Clinical trial NCT03602586
Conditions: Malignant Ovarian Clear Cell Tumor Recurrent Ovarian Carcinoma
Sponsor: National Cancer Institute (NCI)
Start date: 2018-12-21; Completion date: 2024-03-27
Enrollment: 14 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well pembrolizumab and epacadostat work in treating patients with ovarian clear cell carcinoma that has come back (recurrent), remains despite treatment (persistent), or is growing, spreading, or getting worse (progressive). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Epacadostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab and epacadostat may work better compared to usual treatment (surgery, radiation, or cytotoxic chemotherapy) in treating patients with ovarian clear cell carcinoma.

Detailed description:
PRIMARY OBJECTIVE:

I. To assess the objective tumor response (proportion of objective response by Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1 criteria) of the combination of pembrolizumab (MK-3475 \[pembrolizumab\]) and epacadostat in patients with recurrent or persistent clear cell carcinoma of the ovary.

SECONDARY OBJECTIVES:

I. To determine the nature and degree of toxicity of MK-3475 (pembrolizumab) + epacadostat as assessed by Common Terminology Criteria for Adverse Events (CTCAE) in patients with recurrent or persistent clear cell carcinoma of the ovary.

II. To estimate the progression-free survival (PFS) and overall survival (OS) in patients treated with combination of MK-3475 (pembrolizumab) and epacadostat.

EXPLORATORY TRANSLATIONAL OBJECTIVES:

I. Determine whether the ratio of plasma tryptophan to kynurenine (T:K) correlates with response to MK-3475 (pembrolizumab) + epacadostat, by evaluating plasma T:K pre-treatment, during treatment, and at disease progression.

II. Determine whether the presence of PD-L1, IDO-1, tumor-infiltrating regulatory T cells (Tregs), CD8 tumor-infiltrating lymphocytes (TILs), and human leukocyte antigen (HLA) class I in the tumor microenvironment at baseline correlates with objective response to MK-3475 (pembrolizumab) + epacadostat.

III. Determine whether soluble PD-L1 (sPD-L1) levels in plasma are correlated with response to MK-3475 (pembrolizumab) + epacadostat, by evaluating sPD-L1 concentrations pre-treatment, during treatment, and at disease progression.

OUTLINE:

Patients receive epacadostat orally (PO) twice daily (BID) and pembrolizumab intravenously (IV) over 30 minutes once every 3 weeks (Q3W). Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years, then every 6 months for 3 years, and annually thereafter.

Arms: arm 1: Patients receive epacadostat PO BID and pembrolizumab IV over 30 minutes Q3W. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Epacadostat intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Given PO intervention 2: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
 
NRG ONCOLOGY  
 
      NRG-GY016 
(ClinicalTrials.gov NCT #03602586) 
 
A Phase II Study of MK-3475 (Pembrolizumab) (NSC #776864) + Epacadostat (NSC 
#766086) in Recurrent Clear Cell Carcinoma of the Ovary. 
This trial is part of the National Clinical Trials Network (NCTN) program, which is sponsored 
by the National Cancer Institute (NCI).  
 
Lead Organization: NRG / NRG Oncology 
 
 
 
 
 
 
 
 
 
 
Coordinating Center:  
NRG Oncology 
Four Penn Center; 1600 JFK Blvd; Suite 1020;  
Philadelphia, PA 19103 
 
Study Team 
Study Chair 
Study Co-Chair (11-JUN-2020) 
 
 
Sunnybrook Odette Cancer Centre 
Memorial Sloan Kettering Cancer Center 
2705 Bayview Ave, T2-104 
Dept. of Medical Oncology 
Toronto, Ontario, M4N 3M5, Canada 
1275 York Ave 
416-480-4378/FAX: 416-480-6002 
New York, NY 10021 
  
646-888-4217/FAX: 646-888-4267 
 
   
 
 
Scientific Collaborator 
Statistician 
 
 
Mayo Clinic, Dept. of Oncology 
NRG Oncology Statistics and Data   
200 First St. SW  
Management Center-Buffalo 
Rochester, MN 55905 
Roswell Park Cancer Institute 
507-284-3731/FAX: 507-284-1803 
Elm and Carlton Streets 
  
Buffalo, NY 14263 
 
716-854-5702/FAX: 716-845-8393 
 
  
Participating Organizations  
ALLIANCE / Alliance for Clinical Trials in Oncology 
ECOG-ACRIN / ECOG-ACRIN Cancer Research Group 
SWOG / SWOG 
NCTN Group Study Champions: 
ALLIANCE: 
 
SWOG: 
 


 
 
 
Research Nurse 
Translational Scientist (11-JUN-2020) 
 
 
University Hospitals Cleveland Med Ctr 
NRG Oncology-Philadelphia East 
11100 Euclid Ave 
Four Penn Center, 1600 JFK Blvd., Ste 1020 
Cleveland, OH 44106 
Philadelphia, PA 19103 
216-844-8160/Fax: 216-844-8596 
215-854-0770/FAX: 215-8540716 
  
  
 
 
 
 
 
NRG Oncology Contact Information (11-JUN-2020) 
Data Management 
For questions concerning data 
submission 
r 
NRG Oncology Statistics and Data Management Center- 
Pittsburgh  
201 N. Craig St., Suite 500 
Pittsburgh, PA 15213 
412-383-4225/FAX: 412-624-1082 
   
Protocol Development 
For questions concerning protocol 
and informed consent versions and 
amendments 
Protocol Coordinator  
 
NRG Oncology-Philadelphia East 
Four Penn Center, 1600 JFK Blvd., Ste 1020 
Philadelphia, PA 19103 
267-295-9489 
  
Regulatory 
NRG-GY-Regulatory@nrgoncology.org  
Biospecimen Bank 
For questions concerning 
biospecimen collection and 
translational research 
NRG BB-Columbus 
Biopathology Center, Nationwide Children’s Hospital 
700 Children’s Dr, WA1340 
Columbus, OH 43205 
Phone: (614) 722-2865/FAX: 614-722-2897 
Email: bpcbank@nationwidechildrens.org 
Gynecologic Oncology 
Committee Chair 
 
Memorial Sloan Kettering Cancer Center 
Department of Medicine 
1275 York Avenue 
New York, NY 10065 
(646) 888-4217 
  
 
 
 
 
 


Participating Sites 
 U.S. 
 Canada 
 Approved International Member Sites 
Document History 
Version/Update Date 
Closure 
Amendment 6 
June 11, 2020 
Amendment 5 
February 28, 2020 
Amendment 4 
October 16, 2019 
Amendment 3 
April 22, 2019 
Amendment 2 
January 16, 2019 
Amendment 1 
December 11, 2018 
Activation 
August 28, 2018 
Protocol Agent 
NCI-Supplied Agent(s): MK-3475 (Pembrolizumab), NSC 776864; Epacadostat 
(INCB024360), NSC 766086 
IND #: 
IND Sponsor: DCTD, NCI 


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NRG-GY016 
A Phase II Study of MK-3475 (Pembrolizumab) (NSC #776864) + Epacadostat (NSC 
#766086) in Recurrent Clear Cell Carcinoma of the Ovary. 
CONTACT INFORMATION (11 -JUN-2020) 
 
For regulatory requirements: 
For patient enrollments: 
For data submission: 
Regulatory documentation must 
be submitted to the CTSU via 
the Regulatory Submission 
Portal. 
 (Sign in at www.ctsu.org,            
and select the Regulatory > 
Regulatory Submission.)  
 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately at 1-866-651-2878 
to receive further instruction 
and support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 
for regulatory assistance. 
Refer to the patient enrollment 
section of the protocol for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN). OPEN is 
accessed at 
https://www.ctsu.org/OPEN SYS
TEM/ or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related questions 
by phone or email : 1-888-823-
5923 or ctsucontact@westat.com. 
 
 
Data collection for this study 
will be done exclusively through 
Medidata Rave.  Please see the 
data submission section of the 
protocol for further instructions.  
 
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU members’ website located at (https://www.ctsu.org).  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program 
- Identity and Access Management (CTEP-IAM) registration system and requires log in with a CTEP-
IAM username and password. Permission to view and download this protocol and its supporting 
documents is restricted and is based on person and site roster assignment housed in the CTSU 
Regulatory Support System RSS.   
 
For clinical questions (i.e. patient eligibility or treatment-related) contact the Study PI of the Lead 
Protocol Organization. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) Contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Website is located at https://www.ctsu.org. 
 
 
 
 
 
 
 
 
 
This protocol was designed and developed by NRG Oncology. It is intended 
to be used only in conjunction with institution-specific IRB approval for 
study entry.  No other use or reproduction is authorized by NRG Oncology 
nor does NRG Oncology assume any responsibility for unauthorized use of 
this protocol. 


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TABLE OF CONTENTS 
SCHEMA.........................................................................................................................................6 
1.
OBJECTIVES ......................................................................................................................7 
 
Primary Objective ....................................................................................................7 
 
Secondary Objectives ...............................................................................................7 
 
 
2.
BACKGROUND .................................................................................................................7 
 
Recurrent Clear Cell Carcinoma of the Ovary .........................................................7 
 
PD-1 and PD-L1 Targeting......................................................................................8 
 
MK-3475 (Pembrolizumab) Pharmaceutical and Therapeutic Background ............8 
 
MK-3475 (Pembrolizumab) Preclinical and Clinical Study Data ...........................9 
 
Rationale for the Study and Selected Patient Population .......................................12 
 
Rationale for Combination Therapy with IDO-1 Inhibitor ....................................12 
 
Epacadostat Pharmaceutical and Therapeutic Background ...................................13 
 
Epacadostat Preclinical and Clinical Study Data ...................................................14 
 
Epacadostat in combination with MK-3475 (Pembrolizumab) .............................16 
 
Rationale for Dose Selection/Regimen: Fixed Dose MK-3475 
(Pembrolizumab)....................................................................................................17 
 
Rationale for Current Trial .....................................................................................19 
2.13 
Translational Research Background ......................................................................19 
 
Inclusion of Women and Minorities ......................................................................20 
3.
PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILTY CRITERIA .................21 
 
Patient Selection Guidelines ..................................................................................21 
 
Eligibility Criteria ..................................................................................................21 
 
Ineligibility Criteria ...............................................................................................22 
4.
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP ..........24 
5.
TREATMENT PLAN/Regimen description ......................................................................27 
 
Treatment Plan .......................................................................................................27 
 
General Concomitant Medication and Supportive Care Guidelines ......................28 
 
Duration of Therapy ...............................................................................................30 
6.
TREATMENT MODIFICATIONS/managEment.............................................................30 
 
Adverse Drug Reactions requiring Discontinuation or Delays: ............................30 
 
MK-3475 (pembrolizumab) Infusion-Related Reactions ......................................31 
 
Immune-Related Adverse Events (irAEs) General Definition, Monitoring, 
and Management....................................................................................................33 
 
Supportive Care Guidelines ...................................................................................36 
 
Serotonin Syndrome...............................................................................................39 
7.
ADVERSE EVENTS REPORTING REQUIREMENTS .................................................40 
 
Protocol Agents ......................................................................................................40 
 
Adverse Events and Serious Adverse Events ........................................................40 


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Comprehensive Adverse Events and Potential Risks (CAEPR) List for 
CTEP and CIP Study Agents .................................................................................40 
 
Expedited Reporting of Adverse Events ................................................................46 
8.
REGISTRATION, STUDY ENTRY, AND WITHDRAWAL PROCEDURES ..............49 
 
Cancer Trials Support Unit Registration Procedures .............................................50 
8.2 
Patient Enrollment .................................................................................................52 
 
Data Submission/Data Reporting ...........................................................................53 
9.
DRUG INFORMATION ...................................................................................................55 
 
MK-3475 (Pembrolizumab) (NSC 776864) ...........................................................55 
 
Epacadostat (NSC 766086) ....................................................................................57 
 
Agent Ordering and Agent Accountability ............................................................58 
10.
BIOSPECIMEN.................................................................................................................60 
 
Biospecimen Submission Tables ...........................................................................60 
 
 
 
Banking Biospecimens for Future Research ..........................................................61 
11.
ASSESSMENT OF EFFECT ............................................................................................61 
 
Definition of Disease Assessments........................................................................62 
 
Disease Parameters ................................................................................................62 
 
Methods for Evaluation of Measurable Disease ....................................................63 
 
NRG will not allow PET-CT use for RECIST 1.1 response criteria. ....................64 
 
Response Criteria ...................................................................................................64 
 
 
 
Duration of Response .............................................................................................66 
 
Progression-Free Survival ......................................................................................67 
 
Survival ..................................................................................................................67 
12.
DATA AND RECORDS ...................................................................................................67 
 
Summary of Data Submission ...............................................................................67 
 
Global Reporting/Monitoring ................................................................................67 
13.
STATISTICAL CONSIDERATIONS...............................................................................67 
 
Study Design..........................................................................................................67 
 
Study Endpoints .....................................................................................................68 
 
Primary Objectives Study Design..........................................................................68 
 
Study Monitoring of Primary Objectives ...............................................................69 
 
Accrual/Study Duration Considerations ................................................................70 
 
Dose Level Guidelines ...........................................................................................71 
 
Secondary or 
 (including correlative science aims) ...........71 
13.8 
 
13.9 
Gender/Ethnicity/Race Distribution ..................................................................73 
14.
REFERENCES ..................................................................................................................75 
APPENDIX I – PERFORMANCE STATUS CRITERIA ............................................................80 




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Recurrent or persistent clear cell carcinoma of the ovary 
 MK-3475 (Pembrolizumab) 200 mg IV q 3 weeks and epacadostat 100 mg 
po BID (Cycle = 21 days) until disease progression or adverse effects 
prohibit further treatment. 
Cycle = 21 days 
Accrual Goal: 23 
 
 
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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. OBJECTIVES 
Primary Objective 
To assess the objective tumor response (proportion of objective response by RECIST 1.1 
criteria) of the combination of MK-3475 (pembrolizumab) and epacadostat in patients 
with recurrent or persistent clear cell carcinoma of the ovary. 
Secondary Objectives 
To determine the nature and degree of toxicity of MK-3475 (pembrolizumab) + 
epacadostat as assessed by CTCAE in patients with recurrent or persistent clear cell 
carcinoma of the ovary. 
To estimate the progression-free survival (PFS) and overall survival (OS) in patients 
treated with combination of MK-3475 (pembrolizumab) and epacadostat. 
 
 
 
 
 
 
 
 
 
  
 
2. BACKGROUND 
Recurrent Clear Cell Carcinoma of the Ovary 
Clear cell carcinoma of the ovary has an estimated prevalence of 3-12% of all epithelial 
ovarian carcinomas (Anglesio et al., 2011). Clear cell carcinomas of the ovary have a 
distinct clinical behavior when compared to other epithelial ovarian carcinomas, with a 
worse prognosis especially in advanced disease (Sugiyama et al., 2000; Jenison et al., 
1989; Mackay et al., 2010). The low survival rates in clear cell carcinomas of the ovary 
may reflect their lack of sensitivity to platinum-based chemotherapy (Sugiyama et al., 
2000; Takano et al., 2006). Recurrent or persistent clear cell carcinoma of the ovary is 
particularly chemoresistant with response rates of <10% (Takano et al., 2008). Not only 
is this histologic subtype of ovarian cancer disproportionately represented in ovarian 
cancer clinical trials, the lack of effective therapy leads to clear cell carcinoma having 
proportionately increased representation for limited options in the recurrent setting. There 
is an unmet need for therapeutic options in this disease type, given the particularly poor 
prognosis of this tumor type upon recurrence, the lack of effective treatment, and the 
rarity of this disease. Future treatment of this disease may rest on novel therapies. 


