A Phase II Study of the Anti-GITR Agonist INCAGN1876 and the PD-1 Inhibitor INCMGA00012 in Combination With Stereotactic Radiosurgery in Recurrent Glioblastoma
Phase: PHASE2
Conditions: Glioblastoma
Sponsor: University of Pennsylvania

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A PHASE II STUDY OF THE ANTI-GITR AGONIST INCAGN01876 AND THE PD-1 
INHIBITOR INCMGA00012 IN COMBINATION WITH STEREOTACTIC 
RADIOSURGERY IN RECURRENT GLIOBLASTOMA  
 
 
Principal Investigator 
 
 
 
 
 
 
 
Radiation Oncology  
Lead Investigator 
 
Stephen J. Bagley, MD, MSCE 
Department of Medicine, Division of Hematology/Oncology 
Perelman Center for Advanced Medicine  
3400 Civic Center Blvd 
Philadelphia, PA 19104 
215-614-1858 
Sbagley@pennmedicine.upenn.edu 
 
 
Department of Radiation Oncology  
Perelman Center for Advanced Medicine  
3400 Civic Center Blvd 
Philadelphia, PA 19104 
215-615-2255 
 
Regulatory Sponsor  
 
University of Pennsylvania 
3400 Spruce Street 
Philadelphia, PA 19104 
Medical Director 
 
Biostatistician 
 
 
Investigational Products: 
 
INCAGN01876 
INCMGA00012 
IRB Number: 
 
Other protocol Identifiers: 
834197 
 
 
IND Number: 
 
 
ClinicalTrials.gov Number:        NCT04225039 
Protocol version: 
Version 6.0, 28 October 2021 
  
 
The study will be conducted according to the protocol and in compliance with Good Clinical 
Practice (GCP), with the Declaration of Helsinki, and with other applicable regulatory 
requirements including but not limited to Institutional Review Board/Ethics Committee (IRB/EC) 
approval. 
 

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Confidentiality Statement 
All information contained in this document is privileged and confidential. Any distribution, 
copying, or disclosure is strictly prohibited without prior written approval by the Sponsor. 
 
 

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List of Abbreviations 
 
ADP: adenosine diphosphate 
 
AE: Adverse event 
 
AESI: Adverse event of special interest  
 
AIDS: Acquired immunodeficiency syndrome  
 
ALP: alkaline phosphatase  
 
ALT: Alanine aminotransferase  
 
ART: Antiretroviral therapy  
 
AST: Aspartate aminotransferase  
 
AUC: Area under the curve 
 
BID: twice daily  
 
C: Celsius 
 
CBC: Complete blood count 
 
CL: Plasma clearance  
 
CLcr: Creatinine clearance  
 
CLIA: Clinical Laboratory Improvement Amendments  
 
Cmax: mean peak observed concentration 
  
CNS: Central Nervous System  
 
CR: Complete response  
 
CRF: Case report form  
 
CT: Computed tomography 
 
CTCAE: Common Terminology Criteria for Adverse Events 
 
CV: Coefficient of variation  
 
CYP: Cytochrome P450 
 

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DLT: Dose-limiting toxicity  
 
DNA: Deoxyribonucleic acid 
 
ECOG: Eastern Cooperative Oncology Group  
 
eCRF: electronic case report form  
 
EOT: end of treatment  
 
FDA: Food and Drug Administration 
 
FE: Food effect 
 
FFPE: Formalin-fixed paraffin-embedded  
 
FLAIR: fluid attenuation inversion recovery  
 
GBM: Glioblastoma  
 
GSCF: Granulocyte-colony stimulating factor 
 
GGT: gamma-glutamyl transferase  
 
GI: Gastrointestinal  
 
GITR: Glucocorticoid-induced TNFR family related protein 
 
GLP: Good Laboratory Practice  
 
Gy: Gray  
 
h: hour 
 
HBV: Hepatitis B virus 
 
HCV: Hepatitis C virus  
 
HCG: Human chorionic gonadotropin 
 
hfRT: hypofractionated radiotherapy  
 
Hgb: Hemoglobin 
 
HIV: Human immunodeficiency virus  
 
IB: Investigator’s brochure  
 

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ICHL International Conference for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
 
IDH: Isocitrate dehydrogenase 
 
IHC: immunohistochemistry  
 
IMRT: Intensity-modulated radiation therapy  
 
INR: International normalized ratio  
 
IRB: institutional review board  
 
IU: International Units  
 
IUD: intrauterine device  
 
IV: Intravenous (ly) 
 
kDa: kilodaltons 
 
Kg: Kilograms  
 
L: liter 
 
LDH: Lactate dehydrogenase  
 
LFTs: liver function tests  
 
Mg: Milligrams  
 
MGMT: O6-Methylguanine-methyltransferase 
 
mL: milliliter  
 
mM: millimolar 
 
mRANO: modified Response Assessment in Neuro-Oncology Criteria 
 
MRI: Magnetic Resonance Imaging 
 
MTD: maximal tolerated dose  
 
NA: Not available  
 
NOAEL: no-observed-adverse-effect-level  
 
ORR: Objective response rate  

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OS: Overall survival  
 
PAD: pharmacologically active dose  
 
PCR: polymerase chain reaction  
 
PD: Progressive disease  
 
PD-1: programmed cell death protein 1 
 
PD-L1: programmed death-ligand 1 
 
PFS: Progression-free survival  
 
PFS-6mo: Progression-free survival rate at 6 months  
 
P-gp: p-glycoprotein 
 
PK: Pharmacokinetic (s)  
 
PR: Partial response  
 
PRO: Patient reported outcomes 
 
PS: Performance status  
 
PT: Prothrombin time 
 
PTT: Partial thromboplastin time  
 
QD: once a day 
 
Qtc: corrected QT interval  
 
RANO:  Response Assessment in Neuro-Oncology Criteria  
 
RNA seq: Ribonucleic acid sequencing  
 
RT: Radiation therapy  
 
SAE: Serious adverse event  
 
SD: Stable disease  
 
SMC: safety monitoring committee  
 
SRS: stereotactic radiosurgery 

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T1/2: half-life 
 
TEAS: treatment emergent adverse events 
 
TK: toxicokinetic 
 
TMZ: Temozolomide  
 
TRAE: treatment related adverse event 
 
TTFields: Tumor-treating fields  
 
UADE: Unanticipated Adverse Device Experience 
 
ULN: upper limit of normal  
 
VEGF: Vascular endothelial growth factor  
 
Vss: volume of distribution at steady-state  
 
WHO: World Health Organization  
 
WOCBP: Women of child bearing potential  
 
WT: Body weight  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
TABLE OF CONTENTS .......................................................................................................................... 8 
STUDY SYNOPSIS.............................................................................................................................. 12 
1 BACKGROUND............................................................................................................................... 17 
1.1 INTRODUCTION ..................................................................................................................................... 17 
1.2 DISEASE BACKGROUND ........................................................................................................................... 17 
1.3 NAME AND DESCRIPTION OF INVESTIGATIONAL DRUGS ................................................................................ 18 
1.3.1. INCMGA00012 .......................................................................................................................... 18 
1.3.1.1. Nonclinical data .................................................................................................................................................. 18 
1.3.1.2. Clinical Experience ............................................................................................................................................. 19 
1.3.1.3. Potential Risks of INCMGA00012 ....................................................................................................................... 22 
1.3.2 INCAGN01876 ............................................................................................................................ 23 
1.3.2.1. Nonclinical data .................................................................................................................................................. 24 
1.3.2.2. Clinical Experience ............................................................................................................................................. 24 
1.3.2.3. Potential Risks of INCAGN01876 ........................................................................................................................ 27 
1.4 STUDY RATIONALE ................................................................................................................................. 28 
1.5 DOSE AND SCHEDULE RATIONALE ............................................................................................................. 30 
1.5.1. Investigational drugs ................................................................................................................ 30 
1.5.2. Stereotactic Radiosurgery ........................................................................................................ 30 
2  STUDY OBJECTIVES AND ENDPOINTS ............................................................................................ 31 
2.1. STUDY OBJECTIVES ............................................................................................................................... 31 
2.1.1. Primary Objective: .................................................................................................................... 31 
2.1.2. Secondary Objectives: .............................................................................................................. 31 
2.1.3. Exploratory Objectives:............................................................................................................. 31 
2.2. STUDY ENDPOINTS................................................................................................................................ 32 
2.2.1. Primary Endpoint: ..................................................................................................................... 32 
2.2.2. Secondary Endpoints: ............................................................................................................... 32 
2.2.3 Exploratory Endpoints: .............................................................................................................. 32 
3   INVESTIGATIONAL PLAN .............................................................................................................. 32 
3.1. GENERAL DESIGN ................................................................................................................................. 32 
3.1.1. Screening Phase ........................................................................................................................ 33 
3.1.2. Study Intervention Phase .......................................................................................................... 34 
3.1.3. Follow Up Phase ....................................................................................................................... 35 
3.1.3.1. Safety Follow-Up ................................................................................................................................................ 35 
3.1.3.2. Disease Status Follow-Up ................................................................................................................................... 36 
3.1.3.3. Survival Follow-Up ............................................................................................................................................. 36 
3.2 REPLACEMENT OF SUBJECTS .................................................................................................................... 36 
3.3. DURATION OF INDIVIDUAL SUBJECT STUDY PARTICIPATION ......................................................................... 38 
3.4. OVERALL STUDY DURATION ................................................................................................................... 38 
3.5 TOTAL NUMBER OF SUBJECTS AND SITES ................................................................................................... 38 
4.  INCLUSION AND EXCLUSION CRITERIA ......................................................................................... 38 
4.1 INCLUSION CRITERIA .............................................................................................................................. 38 
4.2 EXCLUSION CRITERIA .............................................................................................................................. 41 
5 STUDY INTERVENTION ................................................................................................................... 42 
5.1 DESCRIPTION OF STUDY DRUGS ............................................................................................................... 43 
5.1.1. INCMGA00012 .......................................................................................................................... 43 
5.1.2. INCAGN01876 ........................................................................................................................... 43 

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5.2 RECEIPT OF INVESTIGATIONAL AGENTS ...................................................................................................... 43 
5.3 STORAGE OF STUDY PRODUCTS ................................................................................................................ 43 
5.3.1. INCMGA00012 .......................................................................................................................... 43 
5.3.2. INCMGA01876 .......................................................................................................................... 43 
5.4 STUDY DRUG ACCOUNTABILITY ................................................................................................................ 44 
5.5 STUDY DRUG ADMINISTRATION................................................................................................................ 44 
5.5.1 Administration of INCMGA00012 .............................................................................................. 44 
5.5.2 Administration of INCAGN01876............................................................................................... 44 
5.6 CONCOMITANT MEDICATIONS: ................................................................................................................ 45 
5.7 STUDY DRUG DISCONTINUATION CRITERIA ................................................................................................ 45 
5.8 MANAGEMENT OF STUDY DRUG TOXICITIES............................................................................................... 47 
5.8.1. Supportive care for Immune-Related Adverse Events (irAEs) ................................................... 47 
5.8.2. Management of infusion-related reactions ............................................................................. 48 
5.8.3. Management of cerebral edema .............................................................................................. 49 
5.9 DISPOSAL OF INVESTIGATIONAL PRODUCTS ................................................................................................ 49 
5.10 SURGICAL RESECTION (COHORT B ONLY) ................................................................................................. 49 
5.11 RADIATION PLANNING AND DELIVERY (COHORT A; COHORT B, SUB-ARM #1 ONLY) ....................................... 49 
6    STUDY PROCEDURES ................................................................................................................... 51 
6.1 UNSCHEDULED VISITS ............................................................................................................................ 61 
6.2. SUBJECT WITHDRAWAL FROM THE STUDY ................................................................................................ 61 
7   STUDY EVALUATIONS AND MEASUREMENTS ................................................................................ 61 
7.1 DEMOGRAPHIC AND MEDICAL RECORD REVIEW ......................................................................................... 61 
7.2   PHYSICAL ASSESSMENT ......................................................................................................................... 62 
7.3 VITAL SIGNS ......................................................................................................................................... 62 
7.4 ELECTROCARDIOGRAM (ECG) ................................................................................................................. 63 
7.5 CLINICAL LABORATORY EVALUATIONS ....................................................................................................... 63 
7.6 PREGNANCY TESTING ............................................................................................................................. 63 
7.7 EFFICACY EVALUATIONS .......................................................................................................................... 64 
7.7.1. Anti-Tumor Effect Definitions ................................................................................................... 64 
7.7.2. Response/Progression Categories ............................................................................................ 64 
7.7.3.  Study continuation beyond initial progressive disease ........................................................... 66 
7.7.4. MRI Procedures ........................................................................................................................ 67 
7.8 SAFETY ASSESSMENTS ............................................................................................................................ 68 
7.9 TISSUE/BLOOD COLLECTION FOR CORRELATIVE ANALYSES, PK, AND ADA ....................................................... 68 
7.10 PROTOCOL EXCEPTIONS (PROSPECTIVE ACTION) ........................................................................................ 69 
7.11 PROTOCOL DEVIATIONS (RETROSPECTIVE ACTION) .................................................................................... 69 
8   STATISTICAL PLAN ....................................................................................................................... 70 
8.1 DEFINITION OF PRIMARY ENDPOINT ......................................................................................................... 70 
8.2 STATISTICAL METHODS ........................................................................................................................... 70 
8.2.1 Primary Endpoint Analysis (Efficacy of Regimen) ...................................................................... 70 
8.2.2 Analysis of Secondary and Exploratory endpoints .................................................................... 71 
9    SAFETY AND ADVERSE EVENTS .................................................................................................... 72 
9.1 DEFINITIONS ......................................................................................................................................... 72 
9.1.1. Adverse Event ........................................................................................................................... 72 
9.1.2 Immune-Related Adverse Events ............................................................................................... 72 
9.1.3 Serious Adverse Events .............................................................................................................. 73 
9.1.4 Unanticipated problem ............................................................................................................. 73 
9.2 COLLECTING AND RECORDING OF ADVERSE EVENTS ..................................................................................... 74 

