treatment after achieving disease control following 2 years of 
therapy, procedures will restart following the schedule for all subsequent cycles. CT 
chest/ abdomen/ pelvis with contrast will be performed every 12 weeks (+/- 1 week) in 
these patients.   
 
 
 

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Table 11. Laboratory Assessments for Screening Through Treatment Phase 
 
Procedure 
Screening 
Cycle 1 
Cycle 2 
All subsequent 
cycles  
Day –28 
to –1 1 
C1D1 
C1D8 
± 3d 
C1D15 
± 3d 
C2D1 
± 3d 
Day 1 
± 3d 
Chemistry 2 
X 
X 
 
 
X 
X 
CBC with differential 3 
X 
X 
 
 
X 
X 
Liver function tests 4 
X 
X 
X 
X 
X 
X 
TSH and Free T4 (FT4) 
and Total 
thriiodothyronine (T3) 
X 
X 
 
 
X 
X 
INR and PTT 5 
X 
 
 
 
 
 
Serum pregnancy test 6 
X 
 
 
 
 
 
Urine or serum 
pregnancy test 6 
 
X 
 
 
X 
X 
Serology for HBV and 
HCV 7 
X 
 
 
 
 
 
Blood for correlative 
studies  8 
 
X 
 
 
X 
X 
Blood for PD analysis 
(fasting) 9 
 
X 9 
 
 
X 9 
 
 
1. Baseline clinical laboratory studies must be performed within 28 days before Cycle 1 
Day 1. 
2. Chemistry testing includes: Serum sodium, potassium, chloride, carbon dioxide, blood 
urea nitrogen, creatinine, glucose, calcium, magnesium, phosphorus, lactate 
dehydrogenase 
3. CBC testing includes: WBC count with differential, hemoglobin, hematocrit, platelet 
count 
4. LFTs include: AST, ALT, total bilirubin, and alkaline phosphatase, albumin, protein.  
5. INR and PTT and required only at screening, but may be followed if clinically indicated. 
6. Only in women of child-bearing potential. 
7. Serology for HBV and HCV includes: Hepatitis B surface antigen (HBsAg) and Hepatitis 
C virus Antibody (HCV Ab). If Hepatitis C antibody is positive, reflex to check hepatitis 
C quantitative RNA. 
8. Blood for research correlative studies (non-fasting): Blood samples for ctDNA will be 
collected on day 1 ± 3d for cycles 1-3, and then day 1 ± 3d  of every other cycle 
thereafter. Blood for PBMC collection will be collected on cycle 1 day 1 and cycle 2 day 
1 (±  3d). See section 14.1.2 for collection instructions.   
9. A fasting blood sample for PD analysis will be collected on Cycle 1, Day 1 (pre-dose) 
and Cycle 2, Day 1 ± 3d (pre-dose and +2 hours (+/- 30 minutes)), and at the end of 
treatment. See section 14.1.3 for collection instructions.   
 
 
 

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Table 12. Schedule of Assessments for End of Treatment (EOT) through Follow-up Phase 
 
 
 
 
PROCEDURE 
EOT1 
Follow-up Phase 
 
Safety Follow-up 1 
 
 
+ 7 days 
30 days after EOT 
+/- 7 days 
Follow-up 
(Every 12 weeks) 
+/- 14 days 2 
Survival Follow-up  
(Every 12 weeks) 
+/- 14 days 
Concomitant 
medication review  
X 
X 
 
 
Comprehensive 
physical exam 
X 
 
 
 
Targeted physical 
exam 
 
X 
 
 
Assess for serotonin 
syndrome 
X 
 
 
 
Vital signs and weight 
X 
X 
 
 
O2 saturation 
X 
X 
 
 
ECOG performance 
status 
X 
X 
 
 
AE assessment1 
X 
X1 
 
 
Laboratory 
assessments 3 
X 
X 
 
 
Radiologic tumor 
assessments  
X 4 
 
X 5 
 
Fresh tissue collection 
X 6 
 
 
 
Blood for correlative 
studies 
X 7 
 
 
 
Blood for PD analysis 
(fasting) 
X 8 
 
 
 
Post-study anti-cancer 
therapy status 
 
 
X 
X 
Survival follow-up 
 
 
X 
X 
 
1. Subjects must be followed for AEs and SAEs for 90 days after the last dose of study 
drug.  
2. Subjects will be assessed by either a clinic visit or telephone contact every 12 weeks from 
the last dose of study treatment.  
3. Safety laboratory assessments will be collected at EOT and at the each safety follow-up 
visit. See table 13 for detailed laboratory tests.  
4. If a prior scan was obtained within 4 weeks before the date of discontinuation, then a 
scan at treatment discontinuation is not mandatory. In subjects who discontinue study 
therapy without confirmed disease progression, a radiological evaluation should be 
repeated at the time of treatment discontinuation (+/- 4 week window). 
5. For subjects who discontinue treatment for reasons other than disease progression, every 
effort should be made to continue monitoring their disease status by radiographic imaging 
every 12 weeks until (1) start of new anticancer therapy, (2) documented disease 
progression, (3) death, or (4) the end of study, whichever occurs first.  
6. An optional tumor biopsy sample for research purposes can be obtained at the time of 
disease progression.  

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7. See section 14.1.2 for instructions on blood collection for research correlative analysis. 
8. See section 14.1.3 for instructions on blood collection for PD analysis. 
 

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Table 13. Laboratory Assessments for End of Treatment and Follow-up Phase 
 
 
 
 
PROCEDURE 
EOT 
Follow-up Phase 
 
Safety Follow-up  
 
 
+ 7 days 
30 days after EOT 
+/- 7 days 
Follow-up 
(Every 12 weeks) 
+/- 14 days  
Survival Follow-
up  
(Every 12 weeks) 
+/- 14 days 
Chemistry 1 
X 
X 
 
 
CBC w/ differential 2 
X 
X 
 
 
Liver function testing 
(LFT) 3 
X 
X 
 
 
TSH and Free T4 (FT4) 
and Total 
thriiodothyronine (T3) 
X 
 
 
 
Urine or serum pregnancy 
test 4 
X 
 
 
 
Blood for correlative 
studies 5 
X 
 
 
 
Blood for PD analysis 
(fasting) 6 
X 
 
 
 
 
 
1. Chemistry testing includes: Serum sodium, potassium, chloride, carbon dioxide, blood 
urea nitrogen, creatinine, glucose, calcium, magnesium, phosphorus, lactate 
dehydrogenase 
2. CBC testing includes: WBC count with differential, hemoglobin, hematocrit, platelet 
count 
3. LFTs include: AST, ALT, total bilirubin, alkaline phosphatase, albumin, protein.  
4. For female subjects of childbearing potential only.  
5. Blood (non-fasting) will be collected for research correlative analysis (for ctDNA and 
PBMC collection). See section 14.1.2 for collection instructions.   
6. A fasting blood sample for PD analysis will be collected at the end of treatment. See 
section 14.1.3 for collection instructions.   
 
 

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14. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
14.1. Collection of samples for correlative studies 
 
14.1.1. Tumor biopsy samples 
 
Pre- and on-treatment tumor biopsies are mandatory. Subjects in whom biopsy is technically not 
feasible or in whom would result in unacceptable risk, in the opinion of the investigator, may be 
exempted from the biopsy requirement, with discussion with the principal investigator.  
 
Timing of Biopsy Samples: 
 
A fresh biopsy must be obtained at the following time-points: 
 Prior to treatment (anytime during the screening period) (mandatory) 
 On-treatment (between C2D1 and C3D1 treatment dose)) (mandatory) 
 At the time of disease progression (optional) 
Collection & Processing Instructions: 
 
Collection and processing instructions are the same for all of the specified tumor biopsy time 
points.  
 
A goal of at least 3 cores and up to 8 cores, if safe to obtain, will be obtained at each collection 
time point.  
 
See laboratory manual for detailed processing and shipping instructions for all correlative study 
specimens. 
 
 
Shipping Instructions: 
 
Shipments will be sent to the Schwartz laboratory by batch shipments when possible.  
 