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PD-1 and PD-L1 Targeting 
PD-1 receptor is expressed by activated T-cells resulting in reduced cytokine production, 
cytolytic activity, and lymphocyte proliferation. The activation of PD-1 represents a 
major mechanism for suppressing anti-cancer T-cell responses (Menderes et al., 2016). 
These effects are mediated through its ligands PD-L1 and PD-L2. Many types of human 
tumors, including ovarian cancer, express PD-L1 (Kooi et al., 1996). When PD-L1 binds 
with PD-1, T-cell activity is attenuated, preventing the immune system from eliminating 
the tumor at the tissue level (Mellman et al., 2011). Blockade of PD-1 or PD-L1 with 
monoclonal antibodies can enhance T-cell activity, augmenting the anti-cancer immune 
response with the potential to produce durable clinical responses (Brahmer et al., 2012; 
Topalian et al., 2012). PD-L1 expression is associated with poor prognosis in ovarian 
cancer (Zhang et al., 2003) and PD-L1 also promotes progression of ovarian cancer by 
inducing host immune-suppression of peripheral cytotoxic CD8+ T cell lymphocytes 
(Abiko et al., 2013). 
 
MK-3475 (Pembrolizumab) Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades (Disis 2010). Accumulating evidence shows 
a correlation between tumor-infiltrating lymphocytes (TILs) in cancer tissue and 
favorable prognosis in various malignancies (Dong et al., 2002; Sharpe et al., 2002; 
Brown et al., 2003; Francisco et al., 2010; Thompson et al., 2007). 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) (Talmadge et al., 2007; Usubutun et al., 1998]. The structure of murine PD-1 has 
been resolved (Al-Shibli et al., 2008). 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 
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 CD3, 
PKCӨ and the CD3 T-cell signaling cascade (Talmadge et al., 2007;  
Deschoolmeester et al., 2010; Diez et al., 1998; Galon et al., 2006). The mechanism by 
which PD-1 down modulates T-cell responses is similar to, but distinct from that of 
CTLA-4 as both molecules regulate an overlapping set of signaling proteins (Hiraoka et 
al., 2010; Nobili et al., 2008]. PD-1 was shown to be expressed on activated lymphocytes 


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including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells 
(Hodi et al., 2010; Kloor 2009). Expression has also been shown during thymic 
development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages 
and dendritic cells (Hillen et al., 2008). The ligands for PD-1 (PD-L1 and PD-L2) are 
constitutively expressed or can be induced in a variety of cell types, including non-
hematopoietic tissues as well as in various tumors (Lee et al., 2008; Leffers et al., 2009; 
Nishimura et al., 2000; Hiraoka et al., 2010). 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 (Hiraoka et al., 2010). Although 
healthy organs express little (if any) PD-L1, a variety of cancers were demonstrated to 
express abundant levels of this T-cell inhibitor. PD-1 has been suggested to regulate 
tumor-specific T-cell expansion in subjects with melanoma (MEL) (Liotta et al., 2010). 
This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune 
evasion and should be considered as an attractive target for therapeutic intervention. 
 
MK-3475 (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. MK-3475 (Pembrolizumab) has 
recently been approved in the United States for the treatment of patients with 
unresectable or metastatic melanoma and patients with metastatic non-small cell lung 
cancer whose tumors express PD-L1 as determined by an FDA-approved test and who 
have disease progression on or after platinum-containing chemotherapy. 
 
MK-3475 (Pembrolizumab) Preclinical and Clinical Study Data 
2.4.1 Nonclinical Toxicology 
 
The safety of MK-3475 (pembrolizumab) was evaluated in a 1-month and a 6-month 
repeat-dose toxicity study in Cynomolgus monkeys administered IV doses of 6, 40 or 200 
mg/kg once a week in the 1-month study and once every 2 weeks in the 6-month study, 
followed by a 4-month treatment-free period. No findings of toxicological significance 
were observed and the NOAEL in both studies was ≥200 mg/kg, which produced 
exposure multiples of 19 and 94 times the exposure in humans at doses of 10 and 2 
mg/kg, respectively. The exposure multiple between the NOAEL and a human dose of 
200 mg was 74. 
 
The carcinogenic potential of MK-3475 (pembrolizumab) in long-term animal studies, as 
well as the genotoxic potential of MK-3475 (pembrolizumab) have not been evaluated as 
these studies are not required to support treatment of cancer patients. 
 


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Animal reproduction studies have not been conducted with MK-3475 (pembrolizumab). 
The central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining 
immune tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine 
models of pregnancy to disrupt tolerance to the fetus and to result in an increase in fetal 
loss. These results indicate a potential risk that administration of MK-3475 
(pembrolizumab) during pregnancy could cause fetal harm, including increased rates of 
abortion or stillbirth. 
 
Developmental toxicity studies have not been conducted with MK-3475 
(pembrolizumab). There were no notable effects in the male and female reproductive 
organs in monkeys based on 1-month and 6-month repeat dose toxicity studies. 
 
2.4.2 Clinical Efficacy 
 
Many clinical trials have been conducted to evaluate the efficacy of MK-3475 
(pembrolizumab) to treat various cancers. MK-3475 (pembrolizumab) has demonstrated 
robust, substantial, and clinically meaningful benefit in the treatment of melanoma, non-
small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), 
urothelial carcinoma (UC), and microsatellite instability-high (MSI-H) tumors based on 
Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) criteria and 
immune-related RECIST (irRECIST) recommendations. For classical Hodgkin 
lymphoma (cHL), demonstration of clinically meaningful benefit was based on Revised 
Response Criteria for Malignant Lymphoma (2007) from the International Working 
Group (IWG). 
 
For the treatment of unresectable or metastatic melanoma, MK-3475 (pembrolizumab) 
demonstrated superior efficacy over available treatment options (IPI, Investigator’s 
choice chemotherapy) in participants with advanced melanoma who were treatment-
naïve, as well as those who progressed on prior therapy, including IPI. 
 
MK-3475 (Pembrolizumab) provided substantial, clinically meaningful benefits in OS, 
PFS, and ORR in participants with NSCLC who progressed after platinum-containing 
chemotherapy and whose tumor cells expressed PD-L1. In previously treated participants 
with PD-L1 TPS ≥1% and disease progression following platinum-containing 
chemotherapy, MK-3475 (pembrolizumab) provided a statistically significant and 
clinically meaningful OS benefit compared to standard docetaxel chemotherapy. For 
participants with previously untreated metastatic NSCLC whose tumors express high 
levels of PD-L1, MK-3475 (pembrolizumab) demonstrated significant improvements in 
PFS and OS over standard of care chemotherapy. 
 
For the treatment of advanced HNSCC in a heavily pretreated population, MK-3475 
(pembrolizumab) demonstrated a clinically meaningful response rate and a prolonged 
duration of response that is substantially distinct from what is expected with standard of 
care in previously treated participants with HNSCC, and points to the meaningful clinical 
benefit of MK-3475 (pembrolizumab). 
 


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MK-3475 (Pembrolizumab) for the treatment of relapsed or refractory cHL, has 
demonstrated durable, robust, clinically meaningful responses in this heavily pretreated 
population that generally included standard front-line therapies, salvage therapies, auto-
SCT if eligible with chemo-sensitive disease, other single agent or combination 
chemotherapy regimens as needed, and with or without brentuximab vedotin (BV). 
 
For the treatment of urothelial carcinoma (UC) in participants who have not received 
prior chemotherapy and are cisplatin-ineligible, MK-3475 (pembrolizumab) 
demonstrated a clinically meaningful ORR in participants with locally advanced or 
metastatic UC. In participants with locally advanced or metastatic UC who have received 
platinum-containing chemotherapy, treatment with MK-3475 (pembrolizumab) 
demonstrated a significant improvement in OS and a clinically meaningful benefit in 
durable responses compared with standard of care therapies. 
 
In participants with MSI-H tumors, MK-3475 (pembrolizumab) provided evidence of 
clinically meaningful benefit over standard treatments, regardless of tumor histology. 
 
2.4.3 Clinical Safety 
 
MK-3475 (Pembrolizumab) has a positive benefit-risk profile and is well tolerated in the 
approved indications, as evidenced by a low rate of toxicity Grade 3 to 5 drug-related 
adverse events (AEs) (13.8%), discontinuations due to AEs (11.9%), and deaths due to 
drug-related AEs (0.4%). Furthermore, the frequency of immune-mediated adverse 
events of special interest (AEOSI) is low, and these events are readily managed in the 
clinical setting. 
 
MK-3475 (pembrolizumab) is generally well tolerated and demonstrates a favorable 
safety profile in comparison to chemotherapy. MK-3475 (Pembrolizumab) is an 
immunomodulatory agent, and based on this mechanism of action, immune-mediated 
AEs are of primary concern. The important identified risks for MK-3475 
(pembrolizumab) are of an immune-mediated nature, and included the following in the 
last IB (v13): pneumonitis; colitis; hepatitis; nephritis; endocrinopathies that include 
hypophysitis (including hypopituitarism and secondary adrenal insufficiency), thyroid 
disorder (hypothyroidism, hyperthyroidism), and Type I diabetes mellitus; uveitis; 
myositis; Guillain-Barré syndrome; pancreatitis; myocarditis; severe skin reactions 
including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some 
with fatal outcome; and “solid organ transplant rejection following MK-3475 
(pembrolizumab) treatment in donor organ recipients” (risk applicable to post-marketing 
setting only, as such patients are currently excluded from Merck clinical trials with MK-
3475 (pembrolizumab)). The majority of immune-mediated AEs were mild to moderate 
in severity, manageable with appropriate care, and rarely required discontinuation of 
therapy. 
 
In addition to the immune-related risks noted above, infusion-related reactions are also an 
important identified risk for MK-3475 (pembrolizumab); however, they are not 
considered immune-mediated. 


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Consultation with the appropriate medical specialist should be considered when 
investigating a possible immune-related adverse event (irAE). These events can occur at 
times ranging from after the first dose to several months after the last dose of treatment. 
Mild irAEs are usually treated symptomatically and infrequently require dosing delays or 
discontinuation. Higher grade and persistent lower grade irAEs typically necessitate 
withholding or discontinuing treatment, and administration of systemic steroids or other 
immunosuppressive agents (such as tumor necrosis factor blockers) when systemic 
steroids are not effective. Early recognition of irAEs and initiation of treatment are 
critical to reduce the risk of complications because the majority of irAEs are reversible 
with the use of steroids and other immune suppressants. 
 
Rationale for the Study and Selected Patient Population 
 
In studies evaluating activity of anti-PD-1 or anti-PD-L1 antibodies in ovarian cancer, 
eligible patients have included all histologic subtypes of ovarian cancer, mainly high 
grade serous histology (Haminishi et al., 2015; Disis et al., 2015). Notably, in two 
studies, durable objective responses were seen in patients with ovarian clear cell 
carcinoma. In a phase II study by Hamanishi et al. (2015), 20 patients with platinum-
resistant ovarian cancer were treated with nivolumab, an anti-PD-1 antibody. The disease 
control rate was 45%. Two patients had a durable complete response (CR), one of whom 
had clear cell carcinoma with recurrent disease and peritoneal dissemination. After two 
courses of nivolumab, the peritoneal lesions disappeared and CA-125 decreased to 
normal range. The patient completed a 1-year trial of nivolumab and continued to 
experience a CR at time of study publication. In another phase II study by Disis et al. 
(2015), avelumab, an anti-PD-L1 antibody, was evaluated in recurrent ovarian cancer 
patients with multiple previous lines of chemotherapy. Among 75 patients, there was an 
overall response rate of 17.4% and stable disease in 47.8%. Tumor shrinkage by ≥30% 
was observed in 14.7% of patients, including 2 patients with clear cell histology. These 
cases are compelling given the general chemo-refractory state of recurrent ovarian clear 
cell carcinomas. These immune checkpoint inhibitors may have particular benefit for 
patients with this rare histologic subtype. At this point however, there have been no 
studies of immunotherapy dedicated to clear cell carcinomas of the ovary. 
Rationale for Combination Therapy with IDO-1 Inhibitor 
Although these early studies of immune checkpoint inhibitors in recurrent ovarian cancer 
have demonstrated promise, the overall response rate with these single agents is 
approximately 15%. In order to improve these results, strategies incorporating 
combinations of immunotherapy is needed. Regulatory T cells (Tregs) have an important 
role in ovarian cancer pathogenesis and outcome (Sato et al., 2005; Wolf et al., 2005). 
Low ratio of CD8+ T cells to CD4+CD25+FoxP3+ Tregs is associated with poor 
survival, and therefore Tregs are a potential target to disrupt local immune suppression in 
ovarian cancer (Preston et al., 2013). In clear cell ovarian cancers specifically, inherited 
variants in genes encoding Treg related immune molecules are significantly associated 


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with poorer survival compared to serous cancers (Goode et al., 2013). Moreover, in 
contrast to high grade serous cancers where the increase of CD8+ T cells is associated 
with improved survival (HR 0.57, 95%CI 0.49-0.65, p=4.2 x 10-16), in clear cell cancers 
there is no association between CD8+ T cells and survival (HR 0.92, 95% CI 0.61-1.39, 
p=0.50), possibly because of the prominent role of Tregs in this subtype (Goode et al., 
2017). An agent that can address the high degree of Tregs in the tumor microenvironment 
in combination with an anti-PD-1 antibody could enhance the immunotherapy effect that 
has been initially seen in clear cell carcinoma. 
Indoleamine 2, 3-dioxygenase 1 (IDO1) is an enzyme that catalyzes oxidative catabolism 
of the amino acid tryptophan (Trp) to kynurenine (Takikawa et al., 2005). This 
catabolism of Trp results in the inhibition of antitumor cell–mediated immune responses. 
Histologic evaluation of most human cancers shows extensive infiltration by 
inflammatory and immune cells, suggesting that the immune system does recognize and 
respond to the presence of the malignancy (Galon et al., 2006), but in most cases the 
immune response is ineffective in inhibiting or eradicating tumor growth. Many tumor 
cells or the infiltrating immune cells overexpress IDO1, and there have been multiple 
lines of evidence to suggest that IDO1 is a key regulator in the immunosuppressive 
mechanisms responsible for tumor escape from immune surveillance (Liu et al., 2009). 
Therefore, inhibition of this enzyme may provide a unique method to treat malignancies, 
either alone or in combination with chemotherapeutics or other immune-based therapies. 
 
 
 
 
 
 
 
 
 
 
Epacadostat Pharmaceutical and Therapeutic Background
 
Epacadostat (INCB024360) is a potent, selective oral inhibitor of IDO1. Inhibiting IDO1 
leads to decreased kynurenine, and downstream downregulation of Tregs, thereby 
increasing the antitumor immune response. Because IDO1 catabolism of tryptophan (Trp) 
inhibits T-cell–mediated immune responses and IDO1 expression has been shown to be 
elevated in many human cancers, IDO1 inhibition may restore an effective antitumor 
immune response and may provide a method to treat malignant diseases either alone or in 
combination with chemotherapeutics and/or immunotherapy-based strategies. 
 
 
 
 
 
 


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Epacadostat Preclinical and Clinical Study Data 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.8.2 Clinical Efficacy 
 
There is no evidence of clinically meaningful antitumor activity for epacadostat 
monotherapy. Based on preliminary data from ongoing Study INCB 24360-202, 
epacadostat in combination with MK-3475 (pembrolizumab) demonstrated promising 
antitumor activity in subjects with advanced melanoma, head and neck squamous cell 
carcinoma (HNSCC), NSCLC, UC, and renal cell carcinoma (RCC); the response 
outcomes in triple negative breast carcinoma (TNBC) and ovarian cancer were consistent 
with those previously reported for MK-3475 (Pembrolizumab) monotherapy in PD-L1–
positive subjects. 
 
 
 


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2.8.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
Epacadostat in combination with MK-3475 (Pembrolizumab) 
Preliminary results from a phase I/II study of epacadostat in combination with MK-3475 
(pembrolizumab), an anti-PD-1 antibody, have been reported in patients with advanced 
cancers (Gangadhar et al., 2015). In this dose-escalation and dose-expansion study, 
patients were given MK-3475 (pembrolizumab) 2 mg/kg IV or 200 mg IV every 3 weeks 
with epacadostat at doses of 25 mg PO BID, 50 mg BID, 100 mg BID. Nineteen patients 
were evaluable. Overall response rate was 53% with 3 complete responses. The overall 
disease control rate was 74%, with an especially profound effect in patients with 
melanoma. The latest updated results have demonstrated that epacadostat in combination 
with MK-3475 (pembrolizumab) demonstrates promising anti-tumor activity in patients 
with advanced melanoma, HNSCC, NSCLC, UC, and RCC with ORRs of 33%-56%. The 
disease control rates (DCRs) were 50-71%. 