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9.3 REPORTING OF ADVERSE EVENTS ............................................................................................................. 75 
9.3.1 Follow-up reporting for SAEs ..................................................................................................... 75 
9.3.2 Investigator Reporting: Notifying the Study Sponsor ................................................................ 75 
9.3.3 Investigator Reporting: Notifying the Penn IRB ........................................................................ 75 
9.3.4 Reporting to Incyte .................................................................................................................... 75 
9.4 SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS (SUSARS) .............................................................. 76 
9.5   REPORTING PRODUCT COMPLAINTS FOR INCMGA00012 AND INCAGN01876 .......................................... 76 
9.6   PREGNANCY ........................................................................................................................................ 76 
9.7 SPECIAL SITUATIONS: MISUSE, MEDICATION ERRORS, OVERDOSE, AND ACCIDENTAL OR OCCUPATIONAL EXPOSURE
 ................................................................................................................................................................ 77 
10 STUDY ADMINISTRATION, DATA HANDLING, AND RECORD KEEPING ............................................ 77 
10.1 CONFIDENTIALITY ................................................................................................................................ 78 
10.2 DATA COLLECTION AND MANAGEMENT .................................................................................................. 78 
10.3. RECORDS RETENTION .......................................................................................................................... 78 
11 STUDY MONITORING, AUDITING, AND INSPECTING ...................................................................... 79 
11.1 STUDY MONITORING PLAN ................................................................................................................... 79 
11.2 AUDITING AND INSPECTING ................................................................................................................... 79 
12   ETHICAL CONSIDERATIONS ........................................................................................................ 79 
12.1 RISKS ................................................................................................................................................. 79 
12.2 BENEFITS ........................................................................................................................................... 79 
12.3 RISK BENEFIT ASSESSMENT ................................................................................................................... 80 
12.4 INFORMED CONSENT PROCESS/HIPAA AUTHORIZATION ........................................................................... 80 
13   STUDY FINANCES ....................................................................................................................... 81 
13.1 FUNDING SOURCE ............................................................................................................................... 81 
13.2 CONFLICT OF INTEREST ......................................................................................................................... 81 
14   PUBLICATION PLAN ................................................................................................................... 81 
15   REFERENCES (ALPHABETICAL ORDER) ......................................................................................... 82 
APPENDIX 1. MANAGEMENT GUIDELINES FOR IMMUNE-RELATED ADVERSE EVENTS (IRAES)* ........... 87 
 
 
Table of Tables 
Table 1. Treatment-emergent AEs occurring >=10% of patients in INCMGA0012-101 by tumor type and 
dosage ......................................................................................................................................................... 20 
Table 2. INCMGA00012 Monotherapy: Summary of Frequent (≥ 5%) Treatment-Emergent Adverse 
Events (Safety Population; N = 199) ........................................................................................................... 21 
Table 3. Adverse Events of Special Interest Occurring in Participants in Study INCMGA 0012-   101 (Safety 
Population) .................................................................................................................................................. 22 
Table 4. Study INCAGN 1876-101 (Part 1): Summary of treatment-emergent adverse events occurring in 
>10% of participants ................................................................................................................................... 25 
Table 5. Study INCAGN 1876-101 (Part 2): Summary of treatment-emergent adverse events occurring in 
>10% of participants ................................................................................................................................... 26 
Table 6. Study INCAGN 1876-201: Summary of treatment-emergent adverse events occurring in >5% of 
participants receiving INCAGN01876 in combination with nivolumab ...................................................... 27 
Table 7. Radiation Guidelines ..................................................................................................................... 50 
Table 8: COHORT A (N=16): Schedule of Study Procedures, SCREENING AND INTERVENTION ................. 52 
Table 9: COHORT B (N=16): Schedule of Study Procedures, SCREENING AND INTERVENTION ................. 55 

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Table 10: Schedule of study procedures, FOLLOW-UP ............................................................................... 60 
Table 11. KARNOFSKY PS ............................................................................................................................ 62 
Table 12: Clinical Laboratory Tests ............................................................................................................. 63 
Table 13. Summary of the RANO response Criteria: .................................................................................. 65 
Table 14: CTCAE version 5.0 for assessment of the severity of AEs ........................................................... 72 
 
Table of Figures 
Figure 1 Human GBM samples from The Cancer Genome Atlas, T cell cytolytic activity (gene 
expression signature comprised of GZMA and PRF1 expression) is closely correlated with GITR 
mRNA expression, suggesting that GITR agonism would further increase the effector function 29 
Figure 2 Survival curves of MC38 tumor-bearing mice treated with anti-GITR and/or anti-PD1 
mAb treatment ............................................................................................................................. 29 
Figure 3 Survival curves of GL261 tumor-bearing mice treated with anti-GITR therapy, SRS, or 
the combination ............................................................................................................................ 30 
Figure 4 Anti-GITR combination therapy with anti-PD1 and XRT in 344SQ resistant tumors 
increases overall survival and promotes abscopal effects ........................................................... 30 
 

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 Study Synopsis 
 
Title: 
A PHASE II STUDY OF THE ANTI-GITR AGONIST INCAGN01876 
AND THE PD-1 INHIBITOR INCMGA00012 IN COMBINATION 
WITH STEREOTACTIC RADIOSURGERY IN RECURRENT 
GLIOBLASTOMA 
 
Short title: 
 
GITR/PD1/SRS in GBM 
 
IRB# and other  
Penn IRB # 834197 
Identifiers:   
 
 
Study Center: 
Single center: University of Pennsylvania 
 
Study Rationale: 
Glioblastoma (GBM) is the most common primary malignant brain tumor 
in adults and is near uniformly fatal. Effective treatment options for 
recurrent disease remain elusive.  GBM is characterized by a severely 
immunosuppressive tumor microenvironment and a paucity of 
intratumoral T cells. Combined inhibition of programmed death ligand 1 
(PD-L1) and glucocorticoid-induced TNFR-related protein (GITR) 
augments the anti-tumor immune response in tumor-bearing mice, leading 
to durable responses, improved survival, and the development of T cells 
with a memory phenotype. In addition, preclinical data suggest that 
hypofractionated radiation using stereotactic radiosurgery (SRS) has 
immunostimulatory effects on the tumor immune microenvironment, 
potentially converting an immunologically “cold” tumor to “hot”. 
 
The following protocol is a phase II study of the combination of the GITR 
agonist monoclonal antibody INCAGN01876, the anti-PD1 monoclonal 
antibody INCMGA00012, and SRS for recurrent GBM.  We hypothesize 
that the proposed regimen will be safe and stimulate a robust anti-tumor 
immune response and result in improved tumor responses. 
 
Investigational 
Products 
1. INCAGN01876 (anti-GITR) 300mg IV every 2 weeks until disease 
progression, unacceptable toxicity, or 2 years, whichever occurs first 
 
2. INCMGA00012 (anti-PD1) 500mg IV every 4 weeks until disease 
progression, unacceptable toxicity, or 2 years, whichever occurs first 
 
Treatment Plan: 
The study has 2 arms: 
Arm A (Cohort A) is a nonsurgical arm (N=16) that will serve as the 
primary study cohort and evaluated for the primary study endpoint.  
Subjects in this arm receive a single priming dose of both INCMGA00012 
and INCAGN01876 prior to stereotactic radiosurgery (SRS), then undergo 
SRS (8 Gy x 3 fractions). Following SRS, INCMGA00012 (IV every 4 
weeks) and INCAGN01876 (IV every 2 weeks) are resumed and 
continued until disease progression, unacceptable toxicity, or for 2 years, 
whichever occurs first. 

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Arm B (Cohort B) is a surgical arm (N=16) that will allow for evaluation 
of the effects on the tumor immune microenvironment of INCMGA00012, 
INCAGN01876, and SRS.  In order to be enrolled on this arm, subjects 
must have a clinical indication for surgical resection of the recurrent GBM 
tumor. Prior to planned surgical resection, subjects receive neoadjuvant 
immunotherapy (one of two possible combinations, as outlined below). 
Subjects then undergo surgery. Postoperatively, the immunotherapy 
combination of INCMGA00012 (IV every 4 weeks) and INCAGN01876 
(IV every 2 weeks) is resumed and continued until disease progression, 
unacceptable toxicity, or for 2 years, whichever occurs first. Subjects in 
the surgical arm with a focus of contrast-enhancing tumor that is amenable 
to SRS will be assigned to surgical sub-arm #1 of Cohort B (N=8). These 
subjects will receive neoadjuvant INCMGA00012 + INCAGN01876 + 
SRS.  All other subjects enrolled on Cohort B (N=8) are treated with 
neoadjvuant INCMGA00012 + INCAGN01876 (without SRS). 
Schema: 
 
 

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Objectives:   
Primary Objective: 
● To determine the efficacy of the combination of INCMGA00012, 
INCAGN01876, and SRS in recurrent GBM, as measured by the 
overall objective response rate (ORR)  
 
 
Secondary Objectives:  
●  To evaluate the safety and tolerability of the combination of 
INCMGA00012, INCAGN01876, and SRS in recurrent GBM 
● To determine the progression-free survival (PFS) and overall survival 
(OS) of patients with recurrent GBM treated with the combination of 
INCMGA00012, INCAGN01876, and SRS 
 
 
Exploratory Objectives:  
● To evaluate the biologic effect of the combination of INCMGA00012 
and INCAGN01876 on the GBM tumor immunemicroenvironment 
● To evaluate the biologic effect of the combination of INCMGA00012 
and INCAGN01876, with or without SRS, on the GBM tumor immune 
microenvironment 
● To evaluate the pharmacodynamic impact of the combination of 
INCMGA00012, INCAGN01876, and SRS on peripheral blood 
immune cell populations  
● To evaluate the pharmacokinetics (PK) of INCAGN01876 in patients 
with glioblastoma 
● To determine whether anti-drug antibodies (ADA) form against 
INCAGN01876 in patients with glioblastoma 
● To detect tumor and/or blood biomarkers associated with the outcomes 
of OS, PFS, and/or ORR in patients with recurrent GBM treated with 
the combination of INCMGA00012, INCAGN01876, and SRS 
 
Endpoints:  
Primary Endpoint: 
● Objective radiographic response (ORR), as measured by modified 
Response Assessment in Neuro-Oncology (RANO) criteria 
 
 
Secondary Endpoints: 
● Safety and tolerability will be assessed by monitoring frequency, 
duration, and severity of adverse events (AEs) through physical 
examinations, by evaluating changes in vital signs, and through 
clinical laboratory evaluations.   
● OS, defined as the time from date of enrollment until death from any 
cause PFS, defined as the time from date of enrollment until the 
earliest date of disease progression (as determined by modified RANO 
criteria) or death due to any cause  
 
 
Exploratory Endpoints: 
● Comparison of the following immunocorrelative assays in subjects 
treated with INCMGA00012 + INCAGN01876, with or without SRS: 
○ Multiplex immunohistochemistry on tumor tissue for CD4/8 T cell 
infiltration, Foxp3+ Treg infiltration, and PD-1/PD-L1 expression 

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○ Tumor cell and immune cell GITR expression by a validated
 
immunohistochemistry stain  
○ Flow cytometry/mass cytometry in tumor tissue and peripheral 
blood for T cell and monocyte phenotyping  
○ RNA-Seq on tumor tissue for PD-1/PD-L1 and GITR expression, 
T cell- and interferon-γ-related gene expression, and cell-cycle-
related gene expression 
○ T cell receptor sequencing in tumor tissue and peripheral blood for 
assessment of TCR clonal diversity 
● Association between the above tumor tissue and peripheral blood-
based markers of immune activation, tumor genetic mutations, and 
clinical outcomes of OS, PFS, and ORR 
● PK parameters for INCAGN01876 in patients with glioblastoma 
● Detection of anti-drug antibodies (ADA) against INCAGN01876 
 
Sample Size, Power, 
Statistical Analysis: The total sample size for this trial is 32 subjects.  
● 16 subjects will comprise the non-surgical arm, Cohort A, which 
serves as the cohort for the primary study endpoint analysis (subjects 
do not have clinical indication for surgical resection). 
● 16 subjects will comprise the surgical arm, Cohort B, which is the 
exploratory arm for correlative studies (subjects have clinical 
indication for surgical resection). 
● Once a 3+3 safety run-in phase had been completed in Cohort A, the 
two cohorts will enroll simultaneously. 
 
 
Cohort A (N=16): 
The primary efficacy hypothesis of this study is that the proportion of 
subjects who experience an objective radiographic response will be 25% 
or higher. We will test this hypothesis against the null hypothesis of 5% of 
subjects experiencing an objective response using an exact single-stage 
phase II design for the primary study cohort (Cohort A; Non-surgical). A 
sample size of 16 evaluable subjects is required for 80% power. A one-
sided significance level has been set at 0.05.  
 
Cohort B (N=16) 
This exploratory cohort will consist of subjects who meet all eligibility 
criteria for this trial but in whom surgical resection is clinically indicated 
at the time of study enrollment. These subjects will be assigned to two 
subarms (N=8 in each arm), with each subarm receiving a different 
neoadjuvant regimen prior to surgical resection as diagrammed above in 
the study schema. This sample size is not intended for detecting efficacy 
differences between the surgical subarms, or for detecting efficacy 
differences between the surgical Cohort B and the non-surgical Cohort A.  
Rather, 8 subjects per surgical subarm is the minimum necessary to 
provide enough patient tumor samples to make meaningful inferences 
from the exploratory/correlative tissue studies that will accompany this 

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trial. For efficacy endpoints in the surgical arm, only descriptive statistics 
will be used given the limited sample size.   
 
Statistical analyses for additional secondary and exploratory 
endpoints: Descriptive analyses will be conducted to summarize subject 
characteristics and detect potential selection bias as a result of missing 
data or dropout. Variable distributions will be examined; if needed, 
appropriate transformations will be performed. Kaplan-Meier curves will 
be generated for PFS and OS. Paired t-tests will be used to assess change 
from pre- to post-treatment for exploratory endpoints that are normally 
distributed. Wilcoxon signed-rank tests will be used to assess change from 
pre- to post-treatment for exploratory endpoints that are not normally 
distributed. Multiple comparison adjustment using false discovery rate 
(FDR) will be used. 
 