Schwartz Laboratory 
1130 Saint Nicholas Avenue 
ICRC Room 207 
New York, NY  10032 
 
The 
analyzing 
laboratories 
should 
be 
notified 
by 
email 
(Study 
listserv 
email: 
CPDM_R1581@lists.cumc.columbia.edu) and Grazia Ambrosini (ga2391@cumc.columbia.edu)) 
the day the samples are sent. The email will contain the following information:  
 Subject ID number 
 Subject Initials  
 Date of collection  

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 Time point (e.g. baseline, Cycle 2 Day 1, end of treatment, etc) 
 Name of study center 
 Shipment date 
 Contents of shipment 
 
All samples should be directed to the address listed above. Samples should be shipped via courier 
so that the package is tracked appropriately (specifically Federal Express or UPS). The samples 
should be shipped for morning delivery, Monday through Thursday for optimal processing.  
 
Samples will be tracked through a Microsoft Excel tracker.  
 
 
14.1.2. Peripheral blood samples 
 
 
Blood samples will be used for correlative studies, including, but not limited to, peripheral blood 
lymphocyte subset and cytokine analysis. All peripheral blood samples are mandatory.  
 
Blood for ctDNA analysis will be collected at the following time points:  
 Day 1 ± 3d for cycles 1-3, Day 1 ± 3d  of every other cycle thereafter  
 End of study  
 
Blood for PBMC isolation will be collected at the following time points:  
 Day 1 Day 1, Cycle 1 Day 2 ± 3d   
 End of study 
 
Blood (non-fasting) will be collected for research purposes for PBMC isolation and ctDNA 
studies described below in section 14.2.  
 
See laboratory manual for detailed processing and shipping instructions for all correlative study 
specimens. 
 
 
14.1.3 Blood samples for Phamacodynamic (PD)/ IDO analysis 
 
IDO Phamacodynamic (PD) analysis: 
 
IDO inhibition will be assessed through analysis of tryptophan metabolites. 
 
Patients should be fasting for each of these draws. Patients will withhold their morning dose of 
epacadostat on Cycle 2 Day 1. After the pre-dose sample is draw, subjects will take epacadostat 
and then receive their infusion of pembrolizumab. The timing of the sample for PD analysis below 
is relative to the timing of epacadostat administration. 
 
A fasting blood sample will be obtained at: 

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 Cycle 1 Day 1 (Pre dose) 
 Cycle 2 Day 1 ± 3d (Pre dose, + 2 hours (± 30 minutes)) 
 End of treatment 
 
See laboratory manual for detailed processing and shipping instructions for all correlative study 
specimens. 
 
 
14.2. Correlative Studies 
 
Tissue and blood samples may be used for the following correlative studies. Additional studies 
may be included in the future. 
 
14.2.1. IDO activity and expression 
 
IDO Activity 
Pre- and post-treatment samples will be analyzed for IDO activity by measurement of tryptophan 
and the tryptophan metabolite, kynurenine, using liquid chromatography with tandem mass 
spectrometry.  
 
IDO Expression 
IDO protein expression will be analyzed by IHC.  
 
 
14.2.2. Tumor Infiltrating Lymphocytes 
 
Lymphocyte subsets will be analyzed by IHC for CD3, CD4, CD8, and Foxp3 on FFPE sections 
using IHC with digital quantification.  
 
14.2.3. PD-L1 expression 
 
Baseline tumor PD-L1 will be assessed by IHC.  
 
14.2.4. Whole exome sequencing 
 
To further characterize the mutational landscape of GIST tumors, whole exome sequencing (WES) 
may be performed on baseline tumor tissue samples if sufficient funding is available. As WES is 
being performed for research purposes only, the results of WES testing will not be shared with the 
subject or their treating physician. Smaller targeted cancer panels may be performed; in particular, 
KIT mutation status will be analyzed if not already known. 
 
14.2.5 Cell-free DNA 
 
Cell-free DNA will be evaluated as a measure of tumor burden and response to therapy. 
 
 

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15. MEASUREMENT OF EFFECT 
 
 
15.1. Antitumor Effect – Solid Tumors 
 
 
Initial tumor imaging must be performed within 28 days before the first dose of study treatment. 
For the purposes of this study, patients should be re-evaluated for response every six weeks within 
the first 24 weeks, then every 12 weeks for the remainder of study duration (Section 7.2.6). The 
study will utilize RECIST v.1.1, with responses confirmed at ≥4 weeks, for determination of the 
primary endpoint of ORR.  The immune related RECIST (irRECIST), which is adapted for 
defining PD to account for the unique tumor response seen with immunotherapies (section 15), 
will be applied for clinical assessment of tumor response and as a basis for treating subjects beyond 
initial radiographic progression. 
 
15.2. Definitions 
 
Evaluable for objective response: Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated 
will be considered evaluable for response.  These patients will have their response classified 
according to the definitions stated below.  (Note:  Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response: Patients who have lesions present at baseline that 
are evaluable but do not meet the definitions of measurable disease, have received at least one 
cycle of therapy, and have had their disease re-evaluated will be considered evaluable for non-
target disease.  The response assessment is based on the presence, absence, or unequivocal 
progression of the lesions.  
 
15.3. Disease Parameters 
 
Measurable disease: Measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal 
lesions) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical 
exam.  All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.  If the investigator thinks it appropriate to include them, the conditions 
under which such lesions should be considered must be defined in the protocol. 
 
Malignant lymph nodes: To be 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).  At baseline and in follow-up, only the short axis will be measured 
and followed. 
 

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Non-measurable disease: 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), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. Cystic lesions thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target lesions. 
 
Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements.  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.  A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated 
and reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, then 
only the short axis is added into the sum.  The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions: All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be recorded 
at baseline.  Measurements of these lesions are not required, but the presence, absence, or in rare 
cases unequivocal progression of each should be noted throughout follow-up.  
 
15.4. Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers 
(e.g., skin nodules).  In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
 

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Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  MRI is 
also acceptable in certain situations (e.g., for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement.  Furthermore, the availability of MRI is variable 
globally.  As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease.  Furthermore, 
as with CT, the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence.  It is beyond the scope of the 
RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image acquisition 
protocol should be followed as closely as possible to prior scans.  Body scans should be performed 
with breath-hold scanning techniques, if possible. 
 
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if the 
site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to 
a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time.  Note, however, that the PET portion of the CT introduces 
additional data which may bias an investigator if it is not routinely or serially performed.   
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next.  If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead of 
CT in selected instances. 
 
Endoscopy/Laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised.  However, such techniques may be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint. 
 
Tumor markers: Tumor markers alone cannot be used to assess response.  If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and 
PSA response (in recurrent prostate cancer) have been published [JNCI 96:487-488, 2004; J Clin 

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Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  In addition, the Gynecologic 
Cancer Intergroup has developed CA-125 progression criteria which are to be integrated with 
objective tumor assessment for use in first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology/Histology: These techniques can be used to differentiate between partial responses (PR) 
and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell 
tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
 
FDG-PET: While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment 
of progression (particularly possible 'new' disease).  New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm:  
 
 Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
 No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-PET 
at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT  scans are needed to determine if there is truly progression occurring at that 
site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan).  If the 
positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is 
not progressing on the basis of the anatomic images, this is not PD. 
 FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or scarring.  
The use of FDG-PET in this circumstance should be prospectively described in the protocol 
and supported by disease-specific medical literature for the indication.  However, it must 
be acknowledged that both approaches may lead to false positive CR due to limitations of 
FDG-PET and biopsy resolution/sensitivity. 
  
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
 
 
15.5. Response Criteria 
 
NOTE: Clinical decision making can be made by irRECIST (that is, patients may be treated 
beyond progression) but the primary endpoint will be assessed by RECIST v. 1.1. 
 
Assessment of Disease According to Immune Related RECIST for Solid Tumors  
 

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The immune related RECIST (irRECIST), which is adapted to account for the unique tumor 
response seen with immunotherapies, will be applied for response evaluation.34  
 
The irRECST criteria considers index lesions identified at baseline together with new lesions that 
may occur after the start of treatment, and are incorporated into the calculated tumor burden. The 
appearance of new lesions alone does not constitute PD.  
 
If imaging shows PD, tumor assessment should be repeated ≥4 weeks later to confirm PD with the 
option of continuing treatment for clinically stable subjects.  
 