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In Phase 2 of this study, 294 subjects received ≥ 1 dose of study treatment (epacadostat 
100 mg BID + MK-3475 (Pembrolizumab) 200 mg Q3W) and were included in the 
safety analysis. The median (range) epacadostat exposure was 13.6 (1.0+ to 70.7+) 
weeks. 
 
Treatment-related TEAEs occurred in 67% of Phase 2 subjects and Grade 3/4 treatment-
related TEAEs occurred in 18% of Phase 2 subjects. The most common treatment-related 
TEAEs were fatigue, rash, nausea, and pruritus. The frequency of Grade 3/4 treatment-
related TEAEs was low across all tumor types. 
 
Treatment-related TEAEs leading to dose interruptions occurred in 18% of subjects; the 
most common were rash (3%), fatigue (3%), and lipase increased (3%). Treatment-
related TEAEs leading to dose reductions occurred in 5% of subjects; the most common 
were rash (2%), fatigue (2%), and lipase increased (1%). Treatment-related TEAEs 
leading to treatment discontinuation occurred in 4% of subjects; the most common were 
arthralgia and rash (n = 2 each). 
 
There was 1 treatment-related death due to respiratory failure (secondary to aspiration 
pneumonia; pneumonitis could not be ruled out). TEAEs of special interest and Grade 3/4 
TEAEs of special interest occurred in 11% and 4% of subjects, respectively. 
 
The frequency of Grade 3/4 AEs was low and similar across all tumor types. 
 
Based on this data, a phase III study in melanoma comparing MK-3475 (pembrolizumab) 
+ epacadostat versus MK-3475 (pembrolizumab) alone has been activated 
(clinicaltrials.gov). 
 
Currently, although there is a Phase I/II study of MK-3475 (pembrolizumab) and 
epacadostat in patients with selected cancers, which includes ovarian neoplasms 
(clinicaltrials.gov) to date, there have been no clear cell carcinomas included amongst the 
enrolled ovarian cancer patients due to the rarity of this subtype. 
 
 
 
 
Rationale for Dose Selection/Regimen: Fixed Dose MK-3475 (Pembrolizumab)
 
The dose regimen of 200 mg Q3W of MK-3475 (pembrolizumab) is planned for all 
urothelial cancer trials. Available PK results in subjects with melanoma, NSCLC, and 
other solid tumor types support a lack of meaningful difference in PK exposures obtained 
at a given dose among tumor types. An open-label Phase I trial (PN001) in melanoma 
subjects is being conducted to evaluate the safety and clinical activity of single agent 
MK-3475 (pembrolizumab). 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-


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limiting toxicities were observed. This first in human study of MK-3475 
(pembrolizumab) 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 maximum 
tolerated dose (MTD) has been identified. 
 
In KEYNOTE-001, two randomized cohort evaluations of melanoma subjects receiving 
MK-3475 (pembrolizumab) at a dose of 2 mg/kg versus 10 mg/kg Q3W have been 
completed. The clinical efficacy and safety data demonstrate a lack of clinically 
important differences in efficacy response or safety profile at these doses. For example, 
in Cohort B2, advanced melanoma subjects who had received prior ipilimumab therapy 
were randomized to receive MK-3475 (pembrolizumab) at 2 mg/kg versus 10 mg/kg 
Q3W. The overall response rate (ORR) was 26% (21/81) in the 2mg/kg group and 26% 
(25/79) in the 10 mg/kg group (full analysis set (FAS)). The proportion of subjects with 
drug-related adverse events (AEs), grade 3-5 drug-related AEs, serious drug-related AEs, 
death or discontinuation due to an AE was comparable between groups or lower in the 10 
mg/kg group. 
 
Available pharmacokinetic results in subjects with melanoma, NSCLC, and other solid 
tumor types support a lack of meaningful difference in pharmacokinetic exposures 
obtained at a given dose among tumor types. Population PK analysis has been performed 
and has confirmed the expectation that intrinsic factors do not affect exposure to MK-
3475 (pembrolizumab) to a clinically meaningful extent. Taken together, these data 
support the use of lower doses (with similar exposure to 2 mg/kg Q3W) in all solid tumor 
indications. 2 mg/kg Q3W is being evaluated in NSCLC in PN001, Cohort F30 and 
PN010, and 200 mg Q3W is being evaluated in head and neck cancer in PN012, which 
are expected to provide additional data supporting the dose selection. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Rationale for Current Trial 
 
Inhibition of the PD-1 receptor is promising with early results demonstrating examples of 
durable objective responses in patients with clear cell carcinomas of the ovary. However, 
the immunotherapy studies in ovarian cancer have included all histologic types and there 
has not been a dedicated study for clear cell carcinomas. It is clear from early studies that 
a combination approach for immunotherapy is warranted to improve response rates even 
further. The combination of MK-3475 (pembrolizumab) (anti-PD-1 antibody) and 
epacadostat (IDO1 inhibitor) has demonstrated promising results in melanoma, such that 
a phase III trial in melanoma is being conducted with this combination. This combination 
should be applied to recurrent clear cell carcinomas to determine if the profound effects 
of PD-1 inhibition can be further enhanced with IDO1 inhibition. For recurrent clear cell 
ovarian cancer in particular, where historically the response to standard chemotherapy is 
<10%, an improvement in this outcome is greatly needed. 
2.13
Translational Research Background 
Recurrent clear cell ovarian cancer (CCOC) has a poor prognosis and limited treatment 
options.  The current protocol tests the combination of the PD-1-blocking monoclonal 
antibody MK-3475 (pembrolizumab) (PEM) and the IDO-1 inhibitor epacadostat (EPAC) 
in patients with recurrent CCOC.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Regulatory T cells (Tregs) are key peripheral mediators of immunologic self-tolerance 
and can downmodulate inflammatory responses to self-tissues (Panduro et al., 2016).  
Ovarian tumors are frequently infiltrated by Tregs, and Tregs are associated with poor 
prognosis in ovarian cancer (Curiel et al., 2004).  
 
 
 


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Inclusion of Women and Minorities 
NRG Oncology and NRG participating institutions will not exclude potential subjects 
from participating in this or any study solely on the basis of ethnic origin of 
socioeconomic status. Every attempt will be made to enter all eligible patients into this 
protocol and therefore address the study objectives in a patient population representative 
of the entire ovarian cancer population treated by participating institutions. 


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3. PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILTY CRITERIA 
Note: Per NCI guidelines, exceptions to inclusion and exclusion criteria are not 
permitted.  For questions concerning eligibility, please contact the Statistics and Data 
Management Center (via the contact list on the NRG web site). For radiation therapy-related 
eligibility questions, please contact RTQA (via the contact list on the NRG web site). [Insert 
appropriate center/person and location of contact information] 
Patient Selection Guidelines 
Although the guidelines provided below in 3.1.1 and 3.1.2 are not inclusion/exclusion 
criteria, investigators should consider these factors when selecting patients for this trial. 
Investigators also should consider all other relevant factors (medical and non-medical), as 
well as the risks and benefits of the study therapy, when deciding if a patient is an 
appropriate candidate for this trial. 
 Patients must have the psychological ability and general health that permits completion 
of the study requirements and required follow up. 
 Submission of formalin-fixed, paraffin embedded tumor tissue is required for all 
patients. Investigators should check with their site Pathology Department regarding 
release of biospecimens before approaching patients about participation in the trial. (See 
details of X submissions in Sections 9 and 10.) 
Eligibility Criteria
A patient cannot be considered eligible for this study unless ALL of the following 
conditions are met. 
Primary tumors must be at least 50% clear cell histomorphology in order to be eligible or 
have a histologically documented recurrence with at least 50% clear cell 
histomorphology. Recurrence should be biopsy proven as per standard of care unless the 
tumor is located in an area deemed unsafe to biopsy. Histologic confirmation of the 
original primary tumor is required via the pathology report.  
The percentage of clear cell histomorphology must be documented in the pathology 
report or in an addendum to the original report. If slides of the primary tumor are not 
available for review due to disposal of slides by the histology laboratory (typically 10 
years after diagnosis), a biopsy of the recurrent or persistent tumor is required to confirm 
at least 50% clear cell histomorphology, as long as tumor is located in an area deemed 
safe to biopsy. The percentage of clear cell involvement must be documented in the 
pathology report or in an addendum to the original report. 
All patents must have measurable disease, and at least one “target lesion” to be used to 
assess response as defined by RECIST 1.1. Measurable disease is defined as at least one 
lesion that can be accurately measured in at least one dimension (longest diameter to be 
recorded). Each lesion must be ≥ 10 mm when measured by CT, MRI or caliper measurement 
by clinical exam; or ≥ 20 mm when measured by chest x-ray. Lymph nodes must be ≥ 15 mm 
in short axis when measured by CT or MRI. 
Appropriate stage for study entry based on the following diagnostic workup: 
 History/physical examination within 28 days prior to registration; 
 Imaging of target lesions within 28 days prior to registration; 
 Further protocol-specific assessments  


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o Recovery from adverse effects of recent surgery, radiotherapy or chemotherapy 
(residual grade 1 toxicity is considered recovered)  
o Any other prior therapy directed at the malignant tumor including chemotherapy, 
and biologic/targeted agents must be discontinued at least 4 weeks prior to 
registration. Any hormonal therapy directed at the malignant tumor must be 
discontinued at least 2 weeks prior to registration. 
o Any prior radiation therapy must be completed at least 4 weeks prior to 
registration, and progression must be outside the radiation field.  
o At least 4 weeks must have elapsed since any major surgery prior to registration. 
Age ≥ 18 
The trial is open only to women with recurrent or progressive clear cell carcinoma of the 
ovary 
Patients must have an ECOG Performance Status of 0 or 1 within 28 days prior to 
registration; 
Patients must have had one prior platinum-based chemotherapy for management of 
primary disease. Patients are allowed to receive, but are not required to receive, up to two 
additional cytotoxic regimens for management of recurrent or persistent disease. 
Adequate hematologic function within 14 days prior to registration defined as follows: 
 ANC ≥ 1,500/ul  

Platelets ≥ 100,000/ul
 Hgb ≥ 8.0g/dL (Note: the use of transfusion of other intervention to achieve a Hgb ≥ 
8.0 g/dL is acceptable) 
Adequate renal function within 14 days prior to registration defined as follows: 
 Creatinine ≤ 1.5 x institutional upper limit of normal (ULN) or CrCl ≥ 60mL/min using 
Cockcroft-Gault formula 
Adequate hepatic function within 14 days prior to registration defined as follows: 
 Bilirubin ≤ 2.5 x ULN  
 ALT and AST ≤ 2.5 x ULN  
Normal thyroid function testing (TSH) within 14 days prior to registration 
Negative pregnancy test in women of childbearing potential 
Women of childbearing potential who are sexually active should be willing and able to 
use medically acceptable forms of contraception for the course of the study through 120 
days after the last dose of MK-3475 (pembrolizumab). Women who are not of 
childbearing potential (i.e., who are postmenopausal or surgically sterile, who have had a 
hysterectomy and/or bilateral oophorectomy) do not require contraception. 
The patient or a legally authorized representative must provide study-specific informed 
consent prior to study entry. 
Ineligibility Criteria 
Patients with any of the following conditions are NOT eligible for this study. 


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Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for 
a minimum of 3 years  
Patients who have had prior therapy with MK-3475 (pembrolizumab) or epacadostat or 
with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody 
or drug specifically targeting T-cell co-stimulation or immune check point pathways. 
History of severe hypersensitivity reaction to any monoclonal antibody. 
Patients with active auto-immune disease or history of autoimmune disease that might 
recur, which may affect vital organ function or require immune suppressive treatment 
including systemic corticosteroids, should be excluded. These include but are not limited 
to patients with a history of immune related neurologic disease, multiple sclerosis, 
autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; 
systemic autoimmune disease such as SLE, connective tissue diseases, scleroderma, 
inflammatory bowel disease, Crohn’s, ulcerative colitis, hepatitis; and patients with a 
history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid 
syndrome should be excluded because of the risk of recurrence or exacerbation of 
disease. Patients with vitiligo, endocrine deficiencies including thyroiditis managed with 
replacement hormones including physiologic corticosteroids are eligible. Patients with 
rheumatoid arthritis and other arthropathies, Sjogren’s syndrome and psoriasis controlled 
with topical medication and patients with positive serology, such as antinuclear 
antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target 
organ involvement and potential need for systemic treatment but should otherwise be 
eligible. 
Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or 
active infection, symptomatic congestive heart failure and unstable angina pectoris, 
cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance 
with study requirements.
Patients with history or evidence upon physical examination of CNS disease, including 
primary brain tumor, seizures which are not controlled with non-enzyme inducing 
anticonvulsants, and/or epidural disease, or history of cerebrovascular accident (CVA, 
stroke), transient ischemic attack (TIA) or subarachnoid hemorrhage within six months 
prior to the first date of study treatment.  
Those with brain metastases are permitted as long as they have been treated with brain 
radiation therapy and have been documented stability 4 weeks following completion of 
brain radiation therapy. 
In order for patients with human immunodeficiency virus (HIV) or known acquired 
immunodeficiency syndrome (AIDS) to be eligible, they must be on a stable highly active 
antiretroviral therapy (HAART) regimen with no drug-drug interaction with UGT1A9, have 
CD4+ counts > 350, with no detectable viral load on quantitative PCR, and no opportunistic 
infection. 