 

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1 Background  
1.1 Introduction 
This document is a clinical research protocol.  The described study will be conducted in full 
accordance all applicable University of Pennsylvania Research Policies and Procedures and all 
applicable Federal and state laws and regulations, including 45 CFR 46, 21 CFR Parts 50, 54, 56, 
312, and Good Clinical Practice:  Consolidated Guidelines approved by the International 
Conference of Harmonization (ICH).   
 
The study shall be conducted as described in this approved protocol. The investigator should not 
implement any deviation or change to the protocol without prior review and documented 
approval from the Sponsor (University of Pennsylvania) and IRB of an amendment, except 
where necessary to eliminate an immediate hazard(s) to study subjects.  
 
This is an open-label, single-institution, phase II study of the anti-GITR agonist INCAGN01876 
and the PD-1 inhibitor INCMGA00012 in combination with stereotactic radiosurgery in 
recurrent glioblastoma. The primary objective of the study is to determine the efficacy of this 
regimen in this patient population.  
1.2 Disease Background 
GBM is the most common primary malignant brain tumor in adults and is near uniformly fatal 
(Ostrom et al, Neuro Oncol 2015). Standard first-line treatment for primary GBM includes 
surgical resection of the bulk tumor to the maximal extent possible consistent with neurological 
preservation, followed by radiotherapy, often in combination with temozolomide based on an 
overall survival (OS) benefit (referred to as the Stupp protocol; Stupp et al., 2005). 
Temozolomide is then continued as a maintenance therapy for 6 monthly cycles.  In addition, 
tumor-treating fields (TTFields), manufactured by Novocure and branded as the Optune® 
device, is approved by the United States Food and Drug Administration (FDA) for use in 
combination with maintenance temozolomide in patients 22 year of age or older.  Although this 
was also shown to improve OS compared to temozolomide alone, currently only about 15% of 
newly diagnosed patients in the US are treated with Optune as part of first-line treatment (Burri 
et al, Am J Clin Oncol 2018).  
 
When relapse or progression inevitably occurs in patients who have undergone the Stupp 
protocol, therapeutic options are unfortunately limited and generally not effective; median OS 
for recurrent GBM is typically less than 12 months (Weller et al, Neuro Oncol 2013), and no 
therapeutic intervention has ever been demonstrated to prolong OS compared to supportive care 
alone. Surgery may be indicated in a minority of relapsed patients with disease that is 
symptomatic from mass effect, but it results in only limited prolongation of survival (Keles et al, 
J Neurosurg 2004). When repeat surgery is performed, survival may be improved by adding the 
Gliadel® (carmustine) implant at the time of surgery. However, the majority of patients with 
relapsed disease are not candidates for additional surgery (and hence are not candidates for 
Gliadel) (Weller et al., Neuro Oncol 2013). Avastin® (bevacizumab) is also FDA-approved for 
recurrent GBM based on achieving an overall radiographic response rate of 28% and a 6-month 
progression free survival (PFS) rate of 42.6% (Friedman et al., J Clin Oncol 2009). However, 
duration of response to bevacizumab is generally limited to several months, at which point 
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addition of bevacizumab to salvage cytocytoxic chemotherapies for recurrent GBM, such as 
lomustine (which has very limited efficacy itself, with a response rate <10%), has never been 
demonstrated to improve OS (Wick et al, N Engl J Med 2017).  The Optune (TTFields) device is 
also FDA-approved for recurrent GBM (age 22 years and older) as a monotherapy based on a 
randomized controlled trial demonstrating similar OS between recurrent GBM patients treated 
with TTFields monotherapy versus physician’s choice of chemotherapy, with a more favorable 
toxicity profile in the TTFields arm compared to chemotherapy (Stupp et al, Eur J Cancer 2012). 
Lastly, select patients may be candidates for reirradiation.  In a large retrospective series, the 
median survival after re-irradiation was approximately 11 months (Fogh et al, J Clin Oncol 
2010).  However, the benefit of such therapy is unclear given the paucity of prospective data.   
 
Based on the current lack of any therapy for recurrent GBM that has durable efficacy and/or 
results in improved OS compared to best supportive care, novel therapeutic options for recurrent 
GBM are desperately needed.  
1.3 Name and Description of Investigational Drugs 
1.3.1. INCMGA00012  
INCMGA00012 is a humanized, hinge-stabilized, IgG4κ mAb that recognizes human PD-1. 
INCMGA00012 contains a human IgG4 Fc domain to limit effector function while retaining 
neonatal FcRn binding to extend circulating t½. INCMGA00012 is designed to target PD-1–
expressing cells, including T cells, and sustain/restore their effector function by blocking 
checkpoint inhibitory interactions between PD-1 and its 2 ligands, PD-L1 and PD-L2. 
INCMGA00012 drug product is formulated at a concentration of 25 mg/mL in sodium acetate 
trihydrate, acetic acid, sucrose, and polysorbate 80 at pH 5.1. 
 
PD-1 is expressed on T cells (CD4+ and CD8+), B cells, NK cells and myeloid-derived cells. It 
is well-established that the interaction of PD-1 with its ligands, PD-L1 and PD-L2, forms a 
negative signaling axis in T cells (Chen and Flies 2013, Freeman et al 2000, Parry et al 2005). 
This PD-1–PD-L1/L2 inhibitory signaling pathway is one of several known “immune 
checkpoints” utilized by the immune system to maintain self-tolerance and modulate the duration 
and amplitude of physiological immune responses in peripheral tissues in order to minimize 
collateral tissue damage. Extensive research has shown that cancer cells co-opt certain immune 
checkpoint pathways, including the PD-1 pathway, as a major mechanism of immune 
evasion/resistance, particularly against T cells that are specific for tumor antigens (Chen and 
Mellman 2013, Topalian et al 2015, Yao et al 2013). Disruptors of this pathway, including 
antibodies that inhibit PD-1 receptor-ligand interactions, have been shown to be effective 
inhibitors of tumor growth in murine models (Curran et al 2010, Iwai et al 2005, Pilon-Thomas 
et al 2010, Wong et al 2007). Moreover, clinical evaluation of these molecules has established 
them as a new class of antitumor agents, referred to collectively as checkpoint inhibitors, with 
several molecules targeting this pathway recently gaining marketing approval for several cancer 
indications (Keytruda® 2018, Opdivo® 2018, Libtayo® 2018, Bavencio® 2018, Imfinzi® 2018, 
Tencentriq® 2018). 
1.3.1.1. Nonclinical data 
Nonclinical data on INCMGA00012 are discussed in detail in the INCMGA00012 Investigator’s 
Brochure (IB).  

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In vitro studies with INCMGA00012 have demonstrated high affinity binding to both 
recombinant human and cynomolgus monkey PD-1 as well as to PD-1 naturally expressed on the 
cell surface, including on T cells. Consistent with its intended mechanism of action and 
functional properties, INCMGA00012 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 human 
PBMCs stimulated with the superantigen, SEB. These studies also demonstrated that the in vitro 
biological activity of INCMGA00012 was comparable to that mediated by other anti–PD-1 
mAbs, specifically, 2 mAb replicas of pembrolizumab and nivolumab generated by 
MacroGenics, Inc. based on the published sequences of these antibodies. Mean IC50 values of 
INCMGA00012, the nivolumab replica, and the pembrolizumab replica were 0.010, 0.016, and 
0.014 μg/mL, respectively, for PD-L1 binding and 0.021, 0.028, and 0.028 μg/mL, respectively, 
for PD-L2 binding. 
1.3.1.2. Clinical Experience  
INCMGA00012 clinical data are discussed in detail in the INCMGA00012 IB.  
 
Briefly, INCMGA00012 is currently under development as a therapeutic candidate for the 
treatment of multiple solid tumors, both as a monotherapy and in combination with other agents. 
As of 23 SEP 2018, INCMGA00012 has been administered to approximately 200 participants in 
a Phase 1 study (INCMGA 0012-101, formerly CP-MGA012-01) at weight-based doses ranging 
from 1 to 10 mg/kg Q2W or Q4W and at flat doses of 500 mg Q4W and 750 mg Q4W. 
Preliminary efficacy data demonstrate clinical activity of INCMGA00012 based on durable 
RECIST responses in multiple tumor types. The 500 mg Q4W dose was selected for further 
development based on favorable safety and PK profiles.   
 
INCMGA00012 was well-tolerated at all doses tested in Study INCMGA 0012-101 with no 
dose-limiting toxicities observed in the dose-escalation phase. The MTD was not established. 
Treatment-related AEs were primarily immunologic in nature and representative of previous 
experience with other PD-1 inhibitors (Keytruda 2018, Opdivo 2018, Libtayo 2018). Among the 
199 participants exposed to INCMGA00012 monotherapy in Study INCMGA 0012-101, the 
most frequently reported treatment-emergent adverse events (TEAEs; > 10%, regardless of 
attribution to treatment) were fatigue, anemia, nausea, diarrhea, pyrexia, and vomiting 
(NCT03059823). A complete list of treatment-emergent AEs occurring in >=10% of patients in 
Study INCAMGA0012-101 (cohort expansion phase, safety population) are displayed in Table 
1: 
 
 

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Table 1. Treatment-emergent AEs occurring >=10% of patients in INCMGA0012-101 by 
tumor type and dosage 
 
 
 

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A complete list of treatment-emergent AEs occurring in >=5% of patients in Study 
INCAMGA0012-101 (cohort expansion phase, safety population) is displayed in Table 2: 
Table 2. INCMGA00012 Monotherapy: Summary of Frequent (≥ 5%) Treatment-
Emergent Adverse Events (Safety Population; N = 199) 
 
There were no fatal treatment-emergent AEs (TEAEs) related to INCMGA00012.  In the cohort 
expansion phase participants receiving flat doses of INCMGA00012 Q4W, 3 participants each 
(20.0%) receiving 500 mg and 750 mg experienced serious TEAEs (hyperthyroidism, upper 
abdominal pain, large intestine perforation, pain, pyrexia, cholangitis, sepsis, blood bilirubin 
increased, and renal colic); each preferred term occurred in 1 participant. Serious TEAEs 
considered by the investigator to be at least possibly related to INCMGA00012 were blood 
bilirubin increased and hyperthyroidism.  
 
The first-in-human Study INCMGA 0012-101 protocol specified the following adverse events of 
special interest (AESIs):  
• _Grade 2 or greater immune related adverse events (irAEs)  
• _Grade 3 or greater infusion reactions or cytokine relase syndrome  
• _Abnormal liver enzymes that meet the criteria for potential Hy’s law, defined as AST and/or 
ALT > 3 × ULN and total bilirubin > 2 × ULN and without any alternate etiology  
 

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As of 23 SEP 2018, a total of 27 participants in Study INCMGA 0012-101 have experienced at 
least 1 protocol-specified AESI (Table 3), described in detail below. 
Table 3. Adverse Events of Special Interest Occurring in Participants in Study INCMGA 
0012-   101 (Safety Population) 
 
1.3.1.3. Potential Risks of INCMGA00012 
INCMGA00012 is an investigational drug. Clinical experience with the PD-1 inhibitor class is 
well-described, and no major differences in the INCMGA00012 safety profile compared with 
other PD-1 inhibitors are anticipated based upon nonclinical and preclinical characterization of 
the molecule and the clinical experience as of the data cutoff date. As with any new product, 
however, administration of INCMGA00012 may involve safety concerns that are currently 
unforeseen, and appropriate precautions should be taken as described in the respective study 
protocols. 
 
INCMGA00012 is an IgG4 humanized mAb that has been designed to restore T-cell immune 
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experience with other drugs should be considered when administering INCMGA00012. 
Potentially serious immune-related adverse events (irAEs) include:  
• Pneumonitis  
• Hepatitis  
• Colitis  
• Nephritis  
• Endocrinopathies (thyroiditis, hypophysitis, Type I diabetes)  
• Encephalitis  
• Myocarditis  
• Skin reactions (including SJS/TEN)  
• Rejection of organ transplants  
• Other reactions (including arthritis, uveitis, myositis, Guillain-Barré syndrome, myasthenia 
gravis, vasculitis, pancreatitis, and hemolytic anemia)  
 
As of the data cutoff date, irAEs in participants exposed to INCMGA00012 were generally 
consistent with approved PD-1 inhibitors in frequency and severity. Guidance for assessment, 
management, and reporting of these immune-related toxicities is provided in the remainder of the 
protocol. 
 
Complete, detailed nonclinical and clinical data for INCMGA00012, including complete 
pharmacology, toxicology, and genotoxicity data, is available in the Investigator’s Brochure.  
 
1.3.2 INCAGN01876  
INCAGN01876 is a recombinant, humanized immunoglobulin G1 (IgG1) kappa (κ) mAb that 
binds to the extracellular domain of the human tumor necrosis factor receptor superfamily 
member 18 (TNFRSF18), also known as glucocorticoid-induced TNFR-related protein (GITR). 
INCAGN01876 drug product is formulated at a concentration of 10 mg/mL in histidine, sucrose, 
and polysorbate 80 at pH 6.0.  Agonist GITR antibodies have shown antitumor activity in in vivo 
studies in mice (Turk et al 2004, Ko et al 2005, Bulliard et al 2013). INCAGN01876 is an 
agonistic antihuman GITR mAb, with the potential to enhance the function of tumor-specific T 
cells and promote antitumor immunity in cancer patients. Recent clinical success with 
checkpoint inhibitors has provided rationale for investigating agonists, such as GITR, in order to 
extend clinical benefit to patients. 
 
GITR belongs to the TNF receptor superfamily, and is activated by its cognate ligand, GITRL. 
GITR regulates a variety of immune cell functions including T-cell proliferation, differentiation, 
cytokine production, and survival (Smith et al 1994). GITR expression is generally restricted to 
normal tissues with high immune cell composition, including the peripheral blood, bone marrow, 
spleen, and thymus (Gurney et al 1999). GITR is expressed on some Tregs, is upregulated upon 
T-cell activation of both CD4+ and CD8+ T cells, and is a costimulator in the activation of these 
T cells (Allan et al 2007, Bianchini et al 2011, Schaer et al 2012).  
 