Confirmation of progression will be defined as a >10% increase in tumor burden on a subsequent 
scan (performed at ≥4 weeks) when compared to the initial progression scan. 
 
In determining whether the tumor burden has increased or decreased, investigators should consider 
all target lesions as well as non-target lesions. Subjects who are deemed clinically unstable are not 
required to have repeat imaging for confirmation. If radiologic progression is confirmed, then the 
subject will be discontinued from study treatment as specified in the Protocol, and the first 
radiographic evidence of PD should be the date of progression. If radiologic progression is not 
confirmed, then the subject should resume/ continue study treatment and have their next scan 
according to the Protocol-specified schedule. If progression is not confirmed and the subject 
continues on treatment, the next scan that documents disease progression (and is confirmed by a 
second scan at least 4 weeks later) will be considered the date of disease progression. 
 
15.5.1. Evaluation of Target Lesions by irRECIST 
 
Tumor burden = Sum of diameter (target) + Sum of diameter (new) 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the tumor burden compared with 
baseline. 
 
Progressive Disease (PD): At least a 20% increase in the tumor burden compared, taking 
as reference the smallest sum on study (this includes the baseline sum if that is the smallest 
on study), with confirmation of progression by a scan at least 4 weeks later (Note:  With 
irRECIST, the appearance of new lesions alone is not considered progression). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters while on study. 
 
15.5.2. Evaluation by Choi Criteria 
 
Evaluation of response by Choi Criteria, which is a validated response criteria for GIST 
using change in radiographic density, will be performed for secondary endpoint analysis. 

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“Size” refers to the change from the baseline of the sum of longest diameters of all target 
measurable lesions, as in RECIST criteria.  
 
Complete Response (CR): Disappearance of all disease. No new lesions. 
 
Partial Response (PR): A decrease in size of ≥ 10% OR a decrease in CT density (HU) ≥ 
15%. No new lesions. No obvious progression of non-measurable disease. 
 
Stable Disease (SD): Does not meet the criteria for CR, PR, or PD. No symptomatic 
deterioration attributed to tumor progression. 
 
Progression of Disease (PD): An increase in uni-dimensional tumor size of ≥ 10% AND 
did not meet criteria for PR by CT density. Any new lesions, including new tumor 
nodules in a previous cystic tumor. 
 
15.6. Duration of Response 
 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
 
For patients who have not progressed or died, their follow-up will be censored at the time of last 
clinical evaluation. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
 
15.7. Progression-Free Survival (PFS) 
 
PFS is defined as the duration of time from enrollment to time of progression or death, whichever 
occurs first. For patients who have not progressed or died, their follow-up will be censored at the 
time of last clinical evaluation. 
 
15.8. Response Review 
 
Not applicable. 
 
15.9. Unblinding Procedures 
 
Not applicable. 

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15.10. 
Stopping Rules 
The study may be discontinued if the study is terminated by the data and safety monitoring 
committee, the Food and Drug Administration (FDA), or other regulatory authorities. 
Any unforeseen deaths or serious adverse events may, after a discussion between the principal 
investigator and investigators at other sites, prompt an interruption to study accrual pending a full 
investigation into the circumstances surrounding the event. 
 
15.11. 
Other Response Parameters 
 
Not applicable. 
 
 
 
16. DATA REPORTING / REGULATORY REQUIREMENTS 
 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 10 
(Adverse Events: List and Reporting Requirements). The Data Safety Monitoring Plan is described 
in Section 16. 
 
16.1. Data Collection 
 
The Herbert Irving Comprehensive Cancer Center has an electronic clinical trials and data 
management system (CTMS) that will be used for data collection. Case report forms (CRFs) for 
the study will be built into the CTMS for data entry. The system has full auditing capabilities 
which is web-based and housed on a server in a fully HIPAA compliant server room with restricted 
access and video camera monitoring. All users must login with their own application username 
and password.  Users off campus must first access the Virtual Private Network with their assigned 
campus username and password and then use their application credentials. Users are only able to 
see study information if they are indicated as study personnel in our electronic IRB system. Users 
are limited to access based on the role assigned in their corresponding protocol. Subject data is 
entered directly into the system, which (in the case of Columbia subjects) confirms the correct 
identity of patients via an interface with the electronic medical patient index. Staff with the 
appropriate IRB defined roles can run reports within the system for reporting purposes. 
 
16.2. Data Reporting 
 
Case Report Forms will be completed for each subject enrolled into the clinical study through the 
CTMS. It is the investigator’s responsibility for ensuring that all clinical and laboratory data 
entered on the corresponding CRFs are complete, accurate and authentic. 
 

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16.3. Data and Safety Monitoring Committee 
 
The NCI-approved Data Safety and Monitoring Committee (DSMC) of the Herbert Irving 
Comprehensive Cancer Center (HICCC) will monitor every subject who receives treatment on this 
protocol for toxicity. This protocol will adhere to the policies of the currently approved HICCC 
Data and Safety Monitoring Plan (DSMP), which is in accordance with NCI and CUMC-IRB 
policy and guidelines.  The committee chair is appointed by the HICCC Director. The committee 
consists of HICCC faculty and staff with expertise in oncology, research pharmacy, research 
nursing, and data management. The DSMC convenes twice a month to review patient safety and 
the conduct of the trial. The PI will submit data and safety monitoring reports to the DSMC at a 
frequency to be determined by the DSMC based on risk to the subjects. 
 
At the time of renewal, the study team will submit the most recent DSMC approval letter for safety 
review to the CUMC IRB. Any modifications that are required by the DSMC to ensure patient 
safety will be submitted to the IRB. All protocol deviations, violations, and eligibility waivers will 
be submitted to and approved by the DSMC prior to being reported to the IRB. All study data 
reviewed and discussed during these meetings will be kept confidential.  
 
For multicenter research, the principal investigator will assure that there is a mechanism in place 
to distribute the report to all participating investigators for submission to their local IRB.  The 
report will document that a review of data and outcomes across all centers took place on a given 
date.  It will summarize the DSMC’s review of the cumulative toxicities reported from all 
participating sites without specific disclosure by treatment arm.  It will also inform site 
investigators of the study the DSMC’s conclusion with respect to progress or need for modification 
of the protocol.   
 
16.4. Quality Control and Quality Assurance 
 
Independent monitoring of the clinical study for protocol and GCP compliance will be conducted 
periodically by the CPDM Compliance Core on behalf of the HICCC DSMC.  Additionally, the 
Compliance Oversight Committee of the IRB at Columbia University Medical Center may audit 
the study at any time per institutional policies and procedures. The investigator-sponsor and 
Columbia University Medical Center will permit direct access of the study monitors and 
appropriate regulatory authorities to the study data and to the corresponding source data and 
documents to verify the accuracy of this data. 
 
A risk-based approach will be used by the Compliance Core to determine the frequency, number 
of subject charts, and data elements to be monitored. The Compliance Coordinator will review the 
study status and summarize enrollment, toxicities, SAEs/UPs, dose escalation, statistical endpoints 
(e.g., stopping rules), etc. for the full DSMC membership at the regularly scheduled meetings.   
 
Internal On-site Monitoring: 
 

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 
Initial, recurrent, and close-out on-site monitoring visits will also be conducted at 
remote clinical sites, as appropriate/feasible. Other sites will have monitoring performed 
remotely (see below for further details). 
 
 
The study Monitoring Visit Log will be completed and signed by the monitor and the 
PI/CRNP/CRN and/or CRC and will be filed in the regulatory binder. 
 
 
The Compliance Coordinator will communicate with the site coordinator/Site Principle 
Investigator to schedule the monitoring visit and arrange for access to study materials and 
documentation. 
 
 
The assigned Compliance Coordinator will monitor IIT trials within 1 month after the 
first subject is enrolled and throughout the life of the study to ensure that the study is being 
conducted in accordance with the protocol, GCP, applicable federal and local regulations, and 
per all applicable SOPs. The Compliance Coordinator is responsible to notify the PI and 
CRNP/CRN/CRC of upcoming monitor visits and convey what information and 
documentation will be required for the visit(s).  The Compliance Coordinator is responsible 
for verifying that informed consent is properly obtained, eligibility is met (via the central 
registration process), and all study procedures are conducted according to the study protocol. 
The Compliance Coordinator will also verify that the data reported in the CRF’s accurately 
reflect source documents, that all toxicities have been reported to date, and that all 
SAE’s/UPs/deviations/violations have been reported according to local IRB and HICCC 
DSMC requirements. The Compliance Coordinator will issue queries and ensure resolution in 
a timely and efficient manner.  The Compliance Coordinator will also monitor for applicable 
regulatory compliance and research pharmacy compliance (if applicable) and communicate 
any deficiencies as appropriate. 
 