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Patients with treated hepatitis viral infections (Hepatitis B and C) are eligible if they have 
completed definitive treatment at least 6 months prior, have no detectable viral load on 
quantitative PCR, and LFTs meet eligibility requirements. 
Patients with a condition requiring systemic treatment with either corticosteroids (>10 mg 
daily prednisone equivalents) or other immunosuppressive medications within 14 days of 
study drug administration. 
Therapy with monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake 
inhibitor (SSRIs) within the last 4 weeks or history of Serotonin Syndrome. Concomitant 
use of monoamine oxidase inhibitors or SSRIs with epacadostat (INCB024360) is 
prohibited. 
Patients who have had evidence of active or acute diverticulitis, intra-abdominal abscess, 
abdominal/pelvic fistula, gastrointestinal perforation, GI obstruction and/or who require 
parenteral hydration and/or nutrition. 
Epacadostat (INCB024360) is a substrate of CYP3A4, CYP1A2, CYP2C19, UGT1A9, P-
gp, and BCRP.  Use caution when administered with strong inhibitors/inducers of these 
isoenzymes and transporter proteins.  Because the lists of these agents are constantly 
changing, it is important to regularly consult a frequently-updated medical 
reference.  Appendix V (Patient Drug Information Handout and Wallet Card) should be 
provided to patients.  
History or presence of an abnormal ECG that, in the investigator’s opinion, is clinically 
meaningful. Screening QTc interval >480 milliseconds is excluded (corrected by 
Fridericia). In the event that a single QTc is >480 milliseconds, the subject may enroll if 
the average QTc for the 3 ECGs is <480 milliseconds. For subjects with an 
intraventricular conduction delay (QRS interval > 120 msec), the JTc interval may be 
used in place of the QTc with sponsor approval. The JTc must be <340 milliseconds if 
JTc is used in place of QTc. Subjects with left bundle branch block are excluded. 
Patients who are pregnant or nursing. 
4. REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP 
PRE-TREATMENT ASSESSMENTS 
Assessments 
Prior to Registration 
 (28 calendar days)
History and Physical 
≤ 28 days  
Vital Signs 
≤ 28 days 
Performance status 
≤ 28 days 
Chest imaging (at minimum a 
chest x-ray, or CT chest) 
≤ 28 days 
Imaging of target lesion – CT 
scan or MRI of abdomen and 
pelvis 
≤ 28 days 
Electrocardiogram (ECG) 
≤ 28 days 
Complete blood count with 
≤ 14 days 


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differential 
•ANC ≥ 1,500/ul  
• Platelets ≥ 100,000/ul 
• Hgb ≥ 8.0g/dL 
INR, PTT 
≤ 14 days 
Creatinine ≤ 1.5 x 
institutional upper limit of 
normal (ULN) or CrCl ≥ 
60mL/min using Cockcroft-
Gault formula 
≤ 14 days 
•Total Bilirubin ≤ 2.5 x ULN  
• ALT and AST ≤ 2.5 x ULN  
 
≤ 14 days 
Serum glucose 
≤ 14 days 
TSH 
≤ 14 days 
CA-125 
≤ 14 days 
Serum pregnancy test (for 
women of child-bearing 
potential) 
≤ 14 days 
 


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ASSESSMENTS 
DURING 
TREATMENTAsses
sments 
Note 
for 
Cycle 
1*** 
Prior to Day 
1 of each 
cycle (21 
days) 
12 weeks 
after start 
of 
treatment 
6 
weeks 
(+/- 7 
days) 
for 49 
weeks 
Every 12 
weeks (+/- 7 
days) until 
disease 
progression or 
treatment 
discontinuation 
History and Physical 
 
X 
 
 
 
Vital Signs (blood 
pressure, heart rate, 
and temperature) 
 
X 
 
 
 
Performance status 
 
X 
 
 
 
Toxicity assessment 
 
X 
 
 
 
Bloodwork – CBC, 
Creatinine, glucose, 
Total bilirubin, ALT, 
AST, TSH  
 
X 
(≤3 days) 
 
 
 
INR, PTT (if on 
warfarin) 
 
* 
X 
(≤3 days) 
 
 
 
Serum pregnancy test 
(if potential for 
childbearing exists) 
 
** 
 
 
 
 
CA-125 
 
X 
(≤3 days) 
 
 
 
 
Chest imaging (at 
minimum chest x-ray 
or CT chest) 
 
 
X 
X 
X 
Radiographic tumor 
measurement 
 
 
X 
X 
X 
Patient diary 
documenting 
epacadostat dosing 
 
X 
 
 
 
* Patients who are on warfarin should have INR and PTT repeated on Day 4 and Day 7 of cycle 
1. 
**Women of childbearing potential should repeat serum pregnancy test at 72 hrs of epacadostat 
dosing. 
***Do not need to repeat routine bloodwork prior to Cycle 1, Day 1 if already completed within 
14 days. 
 
 
 
 
 
 


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ASSESSMENTS IN FOLLOW UP 
Assessments (unless consent 
is withdrawn and patient 
does not remain on trial) 
From end of treatment: q3 mos. x 2 yrs.; q6 mos. x 3 years 
(either in person or by phone follow-up); then annually, 
unless otherwise indicated based on symptoms or physical 
signs suggestive of progressive disease. 
History & Physical 
X 
Performance Status 
X 
Vital signs (blood pressure, 
heart rate, and temperature) 
X 
Routine blood tests 
X, as clinically indicated during follow-up after treatment
CT scan or MRI of abdomen 
and pelvis to measure 
detectable tumor 
* 
 
For 3 years (either in person or by phone follow-up), unless 
consent is withdrawn. 
Monitor patients for delayed 
toxicity and survival following 
disease progression 
X 
*In the case that protocol directed therapy is discontinued for reasons other than disease 
progression, follow radiographic tumor measurement schedule as defined under Assessments 
during Treatment (until disease progression documented by RECIST 1.1 or until patient initiates 
a subsequent cancer therapy). 
5. TREATMENT PLAN/REGIMEN DESCRIPTION 
Treatment Plan  
All patients will receive MK-3475 (pembrolizumab) 200 mg IV q 3 weeks and epacadostat 100 
mg orally twice a day continuously until disease progression or adverse effects prohibit further 
treatment. A cycle equals 21 days. 
Patients will be given a Patient Medication Calendar to complete daily for epacadostat 
(Appendix IV). The Patient Medication Calendar should be reviewed prior to the start of 
each cycle.  
Epacadostat 
Route of Administration: Epacadostat will be administered as an oral tablet. 
 
Dose to be Administered: The dose of epacadostat will be 100 mg orally twice a day, in 
the morning and evening, approximately 12 hours apart. 
 
Dosing Instructions:  Oral, may be administered without regard to food. If the morning or 
evening dose is missed by more than 4 hours, that dose should be skipped and the next 


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scheduled dose should be taken at the usual time.  If a patient vomits after taking a tablet, the 
dose should be skipped. 
 
 
5.1.2
MK-3475 (Pembrolizumab)  
Route of Administration: MK-3475 (Pembrolizumab) will be administered as an IV 
infusion.  
 
Dose to be Administered: The dose of MK-3475 (pembrolizumab) will be 200 mg (fixed 
dose) IV every 3 weeks. 
  
Dosing Instructions: Patients will receive MK-3475 (pembrolizumab) as an IV infusion 
over 30 minutes. Sites should make every effort to target infusion timing to be as close to 
30 minutes as possible. However, given the variability of infusion pumps from site to 
site, a window of 25-40 minutes is permitted (i.e., infusion time is 25-40 minutes).  
 
Preparation and Administration: See Section 9.1 for specific instructions for the 
preparation of the MK-3475 (pembrolizumab) infusion fluid and administration of 
infusion solution. 
 
5.1.3   A patient will be permitted to have an infusion delayed up to 7 days (without this being 
considered a protocol violation) for major life events (e.g. serious illness in a family 
member, major holiday, vacation which is unable to be rescheduled). Documentation to 
justify this decision should be provided, and the Study Chair  should be notified. 
It will be acceptable for individual infusions to be delivered within a 24-hour window 
before or after the protocol-defined date. If the treatment due date is a Friday, and the 
patient cannot be treated on that Friday, then the window for treatment would include the 
Thursday (1 day earlier than due) through the Monday (3 days past due). 
General Concomitant Medication and Supportive Care Guidelines
Permitted Supportive/Ancillary Care and Concomitant Medications 
All treatments that the investigator considers necessary for a patient’s welfare may be 
administered at the discretion of the investigator in keeping with the community 
standards of medical care. All concomitant medication will be recorded on the case report 
form (CRF) including all prescription, over-the-counter (OTC), herbal supplements, and 
IV medications and fluids. If changes occur during the trial period, documentation of 
drug dosage, frequency, route, and date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of MK-3475 
(pembrolizumab) and 30 days after the last dose of MK-3475 (pembrolizumab) should be 
recorded. Concomitant medications administered after 30 days after the last dose of MK-
3475 (pembrolizumab) should be recorded for serious adverse events (SAEs) and events 
of clinical interest (ECIs) as defined in Section 7. 
 


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Epacadostat (INCB024360) is a substrate of CYP3A4, CYP1A2, CYP2C19, UGT1A9, P-
gp, and BRCP. Use caution when administering with strong inhibitors/inducers of these 
isoenzymes and transporter proteins. Because there is a potential for interaction of 
epacadostat (INCB024360) with other concomitantly administered drugs. The Principal 
Investigator should be alerted if the patient is taking any agent known to affect or with 
the potential for drug interactions. The study team should check a frequently-updated 
medical reference for a list of drugs to avoid or minimize use of. Appendix V (Patient 
Drug Information Handout and Wallet Card) should be provided to patients. 
 
Caution should be exercised with concomitant administration of warfarin. Close INR 
monitoring is recommended for subjects on a stable dose of warfarin who are starting 
treatment with epacadostat (INCB024360). 
 
Prohibited Therapies 
Patients are prohibited from receiving the following therapies during treatment on this 
trial:  
•  
 Immunotherapy not specified in this protocol;  

Chemotherapy not specified in this protocol; 
 Radiation therapy not specified in this protocol;  
 Investigational agents other than MK-3475 (pembrolizumab) and epacadostat;  
 Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and 
typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed 
virus vaccines and are allowed; however, intranasal influenza vaccines (e.g. Flu-
Mist®) are live attenuated vaccines, and are not allowed. 
 Glucocorticoids for any purpose other than to modulate symptoms from an adverse 
event of suspected immunologic etiology. The use of physiologic doses of 
corticosteroids (defined as 10 mg prednisone) are acceptable, however site 
investigators should consult with the Study Chair for any dose higher than 10 mg 
prednisone. 
 Epacadostat (INCB024360) may cause an increase in serotonin levels which has the 
potential to precipitate serotonin syndrome when administered in combination with 
monoamine oxidase (MAO) inhibitors or serotonergic agents.  Concomitant use of 
MAO inhibitors or serotonergic agents is prohibited.   
 
 
Note: The use of physiologic doses of corticosteroids may be approved after consultation 
with the Principal Investigator.  
Patients who, in the assessment of the treating investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from protocol 
treatment. Patients may receive other medications that the investigator deems to be 
medically necessary. 


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See Section 3.3, which describes other medications, which are prohibited in this trial. 
 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue as 
specified in the above treatment modality sections or until one of the following criteria 
applies: 
 
Disease progression, 
 
Intercurrent illness that prevents further administration of treatment, 
 
Unacceptable adverse event(s), as described in Section 6 
 
Patient decides to withdraw consent for participation in the study, or 
 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
6. TREATMENT MODIFICATIONS/MANAGEMENT 
Adverse Drug Reactions requiring Discontinuation or Delays:
The following adverse drug reactions (ADRs) require permanent treatment 
discontinuation of MK-3475 (pembrolizumab) and epacadostat: 
Any Grade 4 ADRs require permanent treatment discontinuation with MK-3475 
(pembrolizumab) and epacadostat except for single laboratory values out of normal range 
that are unlikely related to trial treatment as assessed by the Investigator, do not have any 
clinical correlate, and resolve within 7 days with adequate medical management. 
Persistent Grade 2 or 3 adverse reactions (excluding endocrinopathies controlled with 
hormone replacement therapy) do not improve to Grade 0-1 within 8 weeks of last dose. 
Unable to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day 
within 8 weeks. 
Any Grade 3 (severe) treatment-related or immune-mediated adverse reaction occurs. 
6.1.5
Patients who experience an unacceptable adverse event strictly due to epacadostat such 
that the patient requires permanent treatment discontinuation of epacadostat alone, 
following resolution of toxicity to ≤ grade 1 and permission from the Study Chair or Co-
Chair, the patient can continue the use of MK-3475 (pembrolizumab) alone. This should 
be confirmed with the Study Chair or Co-Chair on an individual basis. The same 
management guidelines should be followed, and any patient with any further 
unacceptable adverse events while receiving MK-3475 (pembrolizumab) alone should be 
taken off study treatment permanently. 
Tumor assessments should continue if protocol therapy is discontinued for reasons other than 
disease progression (see protocol section 4).


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MK-3475 (pembrolizumab) Infusion-Related Reactions 
Since MK-3475 (pembrolizumab) contains only human immunoglobulin protein 
sequences, it is unlikely to be immunogenic and induce infusion or hypersensitivity 
reactions. However, if such a reaction were to occur, it might manifest with fever, chills, 
rigors, headache, rash, urticaria, angioedema, pruritus, arthralgia, hypo- or hypertension, 
bronchospasm, or other symptoms.  
 
All Grade 3 or 4 infusion reactions should be reported as an SAE if criteria are met. 
Infusion reactions should be graded according to NCI CTCAE version 5.0 guidelines.  
 
Treatment recommendations are provided below and may be modified based on local 
treatment standards and guidelines as medically appropriate:  
 
For Grade 1 infusion reaction: (Mild transient reaction; infusion interruption not 
indicated; intervention not indicated)  
Remain at bedside and monitor subject until recovery from symptoms. Infusion rate may 
be slowed. If the infusion is interrupted, then restart the infusion at 50% of the original 
infusion rate when symptoms resolve; if no further complications ensue after 30 minutes, 
the rate may be increased to 100% of the original infusion rate. Monitor patient closely.  
 
For Grade 2 infusion reaction: (Therapy or infusion interruption indicated but responds 
promptly to symptomatic treatment [e.g., antihistamines, non-steroidal anti-inflammatory 
drugs, narcotics, IV fluids]; prophylactic medications indicated for ≤ 24 hours).  
Stop the MK-3475 (pembrolizumab) infusion, begin an IV infusion of normal saline, and 
treat the subject with diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen 
500 to 1000 mg; remain at bedside and monitor patient until resolution of symptoms. 
Corticosteroid or bronchodilator therapy may also be administered as appropriate. If the 
infusion is interrupted, then restart the infusion at 50% of the original infusion rate when 
symptoms resolve; if no further complications ensue after 30 minutes, the rate may be 
increased to 100% of the original infusion rate. Monitor patient closely. If symptoms 
recur, then no further MK-3475 (pembrolizumab) will be administered at that visit. 
Administer diphenhydramine 50 mg IV, and remain at bedside and monitor the patient 
until resolution of symptoms. The amount of study drug infused must be recorded on the 
electronic case report form (eCRF). The following prophylactic pre-medications are 
recommended for future infusions: diphenhydramine 50 mg (or equivalent) and 
acetaminophen 500 to 1000 mg should be administered at least 30 minutes before 
additional MK-3475 (pembrolizumab) administrations. If necessary, corticosteroids 
(recommended dose: up to 25 mg of IV hydrocortisone or equivalent) may be used.  
For Grade 3 or Grade 4 infusion reaction: Grade 3: (Prolonged [e.g., not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence 
of symptoms following initial improvement; hospitalization indicated for other clinical 
sequelae); or Grade 4: (Life threatening consequences; urgent intervention indicated).  


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Immediately discontinue infusion of MK-3475 (pembrolizumab). Begin an IV infusion of 
normal saline, and treat the subject as follows. Recommend bronchodilators, epinephrine 
0.2 to 1 mg of a 1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 
1:10,000 solution injected slowly for IV administration, and/or diphenhydramine 50 mg 
IV with methylprednisolone 100 mg IV (or equivalent), as needed. Patient should be 
monitored until the investigator is comfortable that the symptoms will not recur. MK-
3475 (Pembrolizumab) will be permanently discontinued. Investigators should follow 
their institutional guidelines for the treatment of anaphylaxis. Remain at bedside and 
monitor patient until recovery from symptoms. In the case of late-occurring 
hypersensitivity symptoms (e.g., appearance of a localized or generalized pruritus within 
1 week after treatment), symptomatic treatment may be given (e.g., oral antihistamine, or 
corticosteroids). 
 
Please note that late occurring events including isolated fever and fatigue may represent 
the presentation of systemic inflammation. Please evaluate accordingly. 
 
Table: 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 
patient 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 
patient 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 patient should be 
premedicated for the next 
scheduled dose. 
 
Patients who develop Grade 2 
toxicity despite adequate 
Patient may be premedicated 1.5h (± 30 
minutes) prior to infusion of MK-3475 
(pembrolizumab) with:  
 
Diphenhydramine 50 mg po (or equivalent 
dose of antihistamine).  
 
Acetaminophen 500-1000 mg po (or 
equivalent dose of antipyretic) 


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premedication should be 
permanently discontinued from 
further trial treatment 
administration. 
 
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 
patient is deemed medically stable 
in the opinion of the investigator. 
Hospitalization may be indicated. 
Patient is permanently 
discontinued from further trial 
treatment administration. 
 
No subsequent dosing 
Immune-Related Adverse Events (irAEs) General Definition, Monitoring, and 
Management  
For the purposes of this protocol, an immune-related adverse reaction irAE is defined as 
an adverse reaction of unknown etiology associated with drug exposure and consistent 
with an immune phenomenon. Efforts should be made to rule out neoplastic, infectious, 
metabolic, toxin or other etiologic causes prior to labeling an event an irAEs. Serologic, 
immunologic, and histologic (biopsy) data should be used to support the diagnosis of an 
immune-related toxicity. Suspected immune-related adverse reactions must be 
documented in CTEP-AERS.  
Overall, immune-related AEs commonly start within 3 to 10 weeks from initiation of 
therapy and are in most cases successfully managed by delaying doses, discontinuing 
dosing, and/or through administering symptomatic or immunosuppressive therapy, 
including corticosteroids, as mentioned below. Immune-related AEs generally resolved 
within days to weeks in the majority of subjects.  
Patients should be informed of and carefully monitored for evidence of clinically 
significant systemic immune-mediated adverse reactions (e.g., systemic lupus 
erythematosus-like diseases) or organ-specific immune-mediated adverse reaction (e.g., 
rash, colitis, uveitis, hepatitis or thyroid disease). If an immune-mediated adverse 
reaction is noted, appropriate work-up (including biopsy if possible) should be 
performed, and steroid therapy may be considered if clinically necessary.  
Below are dose delay tables for MK-3475 (pembrolizumab) (depending on assigned 


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treatment regimen) related to adverse events. Patients may be dose-delayed for evaluation 
and restarted depending on results.  
 
