Safety and Efficacy Study of Retifanlimab and Epacadostat in Combination With Radiation and Bevacizumab in Patients With Recurrent Gliomas
Phase: PHASE2
Conditions: Glioma, Glioblastoma
Sponsor: Washington University School of Medicine

Protocol Version: 06/04/2022 
 
Page 1 of 74 
 
 
Safety and efficacy study of retifanlimab and epacadostat in combination with radiation 
and bevacizumab in patients with recurrent gliomas 
 
Washington University School of Medicine 
Division of Oncology 
660 South Euclid Avenue, Campus Box 8056 
St. Louis, MO  63110 
 
Protocol #: 202003050 
Version Date: 06/04/2022 
 
Coordinating Center: 
Washington University School of Medicine 
 
Principal Investigator: 
Milan Chheda, M.D. 
Phone: (314) 747-7222 
E-mail: mchheda@wustl.edu 
Sub-Investigators 
 
 
Institution 
 
 
Modality 
Christopher Abraham, M.D.  
Washington University 
Radiation Oncology 
George Ansstas, M.D. 
 
Washington University 
Neuro-Oncology 
Omar Butt, M.D., Ph.D 
 
Washington University 
Neuro-Oncology 
Matthew A. Ciorba, M.D. 
 
Washington University 
Gastroenterology 
Jiayi Huang, M.D. 
 
 
Washington University 
Radiation Oncology 
Tanner Johanns, M.D. , Ph.D.  
Washington University 
Medical Oncology 
Jingqin (Rosy) Luo, Ph.D. 
 
Washington University 
Biostatistics 
Dinesh Thotala, Ph.D. 
 
Washington University 
Radiation Oncology 
Roy E. Strowd III, M.D., M.Ed. 
Wake Forest   
 
Neuro-Oncology 
Alyx B. Porter Umphrey, M.D. 
Mayo Clinic – Arizona 
Neuro-Oncology 
Sani H. Kizilbash, M.D., M.P.H.  
Mayo Clinic – Rochester 
Neuro-Oncology 
 
Study Drug(s): 
 
Epacadostat 
(Retifanlimab) 
Bevacizumab (Avastin) 
 
IND #: 
147766 
IND Sponsor: 
Milan Chheda, M.D.  
ClinicalTrials.gov #: 
NCT03532295 
Funded by: 
Incyte Corporation 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them 

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Safety and efficacy study of retifanlimab and epacadostat in combination with radiation 
and bevacizumab in patients with recurrent gliomas 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
03/06/2020 
Amendment #1 Version 
 
 
 
 
 
 
03/27/2020 
Amendment #2 Version 
 
 
 
 
 
 
06/30/2020 
Amendment #3 Version 
 
 
 
 
 
 
01/14/2021 
Amendment #4 Version 
 
 
 
 
 
 
08/06/2021 
Amendment #5 Version 
 
 
 
 
 
 
01/27/2022 
Amendment #6 Version 
 
 
 
 
 
 
03/03/2022 
Amendment #7 Version 
 
 
 
 
 
 
04/19/2022 
Amendment #8 Version 
 
 
 
 
 
 
06/04/2022 
 
 

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Safety and efficacy study of retifanlimab and epacadostat in combination with radiation 
and bevacizumab in patients with recurrent gliomas 
 
Principal Investigator Signature Page 
 
 
Principal Investigator 
(printed): 
      
Name of Institution:       
  
 PI Signature 
 
 
 
 
 
Date 
 
By my signature, I agree to personally supervise the conduct of this study 
and to ensure its conduct in compliance with the protocol, informed 
consent, IRB/HRPO procedures, the Declaration of Helsinki, ICH Good 
Clinical Practices guidelines, and the applicable parts of the United 
States Code of Federal Regulations or local regulations governing the 
conduct of clinical studies. 
 
 
 

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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following:  
 
 United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
 

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Safety and efficacy study of retifanlimab and epacadostat in combination with radiation 
and bevacizumab in patients with recurrent gliomas 
 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Epacadostat* 
Retifanlimab 
Bevacizumab 
Radiation Therapy 
400 mg PO  
Twice daily 
500 mg IV Q4W 
10 mg/kg 
IV Q2W 
3.5 Gy x 10 fx 
(during C1) 
* Regimen B only 
 
At time of activation, the study will enroll patients to Regimen A. When 23 patients have 
enrolled to Regimen A, completed the evaluation period for intolerable toxicity (refer to Section 
5.2), and not exceeded the boundary “b” as specified in the table of Section 15.2, Regimen B will 
open to enrollment. 
 
 
 

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Glossary of Abbreviations 
 
AE 
Adverse event 
ALT (SGPT) 
Alanine transaminase (serum glutamate pyruvic transaminase) 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
AST (SGOT) 
Aspartate transaminase (serum glutamic oxaloacetic transaminase) 
B-HCG 
Beta human chorionic gonadotropin  
BMT 
Bone marrow transplant 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CNS 
Central nervous system 
CR 
Complete response 
CRc 
Cytogenetic complete remission 
CRi 
Complete remission incomplete 
CRm 
Morphologic complete remission 
CRF 
Case report form 
CST 
Central standard time 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DLT 
Dose limiting toxicity 
DNA 
deoxyribonucleic acid 
DSM 
Data and Safety Monitoring  
DSMC 
Data Safety Monitoring Committee 
ECG (or EKG) 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
ethylenediaminetetraacetic acid 
FDA 
Food and Drug Administration 
FISH 
fluorescent in situ hybridization 
FWA 
Federal wide assurance 
GCP 
Good Clinical Practice 
HHS 
Department of Health and Human Services 
HIV 
Human Immunodeficiency Virus 
HRPO 
Human Research Protection Office (IRB) 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
MDS 
Myelodysplastic syndrome 
MM 
Multiple myeloma 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCCN 
National Cancer Center Network 

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NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
NSCLC 
Non-small cell lung cancer 
OHRP 
Office of Human Research Protections  
ORR 
Overall response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 
PI 
Principal investigator 
PR 
Partial response 
PSA 
Prostate-specific antigen 
QASMC 
Quality Assurance and Safety Monitoring Committee 
RECIST 
Response Evaluation Criteria in Solid Tumors (Committee) 
RFS 
Relapse free survival 
RR 
Response rate 
SAE 
Serious adverse event 
SCC 
Siteman Cancer Center 
SCT 
Stem cell transplant 
SD 
Stable disease 
TSH 
Thyroid stimulating hormone 
TTP 
Time to progression 
UPN 
Unique patient number 
US 
Ultrasound 
VEGF 
Vascular endothelial growth factor 
WBC 
White blood cell (count) 
 
 

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Table of Contents 
SCHEMA ........................................................................................................................................ 5 
1.0 
BACKGROUND AND RATIONALE .............................................................................. 10 
1.1 
Glioblastoma .................................................................................................................. 10 
1.2 
Inhibition of Indoleamine 2,3-Dioxygenase 1 as a Target for Cancer ........................... 10 
1.3 
Epacadostat ..................................................................................................................... 11 
1.4 
Radiation Therapy .......................................................................................................... 15 
1.5 
Retifanlimab ................................................................................................................... 16 
1.6 
Bevacizumab .................................................................................................................. 18 
1.7 
Study Rationale .............................................................................................................. 18 
1.8 
Correlative Studies Background..................................................................................... 18 
2.0 
OBJECTIVES .................................................................................................................... 18 
2.1 
Primary Objective .......................................................................................................... 19 
2.2 
Secondary Objectives ..................................................................................................... 19 
2.3 
Correlative Objectives .................................................................................................... 19 
2.4 
Exploratory Objectives ................................................................................................... 19 
3.0 
PATIENT SELECTION .................................................................................................... 19 
3.1 
Inclusion Criteria ............................................................................................................ 19 
3.2 
Exclusion Criteria ........................................................................................................... 21 
3.3 
Inclusion of Women and Minorities ............................................................................... 23 
4.0 
REGISTRATION PROCEDURES ................................................................................... 23 
4.1 
Confirmation of Patient Eligibility ................................................................................. 23 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database ........................... 24 
4.3 
Assignment of UPN ....................................................................................................... 24 
4.4 
Patient Allocation ........................................................................................................... 24 
4.5 
Screen Failures ............................................................................................................... 24 
5.0 
TREATMENT PLAN ........................................................................................................ 24 
5.1 
Agent Administration ..................................................................................................... 24 
5.2 
Toxicity and Response Evaluations ............................................................................... 26 
5.3 
General Concomitant Medication and Supportive Care Guidelines .............................. 26 
5.4 
Women of Childbearing Potential .................................................................................. 29 
5.5 
Duration of Therapy ....................................................................................................... 30 
5.6 
Duration of Follow-up .................................................................................................... 31 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS .................................................................... 31 
6.1 
Dose Holds for Epacadostat ........................................................................................... 31 
6.2 
Procedures for Participants Exhibiting Immune-Related Adverse Events ..................... 32 
6.3 
Dose Modifications for Bevacizumab ............................................................................ 35 
6.4 
Dose Modifications for Radiation Therapy .................................................................... 35 
7.0 
REGULATORY AND REPORTING REQUIREMENTS ............................................... 35 
7.1 
Sponsor-Investigator Reporting Requirements .............................................................. 36 
7.2 
Secondary Site Reporting Requirements ........................................................................ 38 
7.3 
Exceptions to Expedited Reporting ................................................................................ 39 
8.0 
PHARMACEUTICAL INFORMATION .......................................................................... 39 
8.1 
Epacadostat ..................................................................................................................... 39 
8.2 
Retifanlimab .................................................................... Error! Bookmark not defined. 
8.3 
Bevacizumab (Avastin) .................................................................................................. 41 

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9.0 
CORRELATIVE STUDIES .............................................................................................. 42 
9.1 
Peripheral Blood for PBMCs ......................................................................................... 42 
9.2 
Peripheral Blood for Serum ............................................................................................ 44 
9.3 
Tumor Tissue – Optional ................................................................................................ 44 
10.0 STUDY CALENDAR ....................................................................................................... 46 
11.0 DATA SUBMISSION SCHEDULE ................................................................................. 48 
11.1 Adverse Event Collection in the Case Report Forms ..................................................... 48 
12.0 MEASUREMENT OF EFFECT........................................................................................ 48 
12.1 Antitumor Effect – Solid Tumors ................................................................................... 48 
12.2 Disease Parameters ......................................................................................................... 50 
12.3 Methods for Evaluation of Measurable Disease ............................................................ 51 
13.0 DATA AND SAFETY MONITORING ............................................................................ 54 
14.0 AUDITING ........................................................................................................................ 55 
15.0 STATISTICAL CONSIDERATIONS............................................................................... 56 
15.1 Overall Study Design ..................................................................................................... 56 
15.2 Early Stopping Rules for Continuous Toxicity Monitoring ........................................... 57 
15.3 Endpoints ........................................................................................................................ 58 
15.4 Sample Size Justification ............................................................................................... 58 
15.5 Statistical Analysis ......................................................................................................... 59 
15.6 Populations for Analysis ................................................................................................ 59 
16.0 MULTICENTER REGULATORY REQUIREMENTS ................................................... 60 
17.0 REFERENCES .................................................................................................................. 61 
APPENDIX A: Karnofsky Performance Scale ............................................................................. 65 
APPENDIX B: Patient’s Medication Diary .................................................................................. 66 
APPENDIX C: NANO Scale ........................................................................................................ 67 
APPENDIX D: Definitions for Adverse Event Reporting ........................................................... 69 
APPENDIX E: Reporting Timelines ............................................................................................ 71 
APPENDIX F: Washington University Unanticipated Problem Reporting Cover Sheet ............. 74 
 
 

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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Glioblastoma 
 
Glioblastoma (GBM) is the most common and aggressive form of brain tumor in adults. 
Despite maximal surgical resection, irradiation and chemotherapy, median overall survival 
(OS) remains at <15 months for newly diagnosed patients and only 30 weeks for recurrent 
patients, emphasizing the need for novel treatments [1;2]. 
 
Indoleamine 2,3 dioxygenase 1 (IDO1) is an inducible and rate-limiting enzyme that 
catabolizes tryptophan (Trp) into kynurenine (Kyn).  Although not normally expressed 
and/or found at very low levels in the CNS parenchyma, IDO1 is rapidly increased upon 
inflammatory stimulus. IDO1 has been demonstrated to be expressed at elevated levels in 
~90% of patients with malignant glioma [3]. In addition, high IDO mRNA and protein 
expression levels correlate with reduced overall patient survival [4;5]. The selective nature 
of IDO1 expression in malignant glioma provides a higher potential for targeting 
specificity. 
 
1.2 
Inhibition of Indoleamine 2,3-Dioxygenase 1 as a Target for Cancer 
 
Recent interest has focused on the role of IDO1 as a mechanism of induction of tolerance 
to malignancy [6]. Indoleamine 2,3-dioxygenase 1 is a heme-containing, monomeric 
oxidoreductase that catalyzes the degradation of the essential amino acid tryptophan to N-
formyl-kynurenine.  Kynurenine can be subsequently metabolized through a series of 
enzymatic steps to nicotinamide adenine dinucleotide.  Indoleamine 2,3-dioxygenase 1 is 
the first rate-limiting enzyme in one of the breakdown pathways of tryptophan.  In another 
pathway, tryptophan hydroxylase catalysis of tryptophan leads to the formation of 
serotonin and melatonin. 
 
The expression and activity profiles of IDO1 are distinct from those of tryptophan 
dioxygenase, an enzyme predominantly expressed in liver that catalyzes the same 
enzymatic reaction as IDO1 and maintains proper tryptophan balance in response to dietary 
uptake.  In contrast to tryptophan dioxygenase, IDO1 is expressed in a variety of tissues, 
with particularly high levels found in areas of contact with potential sources of immune 
challenge (eg, gut, respiratory tract, placenta, spleen), consistent with a role for regulating 
tryptophan metabolism in a local microenvironment [7].  Within the immune system, IDO1 
activity is specifically induced in cells such as DCs and macrophages at localized sites of 
inflammation [8]. 
 
Indoleamine 2,3-dioxygenase 1–driven oxidation of tryptophan results in a strong 
inhibitory effect on the development of T-cell–mediated responses by blocking T-cell 
activation and inducing T-cell apoptosis [9].  Both the reduction in local tryptophan levels 
and the production of tryptophan catabolites that are inhibitory to cell proliferation 
contribute to the immunosuppressive effects [10].  Indoleamine 2,3-dioxygenase 1 activity 
also promotes the differentiation of naive T cells to cells with a regulatory phenotype 
(Treg) [11].  Because increased Treg activity has been shown to promote tumor growth and 

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Treg depletion has been shown to allow an otherwise ineffectual antitumor immune 
response to occur [12], IDO1 expansion of Treg may provide an additional mechanism 
whereby IDO1 could promote an immunosuppressive environment. 
 
The biological relevance of IDO1 inhibition to immune tolerance was first demonstrated 
when it was shown that treating mice with a small molecule inhibitor of the IDO1 pathway, 
1 methyl tryptophan, could break the tolerogenic state that protects allogeneic concepti 
from the maternal immune system [13]. A critical role for IDO1 in immunomodulation has 
been confirmed in numerous animal models, including models of allograft tolerance, 
inflammation, and cancer [7].  While IDO1 inhibition can exacerbate disease in models of 
autoimmune disorders [7], IDO1 null mice show no evidence of susceptibility to 
developing spontaneous autoimmunity or alterations in immune system development [9], 
suggesting that IDO1 inhibition, in a therapeutic setting, may produce minimal side effects 
in subjects without pre-existing autoimmune conditions. 
 
Within the context of cancer, there are several lines of evidence to suggest that IDO1 is a 
key regulator of the immunosuppressive mechanisms responsible for tumor escape from 
immune surveillance.  Several groups have demonstrated that blockade of IDO1 activity 
can directly influence the ability of tumor-bearing animals to reject tumors [14, 15].  In 
addition, studies with 1-methyl-tryptophan demonstrate that IDO1 inhibition dramatically 
increases the efficacy of various chemotherapeutic agents (eg, platinum compounds, taxane 
derivatives, cyclophosphamide) without increased toxicity [15].  Although the specific 
mechanisms responsible for this potentiation remain to be fully elucidated, the effects were 
not observed in T-cell–deficient animals, suggesting that the results may be the 
consequence of the disablement of immunosuppressive mechanisms that exist within the 
tumor microenvironment. 
 