In mice, the GITR-GITRL system is implicated in development of autoimmune and 
inflammatory responses, as well as promoting protective immunity to pathogens and tumors 
(Nocentini et al 2012). Animals treated with a GITR-Fc fusion protein leading to an attenuated 
GITR signaling showed signs of ameliorated autoimmunity. By contrast, an agonist anti-GITR 
antibody augmented an immune response to viral, bacterial, and parasitic infections. Unlike 
murine models, the cell surface expression of GITR is undetectable on the majority of human 

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peripheral blood immune cell populations. GITR expression among human immune cells seems 
to be exclusively reserved to subpopulations of Treg, transitional memory T cells, and recently 
activated T cells (Schaer et al 2012, Ronchetti et al 2015). This would suggest that an agonistic 
GITR mAb, such as INCAGN01876, would have a focused effect in the human immune 
response leading to the proliferation and augmentation of an ineffectually active antitumor 
immune response. 
 
1.3.2.1. Nonclinical data 
Nonclinical data on INCMGA01876 are discussed in detail in the INCMGA01876 Investigator’s 
Brochure (IB).  
 
INCAGN01876 binds to human GITR with a KD value of 0.21 nM and cross-reacts with African 
Green monkey (Chlorocebus sabeus) GITR with less than a 10-fold difference in affinity. 
Consistent with its binding epitope on human and African Green monkey GITR, INCAGN01876 
does not recognize cynomolgus monkey (Macaca fascicularis) or rodent GITR. African Green 
monkey was therefore considered as a toxicologically relevant nonhuman primate species in 
which to evaluate this molecule.  
 
INCAGN01876 does not bind to related TNFRSF members. INCAGN01876 functions as a 
GITR agonist antibody in human and African Green monkey cells, providing T cell 
costimulation in the context of suboptimal TCR activation that results in enhanced T cell 
proliferation and cytokine production.  
 
Preclinical findings highlight the potential antitumor mechanisms of action of INCAGN01876: 
1) costimulatory agonistic engagement of GITR-enhancing T-effector cells, and 2) 
coengagement of activating FcγRs to selectively deplete immune suppressive Tregs located 
within the tumor (Gonzalez et al 2016). Together, this would suggest that an agonistic GITR 
mAb such as INCAGN01876 would have a focused effect in the human immune response 
leading to the proliferation and augmentation of an ineffectually active antitumor immune 
response. 
 
1.3.2.2. Clinical Experience 
Complete clinical data on INCMGA01876 are discussed in detail in the INCMGA01876 
Investigator’s Brochure (IB).  
 
In brief, as of 14 JAN 2019, 3 Phase 1/2 clinical studies of INCAGN01876 in participants with 
advanced malignancies are ongoing: Study INCAGN 1876-101 is a monotherapy study (96 
participants exposed); Study INCAGN 1876-201 is a study of INCAGN01876 in combination 
with nivolumab (anti-PD1), ipilimumab (anti-CTLA4), or nivolumab + ipilimumab (115 
participants exposed); Study INCAGN 1876-202 is a study of INCAGN01876 in combination 
with pembrolizumab (anti-PD1) + epacadostat (IDO inhibitor) (10 participants exposed). 
 
As of the data cutoff date, a total of 221 participants with advanced or metastatic malignancies 
have been enrolled in the ongoing clinical studies and have received at least 1 dose of 
INCAGN01876.   
 
 

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INCAGN01876 Monotherapy 
In Study INCAGN 1876-101, 96 participants have received INCAGN01876 IV doses of 0.03, 
0.1, 0.3, 1.0, 3.0, 5.0, 10.0, or 20.0 mg/kg Q2W, 300 mg Q2W (RP2D), or 400 mg Q4W. The 
most frequently occurring TEAE was fatigue (37.7% in Part 1 [dose escalation and safety 
expansion], 47.4% in Part 2 [dose expansion]). Part 2 (dose expansion) included 19 participants 
treated at the RP2D of 300 mg Q2W IV. Preliminary, unaudited data as of the clinical data cutoff 
date show that INCAGN01876 is generally well-tolerated. Two DLTs were reported in Part 1: 
Grade 4 hypoxia at a dose of 3.0 mg/kg Q2W and Grade 3 pleurisy at a dose of 5.0 mg/kg Q2W. 
 
Overall, 100% of participants in Part 1 and 89.5% of participants in Part 2 had TEAEs, with the 
most frequent being fatigue. Table 4 and Table 5 summarize the most frequently occurring 
TEAEs (> 10%) in Parts 1 and 2, respectively: 
 
Table 4. Study INCAGN 1876-101 (Part 1): Summary of treatment-emergent adverse 
events occurring in >10% of participants 
 
 
 
 
 

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Table 5. Study INCAGN 1876-101 (Part 2): Summary of treatment-emergent adverse 
events occurring in >10% of participants 
 
 
 
INCAGN01876 Combination Therapy with immune checkpoint inhibitors 
 
In Study INCAGN 1876-201, 115 participants have received INCAGN01876 IV doses of 1.0, 
3.0, 5.0, or 10.0 mg/kg Q2W or 300 mg Q2W (RP2D) in combination with nivolumab and/or 
ipilimumab. 56 participants have received concurrent dosing of INCAGN01876 at the RP2D of 
300 mg Q2W IV + nivolumab 240 mg Q2W IV (the FDA approved dose of nivolumab). Four 
participants at this dose level had DLTs: Grade 3 rash in 1 participant; Grade 3 hepatic enzyme 
increased in 1 participant; Grade 2 diarrhea and Grade 2 hyperthyroidism in 1 participant; and 
Grade 3 chest pain in 1 participant. Overall, 85 of the 86 participants receiving INCAGN01876 + 
nivolumab had TEAEs. The TEAEs occurring in > 20% of participants were fatigue, nausea, and 
anemia. The only TEAE leading to discontinuation of INCAGN01876 that occurred in more than 
1 participant was vomiting in 2 participants (2.3%), both of whom received INCAGN01876 300 
mg Q2W IV. Table 6 summarizes TEAEs occurring in > 5% of participants. 
 

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Table 6. Study INCAGN 1876-201: Summary of treatment-emergent adverse events 
occurring in >5% of participants receiving INCAGN01876 in combination with 
nivolumab 
 
 
1.3.2.3. Potential Risks of INCAGN01876 
Preclinical assessments used to evaluate theoretical safety concerns with INCAGN01876 
eliciting adverse proinflammatory infusion reactions did not induce cytokines that in vivo would 
be predictive of cytokine release syndrome in participants, so the risk of significant infusion 
reactions is considered to be low. For participants who have an infusion reaction associated with 
administration of INCAGN01876, signs and symptoms would usually develop during or shortly 

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after drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Specific infusion reaction treatment guidelines are provided in Section 5.8.2.  
 
INCAGN01876 is an immune modulator, and although no toxicities were identified in 
preclinical models, it is possible that immune related adverse events (irAEs; both nonserious and 
serious), similar to those described with approved immunotherapies, may occur. Adverse events 
of a potential immunologic etiology or irAEs may be defined as an AE consistent with an 
immune phenomenon associated with drug exposure after all other etiologies have been 
eliminated. Immune-related AEs may be expected based on the nature of INCAGN01876, its 
mechanism of action, and based on reported experience with other immunotherapies. 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. Suspected irAEs 
should be discussed with the medical monitor when possible. Guidance for management of 
specific irAEs is provided in Section 5.8.1. 
 
Complete, detailed nonclinical and clinical data for INCAGN01876 is available in the 
Investigator’s Brochure. 
 
1.4 Study Rationale 
This protocol uses the combination of the GITR agonist monoclonal antibody INCAGN01876, 
the anti-PD1 monoclonal antibody INCMGA00012, and stereotactic radiosurgery (SRS) in 
recurrent GBM.  We hypothesize that this combination will lead to in immunostimulatory tumor 
microenvironment, increased anti-tumor CD8 T cell infiltration, and tumor cell death.   
 
Among the array of cancer immunotherapeutics developed over the past decade, PD-1 
monoclonal antibody blockade has yielded promising results in patients with multiple types of 
metastatic cancers (Chen, Nature 2017). PD-1 inhibition is thought to disrupt the engagement of 
PD-1 with its inhibitory ligands, spurring cytotoxic T cell-mediated tumor elimination (Topalian, 
Cancer Cell 2015). Survival benefits and regulatory approvals have been achieved in metastatic 
non-small cell lung cancer, metastatic melanoma, and other aggressive malignancies, including 
in patients with brain metastases (Gandhi, N Engl J Med 2018; Tawbi, N Engl J Med 2018). One 
of the main challenges has been to extend the benefit of PD-1 inhibitors to other cancers such as 
glioblastoma, which has not been responsive to single agent PD-1 inhibition in the trials 
conducted thus far (Reardon, Neuro Oncol 2017).  

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in a separate, PD-1 resistant murine tumor 
model, treatment with anti-GITR, anti-PD1, 
and XRT led to significantly improved 
survival and abscopal responses, with half of 
the mice becoming tumor free (Figure 4; 
Schoenhals, Front Immunol 2018). These 
mice showed durable response and increased 
CD4+ and CD8+ effector memory on tumor 
rechallenge. Regulatory T cells (Tregs) 
expressed the highest level of GITR at the 
tumor site, and anti-GITR therapy drastically 
diminished Tregs at the tumor site.  
 
Taken together, the above studies 
support a trial of anti-GITR agonism 
and PD-1 inhibition in combination 
with SRS for recurrent GBM. 
 
 
 
 
 
 
 
 
1.5 Dose and schedule rationale 
1.5.1. Investigational drugs 
The dose and schedule of INCMGA00012 and INCAGN01876 used in this protocol are the 
recommended phase 2 doses (RP2Ds) derived from phase I studies of these compounds 
conducted by Incyte.  As outlined in the above sections, there is sufficient experience and safety 
data for the combination of INCAGN01876 administered at the RP2D of 300mg IV every 2 
weeks in combination with nivolumab, an FDA-approved PD-1 inhibitor, at its FDA-approved 
dose and schedule. The RP2D of the PD-1 inhibitor used in this protocol, INCMGA00012, is 
500mg IV every 4 weeks. Therefore, the dose and schedule of investigational agents for this 
study is: INCAGN01876 300mg IV ever 2 weeks, and INCMGA00012 500mg IV every 4 
weeks.  
1.5.2. Stereotactic Radiosurgery  
Subjects in Cohort A and in sub-arm #1 of Cohort B will receive hypofractionated radiation 
(stereotactic radiosurgery; SRS) to a dose of 8 Gy in 3 fractions. The dose of 8 Gy in 3 fractions 
was chosen based on preclinical evidence suggesting that it may maximally invoke an anti-tumor 
immune response (Vanpouille-Box, Nature Communications, 2017), compared to a variety of 
other fractionation schedules.  For subjects treated in the nonsurgical cohort (Cohort A), a single 
dose of each systemic therapy (INCMGA00012 and INCAGN01876) is administered 3-7 days 
prior to SRS to prime the tumor immune microenvironment for optimal immune response to the 
SRS.  Following SRS, the systemic agents are resumed according to their dosing schedule (i.e., 
Figure 4 Anti-GITR combination therapy with anti-
PD1 and XRT in 344SQ resistant tumors increases 
overall survival and promotes abscopal effects 
Figure 3 Survival curves of GL261 tumor-
bearing mice treated with anti-GITR 

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INCMGA00012 is resumed 4 weeks from the date of the initial pre-SRS dose, and 
INCAGN01876 is resumed 2 weeks from the date of the initial pre-SRS dose). For the surgical 
arm (Cohort B; Surgical Sub-Arm #1 only), preclinical data suggests that in order to develop a 
maximal anti-tumor immune response the tumor needs to remain in situ for at least 7 days post 
radiation prior to surgical removal (De La Maza et al, Clinical Cancer Research, 2017).  Thus, 
surgical resection (Cohort B; Surgical Sub-Arm #1 only) will take place 7-14 days following 
completion of radiation.   
 
Overall, hypofractionated radiation has been shown to be safe and well-tolerated in recurrent 
GBM. For re-irradiation in general in recurrent GBM, the rate of grade 3 or higher AEs is less 
than 10% (Kazmi et al, J Neurooncol 2019).  For SRS specifically in rGBM, prior studies have 
suggested a rate of grade 3 or higher AEs of ~3% (Holt et al, J Cancer Res Ther 2016; Clarke et 
al, Int J Radiat Oncol Biol Phys 2017).  The rate of symptomatic radionecrosis from SRS in 
rGBM is estimated to be about 15-20% (Imber BS, et al, Neurosurg 2017).  
 
The safety of brain-directed hypofractionated radiation with concurrent immune checkpoint 
blockade, as well as in the preoperative setting has been previously evaluated and is overall safe.  
There are numerous reports that have evaluated the safety of SRS with immune checkpoint 
blockade (primarily anti-PD-1 and anti-CTLA-4) in the treatment of brain metastases.  Although 
the risk of radionecrosis may be higher in this setting and has been reported as high as 5-20% 
(Martin AM, JAMA Oncol 2018) (Lehrer EJ, Radiotherapy Oncology 2019), the therapy is 
overall safe and used routinely in the treatment of patients with brain metastases who are also on 
anti-PD-1 and anti-CTLA-4 agents.  In addition, investigators have evaluated the use of 
neoadjuvant SRS for brain metastases and have not found any increase in morbidity, including 
wound healing complications (Asher AL, International Journal of Radiation Oncology Biology 
and Physics 2014; Patel Kr, Neurosurgery 2016). 
 