Investigators should as a rule evaluate suspected adverse effects early, and with any 
suspicion, erring on the side of caution by withholding drug and instituting 
appropriate treatment as indicated in the management tables and following event 
specific guidelines. 
 
There are no dose reductions for MK-3475 (pembrolizumab). If the patient meets 
retreatment criteria, the full dose of 200 mg will be administered. If patients do not meet 
retreatment criteria, then the dose of MK-3475 (pembrolizumab) will be HELD and the 
patient re-evaluated weekly until retreatment criteria are met. 
 
Adverse events (both non-serious and serious) associated with MK-3475 
(pembrolizumab) exposure may represent an immunologic etiology. These adverse events 
may occur shortly after the first dose or several months after the last dose of treatment. 
MK-3475 (Pembrolizumab) must be withheld for drug-related toxicities and severe or 
life-threatening AEs as per the table below. 
 
If MK-3475 (pembrolizumab) and epacadostat are withheld for drug-related toxicities, 
radiographic tumor measurement and chest imaging should still continue every 6 weeks 
(+/- 7 days), as outlined in Section 4, Assessments During Treatment. Once MK-3475 
(pembrolizumab) and epacadostat are restarted, imaging assessments will resume every 6 
weeks from the time the drugs are restarted until week 49. 
 
Although these guidelines are for immune-related AEs attributable to MK-3475 
(pembrolizumab), it is also meant to be applied to any suspected immune-related AEs 
from epacadostat or the combination of epacadostat with other immune-targeted agents. 
 
Table: Dose Modification Guidelines for Drug-Related Adverse Events 
 
Toxicity 
Hold MK-3475 
(pembrolizumab) 
and epacadostat 
for NCI CTCAE 
grade 
Timing for restarting 
treatment 
Discontinue MK-3475 
(pembrolizumab) and 
epacadostat permanently 
 
 
Diarrhea/Colitis 
2-3 
Toxicity resolves to Grade 0-1 
and the patient has 
successfully tapered off of 
corticosteroids 
Toxicity does not resolve within 
8 weeks of last dose or inability 
to taper off corticosteroids 
within 8 weeks 
4 
 
Permanently discontinue 
Permanently discontinue 
 
 
AST, ALT or increased 
bilirubin 
2  
(ALT/AST >3-5X 
ULN or total 
bilirubin >1.5-3X 
ULN 
 
Toxicity resolves to Grade 0-1 
and the patient has tapered off 
of corticosteroids 
Toxicity does not resolve within 
8 weeks of last dose. 
3-4 
Permanently discontinue 
Permanently discontinue 


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AST/ALT >5 x 
ULN or 
AST/ALT 
increases ≥50% 
relative to 
baseline and lasts 
≥1 week 
in patients with 
liver metastasis 
who begin 
treatment with 
Grade 2 elevation 
of AST/ALT 
or total bilirubin 
>3 x ULN 
(Grade 3 or 
greater) 
 
Type I diabetes 
mellitus (if new onset) 
or hyperglycemia 
T1DM or 3-4 
Hold MK-3475 
(pembrolizumab) and 
epacadostat for new onset 
Type I diabetes mellitus or 
grade 3-4 hyperglycemia 
associated with evidence of 
beta cell failure 
 
Resume MK-3475 
(pembrolizumab) and 
epacadostat when patients are 
clinically and metabolically 
stable 
 
 
 
Hypophysitis 
2-3 
Toxicity resolves to Grade 0-1 
 
Toxicity does not resolve within 
8 weeks of last dose or inability 
to taper corticosteroids to a dose 
of prednisone 10 mg or less 
within 8 weeks. 
 
4 
Permanently discontinue 
Permanently discontinue 
 
 
 
 
Hyperthyroidism 
2-3 
Toxicity resolves to Grade 0-1 
 
Toxicity does not resolve within 
8 weeks of last dose or inability 
to taper off corticosteroids 
within 8 weeks. 
 
4 
Permanently discontinue 
Permanently discontinue 
 
Hypothyroidism 
2-4 
Therapy with MK-3475 
(pembrolizumab) and 
epacadostat can be continued 
while treatment for the thyroid 
disorder is instituted 
Therapy with MK-3475 
(pembrolizumab) and 
epacadostat can be continued 
while treatment for the thyroid 
disorder is instituted. 
 
Infusion reaction 
3-4 
Permanently discontinue 
Permanently discontinue 
 
 
 
Pneumonitis 
2 
Toxicity resolves to grade 0-1 
Toxicity does not resolve within 
8 weeks of last dose or inability 
taper off corticosteroid within 8 
weeks or if second occurrence 
of pneumonitis grade ≥ 2 
 


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3-4 
Permanently discontinue 
Permanently discontinue 
 
 
 
Renal failure or 
nephritis 
2 
Toxicity resolves to grade 0-1 
Toxicity does not resolve within 
8 weeks of last dose or inability 
to taper off corticosteroid within 
8 weeks. 
 
3-4 
Permanently discontinue 
Permanently discontinue 
 
 
Myocarditis 
 
 
1-2 
Withhold both epacadostat 
and MK-
3475(pembrolizumab) until 
Grade 0. May restart at same 
dose level. 
 
Toxicity does not resolve within 
8 weeks of last dose. 
3-4 
Permanently discontinue. 
 
Permanently discontinue. 
 
 
 
All other drug-related 
toxicity* 
3 or severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 
8 weeks of last dose or inability 
taper off of corticosteroids 
within 8 weeks. 
 
4 
Permanently discontinue 
Permanently discontinue 
 
Note: Permanently discontinue MK-3475 (pembrolizumab) and epacadostat for any severe or Grade 3 
drug-related AE that recurs or any life-threatening event. 
* Patients with intolerable or persistent Grade 2 drug-related AE may hold MK-3475 (pembrolizumab) and 
epacadostat at physician discretion. 
Permanently discontinue MK-3475 (pembrolizumab) and epacadostat for persistent Grade 2 adverse reactions for 
which treatment with study drug has been held, and that do not recover to Grade 0-1 within 8 weeks of the last 
dose of MK-3475 (pembrolizumab). 
 
 
Supportive Care Guidelines
Patients should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below. Where appropriate, these 
guidelines include the use of oral or intravenous treatment with corticosteroids as well as 
additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids. Note that several courses of steroid tapering may be necessary as 
symptoms may worsen when the steroid dose is decreased. For each disorder, attempts 
should be made to rule out other causes such as metastatic disease or bacterial or viral 
infection, which might require additional supportive care. The treatment guidelines are 
intended to be applied when the investigator determines the events to be related to MK-
3475 (pembrolizumab). 
 
Note: if after the evaluation the event is determined not to be related, the investigator 
does not need to follow the treatment guidance (as outlined below). 
 


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It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, 
or skin photography as part of evaluation of the event. 
 
Pneumonitis: 
 For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. 
 For Grade 3-4 events, immediately treat with intravenous steroids. Administer 
additional anti-inflammatory measures, as needed. 
 Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration. 
 
Diarrhea/Colitis: 
Patients should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus). 
 All patients who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids. If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion. For Grade 2 or higher diarrhea, 
consider GI consultation and endoscopy to confirm or rule out colitis. 
 For Grade 2 diarrhea/colitis, administer oral corticosteroids. 
 For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by high 
dose oral steroids. 
 When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis 
(DKA) 
 For T1DM or Grade 3-4 Hyperglycemia 
o Insulin replacement therapy is recommended for Type I diabetes mellitus and for 
Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria. 
o Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide. 
 
Hypophysitis: 
 For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 
1 or less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is tapered. 
 For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered. 
 
 


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Hyperthyroidism or Hypothyroidism: 
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (TSH and free T4 at the intervals specified, and as indicated based on 
clinical evaluation) and for clinical signs and symptoms of thyroid disorders. No 
intervention is required for Grade 1 hyperthyroidism or hypothyroidism events. 
 Grade 2 hyperthyroidism events: 
o In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested 
as initial therapy. 
o In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care. 
 Grade 3-4 hyperthyroidism events: 
o Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. Replacement of appropriate hormones may 
be required as the steroid dose is tapered. 
 
Hepatic: 
 For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly). 
o Treat with IV or oral corticosteroids 
 For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours. 
 When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
 
Renal Failure or Nephritis: 
 For Grade 2 events, hold MK-3475 (pembrolizumab) and epacadostat and treat with 
vigorous hydration and oral corticosteroids. Monitor renal function weekly until 
returned to baseline values. 
Note: if event is considered clinically unrelated or unlikely to be related to MK-3475 
(pembrolizumab), and an alternate clinical explanation is likely, probable, or definite in 
the judgment of the investigator (example, attributable to prerenal azotemia in the 
setting of nausea, and responding to hydration), then corticosteroids may be omitted and 
MK-3475 (pembrolizumab) and epacadostat may be administered. 
 For Grade 3-4 events, hospitalization is indicated. Treat with vigorous hydration and 
IV corticosteroids for 24 to 48 hours. Monitor renal function frequently. 
Consultation with nephrology is recommended. 
 When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks 
 
 
 
 
 
 
 
 


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Recommendations to managing irAEs not detailed elsewhere in the protocol are detailed 
in the Table below: 
 
TABLE: General Approach to Handling IRAEs 
irAE 
Withhold/Discontinue MK-3475 
(pembrolizumab) and Epacadostat? 
Supportive Care 
Grade 1 
No action 
 
Provide symptomatic treatment 
Grade 2 
May withhold MK-3475 (pembrolizumab) 
and epacadostat 
Consider systemic corticosteroids in 
addition to appropriate symptomatic 
treatment. 
 
Grade 3 and Grade 4 
Withhold MK-3475 (pembrolizumab) and 
epacadostat 
 
Discontinue if unable to reduce corticosteroid 
dose to < 10 mg per day prednisone 
equivalent within 8 weeks of toxicity. 
 
Systemic corticosteroids are 
indicated in addition to appropriate 
symptomatic treatment. May utilize 
1-2 mg/kg/day prednisone or 
equivalent. 
 
Steroid taper should be considered 
once symptoms improve to Grade 1 
or less and tapered over at least 4 
weeks.  
 
Serotonin Syndrome 
Serotonin syndrome has not been reported in any completed or ongoing studies. 
 
There is a potential concern that epacadostat could cause an increase in serotonin levels 
in the brain that might trigger serotonin syndrome, when administered alone or in 
combination with other serotonergic agents. This rare syndrome has been associated with 
some MAOIs and combinations of serotonergic drugs (Boyer and Shannon 2005). The 
clinical manifestations of serotonin syndrome range from barely perceptible to lethal. 
Nonclinical data suggest that serotonin syndrome is unlikely following treatment with 
either epacadostat alone or in combination with MAOIs such as linezolid (Zhang et al 
2016). As of 29 OCT 2017, 2 subjects treated across the epacadostat program have events 
reported as serotonin syndrome or symptoms of serotonin syndrome; both episodes were 
confounded, mild in severity, and resolved with dose interruption. Neither report was 
clinically substantiated to represent a true case of serotonin syndrome by the sponsor. 
Although the incidence of serotonin syndrome or symptoms of serotonin syndrome is 
rare, use of MAOIs or SSRIs is prohibited during the study. Subjects should be provided 
information describing the signs and symptoms of the syndrome along with instructions 
to seek immediate medical care if any signs or symptoms is observed (Appendix V). 


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7. ADVERSE EVENTS REPORTING REQUIREMENTS
Protocol Agents 
Investigational Agents 
MK-3475 (Pembrolizumab) and Epacadostat are the investigational agents administered 
in NRG-GY016, and are available under IND sponsored by DCTD, NCI.  For MK-3475 
(Pembrolizumab) and Epacadostat, determination of whether an adverse event meets 
expedited reporting criteria, see the reporting table in section 7.4 of the protocol.
Adverse Events and Serious Adverse Events 
This study will utilize the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 for CTEP-AERS (CTEP Adverse Event Reporting System) CAERs 
reporting of adverse events (AEs), located on the CTEP web site, 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm. All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0. 
Definition of an Adverse Event (AE) 
Any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related.  Therefore, an AE can be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product (attribution of unrelated, 
unlikely, possible, probable, or definite). (International Conference on Harmonisation 
[ICH], E2A, E6).  
For multi-modality trials, adverse event reporting encompasses all aspects of protocol 
treatment including radiation therapy, surgery, device, and drug. 
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the 
pregnancy of a study participant must be reported via CTEP-AERS in an expedited 
manner. 
Comprehensive Adverse Events and Potential Risks (CAEPR) List for CTEP and 
CIP Study Agents 
Comprehensive Adverse Events and Potential Risks list (CAEPR) (11-JUN-2020) 
for 
Epacadostat (INCB024360, NSC 766086) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/aeguidelines.pdf  for 
further clarification. Frequency is provided based on 216 patients. Below is the CAEPR for 
Epacadostat (INCB024360). 




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Adverse events reported on epacadostat (INCB024360) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that epacadostat (INCB024360) 
caused the adverse event: 
Blood and lymphatic system disorders - Anemia 
Gastrointestinal disorders - Abdominal distension; Small intestinal obstruction 
General disorders and administration site conditions - General disorders and administration site 
conditions - Other (hyperthermia) 
Infections and infestations - Bacteremia; Lung infection; Sepsis 
Investigations - GGT increased 
Metabolism and nutrition disorders - Hypernatremia; Hyponatremia 
Musculoskeletal and connective tissue disorders - Arthralgia 
Nervous system disorders - Dizziness; Dysgeusia 
Psychiatric disorders - Insomnia 
Renal and urinary disorders - Renal and urinary disorders - Other (renal impairment) 
Respiratory, thoracic and mediastinal disorders - Hypoxia; Pneumonitis; Respiratory failure 
Skin and subcutaneous tissue disorders - Pruritus 
Vascular disorders - Hypertension; Hypotension 
Note: Epacadostat (INCB024360) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for
MK-3475 (pembrolizumab, NSC 776864) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/aeguidelines.pdf 
for further clarification. Frequency is provided based on 3793 patients. Below is the CAEPR for MK-3475 
(pembrolizumab). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
       








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3Acute graft-versus-host disease has been observed in patients treated with MK-3475 (pembrolizumab) 
who received hematopoeitic stem cell transplants. 
4Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
Adverse events reported on MK-3475 (pembrolizumab) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that MK-3475 (pembrolizumab) caused 
the adverse event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(pancytopenia); Disseminated intravascular coagulation; Hemolysis 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Chest pain - cardiac; Heart failure; Myocardial 
infarction; Pericardial effusion; Pericardial tamponade; Ventricular arrhythmia 
EYE DISORDERS - Eye pain 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Constipation; Duodenal 
hemorrhage; Dysphagia; Gastritis; Gastrointestinal disorders - Other (diverticulitis); Gastrointestinal 
disorders - Other (intestinal obstruction); Gastrointestinal disorders - Other (intussusception); Oral pain; 
Rectal hemorrhage; Small intestinal perforation; Upper gastrointestinal hemorrhage; Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; Edema limbs; 
Facial pain; Gait disturbance; General disorders and administration site conditions - Other (general 
physical health deterioration); Generalized edema; Malaise; Non-cardiac chest pain; Pain 
INVESTIGATIONS - Cholesterol high; Creatinine increased; Fibrinogen decreased; Lymphocyte count 
decreased; Neutrophil count decreased; Platelet count decreased; Weight loss; White blood cell 
decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperglycemia; 
Hyperkalemia; Hypertriglyceridemia; Hyperuricemia; Hypoalbuminemia; Hypokalemia; 
Hypophosphatemia; Metabolism and nutrition disorders - Other (failure to thrive); Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Generalized muscle 
weakness; Musculoskeletal and connective tissue disorder - Other (groin pain); Pain in extremity 
NERVOUS SYSTEM DISORDERS - Aphonia; Depressed level of consciousness; Dysarthria; Edema 
cerebral; Encephalopathy; Headache; Hydrocephalus; Lethargy; Meningismus; Nervous system disorders 
- Other (brainstem herniation); Seizure; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Agitation; Confusion 
RENAL AND URINARY DISORDERS - Acute kidney injury; Nephrotic syndrome; Proteinuria; Renal and 
urinary disorders - Other (hydronephrosis); Urinary incontinence; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Pelvic pain 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Dyspnea; Hypoxia; Laryngeal 
inflammation; Pleural effusion; Pneumothorax; Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Skin and subcutaneous tissue 
disorders - Other (drug eruption) 
VASCULAR DISORDERS - Hypertension; Peripheral ischemia; Thromboembolic event 
Note: MK-3475 (pembrolizumab) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
Expedited Reporting of Adverse Events 
All serious adverse events that meet expedited reporting criteria defined in the reporting 
table below will be reported via the CTEP Adverse Event Reporting System, CTEP-
AERS, accessed via the CTEP web site,  
https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613 


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Submitting a report via CTEP-AERS serves as notification to the NRG 
Biostatistical/Data Management Center and satisfies NRG requirements for expedited 
adverse event reporting. 
 