16.5. Confidentiality 
 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act (HIPAA).  Those 
regulations require a signed subject authorization informing the subject of the following:  
 What protected health information (PHI) will be collected from subjects in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (e.g., that the subject is alive) at the end 
of their scheduled study period. 
The subject binders will be maintained with in the CPDM offices, a secured floor within the 
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16.6. Source Documents 
 
Source data is all information, original records of clinical findings, observations, or other activities 
in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are 
contained in source documents   Examples of these original documents, and data records include: 
hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the clinical trial. 
 
16.7. Case Report Forms 
 
The study case report form (CRF) is the primary data collection instrument for the study.  All data 
requested on the CRF must be recorded.  All missing data must be explained.  If a space on the 
CRF is left blank because the procedure was not done or the question was not asked, write “N/D”.  
If the item is not applicable to the individual case, write “N/A”.  
 
16.8. Records Retention 
 
Records relating to a specific research activity, including research records collected by 
investigators, must be maintained for at least three years after completion of the research (45 CFR 
46.115(b); 21 CFR 56.115(b); 21 CFR 312.62). This minimum retention period applies whether 
or not any subjects were enrolled in the study. 
 
If the research is FDA regulated, records should be retained for at least two years after approval of 
the investigational agent by FDA; if it is not approved, records should be retained at least two 
years after the study is terminated and FDA is notified (note the additional requirement below for 
clinical research studies). 
 
Clinical records, including consent forms that document clinical intervention or clinical diagnostic 
procedure research-related procedures, must be retained in medical records by the institution for 
at least seven years, per CUMC and NYP policy which is based on state law. 
 
 
 
17. STATISTICAL CONSIDERATIONS 
 
 
17.1. Study Endpoints and Analysis Plan 
 
Definition of primary outcome/endpoint: 
The primary endpoint is the overall response rate defined as the best response within the first 24 
weeks of the start of study therapy using RECIST v. 1.1 that has been confirmed at a subsequent 

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time point (≥4 weeks). 
 
 
Definition of secondary outcomes/endpoints: 
PFS is defined as time from enrollment to time of clinical or radiographic disease progression as 
defined by RECIST v.1.1 criteria. OS is defined as time from enrollment to time of death from any 
cause. 
 
Analytic plan for primary objective: 
We will estimate the response rate to combination therapy with epacadostat and pembrolizumab 
using the exact 95% confidence interval based on the binomial distribution. 
 
Analytic plan for secondary and exploratory objectives: 
 We will estimate the survival distribution for both PFS and OS endpoints using the 
Kaplan Meier method. The log rank test will be used to examine differences between 
survival curves using prognostic markers such as KIT mutation status.  
 For correlative studies we will apply either the Fisher’s exact test or Wilcoxon rank 
sum test to examine the correlation between response status and markers for categorical 
and continuous variables, respectively. Because of the limited sample size, the 
biomarker data analysis is for exploratory research only.  
 
Sample Size Justification 
The primary endpoint of this trial is the objective response rate defined as the best response within 
the first 24 weeks of the start of study therapy using RECIST v1.1 criteria, and that has been 
confirmed at a subsequent time point (≥4 weeks).. We will use a Simon mini-max two-stage design 
with a target objective response rate of 20%, compared to a historical response rate of 5% with 
salvage tyrosine kinase inhibitor monotherapy10, and the probabilities of type I and type II error 
set at 0.1 and 0.2 respectively. In the first stage, 12 patients will be accrued. If less than 1 patient 
achieves a response among the initial 12 patients, the study will be declared negative and 
terminated. If at least 1 patient achieves a response, an additional 9 patients will be accrued to the 
second stage for a total of 21 evaluable patients. If at least 3 total patients achieve a response, that 
treatment will be declared positive for attaining the primary endpoint. This study design yields at 
least 80% power to detect a 20% response rate (compared to the null hypothesis of 5%) at a 
significance level of 10%. There is a 54% chance of stopping at Stage 1 if the true confirmed 
response rate is at most 5% (null hypothesis). Accounting for 10% dropout, we will plan to enroll 
a total of 23 patients. 
 
 
17.2. Stratification Factors 
 
Not Applicable. 
 
 

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17.3. Reporting and Exclusions 
 
All patients included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible. Each patient will be assigned one of 
the following categories:  1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early 
death because of other cause, or 9) unknown (not assessable, insufficient data).  
 
All of the patients who met the eligibility criteria (with the possible exception of those who 
received no study medication) will be included in the main analysis of the response rate. Patients 
in response categories 4-9 will be considered to have a treatment failure (disease progression).  
Thus, an incorrect treatment schedule or drug administration does not result in exclusion from the 
analysis of the response rate.  
 
All conclusions should be based on all eligible patients.  Sub-analyses may then be performed on 
the basis of a subset of patients, excluding those for whom major protocol deviations have been 
identified (e.g., early death due to other reasons, early discontinuation of treatment, major protocol 
violations, etc.). However, these sub-analyses may not serve as the basis for drawing conclusions 
concerning treatment efficacy, and the reasons for excluding patients from the analysis should be 
clearly reported. The 95% confidence intervals should also be provided.  
 
 
 
18. PROTECTION OF HUMAN SUBJECTS  
 
 
This study is to be conducted in accordance with applicable government regulations and 
Institutional research policies and procedures. An IND annual report will be submitted to the FDA 
in accordance with 21.CFR 312.33. 
 
This protocol and any amendments will be submitted to a properly constituted Institutional Review 
Board (IRB), in agreement with local legal prescriptions, for formal approval of the study conduct.  
The decision of the IRB concerning the conduct of the study will be made in writing to the 
investigator and a copy of this decision will be obtained before commencement of this study.  
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study. This consent form will be submitted with the protocol for review and approval by the IRB 
for the study.  The formal consent of a subject, using the IRB-approved consent form, must be 
obtained before that subject is submitted to any study procedure.  This consent form must be signed 
by the subject or legally acceptable surrogate, as outlined in the IRB approved protocol, and the 
investigator-designated research professional obtaining the consent.  
 
 

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19. STUDY FINANCES 
 
19.1. Conflict of interest  
 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the conflict 
reviewed by the Columbia University Conflict of Interest Committee with a Committee-sanctioned 
conflict management plan that has been reviewed and approved prior to participation in this study.  
All CUMC investigators will follow the University conflict of interest policy. 
 
19.2. Subject Stipends or Payments 
 
There are no subject stipends or payments. 
 
 
20. PUBLICATION PLAN 
 
Neither the complete nor any part of the results of the study carried out under this protocol, nor 
any of the information provided by the sponsor for the purposes of performing the study, will be 
published or passed on to any third party without the consent of the study sponsor.  Any 
investigator involved with this study is obligated to provide the sponsor with complete test results 
and all data derived from the study. 
 
 
21. GUIDELINES FOR AFFILIATE INSTITUTIONS IN MULTICENTER STUDIES 
 
21.1. Multi-site Communication 
 
The CPDM Office at CUMC provides administration, data management, and organizational 
support for the affiliate sites in the conduct of a multicenter clinical trial.  The CPDM Office will 
coordinate regularly scheduled conference calls with affiliate sites.  
 
The following issues will be discussed, as appropriate:  
 Enrollment information 
 Response assessments  
 Adverse events (e.g., new adverse events and updates on unresolved adverse events 
and new safety information) 
 Protocol violations 
 Other issues affecting the conduct of the study 
 
21.2. New Protocol Distribution, IRB Submission, Modifications, and Annual Renewals 
 
 Protocol specific documents are distributed to affiliate sites once CUMC IRB approval 
has been obtained.  
 The affiliate site must submit a draft of site specific revisions to protocol and/or consent 
form documents for review and approval by the sponsor-investigator prior to 
submission to the local IRB. Draft documents should be sent to the study specific email 

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address. The site will be provided confirmation that they are approved to submit to their 
local IRB.  
 Protocol amendments must be approved by the affiliate site’s local IRB within 90 days 
of distribution to the site by the sponsor-investigator.  
 