2  STUDY OBJECTIVES AND ENDPOINTS 
2.1. Study Objectives 
2.1.1. Primary Objective: 
● To determine the efficacy of the combination of INCMGA00012, INCAGN01876, and 
SRS in recurrent GBM, as measured by the overall objective radiographic response rate 
(ORR)  
2.1.2. Secondary Objectives: 
● To evaluate the safety and tolerability of the combination of INCMGA00012, 
INCAGN01876, and SRS in recurrent GBM   
● To determine the progression-free survival (PFS) and overall survival (OS) of patients with 
recurrent GBM treated with the combination of INCMGA00012, INCAGN01876, and SRS  
2.1.3. Exploratory Objectives: 
● To evaluate the biologic effect of the combination of INCMGA00012 and INCAGN01876, 
with or without SRS, on the GBM tumor immune microenvironment 
● To evaluate the pharmacodynamic impact of the combination of INCMGA00012, 
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● To evaluate the pharmacokinetics (PK) of INCAGN01876 in patients with glioblastoma 
● To determine whether anti-drug antibodies (ADA) form against INCAGN01876 in patients 
with glioblastoma 
● To detect tumor and/or blood biomarkers associated with the outcomes of OS, PFS, and/or 
ORR in patients with recurrent GBM treated with the combination of INCMGA00012, 
INCAGN01876, and SRS 
2.2. Study Endpoints  
2.2.1. Primary Endpoint: 
● Objective radiographic response (ORR), as measured by modified Response Assessment in 
Neuro-Oncology (RANO) criteria  
2.2.2. Secondary Endpoints: 
● Safety and tolerability will be assessed by monitoring frequency, duration, and severity of 
adverse events (AEs) through physical examinations, by evaluating changes in vital signs, 
and through clinical laboratory evaluations.   
● OS, defined as the time from date of enrollment until death from any cause  
● PFS, defined as the time from date of enrollment until the earliest date of disease 
progression (as determined by modified RANO criteria) or death due to any cause 
 
2.2.3 Exploratory Endpoints:  
● Comparison of the following immunocorrelative assays in subjects treated with 
INCMGA00012 + INCAGN01876, with or without SRS: 
○ Multiplex immunohistochemistry on tumor tissue for CD4/8 T cell infiltration, Foxp3+ 
Treg infiltration, and PD-1/PD-L1 expression 
○ Tumor cell and immune cell GITR expression by a validated immunohistochemistry 
stain  
○ Flow cytometry/mass cytometry in tumor tissue and peripheral blood for T cell and 
monocyte phenotyping  
○ RNA-Seq on tumor tissue for PD-1/PD-L1 and GITR expression, T cell- and 
interferon-γ-related gene expression, and cell-cycle-related gene expression 
 ○ T cell receptor sequencing in tumor tissue and peripheral blood for assessment of TCR 
clonal diversity 
● Association between the above tumor tissue and peripheral blood-based markers of 
immune activation, tumor genetic mutations, and clinical outcomes of OS, PFS, and ORR 
● PK parameters for INCAGN01876 in patients with glioblastoma 
● Detection of anti-drug antibodies (ADA) against INCAGN01876 
 
3   INVESTIGATIONAL PLAN  
3.1. General Design 
This is a single-center, phase II, open label study evaluating the efficacy and safety of the 
combination of INCMGA00012, INCAGN01876 and SRS for patients with recurrent GBM.  
 
The overall study population will be broken down into two cohorts: Cohort A (N=16) and Cohort 
B (N=16).  Subjects for whom surgical resection is not clinically indicated at the time of study 

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screening will be enrolled into Cohort A (non-surgical cohort).  Subjects for whom surgical 
resection is clinically indicated at the time of study screening will be enrolled into Cohort B 
(surgical cohort).   
 
The first 6 subjects enrolled onto the study must be enrolled onto Cohort A and will be enrolled 
in two groups of 3 subjects (i.e., a “3+3” design) as part of a safety run-in period. After 
enrollment of the first 3 subjects, enrollment is put on hold until all of the first 3 subjects have 
completed the safety monitoring period (completion of SRS and one cycle of INCMGA00012 
and INCAGN01876).  If only 0-1 of the first 3 subjects experiences a criterion for study drug 
discontinuation, as defined in Section 5.7, Study Drug Discontinuation Criteria, then the next 3 
subjects will be enrolled. If 2 of the first 3 subjects experience a criterion for study drug 
discontinuation, the study will be paused for reconsideration of the dosing and schedule of 
investigational agents.   
 
Of the first 6 subjects enrolled during the safety run-in, if 3 or greater subjects experience a 
criterion for study drug discontinuation, then the study will be paused for reconsideration of the 
dosing and schedule of investigational agents.  If only 0-2 of the first 6 subjects enrolled during 
the safety run-in experience a criterion for study drug discontinuation, then enrollment to both 
cohorts A and B will commence uninterrupted.   
 
If at any point during the safety run-in a stopping rule is met and the dose/schedule of 
investigational agents is changed, the safety run-in will start over again with another 6 patients. 
If Cohort A has reached enrollment of 12 subjects and the criteria to move beyond the safety run-
in phase has still not yet been met (i.e., at least 6 patients have been treated at the same 
dose/schedule and only 2 or fewer have experienced a criterion for study drug discontinuation), 
the trial (including Cohort B) will be terminated due to intolerability of the study regimen.  
 
If at any point during the safety run-in a stopping rule is met and the dose/schedule of 
investigational agents is changed, and the safety-run in phase is then successfully completed at 
the new dose/schedule, 16 additional subjects will be enrolled in Cohort A at the new 
dose/schedule to achieve the desire sample size of 16 subjects that are evaluable for the study’s 
primary endpoint. Thus, the total sample size for Cohort A could potentially be more than 16 
subjects (e.g., 6 subjects are enrolled in the initial safety run-in and 3 of them experience a 
toxicity requiring study drug discontinuation; an additional 6 subjects are then enrolled at the 
new dose/schedule that has been decided upon, and this time the safety run-is completed 
successfully with only 1 subject discontinuing study drug due to toxicity; we would then enroll 
10 additional subjects at the current dose/schedule of study drugs to achieve 16 evaluable 
subjects treated at the final dose/schedule; the total sample size for cohort A in this example 
would be 22 subjects). 
 
Cohort B will not start enrollment until the safety run-in phase has been successfully completed.  
 
Details of treatment administered in each cohort are provided below in Section 3.1.2, Study 
Intervention Phase. 
3.1.1. Screening Phase 
Subjects will be recruited from the Medical Oncology, Radiation Oncology, and Neurosurgery 
practices at the University of Pennsylvania Health System.  The treating physician will determine 

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if the patient is a potential research candidate. The treating physician will approach and inform 
the patient about the study, thereby initiating the informed consent process. If the patient 
expresses interest in the study, the treating physician will contact a qualified member of the 
research team in the Neurosurgery Clinical Research Division at the University of Pennsylvania 
and request availability for enrollment. A sub-investigator will continue the formal consent 
process. This person will explain the requirements of the study and provide a copy of the 
Informed Consent Form. The person obtaining consent will state the volunteer nature of research 
and advise the subject to take sufficient time to discuss the study before making her decision to 
sign the informed consent document. If a decision to participate is made, the informed consent 
form is signed after which screening procedures will be performed. Subject eligibility will be 
evaluated based upon the criteria outlined in the protocol. After eligibility is established, a 
subject study number will be issued. Eligibility is confirmed with a clinically-licensed study 
Investigator. All members of the research team will have successfully completed patient oriented 
research training.  
3.1.2. Study Intervention Phase  
 
Schema (Figure 5): 
 
 
 
Cohort A (non-surgical; N=16): 
Within 7 days of enrollment, the subject will receive a single 500mg dose of INCMGA00012 
and a single 300mg dose of INCAGN01876 on the same day. Within 3 to 7 days following these 

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doses, the subject will receive stereotactic radiosurgery (SRS), administered over the course of 3 
consecutive business days (8 Gy x 3 fractions, one fraction per day, total dose 24 Gy). Subjects 
may receive 3 fractions every other day (non-consecutively) for logistical reasons relating to 
COVID-19.  Following SRS, the two study drugs will be resumed according to their respective 
dosing schedule (INCMGA00012 500 mg IV every 4 weeks; INCAGN01876 300mg IV every 2 
weeks).  For example, INCAGN01876 will be resumed 2 weeks from the date that the first pre-
SRS dose was given, and INCMGA00012 will be resumed 4 weeks from the date that the first 
pre-SRS dose was given. Subjects will continue on combined systemic treatment 
(INCMGA00012 500 mg IV every 4 weeks and INCAGN01876 300mg IV every 2 weeks) until 
disease progression, unacceptable AEs, or for 2 years, whichever occurs first.  
 
Cohort B (surgical; N=16): 
Subjects in cohort B are enrolled onto one of two surgical sub-arms (sub-arms 1 or 2; eight 
subjects per sub-arm), with each sub-arm receiving a different neoadjuvant regimen prior to 
surgical resection as diagrammed above in the study schema. The two possible neoadjuvant 
regimens are INCMGA00012 + INCAGN01876, or INCMAG00012 + INCAGN01876 + SRS.  
Subjects with a tumor that is amenable to SRS (i.e., as determined by the Investigator) are 
assigned to sub-arm 1 (INCMAG00012 + INCAGN01876 + SRS) until this arm has reached its 
total enrollment (N=8).  All other subjects enrolled in Cohort B are assigned to the other surgical 
sub-arm (sub-arms 2; INCMGA00012 + INCAGN01876, without SRS).  
 
In both surgical sub-arms, within 7 days of enrollment the subject will receive a single dose of 
the investigational systemic agent(s) according to the sub-arm to which he/she is assigned.  In 
sub-arm # 1 (INCMAG0012 + INCAGN01876 + SRS), within 3 to 7 days following the 
neoadjuvant doses of the systemic study drugs, the subject will receive SRS, administered over 
the course of 3 consecutive business days (8 Gy x 3 fractions, one fraction per day, total dose 24 
Gy). Subjects may receive 3 fractions every other day (non-consecutively) for logistical reasons 
relating to COVID-19.  Within 7-14 days following administration of the study drug(s) (surgical 
sub-arms # 2) or within 7-14 days following SRS (surgical sub-arm # 1), the subject will undergo 
maximal safe surgical resection of the tumor.  Following surgery, the subject will then resume 
systemic therapy with BOTH investigational agents INCMGA00012 and INCAGN01876 
(regardless of which of the two sub-arms the subject was assigned to).  The systemic agents 
should be started as soon as the investigator feels the subject has recovered adequately from 
surgery, but must be restarted within 5 weeks (35 days) from the date of surgery.  Subjects will 
continue on combined systemic treatment (INCMGA00012 500 mg IV every 4 weeks and 
INCAGN01876 300mg IV every 2 weeks) until disease progression, unacceptable AEs, or for 2 
years, whichever occurs first.  
 
3.1.3. Follow Up Phase 
Any subject who permanently discontinues the study drugs based on any reason outlined in 
Section 5.7 will proceed to follow-up.   
3.1.3.1. Safety Follow-Up  
A scheduled safety follow-up visit occurs 30 (+/- 7) days after the EOT visit (the visit that occurs 
when subjects are taken off study treatment (see Section 6;Table 8 and Table 9 for full schedule 
of events).  Reasonable efforts should be made to have the subject return for the follow-up visit 
and report any AEs that may occur during this period. If the subject cannot return to the site for 

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the safety follow-up visit, the subject is contacted by telephone for collection of AEs and SAEs, 
and this should be documented in the eCRF.  
 
Following the scheduled 30-day safety follow-up visit, subjects are contacted by telephone, e-
mail or visit one additional time 12 weeks (+/- 14 days) from the EOT visit to capture additional 
immune related AEs (see sections 1.3.1.3 and 1.3.2.3).  
 
 
3.1.3.2. Disease Status Follow-Up 
Subjects who discontinue study drug treatment but who have not yet met criteria for disease 
progression are assessed by radiologic imaging to monitor disease status. These assessments 
occur every 12 weeks (± 14 days). The imaging assessments occur at the study site if the subject 
continues to receive care at the University of Pennsylvania; otherwise, research staff will obtain 
subject’s outside radiology reports and outside physician notes to determine disease status. If 
possible, the original images from radiology scans will also be obtained for formal radiologic 
interpretation by University of Pennsylvania Neuroradiology.  
 
Every effort should be made to collect information regarding disease status until:  
• The start of new antineoplastic therapy.  
• Disease progression.  
• Death.  
• Termination of the study 
• 5 years after removal from protocol therapy 
3.1.3.3. Survival Follow-Up 
Subjects are contacted by telephone, e-mail, or visit every 12 weeks (+/-14 days) from the 12-
week safety follow-up visit to capture survival status until death, withdrawal of consent, 
termination of the study or 5 years after removal from protocol therapy, whichever occurs first. 
Public records/databases are searched if contact with the subject is lost.  
 
For participants who are thought to be lost to follow-up, at least 3 documented attempts should 
be made to contact the participant before the participant is deemed lost to follow-up. 
3.2 Replacement of Subjects 
Cohort A: Any subject who is enrolled onto Cohort A of the study but meets one of the 
following criteria is replaced by enrollment of a new subject onto Cohort A:  
● The subject is enrolled, but does not receive BOTH systemic agents (INCMGA00012, 
INCAGN01876) 
●   The subject is enrolled, but does not receive SRS 
●   The subject is enrolled as part of the safety run-in cohort and, for any logistical reason 
unrelated to the patient’s clinical condition, does not receive all scheduled components of 
Cycle 1 treatment (i.e., a subject is enrolled on safety run-in cohort but does not receive 
all of the following: 3 fractions of radiation, C1D1 dose of INCMGA00012, C1D1 dose 
of INCAGN01876, and C1D15 dose of INCAGN01876). Examples of such logistical 
reasons include: the current lot of investigational product on site (INCMGA00012 or 
INCAGN01876) tests out of specification, the radiation machine breaks down in the 
midst of the subject’s radiation, a spike in COVID-19 infections results in temporary 
suspension of clinical research at the study site, etc).  

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● The subject receives study drugs (+/- SRS), but becomes pregnant (and therefore is taken 
off study per study drug discontinuation criteria Section 5.7) before the first response 
evaluation (MRI) occurs 
● The subject receives study drugs (+/- SRS), but consent is withdrawn by the 
subject before the first response evaluation (MRI) occurs 
● The subject receives study drugs (+/- SRS), but is subsequently found not to have met 
eligibility criteria, AND the Medical Director, in collaboration with the investigator, 
determined that the subject should be withdrawn from the study, AND the first response 
evaluation (MRI) has not yet taken place  
● The subject receives study drugs (+/- SRS), but is then noncompliant with study 
procedures in the investigator's opinion, AND the sponsor has been consulted and has 
determined that the subject should be withdrawn from the study, AND the first response 
evaluation (MRI) has not yet taken place  
 
As long as the subject has not withdrawn his/her consent, the non-treated (replaced) subject is 
followed for safety follow-up per Table 10 (see Section 6) and all safety-related data collected 
for the subject is included in analysis of the study’s secondary safety/tolerability endpoints. 
However, the subject is not included in the primary endpoint efficacy analysis or in analysis of 
secondary efficacy endpoints (see Section 8, Statistical Plan). In addition, if the replaced subject 
was enrolled during the safety run-in phase, that subject will not be counted for purposes of 
determining whether the pre-specified safety criteria (see Section 3.1; General Design) have 
been met during the safety run-in phase to allow for successful completion of the safety run-in 
phase.  
 