CTEP-AERS provides a radiation therapy-only pathway for events experienced that 
involve radiation therapy only. These events must be reported via the CTEP-AERS 
radiation therapy-only pathway. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be 
made to CTEP by telephone at 301-897-7497, the NRG Biostatistical/Data Management 
Center by phone, (number to be provided) and to the NRG Regulatory Affairs by phone 
at 215-854-0770. An electronic report must be submitted immediately upon re-
establishment of the Internet connection.  
Expedited Reporting Methods 
 Per CTEP NCI Guidelines for Adverse Event Reporting Requirements, a CTEP-
AERS-24 Hour Notification must be submitted within 24 hours of learning of the 
adverse event. Each CTEP-AERS24-hour notification must be followed by a 
complete report within 5 days.  
 Supporting source documentation is requested by the ING Sponsor for this study 
(CTEP/DCTD) and NRG as needed to complete adverse event review. When 
submitting supporting source documentation, include the protocol number, patient ID 
number, and CTEP-AERS ticket number on each page, and fax supporting 
documentation to CTEP at 301-230-0159 and NRG Regulatory Affairs at 215-854-
0716. 
 A serious adverse event that meets expedited reporting criteria outlined in the AE 
Reporting Tables but is assessed by the CTEP-AERS as “an action not 
recommended” must still be reported to fulfill NRG safety reporting obligations. Sites 
must bypass the “NOT recommended” assessment; the CTEP-AERS allows 
submission of all reports regardless of the results of the assessment. 
 
Expedited Reporting Requirements for Adverse Events  
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for 
Adverse Events that Occur on Studies under an IND/IDE within 30 Days of the 
Last Administration of the Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 






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CTEP and Cancer Trials Support Unit (CTSU) websites and applications. In addition, IVRs and 
NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
 Addition to a site roster; 

Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN;
 Act as the site-protocol Principal Investigator (PI) on the IRB approval; and 
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN must be rostered at the 
enrolling site with a participating organization (i.e., Alliance).  
Additional information is located on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact the RCR 
Help Desk by email at RCRHelpDesk@nih.gov. 
 
Cancer Trials Support Unit Registration Procedures 
This study is supported by the NCI CTSU. 
 
IRB Approval  
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical 
Trials Network (NCTN) and NCI Community Oncology Research Program (NCORP) 
Research Bases after March 1, 2019, all U.S.-based sites must be members of the NCI 
Central Institutional Review Board (NCI CIRB). In addition, U.S.-based sites must accept 
the NCI CIRB review to activate new studies at the site after March 1, 2019. Local IRB 
review will continue to be accepted for studies that are not reviewed by the CIRB, or if 
the study was previously open at the site under the local IRB. International sites should 
continue to submit Research Ethics Board (REB) approval to the CTSU Regulatory Office 
following country-specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for 
Local Context (SSW) to the CIRB using IRBManager to indicate their intent to open the 
study locally. The NCI CIRB’s approval of the SSW is automatically communicated to 
the CTSU Regulatory Office, but sites are required to contact the CTSU Regulatory 
Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI 
CIRB approvals across their Signatory Network. Site preferences can be set at the 
network or protocol level. Questions about establishing site preferences can be addressed 
to the CTSU Regulatory Office by email or calling 1-888-651-CTSU (2878). 
 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory 
Office using the Regulatory Submission Portal located in the Regulatory section of the 
CTSU website.  Acceptable documentation of local IRB/REB approval includes: 
 
 Local IRB documentation 
 IRB-signed CTSU IRB Certification Form; and/or 
 Protocol of Human Subjects Assurance Identification/IRB 


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Certification/Declaration of Exemption Form 
 
In addition, the site-protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria in order for the processing of the 
IRB/REB approval record to be completed: 
 Holds an active CTEP status; 
 Rostered at the site on the IRB/REB approval (applies to US and Canadian 
sites only) and on at least one participating roster; 
 If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
 Rostered on the NCI CIRB Signatory record; 
 Includes the IRB number of the IRB providing approval in the Form FDA 
1572 in the RCR profile; and 
 Holds the appropriate CTEP registration type for the protocol. 
 
 
Additional Requirements for Protocol NRG-GY016 Site Registration:  
Additional requirements to obtain an approved site registration status include: 
 An active Federal Wide Assurance (FWA) number; 
 An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); and 
 Compliance with all protocol-specific requirements (PSRs). 
 IRB/REB approved consent. 
 
Submitting Regulatory Documents:  
Submit required forms and documents to the CTSU Regulatory Office using the 
Regulatory Submission Portal on the CTSU website: 
 
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to 
the Regulatory section and select Regulatory Submission. 
 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to 
receive further instruction and support. 
 
Checking Your Site’s Registration Status: 
Site registration status may be verified on the CTSU members’ website.   
 
 Click on Regulatory at the top of the screen; 
 Click on Site Registration; and 
 Enter the sites 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, 
Protocol Status, and/or IRB Type. 


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Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling investigator’s 
status with the NCI or their affiliated networks. 
 
8.2 
Patient Enrollment 
 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the (LPOs) registration/randomization systems or the Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/randomization assignment. 
OPEN will populate the patient enrollment data in NCI’s clinical data management 
system, Medidata Rave. 
 
Requirements for OPEN access:   
 A valid CTEP-IAM account; 
 To perform enrollments or request slot reservations:  Must be on an LPO roster, 
ETCTN Corresponding roster, or participating organization roster with the role of 
Registrar. Registrars must hold a minimum of an Associate Plus (AP) registration 
type; 
 If a Delegation of Tasks Log (DTL) is required for the study, the registrar(s) must 
hold the OPEN Registrar task on the DTL for the site; and 
 Have an approved site registration for the protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR. If a DTL is required for the study, the IVR or 
NPIVR must be assigned the appropriate OPEN-related tasks on the DTL. 
Prior to accessing OPEN, site staff should verify the following: 
 Patient has met all eligibility criteria within the protocol stated timeframes; and  
 All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. You may print this confirmation for your records.  
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website. Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 


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Data Submission/Data Reporting
Medidata Rave is a clinical data management system being used for data collection for 
this trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system 
and role assignments.   
Requirements to access Rave via iMedidata: 
 A valid and active CTEP-IAM account; and  
 Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, 
Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.
Rave role requirements: 
o To hold Rave CRA or Rave CRA (Lab Admin) role must hold a minimum of 
an Associate Plus (AP) registration type; 
o Rave Investigator role must be registered as a Non-Physician Investigator 
(NPIVR) or Investigator (IVR); and 
o Rave Read Only role, must have at minimum an Associates (A) registration 
type. 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types 
and documentation required. 
 
Upon initial site registration approval for the study in Regulatory Support System (RSS), 
all persons with Rave roles assigned on the appropriate roster will be sent a study 
invitation e-mail from iMedidata. To accept the invitation, site staff must log in to the 
Select Login (https://login.imedidata.com/selectlogin) using their CTEP-IAM username 
and password and click on the accept link in the upper right-corner of the iMedidata 
page. Site staff will not be able to access the study in Rave until all required Medidata 
and study specific trainings are completed. Trainings will be in the form of electronic 
learnings (eLearnings) and can be accessed by clicking on the link in the upper right pane 
of the iMedidata screen. If an eLearning is required and has not yet been taken, the link to 
the eLearning will appear under the study name in iMedidata instead of the Rave EDC 
link; once the successful completion of the eLearning has been recorded, access to the 
study in Rave will be granted, and a Rave EDC link will display under the study name.  
 
Site staff that have not previously activated their iMedidata/Rave account at the time of 
initial site registration approval for the study in RSS will receive a separate invitation 
from iMedidata to activate their account. Account activation instructions are located on 
the CTSU website in the Data Management section under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional information 
on iMedidata/Rave is available on the CTSU members’ website in the Data Management 
> Rave section at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-
823-5923 or by e-mail at ctsucontact@westat.com.   


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Rave-CTEP-AERS Integration 
The RAVE Cancer Therapy Evaluation Program Adverse Event Reporting 
System (CTEP-AERS) Integration enables evaluation of post-baseline Adverse 
Events (AE) entered in Rave to determine whether they require expedited 
reporting, and facilitates entry in CTEP-AERS for those AEs requiring expedited 
reporting.   
All AEs that occur after baseline are collected in Medidata Rave using the 
Adverse Event form, which is available for entry at each treatment or reporting 
period, and used to collect AEs that start during the period or persist from the 
previous reporting period. CRA will enter AEs that occur prior to the start of 
treatment on a baseline form that is not included in the Rave-CTEP-AERS 
integration. AEs that occur prior to enrollment must begin and end on the baseline 
Adverse Events form and should not be included on the standard Adverse Events 
form that is available at treatment unless there has been an increase in grade. 
Prior to sending AEs through the rules evaluation process, site staff should verify 
the following on the Adverse Event form in Rave: 
 The reporting period (course/cycle) is correct; and 
 AEs are recorded and complete (no missing fields) and the form is query 
free. 
The CRA reports AEs in Rave at the time the Investigator learns of the event. If 
the CRA modifies an AE, it must be re-submitted for rules evaluation. 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for 
rules evaluation by completing the Expedited Reporting Evaluation form. Both 
NCI and protocol-specific reporting rules evaluate the AEs submitted for 
expedited reporting. A report is initiated in CTEP-AERS using information 
entered in Medidata Rave for AEs that meet reporting requirements. The CRA 
completes the report by accessing CTEP-AERS via a direct link on the Medidata 
Rave Expedited Reporting Evaluation form. 
In the rare occurrence that Internet connectivity is lost; a 24-hour notification is to 
be made to CTEP by telephone at 301-897-7497. Once internet connectivity is 
restored, the 24-hour notification that was phoned in must be entered immediately 
into CTEP-AERS using the direct link from Medidata Rave. 
Additional information about the CTEP-AERS integration is available on the 
CTSU website: 
 Study specific documents: Protocols > Documents> Education and 
Promotion; and   
 Expedited Safety Reporting Rules Evaluation user guide: Resources > 
CTSU Operations Information> User Guides. 
NCI requirements for SAE reporting are available on the CTEP website:  
 NCI Guidelines for Investigators: Adverse Event Reporting Requirements 


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is available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf. 
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
 
The DQP is located on the CTSU members’ website under Data Management. The Rave 
Home section displays a table providing summary counts of Total Delinquencies and 
Total Queries. DQP Queries, DQP Delinquent Forms and the DQP Reports modules are 
available to access details and reports of unanswered queries, delinquent forms, and 
timeliness reports. Review the DQP modules on a regular basis to manage specified 
queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website. Staff that have Rave study access can access the Rave study data using a direct 
link on the DQP. 
 
To learn more about DQP use and access, click on the Help icon displayed on the Rave 
Home, DQP Queries, and DQP Delinquent Forms modules. 
 
Note: Some Rave protocols may not have delinquent form details or reports specified on 
the DQP. A protocol must have the Calendar functionality implemented in Rave by the 
Lead Protocol Organization for delinquent form details and reports to be available on the 
DQP. Site staff should contact the LPO Data Manager for their protocol regarding 
questions about Rave Calendaring functionality.    
9. DRUG INFORMATION  
MK-3475 (Pembrolizumab) (NSC 776864) 
Other Names: Pembrolizumab, SCH 900475, KEYTRUDA® 
Classification: Anti-PD-1 MAb 
Molecular Weight: 148.9-149.5 KDa 
CAS Number: 1374853-91-4 
Mode of Action: The programmed cell death 1 (PD-1) receptor is an inhibitory receptor 
expressed by T cells.  When bound to either of its ligands, PD-L1 or PD-L2, activated PD-1 
negatively regulates T-cell activation and effector function.  The pathway may be engaged by 
tumor cells to suppress immune control.  MK-3475 (pembrolizumab) blocks the negative 
immune regulatory signaling by binding to the PD-1 receptor, inhibiting the interaction between 
PD-1 and its ligands. 


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Description: Pembrolizumab (MK-3475) is a humanized MAb of the IgG4/kappa isotype. 
 
How Supplied: Pembrolizumab (MK-3475) is supplied by Merck & Co., Inc. and distributed by 
the Pharmaceutical Management Branch, CTEP/DCTD/NCI as single-use 100 mg vials containing 
a sterile, non-pyrogenic, and clear to opalescent aqueous solution (25 mg/mL).  Proteinaceous 
particles may be present.  MK-3475 solution for infusion is formulated in 10mM histidine buffer, 
pH 5.2-5.8, containing 7% sucrose and 0.02% polysorbate 80, supplied in Type I glass vials with 
a cap color of red, salmon, or blue. 
 
Preparation: Pembrolizumab (MK-3475) solution for infusion must be diluted prior to 
administration.  Allow the required number of vials to equilibrate to room temperature.  Do not 
shake the vials.  Do not use if opaque or extraneous particulate matter other than translucent to 
white proteinaceous particles is observed.  Do not use if discolored.  To prepare the infusion 
solution add the dose volume of MK-3475 to an infusion bag containing 0.9% Sodium Chloride 
Injection, USP or 5% Dextrose Injection, USP.  Gently invert the bag 10-15 times to mix the 
solution.  The final concentration must be between 1 mg/mL to 10 mg/mL. 
 
Compatible IV bag materials: PVC plasticized with DEHP, non-PVC (polyolefin), EVA, 
or PE lined polyolefin 
 
Storage: Store intact vials between 2°C - 8°C (36°F - 46°F).  Do not freeze.  Protect from light by 
storing in the original box.   
 
If a storage temperature excursion is identified, promptly return MK-3475 to between 2-8°C 
and quarantine the supplies.  Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability: Stability testing of the intact vials is on-going. 
 
Administer prepared solutions immediately after preparation.  If not administered immediately, 
prepared solutions may be stored refrigerated for up to 20 hours.  MK-3475 solutions may be stored 
at room temperature for a cumulative time of up to 4 hours.  This includes room temperature storage 
of liquid drug product solution in vials, room temperature storage of infusion solution in the IV bag, 
and the duration of infusion. 
 
Route of Administration: IV infusion only.  Do not administer as an IV push or bolus injection. 
 
Method of Administration: Infuse over approximately 30 minutes (range: 25 - 40 minutes) using 
an infusion set containing a low-protein binding 0.2 to 5 µm in-line filter made of polyethersulfone 
or polysulfone.  Infusion rate should not exceed 6.7 mL/min.  A central line is not required; 
however if a subject has a central venous catheter in place, it is recommended that it be used for the 
infusion.  Do not co-administer other drugs through the same infusion line.  Following the infusion, 
flush the IV line with normal saline. 
 