21.3. Regulatory Documents 
 
Prior to Site Initiation: 
Sponsor-Investigator will ensure that proper requests are made of sites and that the following 
documentation is collected, prior to the initiation of an affiliate site.   
 
 CV of PI, Co-I’s and other research staff listed on FDA 1572 (signed and dated copy 
within 2 years) 
 Medical Licenses of PI and Co-I’s (current copy) 
 Human subjects training certificates for PI and Co-I’s 
 CLIA/Laboratory  Certifications for Local Laboratories listed on FDA 1572 
 Local Laboratory Director’s CV and License 
 Local Laboratory Reference Ranges  
 IRB roster or statement of compliance 
 FDA Form 1572, if applicable (wet ink originals required) 
 Financial Disclosure forms for all members listed on FDA 1572 (wet ink originals 
required) 
 
Ongoing Regulatory Documentation:  Sponsor-Investigator will ensure that proper requests are 
made of sites and that the following documentation is collected throughout the course of the study. 
 IRB approval letters for all protocol modifications and all renewals 
 IRB-approved consent forms 
 Current IRB roster, if statement of compliance is not provided as part of site initiation  
 FDA Form 1572, if applicable as updates are required 
 Updated investigator and site information where relevant (e.g., CV, medical licensure 
and Financial Disclosure for new sub-investigator, local laboratory information) 
 
Regulatory documents may be sent to CPDM_R1581@lists.cumc.columbia.edu or to the 
following address: 
 
Clinical Protocol & Data Management Office 
161 Fort Washington Ave. 
Herbert Irving Pavilion 
Mezzanine Level, M-203 
New York, NY 10032 
 
21.4. Site activation 
 

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Columbia University will schedule a site initiation visit once IRB approval has been submitted 
from the affiliate site.  
 
21.5. Central Registration Procedures- Affiliate Institution Research Participant 
Registration Process 
 
All Affiliate Institutions must register subjects with the coordinating center (CUMC) prior to any 
administration of study drug/intervention/local institution registration.  Please see instructions 
below: 
 
1. Within 48 hours of obtaining consent (excluding holidays and weekends), the Affiliate 
Institution CRN and/or CRC is required to submit the following documents to the 
coordinating center’s designee (CUMC Multicenter Core) via the study listserv 
CPDM_R1581@lists.cumc.columbia.edu.  The coordinating center’s designee will review 
the documents for accurateness, and subsequently submit the documents to the CPDM 
Central Registration Office via email at CPDMRegistration@columbia.edu (or via fax at 
212.305.5292), with a request to register the patient “pending eligibility.” The title of the 
email should read, “Pending Subject Registration Request (PHI)”.  The following 
documents should be submitted with the pending registration request, as applicable: 
a. Redacted Completed/signed IRB approved/stamped Informed Consent Forms, 
including additional study ICFs (e.g., tissue, DNA, etc.), as applicable 
b. Redacted Signed HIPAA (or institutional equivalent) 
c. MCT CPDM Velos Note to File form  
 
2. The Affiliate Institution’s investigator/research nurse/data manager/coordinator must 
contact the coordinating center’s designee (CUMC Multicenter Core) via telephone or 
email to communicate the following: 
a. Notify of pending registration request  
b. Confirm method of registration request submission (email or fax) 
c. Communicate expected time-line of registration request submission (e.g., same 
day, next day, within the hour, etc.) 
 
3. To complete registration, the Affiliate Institution’s investigator/research nurse/data 
manager/coordinator should then submit the following documents to the CUMC study 
specific designee: 
a. A signed Affiliate Site Eligibility Checklist (signed by the investigator) 
b. Copies of redacted source documentation necessary for each item to be verified on 
the CUMC specific Eligibility Checklist, including but not limited to: 
i. Copy of required laboratory test and procedure reports (e.g., hematology, 
serum chemistry, pregnancy test when applicable, MRI reports, CT/bone 
scans, etc.) 
ii. Copy of pathology and surgical reports 
iii. Copy of clinic note(s) capturing the consent process information, along with 
providing source documentation of any other items needed for 
screening/eligibility that are not captured in other source document forms. 

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(e.g., positive investigator statements of unique eligibility items not 
captured via other direct source documentation, concomitant medication 
lists, etc.) 
iv. Protocol deviation/waiver approvals (if applicable) 
c. Please note: subject line of email or fax should include the following: “AAAR1581 
Complete Subject Registration Request (PHI)”. 
 
4. Upon receipt of the above mentioned documents, the designated study specific Clinical 
Research Coordinator will review all documents and verify patient eligibility.  If any questions 
arise during the review process, queries in the form of emails will be addressed to the 
applicable affiliate site study team personnel for clarification prior to enrollment.  Upon 
verification, the CUMC Multicenter Core will then forward all documents to the CPDM 
Central Registration Office for central registration (as described above). The CPDM Central 
Registration Registrar will review all applicable documents and communicate to the CUMC 
study specific designee in order to clarify any items.  The CUMC study specific designee will 
communicate with the applicable site study team personnel for additional clarifications 
necessary prior to enrollment. 
 
5. Upon receipt of the subject registration notification email, the CUMC Multicenter Core will 
forward the notification email (which will include the study specific patient ID) to the affiliate 
site’s Principal Investigator, Consenting Professional, and applicable research personnel.  
This notification should be filed in the patient research binder accordingly. Protocol therapy 
may not be initiated prior to receipt of this notification from the coordinating center. 
 
6. All screenfail/ineligible subjects, as well as subject’s who withdraw consent prior to 
enrollment/initiation of protocol therapy must be submitted to the Central Registration Office 
in a manner analogous to the procedures noted above. Applicable source documentation will 
be required within the corresponding submissions. 
 
21.6. Protocol Deviation/Subject Waiver request for Affiliate Sites: 
 
The Affiliate site MUST submit a prospective deviation request to the CUMC lead PI for review 
and submission to the HICCC DSMC and CUMC IRB. Approvals must be obtained from all 
entities prior to implementation at the Affiliate site.  If a prospective protocol deviation request is 
submitted for review (from an Affiliate site), the PI/site memo(s), HICCC DSMC approval(s) and 
correspondence and CUMC IRB approval letter(s)/equivalent should be forwarded to the Affiliate 
site for documentation. The Affiliate site is also required to obtain prospective local IRB approval 
as per institutional policies/procedures prior to implementing the proposed deviation and 
registering/enrolling the subject via CUMC Central Registration. All documents and 
determinations must be clearly documented in the study subject’s medical record, research chart 
and regulatory binder, as described. Please note that the HICCC DSMC and PRMC do not approve 
eligibility deviations. If eligibility deviations are submitted, they will not be approved.  
 
 

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21.7. Guidelines for Affiliate Site Monitoring  
 
 
On-Site MCT Monitoring:  
1. Initial, recurrent, and close-out on-site monitoring visits will also be conducted at Affiliate 
sites, as appropriate/feasible. Other sites will have monitoring performed remotely (see 
below for further details). 
a. The study Monitoring Visit Log will be completed and signed by the monitor and 
the PI/CRNP/CRN and/or CRC and will be filed in the regulatory binder. 
2. The Compliance Coordinator will communicate with the Affiliate site coordinator/Site 
Principle Investigator to schedule the monitoring visit and arrange for access to study 
materials and documentation. 
3. The Compliance Coordinator will monitor IIT trials within 1 month after the first subject 
is enrolled at the Affiliate site and throughout the life of the study to ensure that the study 
is being conducted in accordance with the protocol, GCP, applicable federal and local 
regulations, and per all applicable SOPs. The Compliance Coordinator is responsible to 
notify the participating site PI and CRNP/CRN/CRC of upcoming monitor visits and 
convey what information and documentation will be required for the visit(s).  The 
Compliance Coordinator is responsible for verifying that informed consent is properly 
obtained, eligibility is met (via the central registration process), and all study procedures 
are conducted according to the study protocol. The Compliance Coordinator will also 
verify that the data reported in the CRF’s accurately reflect source documents, that all 
toxicities have been reported to date, and that all SAE’s/UPs/deviations/violations have 
been reported according to Coordinating Center, local IRB and HICCC DSMC 
requirements. The Compliance Coordinator will issue queries and ensure resolution in a 
timely and efficient manner.  The Compliance Coordinator will also monitor for applicable 
regulatory compliance and research pharmacy compliance (if applicable) and communicate 
any deficiencies as appropriate. 
 