Based on studies examining serum levels of tryptophan and kynurenine, IDO1 appears to 
be chronically activated in patients with cancer, and IDO1 activation correlates with more 
extensive disease [16, 17].  Indoleamine 2,3-dioxygenase 1 has subsequently been found 
to be overexpressed by a wide variety of human tumor cell types, as well as by the DCs 
that localize to the tumor-draining lymph nodes [14, 18].  Increased expression of IDO1 in 
tumor cells has been shown to be an independent prognostic variable for reduced overall 
survival (OS) in subjects with melanoma, ovarian, colorectal, and pancreatic cancers [19-
24]. 
 
Together, these results suggest that the IDO1 pathway is a key regulatory element 
responsible for the induction and maintenance of tumor immune tolerance.  Small molecule 
inhibitors of IDO1 may provide an innovative and tractable method to treat malignancies 
either alone or in combination with chemotherapeutics and/or immunotherapy-based 
strategies. 
 
1.3 
Epacadostat 
 
Epacadostat (INCB024360) is a novel, potent, and selective inhibitor of the IDO1 enzyme 
and can induce T cell−dependent antitumor immunity in a murine tumor model via the 

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ability to block regulatory T cell activity and promote dendritic cell maturation and 
function.[49]. A Phase 1 monotherapy study in subjects with advanced solid tumors is 
complete and showed epacadostat monotherapy was generally well-tolerated at doses of 
up to 700 mg twice daily (BID). The most common adverse events (AEs) were Grade 1 or 
2 fatigue and gastrointestinal disturbances. No responses were observed; however, 7 out of 
52 subjects had stable disease (SD) for at least 16 weeks [49].  
 
Phase 1 data for the epacadostat-pembrolizumab combination in advanced cancers have 
also been reported [50].  Patients received escalating doses of oral epacadostat (25, 50, 100, 
or 300 mg) twice per day plus intravenous pembrolizumab 2 mg/kg or 200 mg every 3 
weeks. Sixty-two patients were enrolled and received one or more doses of study treatment. 
The maximum tolerated dose of epacadostat in combination with pembrolizumab was not 
reached. The most common treatment-related adverse events (TRAEs) were: fatigue 
(36%), rash (36%), arthralgia (24%), pruritus (23%), and nausea (21%) occurring in > 20%.  
Grade 3/4 TRAEs were reported in 24% of patients. Seven patients (11%) discontinued 
study treatment because of TRAEs. No TRAEs led to death.  In Phase 1, objective 
responses (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) 
occurred in 12 (55%) of 22 patients with melanoma and in patients with non–small-cell 
lung cancer, renal cell carcinoma, endometrial adenocarcinoma, urothelial carcinoma, and 
squamous cell carcinoma of the head and neck. The pharmacokinetics of epacadostat was 
comparable to historical controls for monotherapies.  
 
Preliminary results for the combination of epacadostat with nivolumab have also recently 
been reported [51].  In that study, participants with no prior IDO or checkpoint inhibitor 
treatment (other than first line CTLA-4 inhibitor) received epacadostat in escalating doses 
along with standard doses of nivolumab.  The most common treatment-related TEAEs at 
the RP2D of epacadostat 100 mg BID PO in combination with nivolumab 240 mg Q2W 
IV were rash (25% overall, 10% ≥ Grade 3), fatigue (23%, no ≥ Grade 3), nausea (19%, no 
≥ Grade 3), pruritus (16%, 3% ≥ Grade 3), diarrhea (12%, no ≥ Grade 3), and increased 
AST (12%, 3% ≥ Grade 3).  Dose interruption (26%) or dose reduction (4%) were needed 
only for a minority of participants, and discontinuation due to TEAE occurred in only 6% 
of participants. 
 
Interim results of a Phase 3 randomized, double-blind, placebo-controlled study of 
pembrolizumab in combination with epacadostat 100 mg BID or placebo in participants 
with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252) have been 
reported (52).  This study enrolled 706 patients (randomized 1:1) with dual primary 
endpoints of PFS and OS but was stopped when the external Data Monitoring Committee 
determined that the primary endpoint of PFS was not met and the endpoint of OS was also 
unlikely to reach statistical significance.  The safety profile was consistent with that 
observed in previously reported studies of epacadostat in combination with pembrolizumab 
(52). 
 
Refer to the epacadostat investigator brochure (IB) for detailed information concerning the 
available pharmacology, toxicology, drug metabolism, clinical studies, and AE profile of 
the investigational product (IP). 

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 Potential Risks from Epacadostat 
 
Monotherapy 
In the Phase 1 clinical study in subjects with refractory solid tumors (INCB 24360-
101), epacadostat was well tolerated at doses ranging from 50 mg QD to 700 mg 
BID.  Twenty-five (48.1%) of the 52 subjects administered epacadostat had a single 
SAE.  The most frequently reported SAEs were disease progression (4 subjects, 
7.7%), followed by abdominal pain, nausea, and hypoxia (3 subjects each, 5.8%).  
Treatment-emergent adverse events (TEAEs) were reported in all subjects.  The 
most commonly reported treatment-related TEAEs were fatigue and nausea (25 
subjects, 48.1%).  The incidence and severity of fatigue were not dose-related.  Two 
DLTs occurred:  1 DLT of radiation pneumonitis at the 300 mg dose level and 1 
DLT of fatigue at the 400 mg BID dose level.  
 
Combination Therapy 
Phase 1/2 data for the epacadostat-pembrolizumab combination in advanced 
melanoma have also been reported (53).  Dose interruption or reduction due to 
TEAEs occurred in 25% and 11% of participants, respectively.  Four participants 
discontinued treatment due to TEAEs (arthralgia, 2 participants; autoimmune 
hepatitis and increased lipase, 1 participant each).  Treatment-related SAEs of 
arthralgia, autoimmune hepatitis, and colitis (1 participant each) were manageable 
with standard supportive care.  No treatment-related deaths were reported.  
Immune-related TEAEs were assessed as AEs of special interest and included 
hypothyroidism (4 events, no ≥ Grade 3), severe skin reactions (4 events, 3 ≥ Grade 
3), colitis (2 events, both ≥ Grade 3), uveitis (2 events, no ≥ Grade 3), and 
autoimmune hepatitis (1 event, which was ≥ Grade 3).  The RP2D selected for 
further development was epacadostat 100 mg BID PO with pembrolizumab 200 mg 
Q3W IV. 
 
Preliminary results for the combination of epacadostat with nivolumab have also 
recently been reported (51).  In that study, participants with no prior IDO or 
checkpoint inhibitor treatment (other than first line CTLA-4 inhibitor) received 
epacadostat in escalating doses along with standard doses of nivolumab.  The most 
common treatment-related TEAEs at the RP2D of epacadostat 100 mg BID PO in 
combination with nivolumab 240 mg Q2W IV were rash (25% overall, 10% ≥ 
Grade 3), fatigue (23%, no ≥ Grade 3), nausea (19%, no ≥ Grade 3), pruritus (16%, 
3% ≥ Grade 3), diarrhea (12%, no ≥ Grade 3), and increased AST (12%, 
3% ≥ Grade 3).  Dose interruption (26%) or dose reduction (4%) were needed only 
for a minority of participants, and discontinuation due to TEAE occurred in only 
6% of participants. 
 
A potential concern of IDO1 inhibition is an increase in serotonin levels that could 
precipitate a cluster of AEs termed serotonin syndrome (SS) when administered as 
a single agent or in combination with other serotonergic agents. This rare syndrome 
has been associated with some monoamine oxidase inhibitors (MAOIs) such as 

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meperidine, linezolid, or methylene blue, and combinations of serotonergic drugs 
[25]. The clinical manifestations of SS range from barely perceptible to lethal.  
 
Based on studies in the rat, epacadostat exhibits apparent limited penetration across 
the blood brain barrier and is likely not associated with significant effects on 
tryptophan metabolism in the brain that might impact brain serotonin levels. 
Furthermore, epacadostat did not increase the brain extra extracellular fluid 
concentrations (ECF) of serotonin levels in the rat microdialysis study when 
administered alone (25 mg/kg) or in combination with linezolid (100 mg/kg), a 
monoamine oxidase inhibitor (MAOI) (54). Thus preclinical data suggest that SS 
is unlikely following treatment with either epacadostat alone or in combination with 
MAOIs such as linezolid (54). 
 
As of 29 OCT 2018, 4 participants treated across the entire epacadostat program 
have had events reported as serotonin syndrome or symptoms of serotonin 
syndrome; episodes were confounded, mild in severity, and transient (3 of 4 
resolved with dose interruption while the other resolved following study treatment 
discontinuation). One of the 4 participants had an event of serotonin syndrome that 
was reported as a serious (medically important) event by the investigator. These 
AEs were not clinically substantiated by the sponsor to represent true events of 
serotonin syndrome. 
 
Additional details regarding specific benefits and risks of epacadostat for 
participants in this clinical study may be found in the accompanying Investigator’s 
Brochure and ICF. 
 
 Justification for Dose 
 
The dose of epacadostat will be 400 mg BID to optimally inhibit IDO1 in 
combination with PD-1 pathway inhibition.  Epacadostat 100 mg BID as 
monotherapy achieves an exposure that exceeds the IC50 at steady state and 
epacadostat 400 mg BID and greater (as monotherapy) achieve exposures that 
exceed the IC90 at steady state in peripheral blood.   
 
INCMGA0012-102 (ClinicalTrials.gov Identifier: NCT03589651) is a Phase 1b 
study to evaluate the safety and tolerability of combination of epacadostat and 
INCMGA0012, an anti-PD-1 antibody, in participants with advanced solid tumors. 
Thirty-one participants received retifanlimab 500 mg Q4W plus epacadostat.  Four 
dose levels of epacadostat were studied (100 mg BID, 400 mg BID, 600 mg BID 
and 900 mg BID).  
 
All participants experienced an adverse event (AE). Sixteen participants (52%) 
experienced an AE that was considered related to epacadostat.  
 
Three participants had a DLT, all of which were Grade 3 maculo-papular rash that 
were considered related to  retifanlimab and epacadostat and resulted in 

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discontinuation of epacadostat. One DLT occurred at the epacadostat 400 mg BID 
dose level, and 2 DLTs occurred at the epacadostat 900 mg BID dose level. Two of 
the events also led to discontinuation of  retifanlimab (epacadostat dose levels of 
400 mg BID and 900 mg BID). None of the DLTs were serious, and 2 of the 3 
events had recovered at the time of data cutoff. The dose of 600 mg BID was 
established as the maximum tolerated dose (MTD) of epacadostat in combination 
with  retifanlimab.   
 
Twelve participants received retifanlimab in combination with epacadostat at the 
MTD of 600 mg BID. Six of these participants (50%) experienced an AE related to 
epacadostat. One of these participants experienced a Grade 3 (CTCAE v.5.0) AE 
which was maculopapular rash and fever. Other AEs related to epacadostat at this 
dose were nausea, fatigue, dyspepsia, hypothyroidism, rash, pruritus, and diarrhea.  
Nine participants received retifanlimab in combination with epacadostat 400 mg 
BID. Four of these participants (44%) experienced an AE related to epacadostat. 
One of these was a Grade 3 maculopapular rash. Other AEs related to epacadostat 
reported at this dose included nausea, fatigue, fever, diarrhea, and dyspepsia.  
 
Three participants received retifanlimab in combination with epacadostat 100 mg 
BID. One of them experienced an AE of Grade 1 anorexia that was noted as related 
to epacadostat. 
 
No significant drug related laboratory abnormalities have been reported at any dose 
level.  
 
Serious AEs have been reported in 6 of the 31 participants (19%). Only 1 participant 
had an SAE noted as related to epacadostat, which was the event of fever and 
maculopapular rash. 
 
1.4 
Radiation Therapy 
 
Radiation therapy (RT) is the main treatment for malignant gliomas. Besides directly 
inducing tumor cell death, RT has an immunomodulatory effect. RT delivered in multiple 
fractions over several days increases tumor immunogenicity compared to a single high-
dose RT [26, 28]. Ionizing radiation has also been shown to enhance uptake of tumor 
antigens by dendritic cells and their activation, as well as migration of the activated effector 
T cells back to the tumor. Thus RT could potentially enhance and complement the action 
of different immunotherapy agents [29]. Expression of PD-1 and PD-L1 is found in the 
microenvironment of most high grade gliomas [30]. In addition, recent studies suggest RT 
increases PD-L1 expression [31-33] and IDO expression (Figure 1, 2 and 3) [34; 35; Ciorba 
M, unpublished data].  Numerous clinical trials were conducted or on-going to test the 
combination of immunotherapy with various radiation dosing and fractions [36].  
 

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Retifanlimab is a humanized anti-PD-1 monoclonal antibody directed against the negative 
immunoregulatory human cell surface receptor programmed cell death 1 (PD-1). retifanlimab 
binds to and inhibits PD-1 and its downstream signaling pathways. This may restore immune 
function through the activation of T cells and cell-mediated immune responses against tumor 
cells. This may result in both T-cell activation and the induction of T-cell-mediated immune 
responses against tumor cells. PD-1 checkpoint inhibition has been studied in gliomas. A recent 
study has shown that re-irradiation using hypofractionated RT (HFRT) in combination with anti-
PD1 antibody and bevacizumab (VEGF antibody) is safe and well tolerated in patients with 
recurrent high grade gliomas [37]. The addition of IDO inhibitor to CTLA-4 and PD-L1 decreased 
tumor-infiltrating Tregs and this triple combination was associated with a high survival rate in a 
mouse model of glioma [38]. Most recently, preclinical murine models showed significantly 
improved survival by combining IDO inhibitor with RT and anti-PD1 antibody [Ladomersky E et 
al., 2018]. 

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 Justification for  Retifanlimab Dose 
 
Retifanlimab will be administered at 500 mg Q4W. The selection of this dose was 
based on modeling of clinical PK data from the first-in-human monotherapy study, 
INCMGA00012-101 (NCT03059823), in which 37 participants were treated at 
doses of 1 mg/kg Q2W, 3 mg/kg Q2W, 3 mg/kg Q4W, 10 mg/kg Q2W, and 10 
mg/kg Q4W.   
 
A simulation was conducted to investigate the use of weight-based and fixed doses 
for  retifanlimab with the aim of targeting a steady-state trough concentration of 
approximately 21 μg/mL, which is the median trough concentration for 
pembrolizumab 200 mg Q3W (55).  The median  retifanlimab exposure and 
distribution around the median at 500 mg Q4W were similar to 7 mg/kg Q4W in 
the simulated population, which justified clinical exploration in an expansion 
cohort of the INCMGA0012-101 study. 
 
Based on the flat exposure-response relationships for efficacy and safety from 
pembrolizumab and nivolumab, both weight–based and flat dose regimens are 
considered appropriate for administration of retifanlimab. The 500 mg Q4W dose 
was selected to maintain a steady-state trough serum concentration of ≥ 21 μg/mL 
in clinical trials and to provide additional flexibility in monotherapy or 
combinations (eg, chemotherapy) while maintaining this schedule.  
 
Combination with Epacadostat 
As of December 13th 2021 a total of 100 participants with advanced solid tumors 
have been treated with epacadostat in combination with retifanlimab in Studies 
INCMGA 0012-102 and 204. 
 
The most frequently reported TEAEs were nausea (30.0%), decreased appetite 
(25.0%), fatigue (24.0%), abdominal pain and anemia (18.0% each), and rash 
maculo-papular (17.0%). Serious TEAEs were reported for 39 participants 
(39.0%). The most frequently reported serious TEAEs were dyspnea (6.0%), rash 
maculo-papular (5.0%), and pleural effusion (3.0%). Treatment-emergent AEs led 
to discontinuation of epacadostat for 16 participants (16.0%). The most frequently 
reported TEAE leading to discontinuation of epacadostat was rash 
maculo-papular (7.0%). 
 
The MTD of epacadostat in combination with retifanlimab 500 mg was determined 
to be 600 mg BID. Epacadostat 900 mg BID exceeded the MTD based on the 
occurrence of Grade 3 maculopapular rash in 2 of 3 participants during the DLT 
evaluation period. Overall, the following 
DLTs were reported: 
• 400 mg BID: 1 DLT of Grade 3 rash maculo-papular 
• 600 mg BID: 1 DLT of Grade 3 rash maculo-papular, 1 DLT of Grade 3 dermatitis 
acneiform, 1 DLT of Grade 3 abdominal pain 

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• 900 mg BID: 2 DLTs of Grade 3 rash maculo-papular. 
 