Subject replacement occurs up to and no more than 7 times for Cohort A [i.e., up to 23 subjects 
can be enrolled to obtain 16 subjects who receive both of the study drugs at the same dose and 
schedule AND SRS and are therefore evaluable for the primary endpoint].  
 
Cohort B: Any subject who is enrolled onto Cohort B of the study but meets one of the 
following criteria is replaced by enrollment of a new subject onto Cohort B:  
● The subject is enrolled, but does not receive either of the systemic agents 
(INCMGA00012, INCAGN01876) 
● The subject is enrolled, but does not receive SRS (surgical subarm #1 only) 
● The subject is enrolled, but does not undergo surgery  
 
As long as the subject has not withdrawn his/her consent, the non-treated (replaced) subject is 
followed for safety follow-up per Table 10 (see Section 6) and all safety-related data collected 
for the subject is included in analysis of secondary study endpoints.  
 
Subject replacement occurs up to and no more than 10 times for Cohort B [i.e., up to 26 subjects 
can be enrolled to obtain 16 subjects who receive neoadjuvant therapy AND undergo surgery, 
with 8 patients assigned to each of the 2 sub-arms]. Subjects who need to be replaced in Cohort 
B, will be replaced by a subject enrolled onto the same sub-arm that the replaced subject was 
previously on. 
 
Replaced subjects will be followed for safety only. These subjects will not be included in 
efficacy endpoint analyses, and they will not have tumor tissue available for correlative endpoint 
analyses.  

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3.3. Duration of Individual Subject Study Participation 
After signing the ICF, screening procedures commence.  Each enrolled subject begins study 
treatment. Treatment continues until the subject meets any one or more of the criteria for study 
drug discontinuation (see Section 5.7; Study Drug Discontinuation Criteria). When a subject 
discontinues study drug but has not withdrawn consent, the subject enters the follow-up 
period.  Subjects are taken off study if any of the following criteria apply: 
• Lost to follow-up 
• Withdrawal of consent 
• Death 
• Sponsor decides to terminate the study  
 
3.4. Overall Study Duration 
The study begins at the time that it becomes actively open to patient enrollment (i.e., the site is 
activated for the trial and screening for subjects has commenced).  The study ends when all 
subjects have discontinued the study and the last follow-up visit has been performed.  
 
In addition, the sponsor may terminate the study if required by regulatory decision, or upon 
review of emerging data. If the study is terminated prematurely, the sponsor will notify the 
principal investigator and the FDA of the decision and reason for termination of the study.  
3.5 Total Number of Subjects and Sites  
This is a single center study and subjects are only recruited from the University of Pennsylvania.  
Recruitment for Cohort A ends when (1) the safety run-in phase has been successfully completed 
AND (2) 16 subjects in Cohort A have received at least one dose of each study drug at the same 
dose/schedule as determined by the safety run-in phase. Greater than 16 total subjects may be 
enrolled on Cohort A if the stopping rule for toxicity is met during the safety run-in phase (see 
Section 3.1 General Design). The maximum possible sample size for Cohort A is 22 subjects 
who are evaluable for the study’s primary efficacy endpoint, which would occur if enrollment of 
12 subjects (which is the maximum allowed for the safety run-in phase) is necessary to 
successfully complete the safety run-in phase and an additional 10 subjects are enrolled at the 
same finalized dose/schedule of study drugs that was given to the last 6 subjects enrolled on the 
safety run-on phase.  
 
Recruitment for Cohort B ends with 16 subjects have received study drug(s) AND surgery.  
 
4.  INCLUSION AND EXCLUSION CRITERIA   
4.1 Inclusion Criteria 
Subjects must meet all of the following criteria: 
 
1. Prior histopathologically proven diagnosis of World Health Organization (WHO) grade IV 
glioblastoma, OR histopathologically proven diagnosis of gliosarcoma, OR molecular diagnosis 
of glioblastoma per c-IMPACT-NOW criteria (“diffuse astrocytic glioma, IDH-wildtype, with 
molecular features of glioblastoma, WHO grade IV”; this requires presence of either 
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promoter mutation).   Participants are eligible if the prior diagnosis was low-grade glioma and a 
subsequent histological diagnosis of glioblastoma was made (e.g. secondary GBM). 
 
2. Participants must have glial tumor that is recurrent following prior first-line radiation therapy 
(prior dose must have been 40-75 Gy and may have been either photon or proton radiation), and 
must have unequivocal evidence of tumor progression by MRI scan  
 
3. Cohort A and Sub-Arm 1 of Cohort B only: Patient must have at least one measurable (>=1cm 
x 1cm) contrast-enhancing tumor focus for which stereotactic radiosurgery (SRS) is clinically 
indicated, as determined by the Investigator, and must be able to achieve radiation target 
coverage without exceeding dose constraints.  The contrast-enhancing target must not be larger 
than 4 cm in maximal diameter. Multifocal disease is allowed as long as this criterion is met  
• Sub-Arms 2 of Cohort B can have any size tumor, and the tumor does not need to be 
amenable to SRS 
 
4. Cohort B (surgical) patients only: patients must be undergoing surgery that is clinically 
indicated as determined by their care providers 
 
5. Tumor O-6-methylguanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT) 
methylation status must be available from any prior GBM tumor specimen; results of routinely 
used methods for MGMT methylation testing (e.g. mutagenically separated polymerase chain 
reaction [MSPCR] or quantitative polymerase chain reaction [PCR]) are acceptable) 
 
6. Patients may have had treatment for an unlimited number of prior relapses but must not have 
had prior bevacizumab or other vascular endothelial growth factor (VEGF/VEGFR) inhibitors 
(exception: prior bevacizumab is allowed if it was administered for the treatment of radiation 
necrosis rather than progressive tumor and was stopped at least 4 weeks prior to MRI showing 
demonstrating tumor progression). Prior gliadel wafers are only allowed if placed during the first 
surgery for GBM at initial diagnosis.  
7. Patients must have recovered from severe toxicity of prior therapy; the following intervals 
from previous treatments are required to be eligible: 
• 
12 weeks from completion of radiation 
• 
6 weeks from a nitrosourea cytotoxic chemotherapy 
• 
3 weeks from a non-nitrosourea cytotoxic chemotherapy 
• 
4 weeks from any investigational (not Food and Drug Administration [FDA]-approved for 
glioblastoma) agents, or within a time interval less than at least 5 half-lives of the 
investigational agent whichever is shorter  
• 
3 weeks from any major surgery, including brain surgery for recurrent tumor resection 
 
8. If patient is on systemic corticosteroids to treat brain edema and/or brain edema-related 
symptoms, the dose must be 2mg of dexamethasone (or equivalent) daily or less for a minimum 
of 5 days prior to first dose of study drug. 
 
9.  Patients must be able to swallow oral medications 
 
10.  Age 18 or older  

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11. Karnofsky performance status >= 60  
 
12. Life expectancy >3 months 
 
13. Absolute lymphocyte count >= 500/uL 
 
14. Adequate hepatic function within 7 days prior to start of study treatment, defined as follows 
• Total bilirubin (except patients with Gilbert’s Syndrome, who are eligible for the study but 
exempt from the total bilirubin eligibility criterion) ≤ 2.0 mg/dl  
• ALT and AST ≤ 2.5x upper limit of normal (ULN)  
 
15. Adequate renal function within 7 days prior to start of study treatment, defined as follows: 
• Serum creatinine <=1.5 x institutional ULN OR calculated creatinine clearance 
(glomerular filtration rate can also be used in place of creatinine or CrCl) >=50 mL/min 
for subjects with creatinine levels >1.5x institutional ULN 
 
16. Reproductive Status 
 
a) Women of childbearing potential (WOCBP) must have a negative serum or urine 
 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 7 
 
days prior to the start of study drug. 
b) Women must agree to not breastfeed during the study or for 180 days after the last 
dose of study treatment  
 
c) WOCBP must agree to use an adequate method to avoid pregnancy (as defined below) 
 
from the time of study screening through 180 days from last dose of study drug  
 
d) Males who are sexually active with WOCBP must agree to follow instructions for 
 
method(s) of contraception (as defined below) starting with the first dose of study drug 
 
through 180 days after the last dose of study  
 
e) Azoospermic males and WOCBP who are continuously not heterosexually active are 
 
exempt from contraceptive requirements. However, these WOCBP must still undergo 
 
pregnancy testing as described in this section. 
 
 
At a minimum, participants of childbearing potential who are sexually active and their 
 
partners must agree to the use of a highly effective form of contraception (as defined
 
below) throughout their participation beginning with the time of consent, during the study 
 
treatment, and for 180 days after last dose of study treatment(s).  
 
 
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION: 
• Hormonal methods of contraception including combined oral contraceptive pills, 
vaginal ring, injectables, implants and intrauterine devices (IUDs) by WOCBP 
subject or male subject’s WOCBP partner. Female partners of male subjects 
participating in the study may use hormone-based contraceptives as one of the 
acceptable methods of contraception since they will not be receiving study drug 
• Nonhormonal IUDs 
• Bilateral Tubal ligation 
• Vasectomy 
• Sexual Abstinence 

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o It is not necessary to use any other method of contraception when complete 
abstinence is elected. 
o WOCBP participants who choose complete abstinence must continue to 
have pregnancy tests. 
o Acceptable alternate methods of highly effective contraception must be 
discussed in the event that the WOCBP participants chooses to forego 
complete abstinence. 
17. Participant must, in the opinion of the Investigator, be able to comply with study procedures 
 
18. Patients must be able to understand the study procedures and agree to participate in the study 
by providing written informed consent (or have legally authorized representative sign on 
patient’s behalf if patient physically unable to sign consent due to neurologic deficit)  
4.2 Exclusion Criteria 
Any of the following would exclude the subject from participation in the study: 
 
1.  Contrast-enhancing tumor in brainstem or spinal cord (subjects do not need spinal MRI for 
screening, but known spinal cord tumor is exclusionary) 
 
2.  Diffuse leptomeningeal disease  
 
3. Prior bevacizumab or other vascular endothelial growth factor (VEGF/VEGFR) inhibitors 
(exception: prior bevacizumab is allowed if it was administered for the treatment of radiation 
necrosis rather than progressive tumor and was stopped at least 4 weeks prior to MRI showing 
demonstrating tumor progression). 
 
4. Patients with clinically significant mass effect or midline shift (e.g., 1-2 cm of midline shift) 
 
5. Use of any immunosuppressive medication other than steroids, including but not limited to 
antimetabolites, calcineurin inhibitors, and/or anti-TNF agents within six months of start of study 
drug  
 
6. Prior diagnosis of immunodeficiency 
 
7. Prior solid organ or bone marrow transplantation  
 
8. Autoimmune or connective tissue disease that is EITHER (a) actively flaring OR (b) has 
required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, 
corticosteroids, or immunosuppressive drugs).  
EXCEPTIONS: Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone 
replacement, adrenal insufficiency requiring only replacement dose corticosteroids, skin 
disorders (such as vitiligo, psoriasis, pemphigus, or alopecia) controlled with topical 
medications, or conditions not expected to recur in the absence of an external trigger are 
permitted to enroll. Patients with asthma that is not actively flaring are allowed. Patients with 
history of Grave’s disease that is previously treated with thyroidectomy or radioiodine are 
allowed. Patients with celiac disease whose symptoms are controlled with a gluten-free diet are 
allowed. Patients with rheumatoid arthritis and other arthropathies such as ankylosing 

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spondylitis, Sjogren’s syndrome, Raynaud syndrome, and patients with positive serologies, such 
as antinuclear antibodies (ANA) or anti-thyroid antibodies, should be evaluated for the presence 
of target organ involvement and potential need for systemic treatment but should otherwise be 
eligible.  
 
9. History of non-infectious pneumonitis that required steroid treatment  
 
10. Known active hepatitis B virus (HBsAg reactive) or active hepatitis C virus (HCV RNA 
detectable by PCR) 
 
11. Human immunodeficiency virus (HIV)-positive patients on antiretroviral therapy 
 
12. Patients with a prior or concurrent malignancy whose natural history or treatment has the 
potential to interfere with the safety or efficacy assessment of the investigational regimen are 
excluded from this trial. Otherwise, patients with prior or concurrent malignancy are eligible.  
 
13. Any serious, uncontrolled medical disorder, nonmalignant systemic disease, or active, 
uncontrolled infection that, in the opinion of the investigator, would put the subject at undue risk 
from the study treatment.  
 
14. Patients with uncontrolled or significant cardiovascular disease including, but not limited to, 
any of the following are ineligible:  
• Myocardial infarction or uncontrolled angina within 90 days prior to consent 
• History of clinically significant arrhythmia (such as ventricular tachycardia, 
ventricular fibrillation, or torsades pointes) 
• History of cardiomyopathy, pericarditis, significant pericardial effusion, 
myocarditis, or New York Heart Association (NYHA) functional class III-IV 
congestive heart failure  
 
15. Known hypersensitivity to another monoclonal antibody that cannot be controlled with 
standard measures (e.g., antihistamines and corticosteroids) 
 
16. Prisoners or subjects who are involuntarily incarcerated   
 
17. Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness  
 
18. Pregnant women are excluded  
 
19. Received a live vaccine within 30 days prior to first dose of study drug. Examples include 
but are not limited to measles, mumps, rubella, varicella/zoster, yellow fever, rabies, Bacillus 
Celmette-Guerin (BCG), and typhoid. Intranasal influenza vaccines are not allowed.  
20. Participant must not be simultaneously enrolled in any interventional clinical trial 
 
 
5 STUDY INTERVENTION 

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5.1 Description of Study Drugs 
5.1.1. INCMGA00012 
INCMGA00012 (also known as MGA012) is a humanized, hinge-stabilized, IgG4κ mAb that 
recognizes human PD-1. INCMGA00012 contains a human IgG4 Fc domain to limit effector 
function while retaining neonatal FcRn binding to extend circulating t½. INCMGA00012 is 
designed to target PD-1–expressing cells, including T cells, and sustain/restore their effector 
function by blocking checkpoint inhibitory interactions between PD-1 and its 2 ligands, PD-L1 
and PD-L2. INCMGA00012 is derived from a murine mAb clone that was generated using 
standard hybridoma technology from mice immunized with a His-tagged, human PD-1 
extracellular domain molecule. INCMGA00012 drug product is formulated at a concentration of 
25 mg/mL in sodium acetate trihydrate, acetic acid, sucrose, and polysorbate 80 at pH 5.1. 
 