4. An SIV (or) teleconference will be scheduled and conducted prior to study drug being made 
available (if applicable) and before any subjects are enrolled on a study at the Affiliate site. 
 
Remote MCT Monitoring:  
 When necessary (due to logistical constraints), Affiliate sites will be monitored remotely 
by a designated Compliance Coordinator. Sites will be informed of this remote monitoring 
process on a site by site basis. 
 Affiliate sites will be monitored by the Compliance Coordinator on both a regulatory level, 
as well as a clinical data/source documentation review level. 
 Redacted source documents (applicable to supporting the protocol specific CRF data 
requirements) will be sent to the designated Compliance Coordinator via fax or secure 
email for all subjects enrolled at Affiliate sites. Timelines for submission procedures will 
be defined on a case by case basis.   
 The Compliance Coordinator will review all submitted redacted source documents against 
the data entered on the protocol specific CRFs. The Compliance Coordinator will issue 
queries when/if necessary. 

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 The Affiliate site research staff will respond to queries within 30 days. If queries remain 
outstanding, the Compliance Coordinator will send a delinquent query reminder for the 
outstanding items. 
 The remote monitoring procedures will include review of applicable redacted source 
documentation and supporting applicable documents to determine compliance regarding: 
a. Informed consent procedures 
b. Eligibility criteria 
c. Protocol specific treatment compliance 
d. Protocol specific toxicity/outcome documentation/compliance 
e. Protocol specific schedule of events (e.g., baseline visits, pre-treatment, on study, 
follow-up) 
f. Participating site IRB documents (e.g., IRB amendment approvals, annual 
renewals, SAE/UP submissions, violation/deviation submissions, INDSR 
submissions, etc). 
g. Required specimen submissions (e.g., tissue specimens, research blood specimens, 
etc.) 
h. Pharmacy accountability records 
i. Adherence to the CRF submission timeframes to CUMC (within the protocol 
specified timeframes) 
 Affiliate site remote monitoring reports will be sent to the lead PI, HICCC DSMC, and 
Affiliate sites after each remote monitoring review. Reports will include information 
regarding data submission timeliness/accuracy, protocol adherence items, query resolution 
status, regulatory status, and overall Affiliate site performance. These reports will be 
generated by the Compliance Coordinator and reviewed with the Compliance Core 
Manager prior to dissemination. 
 
21.8. Adverse event reporting 
 
Sponsor reporting: Notifying participating investigators at affiliate sites of adverse events 
 
It is the responsibility of the study sponsor to notify all affiliate sites, in a written IND safety report, 
of any adverse event associated with the use of the drug that is both serious and unexpected, as 
well as any finding from tests in laboratory animals that suggest a significant risk for human 
subjects.  Additionally, sponsors are also required to identify in IND safety reports all previous 
reports concerning similar adverse events and to analyze the significance of the current event in 
light of the previous reports. 
 
Serious Adverse Event Reporting 
 
Each participating investigator is required to abide by the reporting requirements set by Columbia 
University Medical Center. The study must be conducted in compliance with FDA regulations, 
local safety reporting requirements, and reporting requirements of the principal investigator. 
 
Participating investigators must report each serious adverse event to the Columbia University 
Medical Center Overall Principal Investigator within 24 hours of learning of the occurrence using 

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the SAE Report Form. In the event that the participating investigator does not become aware of the 
serious adverse event immediately (e.g., participant sought treatment elsewhere), the participating 
investigator is to report the event within 24 hours after learning of it and document the time of his 
or her first awareness of the adverse event. Report serious adverse events by telephone, email or 
facsimile to: 
 
Richard D. Carvajal, MD 
177 Fort Washington Avenue 
New York, NY 10032 
Telephone: 212-305-2055 
Fax: 212-305-3035 
Email: CPDM_R1581@lists.cumc.columbia.edu 
 
Within the following 24-48 hours, the participating investigator must provide follow-up 
information on the serious adverse event. Follow-up information should describe whether the event 
has resolved or continues, if and how the event was treated, and whether the participant will 
continue or discontinue study participation. 
 
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 re-occurrence, 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 Investigator’s Brochure for the study drug (new 
occurrence) and is thought to be related to the investigational agent, the sponsor-investigator may 
urgently require further information from the investigator for reporting to Health Authorities. 
 
Non-Serious Adverse Event Reporting 
 
Non-serious adverse events will be reported to the Columbia University Medical Center Overall 
Principal Investigator on the toxicity Case Report Forms. 
 
Reporting to the Institutional Review Board (IRB) and the Data and Safety Monitoring Committee: 
 
All Unanticipated Problems (UPs) will be reported to the CUMC IRB.  SAEs not constituting UPs 
will reported to the HICCC DSMC.   
 
Each affiliate site will be responsible for safety reporting to their local IRB.  Investigators are 
responsible for complying with their local IRB’s reporting requirements, though must submit the 
required reports to their IRB no later than 7 calendar days following the occurrence of the UP or 
the Principal’s Investigator’s acquiring knowledge of the UP.  Copies of each report and 
documentation of IRB notification and receipt must be included in the regulatory binder. 

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Expected or unexpected AEs must be reported at the time of continuing review of a protocol. 
 
Guidelines for Processing IND Safety Reports  
 
The U.S. Food and Drug Administration (FDA) regulations require sponsors of clinical studies to 
notify the FDA and all participating investigators of any serious and unexpected adverse 
experiences that are possibly related to the investigational agent. The CUMC Principal Investigator 
will review all applicable IND Safety Reports and has the responsibly for forwarding the IND 
Safety Reports to the Affiliate Institutions. The Affiliate Institution investigators are to review, 
send a copy to their IRB according to their local IRB’s policies and procedures, and file a copy 
with their regulatory documents. All Affiliate site INDSR submissions, along with IRB 
acknowledgment (per local policies and procedures) are to be forwarded to CUMC for placement 
within the trial master file. 
 
Reporting to Hospital Risk Management 
 
Affiliate Site investigators will report to their local Risk Management Office any subject safety 
reports or sentinel events that require reporting according to institutional policy. 
 
21.9. Efficacy analysis/ correlative analysis 
 
Efficacy analysis: 
CT scans will be reviewed by a site radiologist and interpreted according to response criteria 
detailed in section 12.4 for primary and secondary endpoint analysis.  Imaging studies may be 
requested from participating centers for central radiology review.  
 
Correlative analysis: 
All tissue samples collected at each site will be sent to Columbia University Medical Center for 
storage and correlative studies described above.  
 
21.10. 
Confidentiality 
 
Each affiliate site will be assigned a site number. Each subject that signs consent should be 
assigned a unique code number consisting of site number followed by a number with each new 
subject being assigned the next sequential number (e.g., 04-10). All sites will be required to enter 
their data in the Velos eResearch, the Clinical Trial Management System used for all Cancer-
related clinical research at CUMC. All users must login with their own application username and 
password.  Users off campus must first access the Virtual Private Network with their assigned 
campus username and password and then use their application credentials.   
 
Subject confidentiality must be maintained according to HIPAA regulations and GCP 
recommendations.  
 
Except when required by law, study information shared with persons and organizations outside of 

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Columbia University Medical Center must not identify the patient by name, social security 
number, address, telephone number, or any other direct personal identifier. 
 
If the results of this research project are published or presented at a scientific or medical meeting, 
the patient not be identified. Otherwise, all results will be kept confidential and will not be divulged 
(except as required by law) without permission.  
 
21.11. 
Data Reporting Plan 
 
Columbia University Medical Center (CUMC) is deeply committed to research integrity and 
strong credibility when it comes to the discovery of new treatment concepts, implementation of 
new clinical research techniques, and acceptance of its researcher's findings by the medical 
establishment. In accord with these ethics, CUMC encourages and supports its investigators in the 
sharing of final research data and/or details of newly developed clinical treatments. 
 