Five participants (5.0%) had fatal TEAEs: acute respiratory distress syndrome and 
COVID-19 pneumonia (1 participant), and ascites, cardiovascular disorder, respiratory 
failure, and thrombocytopenia (1 participant each). None of the fatal TEAEs were 
considered related to epacadostat.  
1.5 
Bevacizumab 
 
Bevacizumab, a monoclonal antibody against the vascular endothelial growth factor 
(VEGF), is the most commonly used treatment for recurrent and progressive malignant 
gliomas either alone or in combination with other therapy including RT [39-41]. 
Additionally, bevacizumab is effective in the treatment of cerebral radiation necrosis [42] 
and is less immunosuppressive than steroids. A recent large randomized phase II study 
(RTOG 1205) comparing hypofractionated re-irradiation of 35 Gy in 10 fractions with 
bevacizumab versus bevacizumab alone for recurrent GBM has successfully completed 
accrual (NCT01730950). Bevacizumab plus re-irradiation is safe and well-tolerated. 
Although no benefit has been shown in OS, clinically meaningful improvement in PFS has 
been demonstrated (Tsien C et al. 2019).  Therefore, in this study, bevacizumab will be co-
administered with epacadostat and retifanlimab to reduce the risk of cerebral edema from 
re-irradiation and the need for steroids.  
 
1.6 
Study Rationale 
 
Collectively, there is strong preclinical evidence for the combination of IDO inhibitor, RT 
and anti-PD1 therapy in patients with recurrent grade 4 gliomas with very limited treatment 
options. 
 
In this study, we propose to combine retifanlimab with RT and bevacizumab with or 
without epacadostat in the treatment of recurrent grade 4 glioma. We hypothesize that this 
combination provides a powerful synergy between RT and immune modulators to produce 
more robust anti-tumor immune response, induce tumor regression and improve overall 
survival.  
 
1.7 
Correlative Studies Background 
 
One hallmark of poor prognosis grade 4 glioma, such as GBM, is the infiltration and 
accumulation of immunosuppressive and tumor-promoting regulatory T cells (Tregs) [27]. 
Both clinical and preclinical data confirm that IDO expression increases the recruitment of 
Tregs and inhibits the activation of effector T cells [5].  Administration of an IDO inhibitor 
might reverse this process. Therefore, serum Kyn/Trp level will be tested to evaluate the 
on-target effect of epacadostat. T cell phenotype will be tested to evaluate the effect of 
epacadostat. We plan to combine retifanlimab with epacadostat for potential synergic 
effect. Thus tumor mutation burden and PD-L1/PD-L2 expression will be tested. 
 
 
2.0 
OBJECTIVES 

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2.1 
Primary Objective 
 
To evaluate overall survival at 9 months (OS-9) of recurrent grade 4 glioma patients treated 
with the combination of retifanlimab, RT, and bevacizumab with or without epacadostat. 
 
2.2 
Secondary Objectives  
 
1. To determine progression-free survival (PFS) of recurrent grade 4 glioma patients 
treated with the combination of RT, retifanlimab, and bevacizumab with or without 
epacadostat. 
2. To evaluate neurologic functions of recurrent grade 4 glioma patients treated with the 
combination of RT, retifanlimab, and bevacizumab with or without epacadostat using 
the Neurologic Assessment in Neuro-Oncology (NANO) scale. 
3. To evaluate the safety and toxicity of the combination of RT, retifanlimab, and 
bevacizumab with or without epacadostat in patients with recurrent grade 4 glioma. 
 
2.3 
Correlative Objectives 
 
1. To assess the anti-glioma immune response before and after retifanlimab or/and 
epacadostat including assessment of immune cells phenotyping, function and activation 
in the pre-/post-treatment blood.  
2. To evaluate serum Kyn/Trp ratio as a surrogate of IDO1 enzymatic activity.  
3. To evaluate mRNA expressions of IDO1, IDO2, TDO and PD-L1 pre- and post- study 
treatment. 
 
2.4 
Exploratory Objectives  
 
1. To evaluate the correlation between serum Trp and Kyn levels in patients and the 
association with treatment response and overall survival after epacadostat treatment.   
2. To evaluate the correlation between intratumoral expression of IDO and the frequency 
of glioma cell-specific cytotoxic T cells, Tregs, treatment response and overall survival. 
3. To evaluate tumor infiltrating lymphocytes (CD4, CD8, Treg, effector cells etc) in the 
tumor tissue pre- and post retifanlimab or/and epacadostat treatment (if available). 
4. To explore tissue and blood biomarkers that may predict tumor response to epacadostat 
in combination with RT and retifanlimab.  
5. To test tumor mutation burden by a validated comprehensive genomic profiling and 
PD-L1/PD-L2 expression on tumor/immune cells by IHC. 
 
 
3.0 
PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
 
1. Recurrent WHO grade 4 glioblastoma or gliosarcoma, including molecular features of 
glioblastoma and WHO grade 4 astrocytoma or WHO grade high grade glioma. 

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2. Other GBM variants and “secondary GBM” are allowed. All grade 4 gliomas that have 
relapsed more than once may be included, as the prognosis of multiply recurrent grade 
4 glioma patients may not differ based on IDH mutation status. 
 
3. Disease must have recurred, and patient must be a candidate for re-irradiation and 
bevacizumab.  Any number of recurrences is allowed. 
 
4.  Patients must have measurable disease per RANO criteria (section 12.3). Lesions will 
be considered measurable when they are bi-dimensional with clearly defined margins 
of  5 mm in two perpendicular diameters. 
 
5. Prior transient use of bevacizumab for cerebral edema or radiation necrosis is allowed 
without a washout period. Prior bevacizumab use is permitted if used for treatment of 
disease if administered more than 4 months prior to registration. 
 
6. At least 18 years of age. 
 
7. Karnofsky performance status ≥ 60% (see Appendix A) 
 
8. Normal bone marrow and organ function as defined below: 
a. Absolute neutrophil count ≥ 1,000/mcL 
b. Platelets ≥ 75,000/mcL 
c. Hemoglobin ≥ 9.0 g/dL or > 5.6 mmol/L (transfusion is acceptable to meet this 
criterion) 
d. Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 60 mL/min/1.73 m2 by 
Cockcroft-Gault for patients  
e. Serum total bilirubin ≤ 1.5 ULN  
f. AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN 
g. INR or PT ≤ 1.5 x IULN unless subject is receiving anticoagulant therapy as long 
as PT or PTT is within therapeutic range of intended use of anticoagulants 
h. aPTT ≤ 1.5 x IULN unless subject is receiving anticoagulant therapy as long as PT 
or PTT is within therapeutic range of intended use of anticoagulants 
 
At least 28 days from any major surgery such as craniotomy and surgical wound is fully 
healed, and at least 14 days from LITT or biopsy. Prior to surgery, there must be 
imaging evidence of measurable progressive disease (PD) per RANO criteria as noted 
above. 
9. Women of childbearing potential and men must agree to use highly effective 
contraception (hormonal or barrier method of birth control, abstinence) prior to study 
entry and for the duration of study participation.  Should a woman become pregnant or 
suspect she is pregnant while participating in this study, she must inform her treating 
physician immediately. 
 
10. Ability to understand and willingness to sign an IRB approved written informed 
consent document (or that of legally authorized representative, if applicable). 

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11. Prior use of the Optune device is allowed, without a washout period. However, 
concurrent Optune use is not permitted while on  treatment for this trial. 
 
 
3.2 
Exclusion Criteria 
 
1. Currently receiving any other investigational agents. 
 
2. A history of allergic reactions attributed to compounds of similar chemical or biologic 
composition to epacadostat, retifanlimab, bevacizumab, or other agents used in the 
study. 
 
3. Dexamethasone dose > 4 mg daily at the time of registration (higher dose of steroid for 
symptom control is allowed during the study). 
 
4. History of intracranial abscess within 6 months prior to start of study therapy. 
 
5. Has active autoimmune disease or syndrome (i.e. moderate or severe rheumatoid 
arthritis, moderate or severe psoriasis, multiple sclerosis, active inflammatory bowel 
disease) that has required systemic treatment in the past 2 years (i.e. with use of disease-
modifying agents, corticosteroids, or immunosuppressive drugs) or who are receiving 
systemic therapy for an autoimmune or inflammatory disease (i.e. with use of disease 
modifying agents, corticosteroids, or immunosuppressive drugs).  Replacement therapy 
(e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal 
or pituitary insufficiency) is not considered a form of systemic treatment. Subjects are 
permitted to enroll if they have vitiligo, resolved childhood asthma/atopy, type I 
diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring 
hormone replacement, psoriasis not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger. 
 
6. Has a severe acute or chronic medical condition including immune colitis, 
inflammatory bowel disease (may be enrolled at the discretion of the PI), immune 
pneumonitis, or laboratory abnormalities that may increase the risk associated with 
study participation or study treatment administration or may interfere with the 
interpretation of study results and, in the judgment of the investigator, would make the 
patient inappropriate for entry into this study. 
 
7. Has had an allogeneic tissue/solid organ transplant. 
 
8. Has an active infection requiring intravenous antibiotic therapy. 
 
9. Has a known history of active tuberculosis (TB; bacillus tuberculosis). 
 
10. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or IDO 
inhibitor. 

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11. If a patient is enrolled to regimen B, they are prohibited from receiving monoamine 
oxidase inhibitors (MAOIs) or drug which has significant MAOI activity (meperidine, 
linezolid, methylene blue) within the 21 days before screening. 
 
12. If a patient is enrolled to regimen B, the use of any UGT1A9 inhibitor from screening 
through 
follow-up 
period, 
including 
acitretin, 
amitriptyline, 
androsterone, 
cyclosporine, dasatinib, diclofenac, diflunisal, efavirenz, erlotinib, estradiol (17-beta), 
flutamide, gefitinib, gemfibrozil, glycyrrhetinic acid, glycyrrhizin, imatinib, 
imipramine, ketoconazole, linoleic acid supplements, mefenamic acid, mycophenolic 
acid, niflumic acid, nilotinib, phenobarbital, phenylbutazone, phenytoin, probenecid, 
propofol, quinidine, ritonavir, sorafenib, sulfinpyrazone, valproic acid, and verapamil 
is prohibited. 
 
13. If a patient is enrolled to regimen B, the use of probiotics from screening through end 
of treatment is prohibited. 
 
14. If a patient is enrolled to regimen B, the use of warfarin is prohibited. If anti-
coagulation is needed during the conduct of the study and non-warfarin regimens are 
not feasible, the participant must discontinue study therapy. 
 
15. Chronic use of systemic antibiotics (> 14 days) unless medical monitor review and 
approval. 
 
 
16. Any history of serotonin syndrome (SS) after receiving serotonergic drugs. 
 
17. Has uncontrolled HIV (HIV 1/2 antibodies).  Well-controlled HIV is defined as CD4+ 
count > 300 cells, undetectable viral load, and receiving HAART/ART. Study specific 
HIV testing is not required for patients who do not have any prior history of HIV. 
 
18. Has uncontrolled active hepatitis B (e.g., HBsAg reactive or HBV DNA detected by 
quant RT PCR) or hepatitis C (e.g. HCsAg reactive or HCV RNA [qualitative or 
quantitative] is detected). 
 
19. Uncontrolled intercurrent illness including, but not limited to, clinically significant (i.e. 
active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to 
enrollment), myocardial infarction (< 60 months prior to enrollment), congestive heart 
failure (≥ NYHA class II), unstable angina pectoris, or serious cardiac arrhythmia 
requiring medication. 
 
20. History or presence of an abnormal electrocardiogram (ECG) that, in the investigator’s 
opinion, is clinically meaningful.  Screening QTc interval > 480 msec will require 
investigator’s evaluation on patient’s eligibility.  Subjects with left bundle branch block 
are excluded.  
 

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21. Presence of a gastrointestinal condition that may affect drug absorption. 
 
22. Receipt of live attenuated vaccine within 30 days before the first dose of study 
treatment.  Examples of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, chicken pox, yellow fever, rabies, Bacillus Calmette-Guérin 
(BCG), and typhoid vaccine.  Seasonal influenza vaccines for injection are generally 
killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g. 
FluMist) are live attenuated vaccines and are not allowed. 
 
23. Pregnant and/or breastfeeding.  Women of childbearing potential must have a negative 
pregnancy test prior to the start of study treatment. 
 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial. 
 
 
4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility by Washington University 
2. Registration of patient in the Siteman Cancer Center OnCore database 
3. Assignment of unique patient number (UPN) 
 
Once the patient has been entered in the Siteman Cancer Center OnCore database, the WUSM 
coordinator will forward verification of enrollment and the UPN via email. 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below and scanning and 
emailing it to the research coordinator listed in the Siteman Cancer Center Clinical Trials 
Core Protocol Procedures for Secondary Sites packet at least one business day prior to 
registering patient: 
 
1. Your name and contact information (telephone number, fax number, and email 
address) 
2. Your site PI’s name, the registering MD’s name, and your institution name 
3. Patient’s race, sex, and DOB 
4. Three letters (or two letters and a dash) for the patient’s initials 
5. Currently approved protocol version date 
6. Copy of signed consent form (patient name may be blacked out) 

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7. Planned date of enrollment 
8. Completed eligibility checklist, signed and dated by a member of the study team 
9. Copy of appropriate source documentation confirming patient eligibility 
 
 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
Registrations may be submitted Monday through Friday between 8am and 5pm CT. Urgent 
late afternoon or early morning enrollments should be planned in advance and coordinated 
with the Washington University research coordinator.  Registration will be confirmed by 
the research coordinator or his/her delegate by email within one business day. Verification 
of eligibility and registration should be kept in the patient chart. 
 
All patients at all sites must be registered through the Siteman Cancer Center OnCore 
database at Washington University. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  Patients 
will also be identified by first, middle, and last initials.  If the patient has no middle initial, 
a dash will be used on the case report forms (CRFs).  All data will be recorded with this 
identification number on the appropriate CRFs. 
 
4.4 
Patient Allocation 
 
At time of activation, the study will enroll patients to Regimen A.  When 23 patients have 
been enrolled to Regimen A, completed the evaluation period for intolerable toxicity (refer 
to Section 5.2), and not exceeded the boundary “b” as specified in the table of Section 15.2, 
Regimen B will open to enrollment. 
 
4.5 
Screen Failures 
 
Screen failures are defined as participants who consent to participate in the clinical trial 
but are not subsequently entered in the study.  A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants, to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities.  Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse event (if applicable).   
 
 
5.0 
TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Retifanlimab will be given intravenously over the course of 30 to 60 minutes at a dose of 
500 mg on Day 1 of each 28-day cycle.  In order to mitigate infusion-related reactions, 

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patients must be premedicated with an antihistamine and with acetaminophen prior to the 
first 4 infusions of retifanlimab. Premedications should be administered for subsequent 
retifanlimab doses based upon clinical judgment and presence/severity of prior infusion 
reactions. 
 
Bevacizumab will be given intravenously at a dose of 10 mg/kg on Days 1 and 15 of each 
28-day cycle.  The first infusion will be over the course of 90 minutes; the second infusion 
will be over the course of 60 minutes; if tolerated, all subsequent infusions may be over 30 
minutes.  
 
At time of activation, the study will enroll patients to Regimen A.  When 23 patients have 
been enrolled to Regimen A, completed the evaluation period for intolerable toxicity (refer 
to Section 5.2), and not exceeded the boundary “b” as specified in the table of Section 15.2, 
Regimen B will open to enrollment. 
 
Patients enrolled to Regimen B will receive epacadostat.  Epacadostat will be administered 
orally at 400 mg BID.  If the 400 mg BID dose is determined to be intolerable during the 
first cycle of treatment (by continuous toxicity monitoring as described in Section 15.2), 
the patient must be discontinued from treatment with epacadostat.  No dose reduction 
below 400 mg BID is permitted.  Patients enrolled prior to Amendment 8 were enrolled at 
a starting dose of epacadostat 600 mg BID.  Patients beyond cycle 1 of treatment at the 
time of Amendment 8 were instructed to continue at this dose and will follow the protocol 
guidelines regarding dose reduction. Patients currently in cycle 1 of treatment at the time 
of Amendment 8 were instructed to dose reduce to 400 mg BID. 
 
Epacadostat is an oral medication that will be taken twice a day every day without regard 
to food during each 28-day cycle.  If a dose is missed by more than 4 hours, then that dose 
should be skipped and the next dose should be taken at the next scheduled time point.  All 
BID doses will be taken in the morning and evening, approximately 12 hours apart. 
 
The drugs may be given in any order on Day 1 of each cycle; however, for patients enrolled 
to Regimen B, the dose of epacadostat should be taken as close to the regularly scheduled 
12-hour dosing interval as possible. 
 