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Compatible infusion set materials: PVC plasticized with DEHP or DEHT, PVC and tri-
(2-ethylhexyl) trimellitate, polyethylene lined PVC, polyurethane, or polybutadiene 
 
Patient Care Implications: Refer to the protocol for information on evaluation and management 
of potential immune-related adverse events. 
 
Epacadostat (NSC 766086) 
Chemical Name: (Z)-N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-4-(2-(sulfamoylamino) 
ethylamino)-1,2,5-oxadiazole-3-carboximidamide 
Other Names: INCB024360 
Classification: Indoleamine-2, 3-dioxygenase 1 (IDO1) inhibitor 
Molecular Formula: C11H13BrFN7O4S 
M.W.: 438.23 
Approximate Solubility: The solubility of INCB024360 at 25°C is approximately 0.1 mg/mL in 
all aqueous medium types studied (water,  pH 7.4 buffer, pH 8 buffer, and pH 2.1 buffer. 
Mode of Action: The enzyme IDO1 is responsible for the oxidation of tryptophan into 
kynurenine.  The catabolism of tryptophan by IDO1 inhibits T cell-mediated responses.  Within 
the immune system, IDO1 activity is induced in dendritic cells and macrophages localized at 
sites of inflammation.  By inhibiting IDO1 in tumor cells, epacadostat enhances T cell and 
natural killer cell proliferation and gamma interferon production while reducing regulatory T cell 
differentiation and dendritic cell apoptosis. 
Description: The epacadostat drug substance is a white to off-white powder. 
How Supplied:  Epacadostat is supplied by Incyte Corporation and distributed by the 
Pharmaceutical Management Branch, CTEP/DCTD/NCI as 100 mg uncoated tablets (white, 
round, debossed with the strength “100”)   The immediate release tablets contain drug substance, 
lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, colloidal 
silicon dioxide, and magnesium stearate.  Tablets are to be dispensed in the original bottles.  
Each bottle contains 35 tablets. 
Storage: Store at controlled room temperature (15-30°C/59-86°F). 
If a storage temperature excursion is identified, promptly return epacadostat to between 15 and 
30°C and quarantine the supplies. Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
Stability: Shelf-life stability studies of epacadostat tablets are ongoing. 
Route of Administration: Oral administration. May be administered without regard to food. 


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Potential Drug Interactions: Metabolism of INCB024360 occurs via CYP3A4, CYP1A2, 
CYP2C19, and UGT1A9 isoenzymes and via glucuronidation.  The potential for weak to 
moderate inhibitors of UGT1A9 to cause clinically significant drug interactions with epacadostat 
via inhibition of UGT1A9 activity is low. Results suggest that epacadostat is not a CYP inducer 
in vitro. Epacadostat has low potential to cause clinically significant drug-drug interactions 
through CYP and UGT inhibition and induction. Use caution when administered with strong 
inhibitors/inducers of CYP3A4, CYP1A2, CYP2C19, and UGT1A9.  
Epacadostat may cause an increase in serotonin levels which has the potential to precipitate 
serotonin syndrome when administered in combination with monoamine oxidase (MAO) 
inhibitors or serotonergic agents.  Concomitant use of MAO inhibitors or serotonergic agents is 
prohibited.   
Caution should be exercised with concomitant administration of warfarin. Close INR monitoring 
is recommended for subjects on a stable dose of warfarin who are starting treatment with 
epacadostat. The dose of warfarin should be reduced when coadministered with epacadostat 
doses > 100 mg BID.  
Epacadostat and its metabolites are moderate inhibitors of OAT1, OAT3, OCT2, OATP1B1, and 
OATP1B3. The potential for epacadostat to cause clinically relevant drug-drug interactions via 
uptake transporters is low. Studies suggest that epacadostat is likely a substrate of P-gp and 
BCRP. Epacadostat is a weak P-gp inhibitor, however the potential for epacadostat to cause 
drug-drug interactions through P-gp interaction is low at clinically relevant exposures. 
Epacadostat is not an inhibitor of BCRP. Use caution when administered with strong 
inhibitors/inducers of P-gp and BCRP. 
Agent Ordering and Agent Accountability
9.3.1
Availability of MK-3475 (Pembrolizumab) 
 
MK-3475 (Pembrolizumab) is an investigational agent supplied to investigators by the Division 
of Cancer Treatment and Diagnosis (DCTD), NCI. 
MK-3475 (Pembrolizumab) is provided to the NCI under a Collaborative Agreement between 
the Pharmaceutical Collaborator and the DCTD, NCI (see Appendix III). 
Availability of Epacadostat 
Epacadostat is an investigational agent supplied to investigators by the Division of Cancer 
Treatment and Diagnosis (DCTD), NCI. 
Epacadostat is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Appendix III). 
Agent Ordering and Agent Accountability 
NCI-supplied agents may be requested by eligible participating Investigators (or their 


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authorized designee) at each participating institution.  The CTEP-assigned protocol 
number must be used for ordering all CTEP-supplied investigational agents.  The eligible 
participating investigators at each participating institution must be registered with CTEP, 
DCTD through an annual submission of FDA Form 1572 (Statement of Investigator), 
NCI Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF).  If there 
are several participating investigators at one institution, CTEP-supplied investigational 
agents for the study should be ordered under the name of one lead investigator at that 
institution. 
In general, sites may order initial agent supplies when a subject is being screened for 
enrollment onto the study.  
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online Agent Order 
Processing (OAOP) application.  Access to OAOP requires the establishment of a CTEP 
Identity and Access Management (IAM) account and the maintenance of an “active” 
account status and a “current” password.  For questions about drug orders, transfers, 
returns, or accountability, call or email PMB any time.  Refer to the PMB’s website for 
specific policies and guidelines related to agent management.   
 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of all agents received from the PMB using the appropriate NCI 
Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP 
forms page.  Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this protocol. 
 
Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators and 
research staff through the PMB OAOP application.  Access to OAOP requires the 
establishment of a CTEP IAM account and the maintenance of an “active” account status, 
a “current” password, and active person registration status.  Questions about IB access 
may be directed to the PMB IB Coordinator via email. 
 
 
Useful Links and Contacts 
 CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
 NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
 PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
 PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP/CTEP Identity and Access Management 
(IAM) account:  https://ctepcore.nci.nih.gov/iam/ 
 CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
 IB Coordinator:  IBCoordinator@mail.nih.gov  
 PMB email:  PMBAfterHours@mail.nih.gov 






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Definition of Disease Assessments 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria.
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) as ≥10 mm with CT scan, as ≥20 mm by 
chest x-ray, or ≥10 mm with calipers by clinical exam. All tumor measurements must be 
recorded in decimal fractions of centimeters.  
Note: Tumor lesions that are situated in a previously irradiated area will not be considered 
measurable unless progression is documented or a biopsy is obtained to confirm persistence at 
least 90 days following completion of radiation therapy.  
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.  
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. Leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pneumonitis, inflammatory breast disease, and abdominal/pelvic masses 
(identified by physical exam and not CT or MRI), are considered as non-measurable.  
Notes:  
Bone lesions: Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by CT or MRI can be considered as measurable lesions if the 
soft tissue component meets the definition of measurability described above. Blastic bone lesions 
are non-measurable.  
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 


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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, and 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. 
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.  
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), but NOT lung.  
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 


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scanners, body parts, and diseases. Ideally, subsequent image acquisitions should use the same 
type of scanner and follow the baseline imaging protocol as closely as possible. If possible, body 
scans should be performed with breath-hold scanning techniques.  
NRG will not allow PET-CT use for RECIST 1.1 response criteria.  
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.  
CA-125: CA125 cannot be used to assess response or progression in this study. If CA125 is 
initially above the upper normal limit, it must normalize for a patient to be considered in 
complete clinical response. Specific guidelines for CA-125 response (in recurrent ovarian 
cancer) have been published [JNCI 96:487-488, 2004]. In addition, the Gynecologic Cancer 
Intergroup has developed CA-125 progression criteria that are to be integrated with objective 
tumor assessment for use only 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.  
It is mandatory to obtain cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment when measurable disease has met criteria for response or 
stable disease. This confirmation is necessary to differentiate response or stable disease versus 
progressive disease, as an effusion may be a side effect of the treatment. 
Response Criteria  
Determination of response should take into consideration all target and non-target lesions and, if 
appropriate, biomarkers. 
Evaluation of Target Lesions  
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 sum of the diameters of target lesions, 
taking as reference the baseline sum diameters.  


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Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
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 (i.e. the nadir) while on study. 
 
 
Evaluation of Non-Target Lesions  
Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be non-
pathological in size (<10 mm short axis).  
 
Note: If CA-125 is initially above the upper normal limit, it must normalize for a patient to be 
considered in complete clinical response.  
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) Progressive Disease (PD): 
Appearance of one or more new lesions and/or unequivocal progression of existing non-target 
lesions. Unequivocal progression should not normally trump target lesion status. It must be 
representative of overall disease status change, not a single lesion increase.  
 
Not evaluable (NE): When at least one non-target lesion is not evaluated at a particular time 
point.  
 
Although a clear progression of only “non-target” lesions is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
 
 
 
Evaluation of Best Overall Response  
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
≥ 4 wks confirmation** 


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CR 
Non-CR/Non-PD 
No 
PR 
 
≥ 4 wks confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not evaluated 
No 
SD 
Documented at least once ≥ 4 wks from 
baseline** 
PD 
Any 
Yes or No 
PD 
 
No prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.  
** Only for non-randomized trials with response as primary endpoint.  
*** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression.  
Note: Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic deterioration.” 
Every effort should be made to document the objective progression even after discontinuation of treatment. 
  
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PD* 
Not all evaluated 
No 
Not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as 
an endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be 
measured is not advised  
 
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. 
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. 


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Progression-Free Survival 
Progression-Free Survival (PFS) is defined as the duration of time from start of treatment to time 
of progression or death, whichever occurs first. 
Survival 
Survival is defined as the duration of time from start of treatment to time of death or the date 
of last contact. 
12. DATA AND RECORDS 
 
Summary of Data Submission 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Adverse events are reported in a routine 
manner at scheduled times during the trial using Medidata Rave®. Additionally, certain 
adverse events must be reported in an expedited manner for more timely monitoring of 
patient safety and care. See Sections 7.2 for information about expedited and routine 
reporting.  
Global Reporting/Monitoring 
 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means. 
Reports are due January 31, April 30, July 31, and October 31. 
 
Monitoring Method for Protocol NRG-GY016: Complete 
 
Note:  If your study has been assigned to CDUS-Complete reporting, all adverse events 
(both routine and expedited) that have occurred on the study and meet the mandatory 
CDUS reporting guidelines must be reported via the monitoring method identified above.  
If your study has been assigned to CDUS-Abbreviated reporting, no adverse event 
reporting (routine or expedited) is required to be reported via CDUS, but expedited 
adverse events are still required to be submitted via CTEP-AERS. 
 
13. STATISTICAL CONSIDERATIONS 
Study Design 
The primary objective of this study is to assess the anti-tumor activity for women 
receiving the combination of MK-3475 (pembrolizumab) and epacadostat for recurrent or 
persistent clear cell carcinoma of the ovary.  The primary measure of efficacy is the 
objective tumor response rate, defined as a complete response or partial response. 


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This is a single-arm, phase II clinical trial that will use a flexible, two-stage design (Chen 
et al., 1998).  Since it is a single-arm trial, it does not require randomization or 
stratification.  If the trial enters both stages, the total accrual target will be 23 patients but 
will be allowed to range from 21 to 25, due to the difficulty in accruing precise numbers 
of patients in a multicenter trial.  A hard stop on accrual will occur after accrual 
completes to the first stage (see Section 13.3.2).  The study will re-open to accrual in the 
event the study advances to the second stage. 
The biologic mechanism of the study agent is expected to impede the growth of tumors 
already present and inhibit the development of new metastases.  Therefore, the objective 
tumor response rate will be used as the primary measure of efficacy. 
Study Endpoints 
List of endpoints that correspond to the study objectives, e.g. the endpoint of overall 
survival for the study objective to evaluate the impact of drug X on overall survival in X 
population. Include endpoint definitions. 
 
Primary endpoints: 
 Complete or partial objective tumor response within 7 months of study entry as 
assessed by RECIST v. 1.1 criteria
 
Secondary endpoints: 
 Nature and degree of toxicity as assessed using CTCAE version 5 
 Progression-free survival 
 Overall survival 
Primary Objectives Study Design 
13.3.1 Primary Hypothesis and Endpoints 
The primary hypothesis of this study tests the proportion of patients with objective 
complete or partial tumor response (𝜋) evaluated by RECIST v. 1.1 criteria.  Based on 
predicted response rates in similar patient populations, the null hypothesis is that the 
proportion of patients with objective tumor response will be 15% or less, i.e.:
 
H0: 𝜋 ≤ 0.15. 
 
The alternative hypothesis is the complement of the null parameter space (i.e. H1: 𝜋 > 
0.15).  The study is powered to detect a 25 percentage point increase in response: 𝜋 = 
0.40. 
13.3.2 How Primary Endpoints Will Be Analyzed 
The study will use a flexible two-stage design with early stopping guidelines based on 


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tumor response rate intended to limit the accrual of patients to ineffective treatments.  
The first stage of this study will target an accrual of 12 eligible patients, but in practice 
will permit accrual to range from 10 to 14 patients.  A hard stop on accrual will occur 
after 14 patients have enrolled in the study. If the number responding is less than or equal 
to 1, then the study will terminate early and the regimen will be declared uninteresting.  If 
there are at least 2 patients with response, the study advances to the second stage and the 
study re-opens to accrual.  If the study advances to the second stage, then the overall 
study accrual of 23 eligible patients will be targeted, but the actual accrual will be 
permitted to range from 21 to 25 patients.  If the number responding is less than or equal 
to 5 for a sample size of 21 – 23 patients or less than or equal to 6 for a sample size of 24 
– 25 patients, then the regimen will be declared uninteresting to warrant further 
investigation.  All enrolled patients deemed eligible and who initiate study treatment will 
be included in the analysis of objective response.  Exact 95% confidence limits, 
accounting for interim analysis, will be provided in the final report. 
13.3.3 Sample Size and Power Calculations: All supporting assumptions and/or important 
considerations, such as expected sample size or patient cohorts. Also can include 
information such as over-accrual and how many patients are planned for enrollment to 
define power. 
A two-stage design was chosen to allow for flexibility in accrual.  The target sample size 
for the first stage is 12 eligible patients but allowed to vary between 10 and 14.  A hard 
stop on accrual will occur after 14 patients have enrolled in the study. The study will re-
open to accrual in the even the study advances to the second stage. The target cumulative 
sample size at the second stage is 23 eligible patients but allowed to vary between 21 and 
25.  Across all possible accrual combinations and assuming uniform probabilities of 
accrual across these, the average probability of early termination is 45% under the null, 
and the average alpha and power are 0.08 and 0.91 respectively.  For most accrual 
combinations, the alpha is <0.10 and the power is >0.90. 
Table 1. Operating characteristics of the trial design 
True ORR 
Probability of 
early stopping 
Average 
Sample size 
Probability of claiming 
experimental agent is promising 
0.15 (null) 
0.45 
18 
0.08 
0.25 
0.17 
21 
0.44 
0.30 
0.09 
22 
0.65 
0.35 
0.05 
22 
0.81 
0.40 
0.02 
23 
0.91 
0.45 
0.01 
23 
0.96 
Study Monitoring of Primary Objectives 
(Interim Analysis) 
 
See Section 13.3.2 for details regarding study monitoring of primary objectives. 
 
Monitoring of the primary objective and impact on stage transition will be summarized in 


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a formal report provided by the Study Statistician to be reviewed by the protocol 
monitoring committee.  The protocol monitoring team will consist of the Study Chair, the 
Study Statistician, the Study Co-Chairs, the Data Manager, and any others required.  
After review of this information and any other information that may be relevant, the 
protocol monitoring team should reach a consensus on whether the accrual rate is 
sufficient to support completion of accrual, whether the rates of adverse events are low 
enough to be offset by the patient benefit hypothesized for intervention, and whether the 
number of events is sufficient to proceed to the next phase or sufficient to reach the 
definitive analysis. 
 