Complete physical, chemical, and pharmaceutical properties and formulations for 
INCMGA00012 are available in the Investigator’s Brochure. 
 
5.1.2. INCAGN01876 
INCAGN01876 (previously designated as AGEN1876) is a recombinant, humanized 
immunoglobulin G1 (IgG1) kappa (κ) mAb that binds to the extracellular domain of the human 
tumor necrosis factor receptor superfamily member 18 (TNFRSF18), also known as 
glucocorticoid-induced TNFR-related protein (GITR). INCAGN01876 drug product is 
formulated at a concentration of 10 mg/mL in histidine, sucrose, and polysorbate 80 at pH 6.0. 
 
Complete physical, chemical, and pharmaceutical properties and formulations for 
INCAGN01876 are available in the Investigator’s Brochure. 
 
5.2 Receipt of Investigational Agents  
The investigational agents will be shipped from Incyte Corporation to: 
Penn Investigational Drug Service Central 
3400 Civic Center Blvd, 10th Floor (10-020) 
Philadelphia, PA 19104 
215-662-7911 (phone) 
215-615-1308 (fax) 
 
Receipt and product verification will be overseen by the Penn Investigational Drug Service 
(IDS). Shipments of study drugs will be arranged by Penn IDS on an as-needed basis. 
Certificates of delivery should be signed by Penn IDS. 
5.3 Storage of study products 
5.3.1. INCMGA00012 
INCMGA00012 drug product should be stored under refrigeration at 2°C to 8°C.  
5.3.2. INCMGA01876 
INCAGN01876 drug product should be stored under refrigeration at 2°C to 8°C.  

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5.4 Study drug Accountability  
Dispensation of study drugs from IDS should be recorded in the appropriate sections of the 
eCRF.  IDS will only dispense study drugs to study subjects for whom the PI or delegated team 
member has signed an order. The study drugs provided for this study will be used only as 
directed in the study protocol.  
 
The Investigator or designee is responsible for maintaining accurate dispensing records of the 
study treatments throughout the clinical study. The study treatment accountability log includes 
information including a patient identifier, amount and date dispensed, and amount and date 
returned to the pharmacy. Product returned to the pharmacy will be stored under the same 
conditions as products not yet dispensed but will be marked as 'returned' and kept separate from 
the products not yet dispensed.  
5.5 Study drug Administration 
 5.5.1 Administration of INCMGA00012  
INCMGA00012 is administered as an IV infusion over 60 minutes for the first infusion. If well 
tolerated, it may be administered over 30 minutes for subsequent treatments.  On days when both 
study drugs are due to be administered, INCMGA00012 study product is administered first prior 
to administration of INCAGN01876.  The only dose of INCMGA00012 used for this study is 
500mg. There is no dose escalation or reduction. A 1-hour observation period is recommended 
after the INCMGA00012 infusion prior to beginning the INCAGN01876 infusion. 
 
Infusion-related reactions (including anaphylaxis or cytokine release syndrome) may be 
associated with the administration of therapeutic antibodies. Of 199 prior study participants who 
have received infusions of INCMGA00012 in Study INCMGA 0012-101, 5 participants have 
experienced 1 infusion-related reaction each (see IB). This does not exceed the expected 
incidence of IRRs for the PD-1 inhibitor class. Infusion-related reactions were observed in Study 
INCMGA 0012-101 regardless of whether prophylaxis was administered; therefore, routine 
prophylaxis is not recommended. Secondary prophylaxis is recommended for participants who 
have experienced IRRs to INCMGA00012. Participants who experience life-threatening infusion 
reactions should not be retreated with INCMGA00012. Infusions reactions should be managed 
according to the guidelines in Section 5.8.2. 
 
5.5.2 Administration of INCAGN01876  
INCAGN01876 is administered as an IV infusion over 60 minutes for the first infusion. If well 
tolerated, it may be administered over 30 minutes for subsequent treatments.  On days when both 
study drugs are due to be administered, INCMGA00012 study product is administered first prior 
to administration of INCAGN01876. The only dose of INCAGN01876 used for this study is 
300mg. There is no dose escalation or reduction. A 1-hour observation period is recommended 
after the INCMGA00012 infusion prior to beginning the INCAGN01876 infusion. 
 
Preclinical assessments used to evaluate theoretical safety concerns with INCAGN01876 
eliciting adverse proinflammatory infusion reactions did not induce cytokines that in vivo would 
be predictive of CRS in participants, so the risk of significant infusion reactions is considered to 
be low. For participants who have an infusion reaction associated with administration of 
INCAGN01876, signs and symptoms would usually develop during or shortly after drug infusion 

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and generally resolve completely within 24 hours of completion of infusion. Infusions reactions 
should be managed according to the guidelines in Section 5.8.2. 
5.6 Concomitant Medications: 
1) Following start of study drug, concomitant medications and therapies deemed necessary for 
the supportive care and safety of the subject are allowed, provided their use is documented in the 
subject records and on the appropriate case report form.  This includes corticosteroids of any 
dosage for the management of brain edema related to the tumor and/or study drugs.  The 
administration of any other anticancer agents including chemotherapy and biologic agents (such 
as bevacizumab) is NOT permitted.  Similarly, the use of other concurrent investigational drugs 
is not allowed.  
 
2)  List of medications that are prohibited during this study: 
 
 
•  Any anticancer medications, including chemotherapy or biologic therapy other than the study 
medications 
• Any immunological-based treatment for any reason, with the exception of corticosteroids  
• Any investigational agents other than INCAGN01876 and INCMGA00012 
• Radiation therapy other than the SRS (8Gy x 3 fractions) administered as part of this protocol 
• Live vaccines. Examples include but are not limited to measles, mumps, rubella, 
varicella/zoster, yellow fever, rabies, Bacillus Celmette-Guerin (BCG), and typhoid. 
Intranasal influenza vaccines are not allowed. 
 
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the study.  
5.7 Study Drug Discontinuation Criteria 
Subjects must be permanently discontinued from BOTH study drugs (INCMGA00012 and 
INCAGN01876) if any one or more of the following occurs:  
• 
Grade 2 or higher toxicity [per NCI CTCAE v 5.0] that is at least possibly related to one of the 
study drugs AND does not improve with optimal medical management to grade 1 or less within 
12 weeks from last dose of study drugs or results in subject being unable to taper off 
corticosteroids (or, if on corticosteroids prior to the toxicity, unable to taper down to subject’s 
baseline/pre-toxicity dose) within 12 weeks from last dose of study drugs, with the following 
exceptions: 
o Grade 2 Nervous System toxicity (e.g., leg weakness, aphasia, 
etc) that is due to to intratumoral/peritumoral enlargement 
(contrast-enhancing or T2/FLAIR) or intratumoral/peritumoral 
cerebral edema  
o Grade 3-4 Nervous System toxicity (e.g., leg weakness, aphasia, 
etc) that is due to to intratumoral/peritumoral enlargement 
(contrast-enhancing or T2/FLAIR) or intratumoral/peritumoral 
cerebral edema AND improves to grade 2 or less within 7 days 
of optimal medical management  
o Grade 3 Cerebral Edema  
o Grade 4 Cerebral edema that improves to grade 3 within 7 days 
of optimal medical management 

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o Any grade endocrinopathy that is controlled by hormone 
replacement 
• 
Grade 4 irAE, as defined in Section 9.1.2, Immune-Related Adverse Events, with the 
following exception: 
o Grade 4 endocrinopathy that is controlled by hormone 
replacement 
• 
Grade 3 hepatitis, pneumonitis, nephritis, myocarditis, pericarditis, encephalitis, myasthenia 
gravis, posterior- or pan-uveitis, episcleritis, peripheral neuropathy (including Guillain-Barre 
syndrome), autoimmune hemolytic anemia, acquired hemophilia, or autonomic neuropathy 
• 
Recurrent Grade 2 pneumonitis  
• 
Any grade transverse myelitis 
•    The subject becomes pregnant.  
•    Consent is withdrawn by the subject.  
Note: Consent withdrawn means that the subject can no longer be followed and no 
additional data can be collected. Subjects may choose to discontinue study treatment and 
remain in the study to be followed for progression and survival.  
•    Further participation would be injurious to the subject's health or well-being, in the 
investigator's medical judgment.  
•   Confirmed radiographic progression of disease per modified RANO criteria (as defined in 
Section 7). 
o Exception: If subject meets radiographic criteria for PD but then 
undergoes a surgical resection of the area of radiographic PD per 
their treating oncologist’s recommendation, the patient may stay 
on study and resume study drugs postoperatively if (i) 
histopathology from this surgery demonstrates only therapy-
related changes and no viable tumor (scattered/rare atypical glial 
cells only would not count as viable tumor) AND (ii) there are 
no other, separate sites of PD on the immediate post-operative 
MRI.  
o Exception: If radiologic imaging within the first 6 months from 
the first dose of immunotherapy shows confirmed PD by 
mRANO criteria, participants not experiencing significant 
clinical decline may be allowed to continue study treatment for 
up to 3 months from the time of the scan showing confirmed PD. 
It is at the discretion of the treating physician whether to 
continue a participant on study treatment for up to 3 months 
pending confirmation of PD on follow-up imaging.  This clinical 
judgment decision should be based on the participant’s overall 
clinical condition, including performance status, clinical 
symptoms, and laboratory data.  Subjects may receive study 
treatment while waiting for confirmation of PD if they are not 
experiencing significant clinical decline and if: 
o the subject is believed to demonstrate clinical benefit 
from the study regimen as determined by the treating 
physician; 
o the subject is adequately tolerating study therapy  
•    The study is terminated by the Sponsor.  
•    The IRB withdraws approval for the study 

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• 
Any progression or recurrence of any malignancy, or any occurrence of another malignancy 
that requires active treatment  
• 
Occurrence of any AE that is related to either study drug that, in the judgment of the 
Investigator and/or Medical Director, compromises the subject's ability to continue study-
specific procedures or is considered to not be in the subject's best interest.  
 
A subject may be permanently discontinued from BOTH study drugs (INCMGA00012 and 
INCAGN01876) as follows:  
•     If, during the course of the study, a subject is found not to have met eligibility criteria, the 
medical monitor, in collaboration with the investigator, will determine whether the subject 
should be withdrawn from the study.  
•    If a subject is noncompliant with study procedures or study treatment in the investigator's 
opinion, the sponsor should be consulted for instruction on handling the subject.  
 
A subject must be permanently discontinued from ONE study drug (either INCMGA00012 OR 
INCAGN01876) and may continue the other study drug if any of the following occurs:  
•    The subject has a grade 3 or higher infusion reaction that is clearly linked to only one of the 
study drugs. The temporal relationship between study drug administration and the reaction 
must be such that no other reasonable explanation exists for the subject’s reaction beyond 
that specific study drug. If a subject has a grade 3 or higher infusion reaction and it is unclear 
which study drug was responsible, both study drugs must be permanently discontinued.  
 
 
Reasons and procedures for replacing subjects are detailed in Section 3.2 Replacement of 
Subjects.  
5.8 Management of Study Drug Toxicities  
 5.8.1. Supportive care for Immune-Related Adverse Events (irAEs) 
GITR represents an important immune control receptor.  It is anticipated that combining GITR 
agonism PD-1 inhibition could cause more frequent, more severe, and/or new immune-related 
toxicities compared to the well-described immune-related toxicity for single agent PD-1 
inhibition (Brahmer et al, J Clin Oncol 2018). For this reason, a variety of measures are included 
to mitigate these potential risks. These measures are consistent with published guidelines for 
immune-related AEs associated with anti−PD-1 drugs, but are meant to apply to any suspected 
immune-related AEs from other immuno-oncology agents such as the combination of 
INCMGA00012 and INCAGN01876   
 
Immune-related AEs may be defined as an AE of unknown etiology, associated with drug 
exposure and consistent with an immune phenomenon. Immune-related AEs may be predicted 
based on the nature of the INMGA0012 and INCAGN01876 compounds, their mechanism of 
action, and the extensive 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. Subjects who develop a ≥ Grade 2 
irAE should be discussed immediately with the principal investigator.  

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 Recommendations for management of specific immune-mediated AEs such as pneumonitis, 
enterocolitis, hepatitis, dermatitis, neuropathies, endocrinopathies, and other immune-mediated 
AEs, and are based on recently published guidelines for the management of immunotherapy-
related toxicities that have recently been published by the National Comprehensive Cancer 
Network (NCCN) in partnership with the American Society of Clinical Oncology (ASCO), 
available here: 
https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf 
and here: 
http://ascopubs.org/doi/10.1200/JCO.2017.77.6385 
and described in detail in Appendix 1 with specific application to this protocol.  These 
recommendations include management of the toxicity itself, as well as guidance for dose 
interruptions/delays of the investigational agents. There are no dose reductions or dose 
escalations permitted for either investigational agent.  
5.8.2. Management of infusion-related reactions  
Emergency equipment and medication for the treatment of potential adverse effects (e.g. 
antihistamines, bronchodilators, IV saline, corticosteroids, acetaminophen, and or epinephrine) 
secondary to infusion of INCMGA00012 and INCAGN01876 must be available for immediate 
use. 
 
Acute infusion reactions are defined as any AE that occurs during the infusion or within 2 hours 
after the infusion is completed. Emergency equipment and medication for the treatment of these 
potential adverse effects (eg, antihistamines, bronchodilators, IV saline, corticosteroids, 
acetaminophen, and/or epinephrine) must be available for immediate use.  
 
Acute infusion reactions can include cytokine release syndrome, angioedema, or anaphylaxis, 
and differ from allergic/hypersensitive reactions, although some of the manifestations are 
common to both AEs. Signs and symptoms usually develop during or shortly after drug infusion 
and generally resolve during the infusion or within one day after the infusion. 
 