Ten fractions of radiation therapy will be given at a dose of 3.5 Gy per fraction as per 
RTOG 1205 study.  The gross tumor maximum diameter (to be irradiated) to be </= 6cm 
in the first 6 patients. Additionally, if more than 1 target is irradiated, then the sum of all 
the target maximum diameters should be </= 6cm in the first 6 patients. For subsequent 
patients (patients enrolled after the first 6), no more than 3 separate targets for RT is 
allowed. 
 
Retifanlimab and bevacizumab (with or without epacadostat) will be started approximately 
two weeks before the first day of radiation therapy (+/-3 days window).  This means that 
RT may start anywhere between Cycle 1 Day 12 and Cycle 1 Day 18.  Depending on 
scheduling, it is possible that RT may extend into Cycle 2 of retifanlimab and bevacizumab 
(with or without epacadostat).  

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Additionally, for patients being treated on either regimen who have surgical intervention, 
including laser ablation, for a radiographically progressing tumor but the final pathology 
demonstrates a predominant immune-mediated reaction or treatment-related effect, with 
no obvious progression of tumor, such subjects will be deemed not to have progressed and 
be allowed to resume assigned study treatment at a time deemed safe by the treating 
physician, but no later than 8 weeks from the surgery 
 
5.2 
Toxicity and Response Evaluations 
 
All patients who receive any study treatment are evaluable for toxicity.  Patients are 
evaluated from first receiving study treatment until a 90-day follow up after the conclusion 
of treatment or death. 
 
Toxicity evaluations for “intolerable toxicity” (as defined in Section 15.2) will take place 
in each patient in both regimens from first dose of study treatment until 28 days after last 
dose of Cycle 2 treatment; for patients enrolled in Regimen A, this is Cycle 3 Day 1 (28 
days after the C2D1 dose of retifanlimab), and for patients enrolled in Regimen B, this is 
Cycle 3 Day 28 (28 days after the C2D28 dose of epacadostat). 
 
Patients must receive at least one dose of study treatment to be evaluable for intolerable 
toxicities.  If a patient decides to drop out of the study during the first cycle for reasons 
other than treatment-related toxicity, the patient is not evaluable for intolerable toxicities 
and will be replaced. 
 
All patients are evaluable for disease response unless they discontinue treatment prior to 
completion of Cycle 2 and have not had any disease assessment. 
 
Brain MRI with and without contrast (or CT head with and without contrast if participants 
cannot get MRI) will be obtained every 2 cycles to assess disease response. A baseline 
image should be obtained within 4 weeks prior to initiation of study treatment.  
 
5.3 
General Concomitant Medication and Supportive Care Guidelines 
 
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. 
 
Patients are prohibited from receiving the following therapies while in screening for and 
enrolled in this trial: 
 Investigational agents other than retifanlimab and epacadostat 
 Any anticancer medications, including chemotherapy or biologic therapy other than 
the study medications.  Note: denosumab is permitted. 
 Radiation therapy beyond what is described in this protocol (note: radiation therapy 
to a symptomatic solitary lesion or to the brain may be allowed at the investigator’s 
discretion) 

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 Oncologic surgery for tumor control 
 Administration of live attenuated vaccines within 30 days prior to the first dose of 
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 vaccine. Seasonal influenza vaccines for injection 
are generally killed virus vaccines and are allowed; however, intranasal influenza 
vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed. 
 If a patient is enrolled to Regimen B, then the use of the anticonvulsant 
carbamazepine (a UGT1A9 inducer) is discouraged.  Because there is a potential 
interaction that could result in lower epacadostat exposures, an alternative to 
carbamazepine should be used, if possible. 
 Warfarin 
 If a patient is enrolled to Regimen B, then any MAOI or drug associated with 
significant MAOI activity agents is prohibited from 21 days prior Day 1 through 2 
weeks after the final dose of epacadostat. This includes, but is not limited to, 
hydrazines 
(example 
phenelzine), 
meperidine, 
caroxazone, 
linezolid, 
echinopsidine, methylene blue, furazolidone, tranylcypromine, brofaromine, 
metralindole, minaprine, moclobemide, pirlindole, toloxatone, lazabemide, 
pargyline, rasagiline, selegiline. 
 If a patient is enrolled to Regimen B, then the use of any UGT1A9 inhibitor, 
including acitretin, amitriptyline, androsterone, cyclosporine, dasatinib, diclofenac, 
diflunisal, efavirenz, erlotinib, flutamide, gefitinib, gemfibrozil, glycyrrhetinic acid 
glycyrrhizin, imatinib, imipramine, ketoconazole (systemic), linoleic acid 
supplements, mefenamic acid, mycophenolic acid, niflumic acid, nilotinib, 
phenobarbital, phenylbutazone, phenytoin, probenecid, quinidine, ritonavir, 
sorafenib, sulfinpyrazone, valproic acid, and verapamil is prohibited. 
 If a patient is enrolled to Regimen B, then the use of probiotics is prohibited.  
 
Patients who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. 
 
 Procedure for Subjects Exhibiting Serotonin Syndrome 
 
There is a rare chance that epacadostat could cause an increase in serotonin levels 
in the brain that might trigger serotonin syndrome (SS) [25], when administered in 
combination with other serotonergic agents. The clinical manifestations of SS range 
from barely perceptible to lethal; onset is rapid (within 12 hours of drug[s] 
administration). Selective serotonin reuptake inhibitors (SSRIs), selective 
serotonin/norepinephrine reuptake inhibitors (SNRIs), and MAOIs are permitted in 
the study. Due to the results of the preclinical study specifically evaluating the 
effect of epacadostat on the brain ECF concentrations of serotonin with linezolid 
described above by Zhang et al (54), and the clinical experience with related 
medications (eg., SSRIs/SNRIs) that suggest that SS is low risk, the use of MAOIs 
is not prohibited in the current study. 
 

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Serotonin syndrome usually manifests with autonomic changes, mental status 
changes, and neurological findings.  These mild, moderate, and severe signs and 
symptoms of SS (summarized in the table below) should be evaluated in the context 
of possible comorbid conditions as well. Due to its uniqueness, a neurology consult 
is strongly recommended to diagnose or confirm serotonin syndrome or to rule out 
other etiologies. 
 
The following procedures will be implemented if participants exhibit the 
signs/symptoms of SS, including tremor; hyperreflexia; spontaneous, ocular, or 
inducible clonus; together with agitation, fever, diaphoresis, or muscle rigidity: 
 
 Immediately interrupt study treatment (defined as  retifanlimab +/- 
epacadostat). 
 Immediately interrupt any SSRI, SNRI or MAOI administration. 
 Provide appropriate medical management of the participant until all 
signs/symptoms are resolved (eg, IV fluids and/or sympathomimetic amines 
for hypotension, benzodiazepines for agitation, administration of 5-
hydroxytryptamine antagonists such as cyproheptadine). 
 If participant chooses to remain in the study, restart study treatment after 
the SSRI, SNRI or MAOI has been discontinued, no sooner than 5 half-lives 
have elapsed for the specific SSRI or SNRI in question, and after resolution 
of signs/symptoms of SS.  The SSRI or SNRI dosing MAY NOT be 
restarted. 
 If participant chooses to withdraw from the study, or must restart treatment 
with SSRI, SNRI, or MAOI the participant should be scheduled for a 
Follow-up Visit. Treatment with SSRI, SNRI or MAOI may be initiated 2 
weeks after resolution of signs and symptoms of SS. 
 If a participant had experienced moderate or severe unconfounded SS in the 
opinion of the investigator, without concomitant SSRI, SNRI or MAOI 
usage, or serotonergic concomitant medications, only non epacadostat study 
administration may be resumed; epacadostat treatment should be 
permanently discontinued. 
 
Signs and Symptoms of Serotonin Syndrome 
Seriousness 
Autonomic signs 
Neurological signs 
Mental status 
Other 
Mild 
Afebrile or low-grade 
fever 
Tachycardia 
Mydriasis 
Diaphoresis or 
shivering 
Intermittent tremor 
Akathisia Myoclonus 
Mild hyperreflexia 
Restlessness 
Anxiety 
 
Moderate 
Increased tachycardia 
Fever (up to 41°C) 
Diarrhea with 
hyperactive bowel 
sounds 
Hyperreflexia Inducible 
clonus Ocular clonus (slow 
continuous lateral eye 
movements) Myoclonus 
Easily startled 
Increased 
confusion 
Agitation and 
hypervigilance 
Rhabdomyolysis 
Metabolic acidosis 
Renal failure 
Disseminated 
intravascular 
coagulopathy 

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Diaphoresis with 
normal skin color 
(secondary to 
hyperthermia) 
Severe 
Temperature often 
more than 41 °C 
(Secondary 
to increased tone) 
Increased muscle tone 
(lower limb > upper) 
Spontaneous clonus 
Substantial myoclonus or 
hyperreflexia 
Delirium 
Coma 
As above 
Source: [Boyer, E. W. 2005 (25)] 
 
 Guidelines for Management of Suspected Infusion Reactions 
 
Grade 
Descriptiona 
Treatment 
Subsequent Infusions 
1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated. 
Monitor vital signs closely until 
medically stable. 
Premedication with 
acetaminophen/paracetamol and a 
histamine blocker should be 
considered for participants who have 
had previous systemic reactions to 
protein product infusions or when 
recommended by institutional policy. 
2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (eg, antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
≤ 24 hours. 
First occurrence:  Stop infusion and 
initiate appropriate medical measures 
(eg, IV fluids, antihistamines 
NSAIDS, 
acetaminophen/paracetamol, 
narcotics, per institutional 
preferences). 
Monitor vital signs until medically 
stable. 
If symptoms resolve within 1 hour, 
infusion may be resumed at 50% of 
the original infusion rate. 
Subsequent occurrences (after 
recommended prophylaxis):  
Permanently discontinue study 
treatment. 
Premedicate at least 30 minutes before 
infusion with antihistamines (eg, 
diphenhydramine 50 mg PO) and 
acetaminophen/ 
paracetamol (500-1000 mg PO). 
Additional supportive measures may 
be acceptable (per institutional 
preference) but should be discussed 
with medical monitor. 
Next infusion should start at 50% of 
the original infusion rate.  If no 
reaction, rate of infusion can be 
increase by 25% every 15 minutes 
until a rate of 100% has been reached.  
Subsequent infusions can begin at 
100%. 
3 or 4 
Grade 3:  Prolonged (ie, not rapidly 
responsive to symptomatic medication 
and/or brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(eg, renal impairment, pulmonary 
infiltrates). 
Grade 4:  Life-threatening; pressor or 
ventilatory support indicated. 
Stop infusion and initiate appropriate 
medical therapy (eg, IV fluids, 
antihistamines NSAIDS, 
acetaminophen/ 
paracetamol, narcotics, oxygen, 
pressors, epinephrine, corticosteroids, 
per institutional preferences). 
Monitor vital signs frequently until 
medically stable.  Hospitalization may 
be indicated. 
Permanently discontinue study 
treatment. 
a Per NCI CTCAE v5.0, appropriate resuscitation equipment should be available at the bedside and a physician readily available 
during the period of study treatment administration. 
 
5.4 
Women of Childbearing Potential 
 
Women of childbearing potential (defined as women with regular menses, women with 
amenorrhea, women with irregular cycles, women using a contraceptive method that 
precludes withdrawal bleeding, or women who have had a tubal ligation) are required to 
have a negative serum pregnancy test within 14 days prior to the first dose of the study 
treatment. 

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Female and male patients (along with their female partners) are required to use a highly 
effective contraception, including one barrier method, during participation in the study and 
for 4 months following the last dose of study treatment. 
 
If a patient is suspected to be pregnant, study treatment should be immediately 
discontinued. In addition, a positive urine test must be confirmed by a serum pregnancy 
test.  If it is confirmed that the patient is not pregnant, the patient may resume treatment. 
 
If a female patient or female partner of a male patient becomes pregnant during therapy or 
within 4 months after the last dose of study treatment, the investigator must be notified in 
order to facilitate outcome follow-up. 
 
5.5 
Duration of Therapy 
 
 Treatment Duration 
 If at any time the constraints of this protocol are considered to be detrimental 
to the patient’s health and/or the patient no longer wishes to continue protocol 
therapy, the protocol therapy should be discontinued and the reason(s) for 
discontinuation documented in the case report forms. 
 
In the absence of treatment delays due to adverse events, treatment may continue 
for up to two years or until one of the following criteria applies: 
 
 Documented and confirmed disease progression (subjects in Regimen B may 
continue on study treatment after demonstrating progression if they are deriving 
clinical benefit in the opinion the treating MD)  
 Death 
 Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
 General or specific changes in the patient’s condition render the patient unable to 
receive further treatment in the judgment of the investigator 
 Suspected pregnancy 
 Serious noncompliance with the study protocol 
 Lost to follow-up 
 Patient withdraws consent 
 Investigator removes the patient from study 
 The Siteman Cancer Center decides to close the study 
 
Treatment may continue for a maximum of two years if none of the criteria listed 
above are met.  Patients who prematurely discontinue treatment for any reason will 
be followed as indicated in the study calendar. 
 
 Treatment Beyond Progression 
Subjects on regimen B may continue on study after demonstrating progression as 
long as they are deriving clinical benefit in the opinion of the treating physician 

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provided the following criteria are met  
 Participant signs the treatment beyond progression consent 
 The Washington University PI is notified 
 
Participants who remain on treatment after disease progression will follow all 
procedures as described in section 10.0 
 
The subject who remain on despite progression will be removed from study 
treatment when any of the below criteria are met: 
 Persistent progression per iRANO criteria on imaging 6 months after the 
initial scans showing progressive disease 
 Clinical decline with KPS <60 for greater than 2 months 
 Persistent increased dexamethasone use for 2 months (>100% baseline use) 
 Patient is no longer deriving clinical benefit in the opinion of treating 
physician 
 Patient has completed 2 years of treatment 
 Any criteria described in section 5.5.1 are met 
 
 
5.6 
Duration of Follow-up 
 
After coming off treatment, patients will return for a 30-day follow-up visit preferably in 
person but a telephone or video visit is acceptable if a patient’s functional status precludes 
an in-person visit, with an extended safety follow-up at 90 days after last retifanlimab 
administration (which may be performed via a site visit or via a telephone or video call 
with subsequent site visit required if any concerns are noted during the call).  They will 
then be followed, when study treatment is completed, for 2 years or until death, whichever 
occurs first.  Follow-up will take place as per routine care, and data on progression and 
survival will be collected when 2 years has elapsed.  Patients removed from study for 
unacceptable adverse events will be followed until resolution or stabilization of the adverse 
event. 
 
 
 
 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS 
 
Please note that if a patient must discontinue  retifanlimab (for patients in Regimen A) or both 
retifanlimab and epacadostat (for patients in Regimen B), s/he must be removed from study (but 
may continue bevacizumab off study).  Otherwise, if any single drug must be discontinued, the 
patient may remain on study and continue treatment.  In some circumstances, it may be necessary 
to temporarily interrupt both study treatments as a result of AEs that may have an unclear 
relationship to study drug.  If an interruption is necessary, treatment holds and modifications may 
be made at the discretion of the PI and/or treating physician. 
 
6.1 
Dose Holds for Epacadostat 

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Any interruptions of > 2 weeks or for LFT abnormalities must be discussed with the 
medical monitor before resuming treatment.  Treatment with both study drugs should be 
withheld for drug-related Grade 4 hematologic toxicities, non-hematological toxicity ≥ 
Grade 3 (including laboratory abnormalities), and severe or life-threatening AEs. 
 
Epacadostat will be administered as a flat dose of 400 mg BID. Epacadostat may be held 
and restarted at the same dose level provided that fewer than 22 days have elapsed since 
start of dose hold. Patients unable to tolerate this flat dose or unable to restart at the same 
dose level after 21 days on 400 mg BID dosing will discontinue epacadostat but may 
remain on  retifanlimab monotherapy.  
 
Dosing interruptions may be permitted in the case of medical/surgical events or logistical 
reasons not related to study therapy (eg, elective surgery, unrelated medical events, subject 
vacation, and/or holidays).  The reason for interruption should be documented in the 
subject’s study record. 
 
6.2 
Procedures for Participants Exhibiting Immune-Related Adverse Events 
 
Adverse events of a potential immunologic etiology, or irAEs, may be defined as AEs of 
unknown etiology, associated with drug exposure and consistent with an immune 
phenomenon.  Immune-related AEs may be predicted based on the nature of the 
compounds, their mechanism of action, and reported experience with immunotherapies that 
have a similar mechanism of action.  Special attention should be paid to AEs that may be 
suggestive of potential irAEs.  An irAE can occur shortly after the first dose or several 
months after the last dose of treatment. 
 