CUMC's policies that pertain to patient data sharing conform to CUMC IRB rules, local and state 
laws, and HIPAA privacy regulations. The primary reason for this is to protect the privacy of 
patients who participate in clinical trials. The data can be made available for continuing review by 
federal agencies upon request and for ongoing study safety reviews by the Principal Investigator, 
Statistician, Data Safety and Monitoring Board (DSMC), and, in other instances, the CUMC IRB. 
 
Data collected during the course of this clinical trial will primarily be shared with other 
investigators and University staff, the IRB, FDA, and other reporting agencies, and/or transferred 
to other collaborators.  Prior to transfer, the data collected must comply with, and must be limited 
by, the CUMC's guidelines for Protecting the Rights and Privacy of Human Subjects.   
 
21.12. 
Data Acquisition and Submission 
 
Informed consent, including HIPPA authorization, must be obtained on all subjects prior to their 
participation. Always keep the original signed and dated consent form, with the redacted source 
documents and eligibility checklist. Velos eResearch will be used as the electronic clinical trials 
and data management system. Affiliate sites will enter data directly into Velos eResearch via 
customized case report forms for the study. The research staff will generate reports from Velos 
eResearch to ensure timely submission of data by affiliate sites. This resource allows for the timely 
analysis of particular data sets for safety analysis. 
 
21.13. 
Record Keeping and Record Retention 
 
The Principal Investigator is required to maintain adequate records of the disposition of the drug, 
including dates, quantity, and use by subjects, as well as written records of the disposition of the 
drug when the study ends.   
 
The Principal Investigator is required to prepare and maintain adequate and accurate case histories 
that record all observations and other data pertinent to the investigation on each individual 
administered the investigational drug or employed as a control in the investigation. Case histories 

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include the case report forms and supporting data including, for example, signed and dated consent 
forms and medical records including, for example, progress notes of the physician, the individual's 
hospital chart(s), and the nurses' notes. The case history for each individual shall document that 
informed consent was obtained prior to participation in the study. 
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, CHR correspondence and approval, signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
In accordance with FDA regulations, the investigator shall retain records for a period of 2 years 
following the date a marketing application is approved for the drug for the indication for which it 
is being investigated; or, if no application is to be filed or if the application is not approved for 
such indication, until 2 years after the investigation is discontinued and FDA is notified. 

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22. REFERENCES 
 
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tumors: an analysis of 1,458 cases from 1992 to 2000. The American journal of 
gastroenterology. 2005;100(1):162-168. 
2. 
Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human 
gastrointestinal stromal tumors. Science. 1998;279(5350):577-580. 
3. 
Verweij J, Casali PG, Zalcberg J, et al. Progression-free survival in gastrointestinal 
stromal tumours with high-dose imatinib: randomised trial. Lancet. 
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4. 
Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate 
in advanced gastrointestinal stromal tumors. The New England journal of medicine. 
2002;347(7):472-480. 
5. 
Blanke CD, Rankin C, Demetri GD, et al. Phase III randomized, intergroup trial assessing 
imatinib mesylate at two dose levels in patients with unresectable or metastatic 
gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. 
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Oncology. 2008;26(4):626-632. 
6. 
Blanke CD, Demetri GD, von Mehren M, et al. Long-term results from a randomized 
phase II trial of standard- versus higher-dose imatinib mesylate for patients with 
unresectable or metastatic gastrointestinal stromal tumors expressing KIT. Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology. 
2008;26(4):620-625. 
7. 
Heinrich MC, Corless CL. Does tumor mutational status correlate with clinical response 
to imatinib? Nature clinical practice Oncology. 2006;3(11):600-601. 
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Heinrich MC, Corless CL, Blanke CD, et al. Molecular correlates of imatinib resistance 
in gastrointestinal stromal tumors. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology. 2006;24(29):4764-4774. 
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Antonescu CR, Besmer P, Guo T, et al. Acquired resistance to imatinib in gastrointestinal 
stromal tumor occurs through secondary gene mutation. Clinical cancer research : an 
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10. 
Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in 
patients with advanced gastrointestinal stromal tumour after failure of imatinib: a 
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11. 
Demetri GD, Reichardt P, Kang YK, et al. Efficacy and safety of regorafenib for 
advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): 
an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 
2013;381(9863):295-302. 
12. 
Schittenhelm MM, Shiraga S, Schroeder A, et al. Dasatinib (BMS-354825), a Dual 
SRC/ABL Kinase Inhibitor, Inhibits the Kinase Activity of Wild-Type, Juxtamembrane, 
and Activation Loop Mutant KIT Isoforms Associated with Human Malignancies. 
Cancer Research. 2006;66(1):473-481. 
13. 
Dewaele B, Wasag B, Cools J, et al. Activity of Dasatinib, a Dual SRC/ABL Kinase 
Inhibitor, and IPI-504, a Heat Shock Protein 90 Inhibitor, against Gastrointestinal 
Stromal Tumor–Associated PDGFRAD842V Mutation. Clinical Cancer Research. 
2008;14(18):5749-5758. 
14. 
Trent JC, Wathen K, von Mehren M, et al. A phase II study of dasatinib for patients with 
imatinib-resistant gastrointestinal stromal tumor (GIST). J Clin Oncol 29: 2011 (suppl; 
abstr 10006) 2011. 
15. 
Balachandran VP, Cavnar MJ, Zeng S, et al. Imatinib potentiates antitumor T cell 
responses in gastrointestinal stromal tumor through the inhibition of Ido. Nat Med. 
2011;17(9):1094-1100. 
16. 
Lob S, Konigsrainer A, Rammensee HG, Opelz G, Terness P. Inhibitors of indoleamine-
2,3-dioxygenase for cancer therapy: can we see the wood for the trees? Nature reviews 
Cancer. 2009;9(6):445-452. 
17. 
Godin-Ethier J, Hanafi LA, Piccirillo CA, Lapointe R. Indoleamine 2,3-dioxygenase 
expression in human cancers: clinical and immunologic perspectives. Clinical cancer 
research : an official journal of the American Association for Cancer Research. 
2011;17(22):6985-6991. 
18. 
Uyttenhove C, Pilotte L, Theate I, et al. Evidence for a tumoral immune resistance 
mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nature 
medicine. 2003;9(10):1269-1274. 
19. 
Fallarino F, Grohmann U, You S, et al. The combined effects of tryptophan starvation 
and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a 
regulatory phenotype in naive T cells. Journal of immunology. 2006;176(11):6752-6761. 
20. 
Mellor AL, Baban B, Chandler P, et al. Cutting edge: induced indoleamine 2,3 
dioxygenase expression in dendritic cell subsets suppresses T cell clonal expansion. 
Journal of immunology. 2003;171(4):1652-1655. 
21. 
Mellor AL, Munn DH. IDO expression by dendritic cells: tolerance and tryptophan 
catabolism. Nature reviews Immunology. 2004;4(10):762-774. 