Brief minutes of the meeting written by the Study Chair plus the Study Statistician’s 
report will be forwarded to the NRG Operations Office for archiving.  The NRG 
Operations Office will forward the meeting minutes and the report to the NRG Oncology 
Internal Early Phase Trial Oversight Committee for review at their regularly scheduled 
meetings. 
 
See Section 13.7.6 for details regarding the Early Phase Trial Oversight Committee.       
 
 Accrual/Study Duration Considerations 
Section should include as applicable accrual rate, accrual goal, study/accrual duration, 
estimated duration for completion of primary endpoints  
Protocol 
Number
Accrual Start 
Date 
Temporary 
Accrual 
Closure 
Final Accrual 
Date 
Accrual/Month 
Rate (excluding 
temporary closure 
period) 
Number of 
Patients 
Enrolled 
NRG-GY001 
April 1, 2015 
Nov. 1, 2015 
 
1.7/month 
13 
GOG-0283 
Feb. 3, 2014 
Dec. 19, 2014 – 
Oct. 6, 2015 
Aug. 10, 2016 
 
2.4/month in first 
11 months 
1.7/month overall 
35 
GOG-0254 
April 19, 2010 
Feb. 6 2012 – 
Oct. 1, 2012 
Sept. 30, 2013 
1.1/month 
35 
There have been several trials recruiting patients with clear cell carcinoma of the ovary 
through NRG Oncology.  GOG-0254 was a two-stage, phase II trial of sunitinib that 
accrued 35 patients over 34 total months.  GOG-0283, a Phase II single-agent, open-label 
trial of dasatinib, accrued Stage I (all comers) with 26 evaluable in 11 months (2.4 
patients per month), with 1.7 patients per month overall.  NRG-GY001 (cabozantinib) 
activated April 1, 2015 and enrolled its first stage (n=13) in 7 months.  The ovarian clear 
cell carcinoma community is active and a frequent inquirer for clinical trials.  Based on 
the accrual information above, the present trial is expected to accrue 1.5 patients/month 
(18 patients/year). 
 
Twelve eligible patients are required for the first stage (allowable range 10-14), with a 
cumulative target of 23 eligible patients (allowable range 21-25) in the second stage.   A 
hard stop on accrual will occur after 14 patients have enrolled in the study.  The study 
will re-open to accrual in the event the study advances to the second stage.    


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Approximately eight months are expected to be required for the first stage of accrual, 
followed by approximately eight months of evaluation of objective tumor response to 
determine whether to open the second stage; if required, eight months are expected for 
accrual for the second stage, followed by eight months of evaluation for response.  If the 
study requires two stages, final analysis is expected in approximately three years. 
Dose Level Guidelines 
(Escalation or de-escalation): Mandatory for phase I or phase I/II trials 
Dose level guidelines are not applicable for this study. 
Secondary 
 (including correlative science aims) 
If there are secondary 
aims, they must be addressed in the Statistical 
Considerations section. 
Secondary Hypotheses and Endpoints: The expected level of detail for secondary 
hypotheses will be less than for the primary hypothesis and endpoint. 
The secondary endpoints of adverse events, progression-free survival and overall survival 
will be estimated as described in Section 13.7.2. 
Definitions of Secondary Endpoints and How These Will Be Analyzed 
CTCAE version 5 will be used to grade and categorize adverse events.  Descriptive 
statistics, including frequencies, of maximum grade of adverse events by term and 
category will be reported.  Adverse events categorized as Grade 5 will be individually 
reported. 
 
Disease progression will be defined using RECIST v. 1.1 criteria.  Progression-free 
survival (PFS) is defined as the duration of time from the start of study treatment to time 
of progression or death, whichever occurs first.  Overall survival (OS) is defined as the 
duration of time from the start of study treatment to time of death or the date of last 
contact.  The distributions of PFS and OS will be estimated and graphed using the 
Kaplan-Meier product limit method. 
Interim Analysis for All Other Endpoints (Goals): Include as applicable 
No interim analyses are planned for secondary endpoints. 
13.7.4 Power Calculations: power can be provided as applicable for selected secondary 
endpoints, if any. The power is based on the sample size for the primary endpoints. 
Power calculations are not needed for the secondary endpoints because only estimation, 
not testing, will be done for these endpoints. 
13.7.5 Expected Sample Size or Patient Cohorts:  


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Not applicable. 
 
13.7.6 Data and Safety Monitoring 
 
The Data Manager will work with the Study Statistician to keep the data up-to-date on a 
regular basis.   
 
Accrual and safety data on this protocol will be reviewed by the protocol monitoring 
team on a quarterly basis (every three months) via conference call.  The protocol 
monitoring team will consist of the Study Chair, the Study Statistician, the Study Co-
Chairs, the Data Manager, and any others required.  The Study Statistician will assemble 
the necessary data and prepare a report for review.  The report will include information 
related to patient accrual, basic patient and tumor characteristics, follow-up information, 
and adverse events and toxicities. 
 
The protocol monitoring team will consider information in the provided report and the 
recommendations of the Study Statistician.  After review of this information and any 
other information that may be relevant, the protocol monitoring team should reach a 
consensus on whether the accrual rate is sufficient to support completion of accrual, 
whether the rates of adverse events are low enough to be offset by the patient benefit 
hypothesized for intervention, and whether the number of events is sufficient to proceed 
to the next phase or sufficient to reach the definitive analysis. 
 
Brief minutes of each meeting written by the Study Chair plus the Study Statistician’s 
report will be forwarded to the NRG Operations Office for archiving.  The NRG 
Operations Office will forward the meeting minutes and the report to the NRG Oncology 
Internal Early Phase Trial Oversight Committee for review at their regularly scheduled 
meetings. 
 
The Early Phase Trial Oversight Committee will review the study quarterly (every three 
months) with respect to patient accrual and morbidity.  Face-to-face meetings will be held 
at the semiannual NRG Oncology group meetings and intervening quarterly meetings 
will be held by conference call.  Each quarterly report will be forwarded to the CIRB. 
 
The frequency and severity of all toxicities are tabulated from submitted case report 
forms and summarized for review by the Study Chairperson, Gynecologic Rare Tumor 
Committee, and NRG Safety Review Committee (SRG) in conjunction with each semi-
annual meeting (twice per year). For studies sponsored by CTEP of the National Cancer 
Institute (NCI), standardized toxicity reports are also submitted to the drug and disease 
monitors at the Investigational Drug Branch (IDB) and Clinical Investigation Branch 
(CIB).   
 
All serious adverse events (SAEs) are reported to the Study Chairperson, Sponsor, 
Pharmaceutical company, and regulatory agencies as mandated in the protocol.  SAE 
reports are reviewed by the Study Chairperson (or designated co-chairperson) 


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immediately for consideration of investigator notification of a suspected unexpected 
serious adverse reaction (SUSAR), protocol amendment, and/or immediate study 
suspension.  All participating institutions will receive notification of the SUSAR from 
NRG as well as the reason study suspension, if applicable.  Upon suspension, accrual 
cannot be re-activated until review of the study by the SRG.  However, patients currently 
receiving treatment may continue to receive treatment in accordance with protocol 
guidelines at the discretion of their physicians, unless otherwise directed. 
 
13.8 
 
 
 
 
 
         
 
 
 
         
 
 
 
 
         
 
 
. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
13.9 
Gender/Ethnicity/Race Distribution 
 
The distribution below is based on the maximum, two-stage sample size of 25 patients. 
 
 
 
 
Racial Categories 
DOMESTIC PLANNED ENROLLMENT REPORT 
Ethnic Categories 
Not Hispanic or 
Latino 
Hispanic or Latino 
 
Total 
Female 
Male 
Female 
Male 




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nivolumab in metastatic melanoma. Oncoimmunology. 2016 Jun 30; 5(9):e1204507.  
 
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Leffers N, Gooden MJM, de Jong RA, Hoogeboom B-N, ten Hoor KA, Hollema H, et al. Prognostic 
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Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, et al. Frequency of regulatory T cells in 
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APPENDIX I – PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
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). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 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. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 


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APPENDIX II – NYHA CLASSIFICATION 
 
Congestive Heart Failure – New York Heart Association Classification 
 
Class 
Definition 
I 
No limitation: Ordinary physical activity does not cause undue fatigue, 
dyspnea, or palpitation 
II 
Slight limitation of physical activity: Such patients are comfortable at rest. 
Ordinary physical activity results in fatigue, palpitations, dyspnea, or angina. 
III 
Marked limitation of physical activity: Although patients are comfortable at 
rest, less than ordinary physical activity will lead to symptoms. 
IV 
Inability to carry on physical activity without discomfort: Symptoms of 
congestive heart failure are present even with rest. With any physical activity, 
increased discomfort is experienced. 
 
Source: Criteria Committee, New York Heart Association, Inc. Diseases of the heart and blood 
vessels. Nomenclature and criteria for diagnosis. 6th ed. Boston, Little, Brown and Co, 1964: 
114. 
 
 


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APPENDIX III – COLLABORATIVE AGREEMENT 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 


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4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email: ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
 


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APPENDIX IV – PATIENT PILL CALENDAR 
 
This is a calendar on which you are to record the time and number of tablets you take each day. 
Complete one form for each cycle (21 days). You should take your scheduled dose of each pill. 
You can take the pill either with or without food. Note the times and the number of tablets 
that you take each day. If you develop any side effects, please record them and anything you 
would like to tell the doctor in the space provided.  Bring any unused tablets and your completed 
pill calendar to your doctor’s visits. 
Epacadostat 
DAY 
Date 
Time pills taken 
(circle AM/PM 
 
           
Number of pills 
taken each day 
(100 mg) 
Comments 
Month 
Day 
Year 
1 
 
 
 
 
AM/PM 
 
 
2 
 
 
 
 
AM/PM 
 
 
3 
 
 
 
 
AM/PM 
 
 
4 
 
 
 
 
AM/PM 
 
 
5 
 
 
 
 
AM/PM 
 
 
6 
 
 
 
 
AM/PM 
 
 
7 
 
 
 
 
AM/PM 
 
 
8 
 
 
 
 
AM/PM 
 
 
9 
 
 
 
 
AM/PM 
 
 
10 
 
 
 
 
AM/PM 
 
 
11 
 
 
 
 
AM/PM 
 
 
12 
 
 
 
 
AM/PM 
 
 
13 
 
 
 
 
AM/PM 
 
 
14 
 
 
 
 
AM/PM 
 
 
15 
 
 
 
 
AM/PM 
 
 
16 
 
 
 
 
AM/PM 
 
 
17 
 
 
 
 
AM/PM 
 
 
18 
 
 
 
 
AM/PM 
 
 
19 
 
 
 
 
AM/PM 
 
 
20 
 
 
 
 
AM/PM 
 
 
21 
 
 
 
 
AM/PM 
 
 
Patient Signature: __________________________________ Date: _____________ 
 
 


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APPENDIX V:  PATIENT DRUG INFORMATION HANDOUT AND WALLET 
CARD  
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
 
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug epacadostat (INCB024360).  This clinical trial is sponsored by the 
National Cancer Institute.  This form is addressed to the patient, but includes important 
information for others who care for this patient.  
 
These are the things that you as a prescriber need to know: 
 
Epacadostat (INCB024360) interacts with certain specific enzymes in the liver and certain 
transport proteins that help move drugs in and out of cells. 
 
• 
The enzymes in question are CYP 3A4, CYP1A2, CYP2C19, and UGT1A9.  
Epacadostat (INCB024360) is metabolized by CYP3A4, CYP1A2, CYP2C19, and UGT1A9 and 
may be affected by other drugs that inhibit or induce these enzymes.   
• 
The proteins in question are OAT1, OAT3, OCT2, OATP1B1, OATP1B3, P-gp, and 
BCRP.  Epacadostat (INCB024360) is a substrate of P-gp and BCRP and may be affected by 
other drugs that inhibit or induce these transporters.  Epacadostat (INCB024360) is an inhibitor 
of OAT1, OAT3, OCT2, OATP1B1, OATP1B3, and P-gp and may affect transport of other 
drugs in and out of cells. 
• 
Epacadostat (INCB024360) may cause an increase in serotonin levels when 
administered in combination with monoamine oxidase (MAO) inhibitors.  Use of MAO 
inhibitors is prohibited. 
• 
Caution should be exercised with concomitant administration of warfarin and 
epacadostat (INCB024360).  Patients taking these medications should be monitored more 
frequently. 
 
To the patient: Take this paper with you to your medical appointments and keep the attached 
information card in your wallet.   
 
Epacadostat (INCB024360) may interact with other drugs which can cause side effects.  For this 
reason, it is very important to tell your study doctors of any medicines you are taking before you 
enroll onto this clinical trial.  It is also very important to tell your doctors if you stop taking any 
regular medicines, or if you start taking a new medicine while you take part in this study.  When 
you talk about your current medications with your doctors, include medicine you buy without a 
prescription (over-the-counter remedy), or herbal supplements such as St. John’s Wort.  It is 
helpful to bring your medication bottles or an updated medication list with you. 
 
Many health care providers can write prescriptions.  You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, or pharmacists) you are taking part 
in a clinical trial.  


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These are the things that you and they need to know:  
 
Epacadostat (INCB024360) must be used very carefully with other medicines that need certain 
liver enzymes or transport proteins to be effective or to be cleared from your system.  Before you 
enroll onto the clinical trial, your study doctor will work with your regular health care providers 
to review any medicines and herbal supplements that are considered “strong inducers/inhibitors 
or substrates of CYP 3A4, 1A2, 2C19, UGT1A9, OAT1, OAT3, OCT2, OATP1B1, OATP1B3, 
P-gp, and BCRP.  MAO inhibitors are prohibited.  Warfarin must be used with caution and 
closely monitored.” 
 
• 
 
Please be very careful!  Over-the-counter drugs (including herbal 
supplements) may contain ingredients that could interact with your study drug.  Speak to your 
doctors or pharmacist to determine if there could be any side effects.  
• 
You may need to be monitored more frequently if you are taking warfarin with 
epacadostat (INCB024360). 
• 
Your regular health care provider should check a frequently updated medical 
reference or call your study doctor before prescribing any new medicine or discontinuing any 
medicine.  Your study doctor’s name is  
 
_____________________________________ and he or she can be contacted at  
 
_____________________________________.                                                                                                         
12/2017 
 
 
 
 
 
 
 
 
 
 
STUDY DRUG INFORMATION WALLET CARD   
 
You are enrolled on a clinical trial using the experimental study drug 
epacadostat (INCB024360).  This clinical trial is sponsored by the NCI.  
Epacadostat (INCB024360) may interact with drugs that are 
processed by your liver, or use certain transport proteins in your 
body.  Because of this, it is very important to: 
 Tell your doctors if you stop taking any medicines or if you start 
taking any new medicines. 
 Tell all of your health care providers (doctors, physician assistants, 
nurse practitioners, or pharmacists) that you are taking part in a 
clinical trial. 
 Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
 MAO inhibitors are prohibited.   
 Warfarin must be used with caution and closely monitored. 
Epacadostat (INCB024360) interacts with CYP 3A4, 1A2, 2C19, 
UGT1A9, OAT1, OAT3, OCT2, OATP1B1, OATP1B3, P-gp, and BCRP, 
and must be used very carefully with other medicines that interact 
with these enzymes and proteins. 
 Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines and herbal supplements that are considered “strong 
inducers/inhibitors or substrates of CYP 3A4, 1A2, 2C19, 
UGT1A9, OAT1, OAT3, OCT2, OATP1B1, OATP1B3, P-gp, and 
BCRP” 
 Before prescribing new medicines, your regular prescribers 
should go to a frequently-updated medical reference for a list of 
drugs to avoid, or contact your study doctor.   
 Your study doctor’s name is ________________________  
and can be contacted at _________________________.  


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