If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, 
toxin or other etiologic causes before labeling an AE as an irAE. 
 
Recommendations for management of specific immune-mediated AEs known to be 
associated with other PD-1 inhibitors (eg, pembrolizumab, nivolumab) are detailed in the 
table below.  Algorithms for evaluation of selected immune toxicities that have previously 
been attributed to PD-1 inhibitors and management guidelines for irAEs not detailed 
elsewhere in the protocol should follow the ASCO or ESMO Clinical Practice Guidelines 
(56, 57). 

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Immune-Related 
Adverse Event 
Toxicity Grade or 
Conditions (CTCAE v5.0) 
Action Taken With  retifanlimab and 
Epacadostat 
AE Management With Corticosteroid and/or 
 Other Supportive Care Therapies 
Pneumonitis 
Grade 1 
No action. 
None. 
Grade 2 
Withhold until ≤ Grade 1. 
 Administer systemic corticosteroids per local practice followed by taper. 
 Evaluate participants with suspected pneumonitis with radiographic 
imaging and initiate corticosteroid treatment. 
 Add prophylactic antibiotics for opportunistic infections. 
Grades 3 or 4, or recurrent 
Grade 2 
Permanently discontinue. 
Diarrhea/colitis 
Grade 1 
No action. 
None. 
Grades 2 or 3 
Withhold until ≤ Grade 1. 
 Consider prompt initiation of standard anti-diarrheal agents. 
 Administer systemic corticosteroids per local practice followed by taper. 
 Consider prophylactic antibiotics per local practice. 
 Consider gastrointestinal consultation and performing endoscopy to rule 
out colitis. 
Grade 4 or recurrent 
Grade 3 
Permanently discontinue. 
AST/ALT elevation 
and/or increased 
bilirubin/Hepatitis 
Grade 1 
No action. 
None. 
Grade 2 
Withhold until ≤ Grade 1. 
 Administer systemic corticosteroids per local practice followed by taper. 
 Consider monitoring liver enzymes weekly (or more frequently) until 
liver enzyme value returns to baseline or is stable. 
Grade 3 or 4,  
or in participants with liver 
metastasis with baseline 
Grade 2 elevation of AST 
or 
ALT, hepatitis with AST or 
ALT increases ≥ 50% and 
lasts ≥ 1 week 
Permanently discontinue. 
Endocrinopathies 
Type 1 diabetes 
mellitus 
Hyperglycemia 
Hyperthyroidism 
Hypothyroidism 
Hypophysitis 
Adrenal insufficiency 
 
Grades 1 and 2 
No action. 
None. 
Grades 3 and 4 
hyperthyroidism 
No action. 
For hypothyroidism, initiate thyroid replacement hormones (eg, 
levothyroxine or liothyronine) per standard of care. 
Grades 3 or 4 
Withhold until ≤ Grade 1. 
May restart retifanlimab if 
endocrinopathy has improved to ≤ Grade 
2 and is controlled with hormone 
replacement, if indicated, and steroid 
taper is complete. 
 For Type 1 diabetes mellitus, initiate insulin replacement therapy. 
 For hyperglycemia, administer antihyperglycemic. 
 For hyperthyroidism, treat with nonselective beta-blockers 
(eg, propranolol) or thionamides as appropriate. 
 For hypophysitis or adrenal insufficiency, administer corticosteroids and 
initiate hormonal replacements as clinically indicated. 
Nephritis and renal 
dysfunction 
Grade 1 
No action. 
None. 
Grade 2 
Withhold until ≤ Grade 1. 
Administer corticosteroids per local practice followed by taper. 
Grade 3 or 4  
Permanently discontinue. 

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Immune-Related 
Adverse Event 
Toxicity Grade or 
Conditions (CTCAE v5.0) 
Action Taken With  retifanlimab and 
Epacadostat 
AE Management With Corticosteroid and/or 
 Other Supportive Care Therapies 
Rash 
Grade 1 
No action. 
None. 
Grade 2 
No action. 
Manage with topical steroids with or without drug interruption. 
Grade 3i) or persistent 
Grade 2 (≥ 2 weeks) or 
suspected Stevens-Johnson 
syndrome or toxic 
epidermal necrolysis 
Withhold until ≤ Grade 1. 
Administer corticosteroids per local practice followed by taper. 
Grade 4 or confirmed 
Stevens-Johnson syndrome 
or toxic epidermal 
necrolysis 
Permanently discontinue. 
Myocarditis 
Grade 2 
Withhold until ≤ Grade 1. 
 Treatment with systemic corticosteroids should be initiated (initial dose of 
1-2 mg/kg per day of prednisone or equivalent).  Taper as appropriate. 
 Management of cardiac symptoms according to standard of care and with 
guidance from cardiology.  Consider cardiac MRI and myocardial biopsy 
for diagnosis. 
Grades 3 or 4 
Permanently discontinue. 
All other irAEs 
Grade 3 or intolerable/ 
persistent Grade 2 
Withhold until ≤ Grade 1. 
Based on severity of AE, administer corticosteroids. 
Recurrent Grade 3 
Consider discontinuation. 
Grade 4 
Permanently discontinue. 
 

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6.3 
Dose Modifications for Bevacizumab 
 
There are no recommended dose reductions.  Discontinue bevacizumab for: 
 Gastrointestinal perforations, fistula formation in the gastrointestinal tract, intra-
abdominal abscess, fistula formation involving an internal organ 
 Wound dehiscence and wound healing complications requiring medical 
intervention 
 Serious hemorrhage (i.e., requiring medical intervention) 
 Severe arterial thromboembolic events 
 Live-threatening (grade 4) venous thromboembolic events, including pulmonary 
embolism 
 Hypertensive crisis or hypertensive encephalopathy 
 Posterior Reversible Encephalopathy Syndrome (PRES) 
 Nephrotic syndrome 
 
Temporarily suspend bevacizumab for: 
 At least 4 weeks prior to elective major surgery 
 Severe hypertension not controlled with medical management 
 Severe proteinuria 
 Severe infusion reactions 
 
6.4 
Dose Modifications for Radiation Therapy 
 
There are no protocol-mandated radiation therapy dose modifications.  Dosing may be 
adjusted at the discretion of the treating radiation oncologist. 
 
 
7.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outlined below.  Please refer to Appendix D for definitions and Appendix E for a grid of reporting 
timelines. 
 
Adverse events will be tracked from time of consent through 90 days following the last day of 
treatment.  All adverse events must be recorded on the toxicity tracking case report form (CRF) 
with the exception of: 
 Baseline adverse events, which shall be recorded on the medical history CRF 
 
Refer to the data submission schedule in Section 11 for instructions on the collection of AEs in the 
EDC. 
 
Reporting requirements for Washington University study team may be found in Section 7.1.  
Reporting requirements for secondary site study teams participating in Washington University-
coordinated research may be found in Section 7.2. 
 

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7.1 
Sponsor-Investigator Reporting Requirements 
 
 Reporting to the Human Research Protection Office (HRPO) at 
Washington University 
 
Reporting will be conducted in accordance with Washington University IRB 
Policies. 
 
Pre-approval of all protocol exceptions must be obtained prior to implementing 
the change. 
 
 Reporting to the Quality Assurance and Safety Monitoring Committee 
(QASMC) at Washington University 
 
The Washington University Sponsor-Investigator (or designee) is required to notify 
the QASMC of any unanticipated problems involving risks to participants or others 
occurring at WU or any BJH or SLCH institution that has been reported to and 
acknowledged by HRPO.  (Unanticipated problems reported to HRPO and 
withdrawn during the review process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via 
email to qasmc@wustl.edu. Submission to QASMC must include the myIRB form 
and any supporting documentation sent with the form. 
 
For events that occur at secondary sites, the Washington University Sponsor 
Investigator (or designee) is required to notify the QASMC within 10 days of 
Washington University notification via email to qasmc@wustl.edu.  Submission to 
QASMC must include either the myIRB form and supporting documentation or (if 
not submitted to myIRB) the date of occurrence, description of the event, whether 
the event is described in the currently IRB approved materials, the event outcome, 
determination of relatedness, whether currently enrolled participants will be 
notified, and whether the informed consent document and/or any study procedures 
will be modified as a result of this event. 
 
 Reporting to Incyte 
 
The Principal Investigator (PI) must report all Serious Adverse Events (SAEs) to 
Incyte within 24 hours of learning of an event, regardless of the PI’s causality 
assessment. This notification should be provided on a completed Serious Adverse 
Event (SAE) form.  SAE reporting for each subject begins the day the informed 
consent is signed by the patient and within 90 days after subject has completed or 
discontinued from the study or has taken last dose of the study drug, or as described 
in the protocol. 
 
SAEs, occurring using Incyte study drug, are reported in accordance with the 
effective protocol.  SAEs occurring with any other commercial drug are reported to 

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the manufacturer of that drug in accordance with regulations and protocol.  
 
Initial SAEs and/or subsequent follow-up reports should be reported via email to 
SafetyReporting@Incyte.com  or fax (+) 1-866-981-2057.  SAE reports should be 
for a single subject.  SAE forms should be sent with a cover sheet and any additional 
attachments. 
 
All adverse event information is reported to Incyte on the Principal 
Investigator’s/Institution’s Adverse Event Report Form, or a CIOMS-I or 
MedWatch Form FDA 3500A, or on an Adverse Event Report Form which may be 
provided by Incyte upon request. The Principal Investigator does not provide 
medical records (e.g., discharge summary) to Incyte, unless specifically requested. 
 
7.1.3.1 Reporting Pregnancy 
 
An “Initial Pregnancy Report” or equivalent must be completed in full and 
emailed to SafetyReporting@Incyte.com or faxed to (+) 1-866-981-2057 
within 24 hours of discovery of a pregnancy of a subject who has taken the 
Incyte product or the pregnancy of a partner for a subject who has taken the 
Incyte product.  The “Follow-up Pregnancy Report Form” or equivalent 
must be completed and emailed to SafetyReporting@Incyte.com or faxed 
to (+) 1-866-981-2057 within 30 days after delivery, so that Incyte is 
provided with information regarding the outcome of the pregnancy.  If the 
pregnancy results in any events which meet the serious criteria (i.e., 
miscarriage or termination), the SAE reporting process needs to be followed 
and the timelines associated with a SAE should be followed. 
 
 Reporting to the FDA 
 
The conduct of the study will comply with all FDA safety reporting requirements.  
PLEASE NOTE THAT REPORTING REQUIREMENTS FOR THE FDA 
DIFFER FROM REPORTING REQUIREMENTS FOR HRPO/QASMC.  It 
is the responsibility of the Washington University Sponsor-Investigator to report to 
the FDA as follows: 
 
 Report any unexpected fatal or life-threatening suspected adverse reaction 
(refer to Appendix D for definitions) no later than 7 calendar days after 
initial receipt of the information.   
 Report a suspected adverse reaction that is both serious and unexpected 
(SUSAR, refer to Appendix D) no later than 15 calendar days after it is 
determined that the information qualifies for reporting.  Report an adverse 
event (refer to Appendix D) as a suspected adverse reaction only if there is 
evidence to suggest a causal relationship between the drug and the adverse 
event, such as: 
o A single occurrence of an event that is uncommon and known to be 
strongly associated with drug exposure 

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o One or more occurrences of an event that is not commonly associated 
with drug exposure but is otherwise uncommon in the population 
exposed to the drug 
o An aggregate analysis of specific events observed in a clinical trial that 
indicates those events occur more frequently in the drug treatment 
group than in a concurrent or historical control group 
 Report any findings from epidemiological studies, pooled analysis of 
multiple studies, or clinical studies that suggest a significant risk in humans 
exposed to the drug no later than 15 calendar days after it is determined 
that the information qualifies for reporting. 
 Report any findings from animal or in vitro testing that suggest significant 
risk in humans exposed to the drug no later than 15 calendar days after it 
is determined that the information qualifies for reporting.  
 Report any clinically important increase in the rate of a serious suspected 
adverse reaction of that listed in the protocol or IB within 15 calendar days 
after it is determined that the information qualifies for reporting. 
 
Submit each report as an IND safety report in a narrative format or on FDA Form 
3500A or in an electronic format that FDA can process, review, and archive.  Study 
teams must notify the Siteman Cancer Center Protocol Development team of each 
potentially reportable event within 1 business day after initial receipt of the 
information, and must bring the signed 1571 and FDA Form 3500A to the Siteman 
Cancer Center Protocol Development team no later than 1 business day prior to the 
due date for reporting to the FDA. 
 
Each notification to FDA must bear prominent identification of its contents (“IND 
Safety Report”) and must be transmitted to the review division in the Center for 
Drug Evaluation and Research (CDER) or in the Center for Biologics Evaluation 
and Research (CBER) that has responsibility for review of the IND.  Relevant 
follow-up information to an IND safety report must be submitted as soon as the 
information is available and must be identified as such (“Follow-up IND Safety 
Report”). 
 
 Reporting to Secondary Sites 
 
The Washington University Sponsor-Investigator (or designee) will notify the 
research team at each secondary site of all unanticipated problems involving risks 
to participants or others that have occurred at other sites within 10 working days 
of the occurrence of the event or notification of the Sponsor-Investigator (or 
designee) of the event.  This includes events that take place both at Washington 
University and at other secondary sites, if applicable. Refer to Section 16.0 
(Multicenter Management) for more information. 
 
7.2 
Secondary Site Reporting Requirements 
 
The research team at each secondary site is required to promptly notify the Washington 

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University Sponsor-Investigator and designee of all serious adverse events (refer to 
Appendix D, Section D) within 1 working day of the occurrence of the event or 
notification of the secondary site’s PI of the event.  This notification may take place via 
email if there is not yet enough information for a formal written report (using FDA Form 
3500a (MedWatch) and Washington University’s cover sheet (Appendix F)).  A formal 
written report must be sent to the Washington University Sponsor-Investigator and 
designee within 4 calendar days (for fatal or life-threatening suspected adverse reactions) 
or 11 calendar days (for serious unexpected adverse reactions) of the occurrence of the 
event or notification of the secondary site’s PI of the event. 
 
The research team at a secondary site is responsible for following its site’s guidelines for 
reporting applicable events to its site’s IRB according to its own institutional guidelines.  
The research team at Washington University is responsible for reporting all applicable 
events to the FDA and Incyte as needed. 
 
Washington University pre-approval of all protocol exceptions must be obtained prior to 
implementing the change.  Local IRB approval must be obtained as per local guidelines.  
Washington University IRB approval is not required for protocol exceptions occurring at 
secondary sites. 
 
7.3 
Exceptions to Expedited Reporting 
 
Events that do not require expedited reporting as described in Section 7.1 include: 
 planned hospitalizations 
 hospitalizations < 24 hours 
 respite care 
 events related to disease progression 
 
Events that do not require expedited reporting must still be captured in the EDC. 
 
 
8.0 
PHARMACEUTICAL INFORMATION 
 
8.1 
Epacadostat 
 
 Epacadostat Description 
 
Epacadostat is an inhibitor of the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) 
that is proposed for development for the treatment of malignant diseases.  Its 
chemical 
name 
is 
(Z)-N-(3-bromo-4-fluorphenyl)-N’-hydroxy-4-(2-
(sulfamoylamino)ethylamino)-1,2,5-oxadiazole-3-carboximidamide.  It has a 
molecular formula of C11H13BrFN7O4S and a molecular weight of 438.23. 
 
 Clinical Pharmacology 
 
Epacadostat represents a novel, potent, and selective inhibitor of the enzyme 

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indoleamine 2,3-dioxygenase 1 (IDO1) in both human tumor cells and human 
dendritic cells (DCs). 
 
 Pharmacokinetics and Drug Metabolism 
 
After oral dose administration in the fasted state, the peak plasma concentration of 
epacadostat was typically attained at 2 hours post-dose.  Epacadostat was 
eliminated with a geometric mean terminal disposition half-life of 2.9 hours. 
 
Systemic accumulation after BID administration increased the mean epacadostat 
Cmax and AUC0-t by 16% and 33%, respectively, suggesting an effective half-life 
of 4 to 6 hours. 
 
 Supplier(s) 
 
Epacadostat will be supplied by Incyte. 
 
 Dosage Form and Preparation 
 
Epacadostat is available as 100mg tablets or 300 mg tablets packaged in high-
density polyethylene bottles. 
 
 Storage and Stability 
 
Epacadostat drug product should be stored at ambient conditions (59°F-86°F). 
 
 Administration 
 
Refer to Section 5.1. 
 