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22. 
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, potentiates cancer chemotherapy. Nature medicine. 2005;11(3):312-319. 
23. 
Okamoto A, Nikaido T, Ochiai K, et al. Indoleamine 2,3-dioxygenase serves as a marker 
of poor prognosis in gene expression profiles of serous ovarian cancer cells. Clinical 
cancer research : an official journal of the American Association for Cancer Research. 
2005;11(16):6030-6039. 
24. 
Brandacher G, Perathoner A, Ladurner R, et al. Prognostic value of indoleamine 2,3-
dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells. Clinical 
cancer research : an official journal of the American Association for Cancer Research. 
2006;12(4):1144-1151. 
25. 
Holmgaard RB, Zamarin D, Munn DH, Wolchok JD, Allison JP. Indoleamine 2,3-
dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy 
targeting CTLA-4. The Journal of experimental medicine. 2013;210(7):1389-1402. 
26. 
D'Angelo SP, Shoushtari AN, Agaram NP, et al. Prevalence of tumor-infiltrating 
lymphocytes and PD-L1 expression in the soft tissue sarcoma microenvironment. Hum 
Pathol. 2015;46(3):357-365. 
27. 
Rusakiewicz S, Semeraro M, Sarabi M, et al. Immune infiltrates are prognostic factors in 
localized gastrointestinal stromal tumors. Cancer research. 2013;73(12):3499-3510. 
28. 
Shoushtari AN, D'Angelo SP, Keohan ML, et al. Combined KIT and CTLA-4 blockade 
in patients with refractory GIST and other advanced sarcomas. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology. 2014;32(5s 
(suppl; abstr 10521)). 
29. 
D'Angelo SP, Shoushtari AN, Keohan ML, et al. Combined KIT and CTLA-4 Blockade 
in Patients with Refractory GIST and Other Advanced Sarcomas: A Phase Ib Study of 
Dasatinib Plus Ipilimumab. Clinical cancer research : an official journal of the American 
Association for Cancer Research. 2016. 
30. 
Seifert AM, Zeng S, Zhang JQ, et al. PD-1/PD-L1 Blockade Enhances T-cell Activity 
and Antitumor Efficacy of Imatinib in Gastrointestinal Stromal Tumors. Clinical cancer 
research : an official journal of the American Association for Cancer Research. 
2017;23(2):454-465. 
31. 
Seifert AM, Kim TS, Greer JB, et al. PD-1/PD-L1 Blockade Enhances the Efficacy of 
Imatinib in Gastrointestinal Stromal Tumor (GIST). Journal of the American College of 
Surgeons. 2014;219(3, Supplement):S129. 
32. 
Gangadhar TC, Hamid O, Smith DC, et al. Epacadostat plus pembrolizumab in patients 
with advanced melanoma and select solid tumors: Updated phase 1 results from ECHO-

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202/KEYNOTE-037. Paper presented at: ESMO 2016 Congress2016; Copenhagen, 
Demark. 
33. 
Pembrolizumab [Investigator's Brochure]. Merck Pharmaceuticals Inc: October 2016. 
2016. 
34. 
Bohnsack O, Hoos A, Ludajc K. Adaptation of the Immune Related Response Criteria: 
IRRECIST. Annals of Oncology. 2014;25 (Supplement 4):iv369. 
35. 
Trussell J. Contraceptive failure in the United States. Contraception. 2004;70(2):89-96. 
 
 
 

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23. APPENDIX 
 
23.1. Appendix A: ECOG Performance Status Criteria. 
 
 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease performance 
without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., 
light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% of 
waking hours. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined to bed 
or chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
Dead. 
 
 
 
 

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23.2. Appendix B: Appropriate contraceptive methods for study subjects.  
 
The following methods have been determined to be more than 99% effective (<1% failure rate 
per year) when used consistently and correctly35 and are permitted under this Protocol for use by 
the subject and his/her partner: 
 
 Complete abstinence from sexual intercourse 
 A barrier method (male or female condom) in addition to one of the following: 
o Diaphragm or cervical cap with spermicide 
o Intrauterine device (IUD) 
o Birth control patch or vaginal ring 
o Oral, injectable, or implanted contraceptives 
 
 
 
 

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23.3. Appendix C: Prohibited Monoamine Oxidase Inhibitors (MAOi) and Drugs Associated 
with Significant MAOi Activity.  
 
 
Monoamine Oxidase Inhibitors (MAOi) 
Drugs Associated with Significant MAOi 
Activity 
Hydrazines (ex: phenelzine) 
Meperidine 
Caroxzone 
Linezolid 
Echinopsidine 
Methylene blue 
Furazolidone 
 
Tranylcypromine 
 
Brofaromine 
 
Metralindole 
 
Minaprine 
 
Moclobemide 
 
Pirlindole 
 
Toloxatone 
 
Lazbemide 
 
Pargyline 
 
Rasagiline 
 
Selegiline 
 
 
 
 
 

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23.4. 
Appendix D: Pill Diary 
 
 
Name:_______________        Date: _______________       Study ID/ MRN: _______________ 
 
Medication Diary for: A Phase II Study of Epacadostat (IDO inhibitor) and Pembrolizumab in 
Patients with Imatinib-Refractory Advanced Gastrointestinal Stromal Tumors 
 
 
Number of Capsules/Tablets Given   
Medication Bottle(s) returned:  Circle Yes or No 
Epacadostat: ______ 
 
 
Number of Capsules/Tablets returned 
 
 
 
 
Epacadostat: ______ 
 
Total Daily Dose (To be Completed by RN)  
Epacadostat: ______ 
 
 
   PLEASE FILL OUT AND BRING THIS SHEET AT YOUR NEXT VISIT. 
 
 
Please take dose of Epacadostat by mouth twice daily. Please allow for adequate time 
(approximately 12 hours) between your AM and PM dosing time and record below.  You are 
encouraged to remain consistent with your daily dosing schedule throughout your treatment.  Do 
not chew the capsules. 
 
Any dose missed or vomited should not be replaced. 
 
If you forget a dose but within 4 hours of its scheduled administration time, you should take it; if 
more than 4 hours have passed, note as dose missed and continue treatment with the next 
scheduled dose. 
 
Study Medication can be taken without regard to food (i.e., study medication can be taken with or 
without food).  
 
Please store study medications at room temperature. 
 
Please bring this diary with you to each appointment.   
 
 
 
 
 
CYCLE #: _______    # of WEEKS___________ 
DAY 
DATE 
TIME 
 
NUMBER of  
XXmg capsules 
taken 
Example 
01/01/2010 
9:00 
AM 
 
Epacadostat 
 
1 100mg tablet 
taken 
9:00 
PM 
 
Epacadostat 
 
1 100mg table 
taken 
Day 1 
 
 
 
AM 
 
 
Epacadostat 
 
 
 
PM 
 
 
Epacadostat 
 

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Day 2 
 
 
AM 
 
Epacadostat 
 
 
 
PM 
 
Epacadostat 
 
 
Day 3 
 
 
AM 
 
Epacadostat 
 
 
 
PM 
 
Epacadostat 
 
 
Day 4 
 
 
AM 
 
Epacadostat 
 
 
 
PM 
 
Epacadostat 
 
 
Day 5 
 
 
AM 
 
Epacadostat 
 
 
 
PM 
 
Epacadostat 
 
 
Day 6 
 
 
AM 
 
Epacadostat 
 
 
 
PM 
 
Epacadostat 
 
 
Day 7 
 
 
AM 
 
Epacadostat 
 
 
 
PM 
 
Epacadostat 
 
 
Day 8 
 
 
AM 
 
Epacadostat 
 
 
 
PM 
 
Epacadostat 
 
 
Day 9 
 
 
AM 
 
Epacadostat 
 
 
 
PM 
 
Epacadostat 
 
 

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Day 10 
 
 
AM 
 
Epacadostat 
 
 
 
PM 
 
Epacadostat 
 
 
Day 11 
 
 
AM 
 
Epacadostat 
 
 
 
PM 
 
Epacadostat 
 
 
Day 12 
 
 
AM 
 
Epacadostat 
 
 
 
PM 
 
Epacadostat 
 
 
Day 13 
 
 
AM 
 
Epacadostat 
 
 
 
PM 
 
Epacadostat 
 
 
Day 14 
 
 
AM 
 
Epacadostat 
 
 
 
PM 
 
Epacadostat 
 
 
Day 15 
 
 
AM 
 
Epacadostat 
 
 
 
PM 
 
Epacadostat 
 
 
Day 16 
 
 
AM 
 
Epacadostat 
 
 
 
PM 
 
Epacadostat 
 
 
Day 17 
 
 
AM 
 
Epacadostat 
 
 
 
PM 
 
Epacadostat 
 
 

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Day 18 
 
 
AM 
 
Epacadostat 
 
 
 
PM 
 
Epacadostat 
 
 
Day 19 
 
 
AM 
 
Epacadostat 
 
 
 
PM 
 
Epacadostat 
 
 
Day 20 
 
 
AM 
 
Epacadostat 
 
 
 
PM 
 
Epacadostat 
 
 
Day 21 
 
 
AM 
 
Epacadostat 
 
 
 
PM 
 
Epacadostat 
 
 
 
 
 
Patient Signature: ________________________________________Date: ___________ 
 
Research RN Signature: _____________________________________Date: ____________ 
 
Research RN Comments:_________________________________