8.2 
 Retifanlimab 
 
 Retifanlimab Description 
 
Retifanlimab is a humanized, hinge-stabilized, IgG4κ monoclonal antibody that 
recognizes human PD-1.  Retifanlimab contains a human IgG4 Fc domain to limit 
effector function while retaining neonatal Fc receptor binding to extend circulating 
half-life.  Retifanlimab is designed to target PD-1–expressing cells, including T 
cells, and to sustain/restore their effector function by blocking checkpoint 
inhibitory interactions between PD-1 and its 2 ligands, PD-L1 and PD-L2.  
 
 Clinical Pharmacology 
 
Consistent with its intended mechanism of action and functional properties, 
retifanlimab has been shown to inhibit the binding of PD L1 and PD L2 to PD-1, to 
disrupt the PD-1/PD-L1 inhibitory axis, and to enhance IFN γ secretion in SEB-

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stimulated human PBMCs with activity comparable to pembrolizumab and 
nivolumab replicas. 
 
 Supplier 
 
Retifanlimab will be supplied by Incyte. 
 
 Dosage Form and Preparation 
 
Retifanlimab will be provided in a glass vial for single use.  Each vial will be 
labeled as required per country requirement. 
 
 Storage and Stability 
 
Retifanlimab drug product must be stored at 2°C to 8°C until use.  It must be stored 
upright and protected from light. 
 
 Administration 
 
Refer to Section 5.1. 
 
8.3 
Bevacizumab (Avastin) 
 
 Bevacizumab Description 
 
Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that binds to 
and inhibits the biologic activity of human vascular endothelial growth factor 
(VEGF) in in vitro and in vivo assay systems.  It as an approximate molecular 
weight of 149 kD.  It is produced in a mammalian cell (Chinese Hamster Ovary) 
expression system in a nutrient medium containing the antibiotic gentamicin. 
 
 Clinical Pharmacology 
 
Bevacizumab binds VEGF and prevents the interaction of VEGF to its receptors 
(Flt-1 and KDR) on the surface of endothelial cells.  The interaction of VEGF with 
its receptors leads to endothelial cell proliferation and new blood vessel formation 
in in vitro models of angiogenesis.  Administration of bevacizumab to 
xenotransplant models of colon cancer in nude (athymic) mice caused reduction of 
microvascular growth and inhibition of metastatic disease progression. 
 
 Pharmacokinetics and Drug Metabolism 
 
The pharmacokinetic profile of bevacizumab was assessed using an assay that 
measures total serum bevacizumab concentrations.  Based on a population 
pharmacokinetic analysis of 491 patients who received 1 to 20 mg/kg of 
bevacizumab weekly every 2 or every 3 weeks, the estimated half-life of 

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bevacizumab was approximately 20 days.  The predicted time to reach steady state 
was 100 days. 
 
The clearance of bevacizumab varied by body weight, gender, and tumor burden. 
 
 Supplier(s) 
 
Bevacizumab is commercially available. 
 
 Dosage Form and Preparation 
 
Bevacizumab is a clear to slightly opalescent, colorless to pale brown, sterile, pH 
6.2 solution for intravenous infusion.  It is supplied in 100 mg and 400 mg 
preservative-free, single-use vials to deliver 4 mL or 16 mL of bevacizumab (25 
mg/mL).  
 
 Storage and Stability 
 
Bevacizumab vials are stable at 2-8ºC.  They should be protected from light.  Do 
not freeze or shake.  Diluted bevacizumab solutions may be stored at 2-8ºC for up 
to 8 hours.  Store in the original carton until time of use. 
 
 Administration 
 
Do not administer as an IV push or bolus.  Administer only as an IV infusion.  The 
first infusion should be administered over 90 minutes.  The second infusion may be 
administered over 60 minutes if the first infusion is tolerated; all subsequent 
infusions over 30 minutes if the 60-minute infusion is tolerated. 
 
For this study, bevacizumab should be administered at a dose of 10 mg/kg on Days 
1 and 15 of each 28-day cycle. 
 
Please note that biosimilars are permitted for bevacizumab (Avastin). 
 
 Special Handling Instructions 
 
None. 
 
 
9.0 
CORRELATIVE STUDIES 
 
9.1 
Peripheral Blood for PBMCs 
 
 Collection of Specimens 
 
A total of 40 mL of blood will be collected in 5 cellular preparation tubes (8 mL 

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each) containing sodium heparin (CPTs) or 4 ethylenediamine tetraacetic acid 
(EDTA) tubes (10 mL each) for isolation of PBMCs at each of the following time 
points (NOTE-: +/- 7 days are allowed): 
 Baseline (prior to administration of any study treatment) 
 Before initiation of RT (up to 7 days prior to start of RT; may be on the 
same day as RT before RT treatment) 
 At the end of RT and/or Cycle 2 Day 1 prior to administration of  
retifanlimab with or without epacadostat (end of RT will typically 
correspond with C2D1, but if it doesn’t, either or both of these time points 
may be captured on a +/- 7 day window) 
 Cycle 3 Day 1 prior to administration of retifanlimab with or without 
epacadostat(+/- 7 days). 
 Cycle 5 Day 1 prior to administration of retifanlimab with or without 
epacadostat (+/- 7 days). 
 Time of disease progression. 
Additionally, ~3-10mL of plasma will be saved along with PBMC collection. 
 
 Handling of Specimens 
 
Cellular preparation tubes (CPTs) can be purchased from BD Biosciences.  A total 
of 40 mL of blood will be collected in CPTs or EDTAs and PBMCs will be 
collected by centrifugation per each site’s standard protocol. PBMC and plasma 
will be saved in -80°C or liquid nitrogen for immunologic studies.   
 
 Shipping and Storage of Specimens 
 
Blood samples collected at CAM should be transported at room temperature to 
either the Siteman Cancer Center’s Tissue Procurement Core (located on the 5th 
floor of the BJCIH) or Dr. Matthew Ciorba’s lab (located on the 10th floor of the 
CSRB-North Tower Annex Room 1021) at ambient temperature immediately after 
collection and processed immediately upon arrival.  
 
 
Coded samples may be distributed from the Tissue Procurement Core and mailed 
to Dr. Timothy Garrett’s lab at the University of Florida for processing key 
correlative analyses such as calculation of study specified kynurenine to tryptophan 
(K/T) ratio. 
 
Blood samples that are collected at secondary sites will be transported to the site’s 
local processing lab at ambient temperature immediately after collection and 
processed immediately upon arrival. At the conclusion of the study, all samples 
collected at the secondary site will be batch shipped to Washington University in 
St. Louis for final analysis. This final analysis will be performed in Dr. Matthew 
Ciorba’s lab. 
 
NOTE: After analysis are performed at Dr. Matthew Ciorba’s Lab, selected 

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remaining study samples could be saved at the Siteman Cancer Center’s Tissue 
Procurement Core (located on the 5th floor of the BJCIH) for future studies. 
 
 
 
9.2 
Peripheral Blood for Serum 
 
 Collection of Specimens 
 
A total of 5 mL of blood will be collected in one red-top tube at each of the 
following time points: 
 Baseline (up to 7 days prior to administration of any study treatment) 
 Before initiation of RT (up to 7 days prior to start of RT; may be on the 
same day as RT before RT treatment) 
 At the end of RT and/or Cycle 2 Day 1 prior to administration of  
retifanlimab with or without epacadostat (end of RT will typically 
correspond with C2D1, but if it doesn’t, either or both of these time points 
may be captured on a +/- 7 day window) 
 Cycle 3 Day 1 prior to administration of retifanlimab with or without 
epacadostat (+/- 7 days) 
 Time of disease progression 
 
 Handling of Specimens 
 
Serum will be collected via centrifugation per standard protocol. Serum will be 
saved in -80°C refrigerator for biomarker assays. 
 
 Shipping and Storage of Specimens 
 
Samples should be stored and shipped as described in Section 9.1.3. 
 
9.3 
Tumor Tissue – Optional  
 
 Collection of Specimen 
 
Any tissue (from either surgical debulking or biopsy or MLA/biopsy) available 
after histopathologic diagnosis of  glioma will be collected for correlated studies as 
follows: 
 
 Flash frozen for DNA and RNA isolation 
 Fixed and embedded in paraffin for IHC  
 Acutely dissociated to generate patients’ primary glioma cell lines and 
tumor infiltrating lymphocyte cultures if adequate tissue is available. 
 

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The amount of tissue saved will be variable depending on how much is removed at 
the time of the standard of care procedure and how much is left over after pathology.  
Tissue need not be requested right away. 
 
For patients who have a post-treatment biopsy or surgery as part of their clinical 
care, any tissue available for research use after it has been evaluated by pathology 
will be requested for this study. 
 
 Handling of Specimen 
 
Tissue cryopreservation and paraffin embedding are per standard protocol. One half 
of the tissue will be equally divided into 2 parts: one part will be flash frozen, and 
the other part will be fixed and embedded in paraffin (FFPE). FFPE samples will 
be batch shipped to a designated laboratory (TBD) for PD-L1 IHC.  
 
Flash frozen samples will be taken to the TPC and then sent to Matthew Ciorba’s 
lab for RNA isolation. mRNA expressions of the biomarkers will be tested.  
 
 Shipping and Storage of Specimen 
 
Brain tumor samples collected at WU should be placed in a buffered solution (e.g. 
PBS, a tissue culture media), transported to the Siteman Cancer Center Tissue 
Procurement Core at ambient temperature, and processed immediately upon arrival.   
 
Tissue samples that are collected at secondary sites should be placed in a buffered 
solution (e.g. PBS, a tissue culture media) and transported to the site’s local 
processing lab at ambient temperature after collection and processed immediately 
upon arrival. At the conclusion of the study, all samples collected at the secondary 
site will be batch shipped to Washington University in St. Louis for final analysis. 
 
 

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10.0 
STUDY CALENDAR 
Screening/baseline evaluations are to be conducted within 2 weeks prior to Day 1 of treatment.  Scans must be done no more than 4 
weeks prior to the start of the protocol therapy.  Each cycle is 28 days.  There is a +/- 7 day window for all assessments/dosing. 
 
Screening 
Baseline 
Before start 
of RT 
End of 
RT 
Day 1 of each 
cycle 
Day 15 of each 
cycle 
End of every even-
numbered cycle 
(Eg. before C3D1, 
C5D1, etc.) 
End of 
treatment 
Follow-
up2 
Informed consent 
X14 
 
 
 
 
 
 
 
 
H&P, KPS, BP, wt 
X 
 
 
 
X 
 
 
X 
 
NANO 
X 
 
 
 
 
 
X13 
X 
 
CBC 
X 
 
 
 
X 
X 
 
X 
X7 
CMP 
X 
 
 
 
X 
X 
 
X 
X7 
PT, PTT, INR 
X 
 
 
 
 
 
 
 
 
Free T4 and TSH 
X 
 
 
 
X6 
 
 
 
 
Urine β-hCG1 
X 
 
 
 
 
 
 
 
 
Hepatitis B and C testing 
X 
 
 
 
 
 
 
 
 
UA Macro reflex to 
Micro 
X 
 
 
 
X 
X 
 
 
 
Brain MRI15 
X 
 
 
 
 
 
X 
X 
 
ECG12  
X 
 
 
 
 
 
 
 
 
RT 
 
 
 
 
10 fx during C1 
 
 
 
 
Epacadostat8,9 
 
 
 
 
twice daily 
 
 
 
 
 Retifanlimab9 
 
 
 
 
X 
 
 
 
 
Bevacizumab9 
 
 
 
 
X 
X 
 
 
 
Blood for PBMCs 
 
X 
X 
X 
X3 
 
 
X3 
 
Blood for serum 
 
X 
X 
X10 
X11 
 
 
X3 
 
Research tissue 
 
X --------------------------------------------- X5 
 
 
X5 
 
AE assessment 
 
X---------------------------------------------------------------------------------------------------------------------------------- X4 
Survival 
 
 
 
 
 
 
 
 
X 
1. 
Women of childbearing potential only 
2. 
Every 2 months for 2 years 
3. 
C3D1, C5D1, time of progression 
4. 
For 90 days after last day of treatment; the extended safety follow-up beyond 30 days after last  retifanlimab administration may be performed via a site visit or via a telephone call 
with subsequent site visit required if any concerns are noted during the call 
5. 
Any tissue from surgical debulking, biopsy, or MLA/biopsy available after pathology will be collected.  If a post-treatment surgical procedure is performed as part of the patient’s clinical care, 
available tissue will be requested for research purposes as well. 

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6. 
To be performed every 8 weeks (Day 1 of every odd-numbered cycle) 
7. 
At 30-day follow-up only 
8. 
Regimen B patients only 
9. 
Treatment with retifanlimab and bevacizumab (and epacadostat, if applicable) will start 2 weeks before the first day of RT; RT is intended to start on Cycle 1 Day 15 (+/- 3 days). 
10. And/or C2D1 (prior to administration of retifanlimab with or without epacadostat) 
11. C3D1 only (prior to administration of retifanlimab with or without epacadostat) 
12. Subjects with left bundle branch block are excluded. 
13. +/- 7 days from MRI 
14. Initial consent must be completed within 6 weeks prior to Day 1 of treatment  
15. The timing of MRIs should be done based on the date of C1D1 and done every 8 weeks (+/- 2 weeks) thereafter 

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11.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
On-Study Form 
Medical History Form 
Prior to starting treatment 
Treatment Form 
Every cycle 
Toxicity Form 
Continuous 
Correlatives Form 
Baseline, end of RT, C2D1, C6D1, C12D1/Time of progression 
Treatment Summary Form 
Completion of treatment 
Follow Up Form 
Every 2 months for 2 years 
Tumor Measurement Form 
Baseline, end of every second cycle, and end of treatment 
Progression Form 
Time of disease progression 
Death Form 
Time of death 
MedWatch Form 
See Section 7.0 for reporting requirements 
  
Any queries generated by Washington University must be responded to within 28 days of receipt 
by the participating site.  The Washington University research team will conduct a regular review 
of data status at all secondary sites, with appropriate corrective action to be requested as needed. 
 
11.1 
Adverse Event Collection in the Case Report Forms 
 
All adverse events that occur beginning with start of treatment (minus exceptions defined 
in Section 7.0) must be captured in the Toxicity Form.  Baseline AEs should be captured 
on the Medical History Form. 
 
Participant death due to disease progression should be reported on the Toxicity Form as 
grade 5 disease progression.  If death is due to an AE (e.g. cardiac disorders: cardiac arrest), 
report as a grade 5 event under that AE.  Participant death must also be recorded on the 
Death Form. 
 
 
12.0 
MEASUREMENT OF EFFECT 
 
12.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients will be re-evaluated for recurrence or progression 
every 8 (+/- 2) weeks.  Response and progression will be evaluated in this study using the 
updated response assessment criteria for high-grade gliomas: immunotherapy Response 
Assessment in Neuro-Oncology (iRANO) working group guideline [44]. 
 
 

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Criteria for Response Assessment Incorporating MRI and Clinical Factors (Adapted from [47]) 
Response 
Criteria 
Complete response 
Requires all of the following:  
 Disappearance of all enhancing measurable and nonmeasurable disease 
sustained for at least 4 weeks.  
 No new lesions; stable or improved nonenhancing (T2/FLAIR) lesions 
 Patients must be off corticosteroids (or on physiologic replacement 
doses only) and stable or improved clinically. Note: Patients with 
nonmeasurable disease only cannot have a complete response; the best 
response possible is stable disease.  
Partial response 
Requires all of the following:  
 ≥ 50% decrease compared with baseline in the sum of products of 
perpendicular diameters of all measurable enhancing lesions sustained 
for at least 4 weeks 
 No progression of nonmeasurable disease 
 Stable or improved nonenhancing (T2/FLAIR) lesions on same or lower 
dose of corticosteroids compared with baseline scan; the corticosteroid 
dose at the time of the scan evaluation should be no greater than the 
dose at time of baseline scan 
 Stable or improved clinically. Note: Patients with nonmeasurable 
disease only cannot have a partial response; the best response possible 
is stable disease.  
Stable disease 
Requires all of the following:  
 Does not qualify for complete response, partial response, or progression  
 Stable nonenhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared with baseline scan. In the event that the 
corticosteroid dose was increased for new symptoms and signs without 
confirmation of disease progression on neuroimaging, and subsequent 
follow-up imaging shows that this increase in corticosteroids was 
required because of disease progression, the last scan considered to 
show stable disease will be the scan obtained when the corticosteroid 
dose was equivalent to the baseline dose  
 Stable or improved clinically 
Progression 
Defined by any of the following:  
 ≥ 25% increase in sum of the products of perpendicular diameters of 
enhancing lesions compared with the smallest tumor measurement 
obtained either at baseline (if no decrease) or best response, on stable or 
increasing doses of corticosteroids*. The absolute increase in any 
dimension must be at least 5mm when calculating the products.  
 Significant increase in T2/FLAIR nonenhancing lesion on stable or 
increasing doses of corticosteroids compared with baseline scan or best 
response after initiation of therapy* not caused by comorbid events (e.g. 
radiation therapy, demyelination, ischemic injury, infection, seizures, 
postoperative changes, or other treatment effects) 

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Response 
Criteria 
 Any new measureable lesion 
 Clear clinical deterioration not attributable to other causes apart from 
the tumor (e.g. seizures, medication adverse effects, complications of 
therapy, cerebrovascular events, infection, and so on) or changes in 
corticosteroid dose. 
 Failure to return for evaluation as a result of death or deteriorating 
condition; or clear progression of nonmeasurable disease.  
 
NOTE. All measurable and nonmeasurable lesions must be assessed using the same techniques as at 
baseline. 
 
Abbreviations: MRI, magnetic resonance imaging; FLAIR, fluid-attenuated inversion recovery. 
 
Stable doses of corticosteroids include patients not on corticosteroids. 
 
iRANO criteria for progression: Confirmation of progression on follow-up imaging 3 
months after initial radiographic progression if: 
1. No new or significantly worsened neurologic deficits not due to co-morbid event 
or concurrent medication 
2. < 6 months from initiation of immunotherapy; If follow-up imaging confirms 
progression, the date of actual progression should be back-dated to the date of initial 
radiographic progression. Note the appearance of new lesions solely does not define 
progressive disease≤ 6 months from initiation of immunotherapy. Rather, the 
lesions are added to the total lesion areas for follow-up assessments. 
 
Otherwise, progressive disease will be defined as radiographic evidence of progression 
with significant clinical decline that is felt to be unrelated to co-morbid event or concurrent 
medication, or if there is radiographic evidence of progression > 6 months after initiation 
of immunotherapy.   
  
12.2 
Disease Parameters 
 
Measurable disease:  Bi-dimensionally measurable lesions with clearly defined margins 
by MRI scan.  All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters).   
 
Non-measurable or evaluable disease:  Uni-dimensionally measurable lesions or lesions 
with margins not clearly defined such as areas of T2/FLAIR signal abnormality or poorly 
defined enhancing abnormality.  
 
Note: For cystic lesions, the only measurable part is any enhancement area around the cyst 
that is clearly defined and bi-dimensionally measurable. The cyst itself should not be 
considered measurable or non-measureable disease. 
 
Target lesions: All measurable lesions should be identified as target lesions and recorded 
and measured.  Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), but in addition should be those that lend themselves to reproducible 
repeated measurements.  It may be the case that, on occasion, the largest lesion does not 

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lend itself to reproducible measurement in which circumstance the next largest lesion, 
which can be measured reproducibly should be selected.  When there are too many 
measurable lesions, choose the largest 3 lesions as target lesions to follow.  The other 
measurable lesions should be considered evaluable for the purpose of objective status 
determination. 
 
Non-target lesions:  All non-measurable 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.  
 
12.3 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler.  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. 
 
Clinical lesions:  Clinical lesions will only be considered measurable on brain MRI when 
they are  5 mm diameter as assessed using a ruler. 
 
Histology:  This technique can be used to differentiate between partial responses (PR) and 
complete responses (CR) in rare cases when biopsy or surgical resection of a measureable 
lesion is clinically indicated.  
 
Perfusion/CBV: This advanced brain MRI technique can be used as an adjunct test to 
determine treatment response or disease status.  However, it should not be used as the 
primary or sole method to determine response or disease status.  
 
Brain FDG-PET coupled with head CT or brain MRI: This advanced metabolic 
imaging technique can be used as an adjunct test to determine response or disease status. 
However it should be used as the primary or sole method of determining response or 
disease status. 
 
 Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions. 
 
Partial Response (PR):  ≥ 50% decrease compared with baseline in the sum of 
products of perpendicular diameters of all target lesions sustained for at least 4 
weeks. 
 
Progressive Disease (PD):  At least a 25% increase in the sum of products of 
perpendicular diameters of at least 1 target lesion, taking as reference the smallest 
sum of products of perpendicular diameters on study (this includes the baseline sum 
if that is the smallest on study).  The absolute increase in any dimension must be at 
least 5mm when calculating the products of perpendicular diameters. 

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Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum of products of 
perpendicular diameters while on study. 
 
 Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions.  
 
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 on stable or increasing doses 
of corticosteroids compared with baseline scan or best response after initiation of 
therapy* not caused by comorbid events (e.g. radiation therapy, demyelination, 
ischemic injury, infection, seizures, postoperative changes, or other treatment 
effects). It must be representative of overall disease status change, not a single 
lesion increase.     
 
In the event of surgical intervention for clinical reasons of a radiographically 
progressing tumor when subsequent surgical pathology demonstrates a 
predominant immune-mediated reaction with no obvious progression of tumor, the 
subject will be deemed not progressed and allowed to resume study treatment as 
assigned prior to the surgery at a time deemed safe by the treating physician, but no 
later than 8 weeks from the surgery. 
 
Although a clear progression of “non-target” lesions only 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. 
 
Summary of the iRANO Response Criteria (Adapted from [44]) 
Criterion 
CR 
PR 
SD 
PD 
T1 gadolinium 
enhancing disease 
None 
≥ 50% ↓ 
< 50% ↓ but < 25% ↑ ≥ 25% ↑* 
T2/FLAIR 
Stable or ↓ Stable or ↓ Stable or ↓ 
↑* 

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Criterion 
CR 
PR 
SD 
PD 
New lesion 
None 
None 
None 
Present* 
Corticosteroids 
None 
Stable or ↓ Stable or ↓ 
NA† 
Clinical status 
Stable or ↑ Stable or ↑ Stable or ↑ 
↓* 
Requirement for 
response 
All 
All 
All 
Any* 
Abbreviations: iRANO, immunotherapy Response Assessment in Neuro-Oncology; CR, complete 
response; PR, partial response; SD, stable disease; PD, progressive disease; FLAIR, fluid-
attenuated inversion recovery; NA, not applicable.  
* Progression occurs when this criterion is present.  
† Increase in corticosteroids alone will not be taken into account in determining progression in the 
absence of persistent clinical deterioration.  
 
 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). If the subject does not have an event of disease 
progression and the subject has not died, the subject data will be censored for 
duration of overall response at the date of the last disease assessment.  
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.  
 
 Neurological Exam and Performance Status  
 
Patients will be graded using the Karnofsky Performance Status scale and their 
neurological function evaluated as improved, stable or deteriorated in addition to 
objective measurement of tumor size. These parameters will be used to determine 
the overall response assessment. 
 
 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of radiographic 
progression or death due to any cause, whichever occurs first. 
 
Radiographic disease progression will be assessed using the RECIST 1.1 criteria. 
If the disease recurrence/progression assessment involves more than one date, the 
earliest date will be used as the event date. A patient will be censored at the date of 

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the last radiographic disease assessment indicating a lack of disease progression, if 
any of the following occurs before documented disease progression: 
 Patient is alive and lack evidence of progression at the end of study or at the 
time of analysis data cut-off. 
 Disease progression or death occurs right after missing data for a scheduled 
radiographic disease assessment (including missing the assessment or 
assessment results in an inevaluable status for overall response per RECIST 
1.1). 
 Patient receives non-protocol treatment. 
 For equivocal findings of recurrence (e.g., very small and uncertain new 
lesions; cystic changes or necrosis in existing lesions), treatment may 
continue until the next scheduled assessment. If recurrence is confirmed at 
the next scheduled assessment, the date of recurrence should be the earlier 
date when recurrence was suspected.  
 
 
13.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, an 
independent Data and Safety Monitoring Board (DSMB) will be specifically convened for this 
trial to review toxicity data.  A DSMB will consist of no fewer than 3 members including 2 clinical 
investigators and a biostatistician.  DSMB members must be employed by Washington University, 
Barnes-Jewish  Hospital, or St. Louis Children’s Hospital.  Like investigators, DSMB members 
are subject to the Washington University School of Medicine policies regarding standards of 
conduct. Individuals invited to serve on the DSMB will disclose any potential conflicts of interest 
to the trial principal investigator and/or appropriate university officials, in accordance with 
institution policies. Potential conflicts that develop during a trial or a member’s tenure on a DSMB 
must also be disclosed.  
 
Until such a time as the first secondary site enrolls its first patient, a semi-annual DSM report to 
be prepared by the study team will be submitted to the Quality Assurance and Safety Monitoring 
Committee (QASMC) semi-annually beginning six months after study activation at Washington 
University (if at least one patient has been enrolled) or one year after study activation (if no patients 
have been enrolled at the six-month mark). 
 
The DSM report for the DSMB will be prepared by the study team with assistance from the study 
statistician, will be reviewed by the DSMB, and will be submitted to the QASM Committee.  The 
DSMB must meet at least every six months beginning six months after enrollment of the first 
patient at a secondary site, no more than one month prior to the due date of the DSM report to 
QASMC.   This report will include: 
 HRPO protocol number, protocol title, Principal Investigator name, data coordinator name, 
regulatory coordinator name, and statistician 
 Date of initial HRPO approval, date of most recent consent HRPO approval/revision, date 
of HRPO expiration, date of most recent QA audit, study status, and phase of study 

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 History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
 Study-wide target accrual and study-wide actual accrual including numbers from 
participating sites 
 Protocol activation date at each participating site 
 Average rate of accrual observed in year 1, year 2, and subsequent years at each 
participating site 
 Expected accrual end date, accrual by site, and accrual by regimen 
 Objectives of protocol with supporting data and list the number of participants who have 
met each objective 
 Measures of efficacy 
 Early stopping rules with supporting data and list the number of participants who have met 
the early stopping rules 
 Summary of toxicities at all participating sites separated by regimens with the number of 
dose-limiting toxicities indicated 
 Abstract submissions/publications 
 Summary of any recent literature that may affect the safety or ethics of the study  
 
Further DSMB responsibilities are described in the DSMB charter. 
 
The study principal investigator and coordinator will monitor for serious toxicities on an ongoing 
basis. Once the principal investigator or coordinator becomes aware of an adverse event, the AE 
will be reported to the HRPO and QASMC according to institutional guidelines (please refer to 
Section 7.0).  
 
Refer to the Washington University Quality Assurance and Data Safety Monitoring Committee 
Policies and Procedures for full details on the responsibilities of the DSMB. This is located on the 
QASMC website at https://siteman.wustl.edu/research/clinical-research-resources/protocol-
office-prmcqasmc/.   
 
 
14.0 
AUDITING 
 
As coordinating center of this trial, Washington University (via the Quality Assurance and Safety 
Monitoring Committee (QASMC) will monitor each participating site to ensure that all protocol 
requirements are being met; that applicable federal regulations are being followed; and that best 
practices for patient safety and data collection are being followed per protocol.  Participating sites 
will be asked to send copies of all audit materials, including source documentation.  The audit 
notification will be sent to the Washington University Research Patient Coordinator, who will 
obtain the audit materials from the participating institution. 
 
Notification of an upcoming audit will be sent to the research team one month ahead of the audit. 
Once accrual numbers are confirmed, and approximately 30 days prior to the audit, a list of the 
cases selected for review (up to 10 for each site) will be sent to the research team. However, if 

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during the audit the need arises to review cases not initially selected, the research team will be 
asked to provide the additional charts within two working days. 
 
Items to be evaluated include: 
 Subject screening and enrollment 
 Reporting of adverse events 
 Maintenance of HIPAA compliance 
 Completeness of regulatory documentation 
 Completeness of participant documentation 
 Acquisition of informed consent 
 IRB documentation 
 Issues of protocol adherence 
 
Additional details regarding the auditing policies and procedures can be found at 
https://siteman.wustl.edu/research/clinical-research-resources/protocol-office-prmcqasmc/. 
 
 
15.0 
STATISTICAL CONSIDERATIONS 
 
15.1 
Overall Study Design 
 
This is an open-label nonrandomized Phase II study on two regimens in bevacizumab-naïve 
recurrent or progressive grade 4 glioma patients:  retifanlimab + bevacizumab+ RT 
(regimen A), and retifanlimab + epacadostat + bevacizumab + RT (regimen B), each with 
24 efficacy evaluable patients. The study will start to enroll patients to receive regimen A 
while regimen B will open to enrollment later after regimen A starts or even after the 
completion of regimen A. The dosage of retifanlimab and epacadostat are fixed at 500mg 
Q4W and 400mg BID respectively, based on prior clinical trial data (INCMGA00012: 
NCT03059823). If a patient experiences toxicity, the next dose can be skipped to resolve 
the adverse event (see Section 6 for more details for the handling). The objective is not to 
compare the two regimens but to evaluate efficacy and safety of the two treatment regimens 
in parallel and to compare the efficacy of each regimen to historical controls.  
 
To ensure patient safety in both regimens, we will perform continuous monitoring of 
intolerable toxicities.  “Intolerable toxicity” is defined as grade 4 or higher dermatological 
or grade 3 or higher non-dermatological adverse events as graded by CTCAE version 5.0 
that cannot be resolved within a week and are considered at least possibly related to study 
treatment. Patients enrolled to Regimen A will follow the toxicity monitoring described in 
Section 15.2.  Enrollment to Regimen A will stop if the boundary “b” is crossed. Thus, 
Regimen A will be discontinued in a timely fashion should any excessive intolerable 
toxicity occur in Regimen A.  See details on criteria for evaluability and the stopping 
boundary in Section 15.2. 
 
Enrollment to Regimen B will begin when the first 23 (of a total 24) patients have been 
enrolled to Regimen A, received a cycle of treatment, completed the evaluation period for 
intolerable toxicity, and not exceeded the boundary “b” as specified in the table of Section 

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15.2 (i.e., 10 or fewer patients among the first 23 patients enrolled to Regimen A experience 
intolerable toxicities). Once enrollment to Regimen B starts, we will use the same table to 
monitor toxicity in patients enrolled to Regimen B.  See details on criteria for evaluability 
and the stopping boundary in Section 15.2. 
 
15.2 
Early Stopping Rules for Continuous Toxicity Monitoring 
 
“Intolerable toxicity” is defined as grade 4 or higher dermatological or grade 3 or higher 
non-dermatological adverse events as graded by CTCAE version 5.0 that cannot be 
resolved within a week and are considered at least possibly related to study treatment.  
Intolerable toxicity will be separately monitored for each regimen. Patients must receive at 
least one dose of study treatment to be evaluable for intolerable toxicities. Toxicity 
evaluations for “intolerable toxicity” will take place in each patient in both regimens from 
first dose of study treatment until 28 days after last dose of Cycle 2 treatment; for patients 
enrolled in Regimen A, this is Cycle 3 Day 1 (28 days after the C2D1 dose of  retifanlimab) 
and for patients enrolled in Regimen B, this is Cycle 3 Day 28 (28 days after the C2D28 
dose of epacadostat).    If a patient decides to drop out of the study during the first cycle 
for reasons other than treatment-related toxicity, the patient is not evaluable for intolerable 
toxicities and will be replaced. 
 
Intolerable toxicity will be routinely monitored after three patients are treated on a regimen, 
using a Bayesian Binomial-beta hierarchical model as implemented in Multc Clean 
(version2.1.0). The trial will stop if there is more than 0.9 likelihood that the estimated rate 
of intolerable toxicities (𝜃) is above 0.3, i.e., Pr(𝜃≥0.3) > 0.9 with the specific 
boundaries (b) out of total number of patients treated (n) detailed in the table below. 
 
n 
b  
# of patients (inclusive) 
stop the trial if the # patients with toxicities >= b 
(inclusive) 
3 
2-3 
4-5 
3-5 
6-8 
4-8 
9-10 
5-10 
11-13 
6-13 
14-15 
7-15 
16-18 
8-18 
19-21 
9-21 
22-23 
10-23 
24 
always stop with this many patients 
 
Specifically, the trial will stop if 2 out of the first 3 patients, or 3 out of the first 5 patients, 
4 out of the first 6 patients, 5 out of the first 9 patients, 6 out of the first 11 patients, 7 out 
of the first 14 patients, 8 out of the first 16 patients, 9 out of the first 19 patients, 10 out of 
the first 22 patients are observed to experience intolerable toxicities.  
 

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Accrual will be paused and the event will be reviewed by the PI and study statistician, with 
possible referral to the Data Safety and Monitoring Board, if a grade 5 toxicity (non-
hematological, non-dermatologic, non-progression)  is observed within 30 days of the last 
dose of INCGMA00012, bevacizumab, or epacadostat (whichever is latest). 
 
Additionally, the study will be suspended or possibly stopped prematurely for any of the 
following reasons: 
 
1. A death that is unexpected and at least probably related to epacadostat, or to the 
combination of radiotherapy,  retifanlimab and epacadostat. 
2. Anaphylactic reaction to epacadostat. 
3. Any events that, in the judgment of the medical monitor, are at least probably 
related to epacadostat and are deemed serious enough to warrant immediate review 
by the data safety monitoring panel. This may include any symptomatic and/or 
irreversible treatment-related grade 4 pneumonitis, colitis, dermatitis, or hepatitis 
or any symptomatic treatment-related related grade ≥ 3 neurological toxicity or 
uveitis. 
4. Any other safety finding assessed as related to epacadostat or its respective 
combinations with radiotherapy or anti-PD-1 agent that, in the opinion of the 
internal data safety monitoring panel, contraindicates further dosing of study 
subjects. 
 
15.3 
Endpoints 
 
The primary endpoint of phase II trials for both regimen A and B is overall survival (OS). 
Overall survival is defined as the time interval from date of treatment start to date of first 
documented death event (death due to any cause) or date of censoring. If a patient has not 
had an event, OS will be censored at the date of last follow up. The secondary endpoints 
of phase II include progression-free survival (PFS), as defined from date of treatment start 
to date of progression of the disease or death to any cause . Patients who do not have disease 
progression and have not died will be censored at the date of last disease assessment. 
 
15.4 
Sample Size Justification 
 
For the phase II trials, a total of 24 efficacy evaluable patients will be enrolled for each of 
regimen A and B, as justified below 
 
The 9-month OS probability estimated from the Kaplan-Meier method of Bevacizumab 
naïve recurrent grade 4 glioma patients treated with bevacizumab alone is 38 %, based on 
the 2014 BELOB study [45]. An increase of the 9-month OS from 38% to 60% in this 
regimen is considered clinically relevant and warrants further investigation of regimen A 
and regimen B. Assuming an enrollment period of 18 months and a total duration of 30 
months, based on a one-sided one-sample log rank test at a 0.1 alpha level, a total of 24 
patients with 16 events at the end of study provides 89.09% power to test a favorable 9-
month OS ≥60% against an unfavorable 9-month OS ≤38% in this regimen, corresponding 
to a hazard ratio of 0.528. (58, 59) In the event of slower than anticipated accrual, we will 

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extend the accrual period. The sample size was calculated under the assumption of 
exponential survival distribution using PASS (version 15.0.5). 
15.5 
Statistical Analysis 
 
The two regimens will be analyzed separately. All data will be evaluated as observed, and 
no imputation method for missing values will be used. Descriptive statistics will be used 
to summarize the trial results, i.e., statistics for continuous variables may include mean, 
median, range and appropriate measures of variability such as standard deviation and inter-
quartile range. Qualitative variables will be summarized by counts and percentages. The 
uncertainty of estimates will be assessed by confidence intervals.  
 
PFS and OS will be separately analyzed using the Kaplan-Meier (KM) method to estimate 
the empirical survival probabilities. Median PFS and OS and OS and PFS probability at 9 
month will be estimated with 90% confidence interval from KM analyses. In consideration 
that MGMT methylated and/or IDH mutated patients exhibit better survival, MGMT 
promoter methylation and IDH mutation status adjusted KM curves and hazard ratio will 
be generated. Cox proportional hazard model will be used to estimate hazard ratio of a risk 
factor of interest (but not treatment since single arm) without and with adjustment for 
patient characteristics.  
 
Safety is assessed through summaries of AEs, changes in laboratory test results, changes 
in vital signs, physical examination findings, changes in KPS, and changes in cardiac 
ejection fraction results. AEs will be classified by system organ class (SOC) and preferred 
term using the Medical Dictionary for Regulatory Activities (MedDRA); AE severities will 
be classified using the CTCAE criteria Version 5.0. All the safety data will be summarized 
as appropriate by descriptive statistics (mean, median, standard deviation etc for 
continuous and count/percentages for categorical variables), by grade, relationship to study 
drugs, patient characteristics within each regimen.  
 
Neurologic function scores using the NANO scale will be summarized by descriptive 
statistics including mean, median, standard deviation, inter-quartile range and range for 
each regimen at each time point. Within regimen, the scores will be compared between two 
time points by Wilcoxon signed rank test or paired-sample t test.  
 
For correlative studies, to assess predictive, prognostic, and pharmacodynamic exploratory 
biomarkers in archival and/or fresh tumor tissue and blood and their association with 
disease status and/or response to study treatment, logistic regression or Cox proportional 
hazard model will be used. Paired t-test will be used to compare the anti-glioma immune 
response before and after. All analyses and estimates will be conducted among all patients 
overall, as well as by subgroups of interest.   
 
15.6 
Populations for Analysis 
 
 All Enrolled Subjects Analysis Set:  this analysis set contains all subjects who signed 
an informed consent for the study 
 Safety/toxicity evaluable analysis set:  this analysis set contains all subjects who 

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receive any dose level of the drug combinations from the time of their first treatment. 
 Efficacy-Evaluable Subjects:  this analysis set contains all subjects who receive the 
study drug combinations of any of two regimens for at least 1 cycle.  
 
 
16.0 
MULTICENTER REGULATORY REQUIREMENTS 
 
Washington University requires that each participating site sends its informed consent document 
to be reviewed and approved by the Washington University Regulatory Coordinator (or designee) 
prior to IRB/IEC submission.    
 
Site activation is defined as when the secondary site has received official written documentation 
from the coordinating center that the site has been approved to begin enrollment.  At a minimum, 
each participating institution must have the following documents on file at Washington University 
prior to study activation: 
 Documentation of IRB approval of the study in the form of a letter or other official 
document from the participating institution’s IRB.  This documentation must show which 
version of the protocol was approved by the IRB. 
 Documentation of IRB approval of an informed consent form. The consent must include a 
statement that data will be shared with Washington University, including the Quality 
Assurance and Safety Monitoring Committee (QASMC), the DSMC (if applicable), and 
the Washington University study team. 
 Documentation of FWA, signed FDA Form 1572 (if applicable), and the CVs of all 
participating investigators. 
 Protocol signature page signed and dated by the investigator at each participating site. 
 
The coordinating center Principal Investigator (or designee) is responsible for disseminating to the 
participating sites all study updates, amendments, reportable adverse events, etc.  Protocol/consent 
modifications and IB updates will be forwarded electronically to the secondary sites within 4 
weeks of obtaining Washington University IRB approval.  Activated secondary sites are expected 
to submit protocol/consent/IB modifications to their local IRBs within 4 weeks of receipt unless 
otherwise noted.  Upon the secondary sites obtaining local IRB approval, documentation of such 
shall be sent to the Washington University study team within 2 weeks of receipt of approval.  
Secondary sites will also notify the Washington University study team of any regimen B subjects 
continuing on study past progression. 
 
Documentation of participating sites’ IRB approval of annual continuing reviews, protocol 
amendments or revisions, all SAE reports, and all protocol violations/deviations/exceptions must 
be kept on file at Washington University. 
 
The investigator or a designee from each institution must participate in a regular conference call 
to update and inform regarding the progress of the trial. 
 
 

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We would like to thank the Alvin J. Siteman Cancer Center at Washington University School of 
Medicine and Barnes-Jewish Hospital in St. Louis, Missouri, for the use of the Clinical Trials 
Core which provided protocol development services. The Siteman Cancer Center is supported in 
part by an NCI Cancer Center Support Grant #P30 CA91842. 
 
 
 

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APPENDIX A: Karnofsky Performance Scale 
 
Able to carry on normal activity and to work; no 
special care needed. 
  100   Normal no complaints; no evidence of 
disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
80 
Normal activity with effort; some 
signs or symptoms of disease.  
Unable to work; able to live at home and care for 
most personal needs; varying amount of 
assistance needed. 
70 
Cares for self; unable to carry on 
normal activity or to do active work. 
60 
Requires occasional assistance, but is 
able to care for most of his personal 
needs. 
50 
Requires considerable assistance and 
frequent medical care.  
Unable to care for self; requires equivalent of 
institutional or hospital care; disease may be 
progressing rapidly. 
40 
Disabled; requires special care and 
assistance. 
30 
Severely disabled; hospital admission 
is indicated although death not 
imminent. 
20 
Very sick; hospital admission 
necessary; active supportive treatment 
necessary. 
10 
Moribund; fatal processes progressing 
rapidly. 
0 
Dead 
 
 
 
 

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APPENDIX B: Patient’s Medication Diary 
Today’s Date:    
 
 
 
 
 
 
Agent:  Epacadostat 
 
Cycle:    
 
 
 
 
 
 
 
Study ID#:   
 
 
 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each month.  Take _____mg ( ___capsules) of epacadostat twice daily at 
approximately the same times each day.  Take it with a glass of water and drink the glass of 
water in as little time as possible.  Swallow the capsules whole and do not chew the capsules.   
2. Record the date, the number of capsules taken, and when you took them. 
3. If you forget to take a dose within 4 hours of your regular time, then do not take that dose.  
Restart taking it with the next scheduled dose. 
4. If you have any questions or notice any side effects, please record them in the comments section.  
Record the time if you should vomit. 
5. Please return the forms to your physician or your study coordinator when you go to your next 
appointment.  Please bring your unused study medications and/or empty bottles with you to each 
clinic visit so that a pill count can be done. 
Day 
Date 
What time was dose taken? 
# of tablets taken 
Comments 
AM dose 
PM dose 
AM dose 
PM dose 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
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APPENDIX C: NANO Scale 
 
 
 
 

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APPENDIX D: Definitions for Adverse Event Reporting 
 
A. Adverse Events (AEs) 
 
As defined in 21 CFR 312.32: 
 
Definition: any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug-related. 
 
Grading: the descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting.  A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the terms 
listed that should be used are those provided by the Department of Health and Human Services’ 
Office for Human Research Protections (OHRP).  A copy of this guidance can be found on 
OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
B. Suspected Adverse Reaction (SAR) 
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse event for which there is a reasonable possibility that the drug caused 
the adverse event.  “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event.  “Suspected adverse reaction” implies a 
lesser degree of certainty about causality than adverse reaction, which means any adverse event 
caused by a drug. 
 
C. Life-Threatening Adverse Event / Life Threatening Suspected Adverse Reaction  
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse drug event or suspected adverse reaction is considered “life-
threatening” if, in the view of the investigator, its occurrence places the patient at immediate 
risk of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 
 
D.  Serious Adverse Event (SAE) or Serious Suspected Adverse Reaction 
 
As defined in 21 CFR 312.32: 
 
Definition:  an adverse event or suspected adverse reaction is considered “serious” if, in the 
view of the investigator, it results in any of the following outcomes: 
o Death 
o A life-threatening adverse event 

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o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
o A congenital anomaly/birth defect 
o Any other important medical event that does not fit the criteria above but, based upon 
appropriate medical judgment, may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above 
 
E. Protocol Exceptions 
 
Definition: A planned change in the conduct of the research for one participant. 
 
F. Deviation 
 
Definition: Any alteration or modification to the IRB-approved research without prospective 
IRB approval.  The term “research” encompasses all IRB-approved materials and documents 
including the detailed protocol, IRB application, consent form, recruitment materials, 
questionnaires/data collection forms, and any other information relating to the research study. 
 
A minor or administrative deviation is one that does not have the potential to negatively impact 
the rights, safety, or welfare of participants or others or the scientific validity of the study. 
 
A major deviation is one that does have the potential to negatively impact the rights, safety, or 
welfare of participants or others or the scientific validity of the study. 
 

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APPENDIX E: Reporting Timelines 
 
Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Incyte 
Serious AND 
unexpected suspected 
adverse reaction 
 
 
Report no later than 15 calendar 
days after it is determined that the 
information qualifies for reporting 
 
Unexpected fatal or 
life-threatening 
suspected adverse 
reaction 
 
 
Report no later than 7 calendar days 
after initial receipt of the 
information 
 
Unanticipated 
problem involving risk 
to participants or 
others 
Report within 10 working days.  If the event 
results in the death of a participant enrolled 
at WU/BJH/SLCH, report within 1 working 
day. 
Report via email after 
IRB acknowledgment 
 
 
Serious adverse events 
 
 
 
Report within 24 hours of 
learning of the event 
regardless of causality. 
Major deviation 
Report within 10 working days.  If the event 
results in the death of a participant enrolled 
at WU/BJH/SLCH, report within 1 working 
day. 
 
 
 
A series of minor 
deviations that are 
being reported as a 
continuing 
noncompliance 
Report within 10 working days.   
 
 
 
Pregnancy 
 
 
 
Report within 24 hours of 
discovery 
Protocol exception 
Approval must be obtained prior to 
implementing the change 
 
 
 
Clinically important 
increase in the rate of 
a serious suspected 
adverse reaction of 
 
 
Report no later than 15 calendar 
days after it is determined that the 
information qualifies for reporting 
 

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Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Incyte 
that list in the protocol 
or IB 
Complaints 
If the complaint reveals an unanticipated 
problem involving risks to participants or 
others OR noncompliance, report within 10 
working days.  If the event results in the 
death of a participant enrolled at 
WU/BJH/SLCH, report within 1 working 
day.  Otherwise, report at the time of 
continuing review. 
 
 
 
Breach of 
confidentiality 
Within 10 working days. 
 
 
 
Incarceration 
If withdrawing the participant poses a safety 
issue, report within 10 working days.   
 
If withdrawing the participant does not 
represent a safety issue and the patient will 
be withdrawn, report at continuing review. 
 
 
 
 
Routine Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Incyte 
Adverse event or SAE 
that does not require 
expedited reporting 
If they do not meet the definition of an 
unanticipated problem involving risks to 
participants or others, report summary 
information at the time of continuing review 
Adverse events will be 
reported in the toxicity 
table in the DSM report 
which is typically due 
every 6 months. 
The most current 
toxicity table from the 
DSM report is provided 
to the FDA with the 
IND’s annual report. 
 
Minor deviation 
Report summary information at the time of 
continuing review. 
 
 
 
Complaints 
If the complaint reveals an unanticipated problem 
involving risks to participants or others OR 
noncompliance, report within 10 working days.  If 
the event results in the death of a participant 
enrolled at WU/BJH/SLCH, report within 1 
 
 
 

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Routine Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Incyte 
working day.  Otherwise, report at the time of 
continuing review. 
Incarceration 
If withdrawing the participant poses a safety 
issue, report within 10 working days.   
 
If withdrawing the participant does not represent a 
safety issue and the patient will be withdrawn, 
report at continuing review. 
 
 
 
 
Expedited Reporting Timelines for Secondary Sites 
Event 
WU (Coordinating Center) 
Local IRB 
FDA 
Incyte 
Serious AND unexpected 
suspected adverse reaction 
Report no later than 11 calendar days 
after it is determined that the information 
qualifies for reporting. 
Report all applicable 
events to local IRB 
according to local 
institutional guidelines. 
The research team at 
Washington University is 
responsible for reporting all 
applicable events to the 
FDA as needed. 
The research team at 
Washington University is 
responsible for reporting all 
applicable events to Incyte as 
needed. 
Unexpected fatal or life-
threatening suspected 
adverse reaction 
Report no later than 4 calendar days after 
initial receipt of the information. 
Unanticipated problem 
involving risk to participants 
or others 
Report no later than 4 calendar days after 
initial receipt of the information. 
Adverse event or SAE that 
does not require expedited 
reporting 
As per routine data entry expectations 
Protocol exception 
Approval must be obtained prior to 
implementing the change. 
 
 
 

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APPENDIX F: Washington University Unanticipated Problem Reporting Cover Sheet 
 
SAE COVER SHEET- Secondary Site Assessment 
 
Washington University HRPO#:  
Sponsor-Investigator:  
Subject Initials:   
Subject ID:  
Treating MD:  
Treating Site:  
EVENT TERM:  
Admission Date:  
EVENT GRADE: 
Date of site’s first notification: 
 
Treating MD Event Assessment:  
 
 
Is this event possibly, probably, or definitely related study treatment? 
 
 yes  
 
 no 
 
If yes, please list which drug (if more than one)______________________________ 
 
       
Explain ______________________________________________________________________ 
 
______________________________________________________________________________ 
 
 
 
_________________________           ___________________________      _________________  
Physician’s Name 
 
 
Physician’s Signature 
 
Date