Signs/symptoms may include: allergic reaction/hypersensitivity (including drug fever); arthralgia 
(joint pain); bronchospasm; cough; dizziness; dyspnea (shortness of breath); fatigue (asthenia, 
lethargy, malaise); headache; hypertension; hypotension; myalgia (muscle pain); nausea; 
pruritus/itching; rash/desquamation; rigors/chills; sweating (diaphoresis); tachycardia; tumor 
pain (onset or exacerbation of tumor pain due to treatment); urticaria (hives, welts, wheals); and 
vomiting.  The infusion should be interrupted if any of the following AEs are observed: 
• Cough 
• Rigors/chills 
• Rash, pruritus (itching) 
• Urticaria (hives, welts, wheals) 
• Diaphoresis (sweating) 
• Hypotension 
• Dyspnea (shortness of breath) 
• Vomiting 
• Flushing 
 
The reaction(s) should be treated symptomatically, and the infusion may be restarted at 

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50% of the original rate. 
 
If Investigators feel there is a medical need for treatment or discontinuation of the infusion 
other than described above, they should use clinical judgment to provide the appropriate 
response according to typical clinical practice. 
 
The infusion should be terminated and NOT restarted if any of the following AEs occur: 
• Anaphylaxis 
• Laryngeal/pharyngeal edema or severe bronchospasm 
• Chest pain 
• Seizure 
 
5.8.3. Management of cerebral edema  
Due to the immunologic nature of anti-PD-1 and GITR therapy, cerebral edema could 
theoretically result as a consequence of immune infiltration of the brain.  In addition, SRS is 
expected to elicit cerebral edema. Symptoms related to cerebral edema may include headache or 
neurologic deficit that is either new or worsened. Participants with any signs or symptoms of 
cerebral edema in the investigator’s judgment should be treated as clinically appropriate 
including initiation or increased dosing of systemic corticosteroids, osmotic diuretics, and/or 
surgical decompression. Subsequent study drug treatment should be immediately interrupted if 
significant clinical symptoms attributable to cerebral edema in the investigator’s judgment 
develop.  Treatment with additional study drug may only be re-initiated if clinically significant 
symptoms attributable to cerebral edema have stabilized or significantly resolved in the 
investigator’s judgment.  
 
Participants who develop grade 4 cerebral edema (CTCAE v5) attributable to study drug 
administration should not receive further study drug.  Grade 4 cerebral edema is defined as life-
threatening or requiring urgent intervention. For this study, urgent intervention refers to 
urgent/emergent intensive care unit admission, intubation for hyperventilation, administration of 
hypertonic or hyperosmotic agents, and/or urgent/emergent surgical decompression.  
 
 
5.9 Disposal of Investigational Products 
Study drug containers should not be destroyed until permitted by the Sponsor. Any unused study 
drug will be destroyed at the study site, per SOP.   
5.10 Surgical Resection (Cohort B only)   
For subjects enrolled onto cohort B, surgical resection for maximal safe tumor resection will be 
performed according to standard clinical practice. There is no aspect of this surgery that is 
different from standard practice.  
5.11 Radiation Planning and Delivery (Cohort A; Cohort B, sub-arm #1 only)   
Treatment will consist of 24 Gy delivered in 3 fractions over 3 consecutive business days. 
Subjects may receive 3 fractions every other day (non-consecutively) for logistical reasons 
relating to COVID-19. Therapy will be delivered according to standard guidelines of brain 

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directed SRS using the Cyberknife system or other linear accelerators commissioned for SRS.  
Patients will be simulated as per standard procedures with a CT and MRI scan in the treatment 
position with the patient immobilized in a thermoplastic mask. CT scan slice thickness will be 
1.5mm.  MRI images obtained at the time of simulation or diagnostic images will be fused as per 
department guidelines by a qualified physicist or dosimetrist and alignment confirmed by the 
treating radiation oncologist. For daily treatments patients will be immobilized in the custom 
thermoplastic masks created at simulation and undergo standard image guidance per routine care 
(6D skull tracking for Cyberknife treatments and volumetric cone beam CT for LINAC based 
treatments).  
 
The gross tumor volume (GTV) will be defined as the enhancing tumor on the T1 post 
Gadolinium MRI scan.  No expansion to a clinical target volume (CTV) will be applied (ie 
GTV=CTV).  A planning target volume (PTV) expansion to account for setup uncertainty will be 
1-2mm.  Normal tissues to be contoured include the brainstem, optic nerves, optic chiasm, eyes, 
lens, cochlea. All radiation plans will undergo standard peer review prior to imitation of therapy. 
Target coverage and dose constraints are listed below in Table 7: 
 
Table 7. Radiation Guidelines 
 
Dose Metric 
Per Protocol 
Variation excepted 
PTV_2400 
Greater than or equal to 95% 
of the PTV should receive 
greater than or equal to 22.8 
Gy.  Max dose less than 28.8 
Gy. 
Greater than or equal to 90% 
of the PTV should receive 
greater than or equal to 22.8 
Gy.  Max dose less than 28.8 
Gy. 
Brainstem 
Maximum dose from current 
plan (0.03cc) <23 Gy 
 
Maximum dose from 
combined plans (0.03cc)< 
68Gy 
 
Optic Chiasm 
Maximum dose from current 
plan (0.03cc) <17 Gy 
 
Maximum dose from 
combined plans (0.03cc)< 
63Gy 
 
Optic Nerve 
Maximum dose from current 
plan (0.03cc) <17 Gy 
 
Maximum dose from 
combined plans (0.03cc)< 
63Gy 
 
Eyes 
Maximum dose from current 
plan (0.03cc) <14 Gy 
 
 

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Maximum dose from 
combined plans (0.03cc)< 
58Gy 
Cochlea 
Maximum dose from current 
plan (0.03cc) <17 Gy 
 
Maximum dose from 
combined plans (0.03cc)< 
53Gy 
 
Mean dose from combined 
plans (0.03cc)< 50Gy 
 
Maximum dose from current 
plan (0.03cc) <25 Gy 
 
Maximum dose from 
combined plans (0.03cc)< 
60Gy 
 
Mean dose from combined 
plans (0.03cc)< 55Gy 
 
 
 
6    STUDY PROCEDURES 
Screening assessments are to be conducted within 14 days prior to initiating protocol therapy 
unless otherwise specified.  Screening assessments occurring prior to initiating study treatment 
do not need to be repeated on Cycle 1 Day 1 unless otherwise specified.  Screening laboratory 
assessments must be done within 7 days prior to initiating protocol therapy.   
 
For women of childbearing potential, as defined in the eligibility criteria, a pregnancy test must 
be completed within 7 days prior to initiating protocol therapy.  If a urine pregnancy test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required.   
 
The schedule of study procedures for the screening and intervention phases of the study for 
Cohort A is displayed in Table 8 and for Cohort B in Table 9.  The schedule of procedures for 
the follow-up phase of the study for both cohorts is displayed in Table 10.  
 

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Table 8: COHORT A (N=16): Schedule of Study Procedures, SCREENING AND INTERVENTION 
Study Week 
Screen 
W1 
W1 
W2 
W3 
W5 
W7 
 
Q 4  
weeks 
 
Q 8  
weeks 
EOT§ 
Cycle # (28-day cycles) 
  
Cycle 1 
Cycle 1 
Cycle 1 
Cycle 1 
Cycle 2 
Cycle 2 
Cycle X 
Cycle X  
Cycle X 
(pre-odd 
cycles 
only)  
Day (and window) 
-14 to 1 
1 
5 ± 2 
8 
15 ± 2 
1 ± 2 
15 ± 2 
1 ± 2 
15 ± 2 
1 ± 2 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Review Inclusion/Exclusion 
Criteria (Section 4) 
X 
 
 
 
 
 
 
 
 
 
 
Karnofsky Performance Status 
(Section 7) 
X 
X 
 
 
X 
X 
X 
X 
X 
 
X 
Demographics/Medical History 
(Section 7) 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Assessment (targeted 
after screening visit) 
(Section 7) 
X 
X 
 
 
X 
X 
X 
X 
X 
 
X 
 
X 
Vital Signs: BP, HR, RR 
(Section 7) 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
X 
ECG 
(Section 7) 
 
 
 
 
 
 
 
 
 
 
 
Weight (Section 7) 
X 
X 
 
 
 
X 
 
X 
 
 
X 
Height (Section 7) 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test (Section 7; 
within 7d of first dose of study 
drug) 
X 
 
 
 
 
 
 
X 
 
 
X 
Concomitant Medications 
(Section 7) 
 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
 

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Study Week 
Screen 
W1 
W1 
W2 
W3 
W5 
W7 
 
Q 4  
weeks 
 
Q 8  
weeks 
EOT§ 
Cycle # (28-day cycles) 
  
Cycle 1 
Cycle 1 
Cycle 1 
Cycle 1 
Cycle 2 
Cycle 2 
Cycle X 
Cycle X  
Cycle X 
(pre-odd 
cycles 
only)  
Day (and window) 
-14 to 1 
1 
5 ± 2 
8 
15 ± 2 
1 ± 2 
15 ± 2 
1 ± 2 
15 ± 2 
1 ± 2 
 
Clinical Laboratory Evaluation – 
non-endocrine (CBC, CMP, 
Mag, Phos, LDH) 
(Section 7; within 7d of first 
dose of study drug; Labs can be 
collected up to -3 days prior to 
treatment).  
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
X 
HBV/HCV screening (Section 7) 
X 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory Evaluation – 
endocrine (TSH, T4) 
(Section 7) Labs can be collected 
up to -3 days prior to treatment. 
X 
 
 
 
 
 
 
 
 
X 
X 
Urinalysis 
(Section 7) 
X 
 
 
 
 
 
 
 
 
 
X 
Blood collected for 
INCAGN01876 PK  
(Section 7) 
 
X*** 
 
X 
X 
 
X 
X***† 
X***† 
 
 
Blood collected for 
INCAGN01876 ADA 
(Section 7) 
 
X 
 
 
X 
 
X 
 
X 
 
 
Blood collected for correlatives 
(Section 7) 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 

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Study Week 
Screen 
W1 
W1 
W2 
W3 
W5 
W7 
 
Q 4  
weeks 
 
Q 8  
weeks 
EOT§ 
Cycle # (28-day cycles) 
  
Cycle 1 
Cycle 1 
Cycle 1 
Cycle 1 
Cycle 2 
Cycle 2 
Cycle X 
Cycle X  
Cycle X 
(pre-odd 
cycles 
only)  
Day (and window) 
-14 to 1 
1 
5 ± 2 
8 
15 ± 2 
1 ± 2 
15 ± 2 
1 ± 2 
15 ± 2 
1 ± 2 
 
Adverse Event / Unanticipated 
Problems Assessment (Section 
7) 
X 
X 
 
 
X 
X 
X 
X 
X 
 
X 
INCMGA00012 Administration     
(Section 5) 
 
X 
 
 
 
X 
 
X 
 
 
 
INCAGN01876 Administration 
(Section 5) 
 
X 
 
 
X 
X 
 
X 
X 
 
 
MRI brain (tumor assessment by 
mRANO criteria) (Section 7) 
X 
 
 
 
 
 
 
 
 
X* 
X†† 
SRS planning 
(Section 5) 
X 
 
 
 
 
 
 
 
 
 
SRS delivery**  
(Section 5) 
 
 
X 
 
 
 
 
 
 
 
 
 
* MRI scan should be performed within 7 days prior to the cycle start (and ideally within 3 days prior). Adjustments to this 7 day window 
are allowable per the treating physician’s discretion; however restaging scans MUST BE performed and reviewed before the subsequent 
cycle’s dose may be initiated  
**SRS delivery: Total 24 Gy delivered over 3 consecutive days (8 Gy per day). Subjects may receive 3 fractions every other day (non-
consecutively) for logistical reasons relating to COVID-19. Must start between 3 and 7 days after first dose of study drugs 
*** PK samples for INCAGN01876 collected pre-dose and at end of infusion on Cycle 1 Day 1 and Cycle 3 Day 15. All other PK draws 
for INCAGN01876 are pre-dose.  
† After the first 2 cycles, PK samples for INCAGN01876 are drawn only on Cycle 3 Day 15, Cycle 4 Day 1, Cycle 4 Day 15, and then only 
on day 15 of each cycle starting with Cycle 5 
†† MRI and mRANO assessment at EOT are only necessary if this has not already been performed within 28 days of the EOT visit 
§ EOT  visit occurs within 14 days from when the subject is taken off study.

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Table 9: COHORT B (N=16): Schedule of Study Procedures, SCREENING AND INTERVENTION 
Study Week 
Screen 
Neo-  
adjuvant 
week 
Peri-op weeks 
W1 
W2 
W3 
W5 
W7 
 
Q 4 
weeks 
 
Q 8 
weeks 
EOT§ 
Cycle # (28-day 
cycles) 
  
Neo- adjuvant 
cycle 
Pre-Op 
Post-Op 
Cycle 
1 
Cycle 1 
Cycle 1 
Cycle 2 
Cycle 2 
Cycle X 
Cycle X 
Cycle X 
(pre-odd 
cycles 
only) 
Day (and window) 
-14 to 1 
1 
5 ± 2 
Within 1 
day of 
surgery 
 
Up to 3 
days from 
surgery 
1 ± 2 
8 
15 ± 2 
1 ± 2 
15 ± 2 
1 ± 2 
15 ± 2 
1 ± 2 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review Inclusion 
/Exclusion Criteria 
(Section 4) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Karnofsky 
Performance Status    
(Section 7) 
X 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
X 
Demographics/ 
Medical History 
(Section 7) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Assessment(targeted 
after screening 
(Section 7) 
X 
X 
 
 
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
       X 
 
 
 
 
 
X 
 
 
 
 
 

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Study Week 
Screen 
Neo-  
adjuvant 
week 
Peri-op weeks 
W1 
W2 
W3 
W5 
W7 
 
Q 4 
weeks 
 
Q 8 
weeks 
EOT§ 
Cycle # (28-day 
cycles) 
  
Neo- adjuvant 
cycle 
Pre-Op 
Post-Op 
Cycle 
1 
Cycle 1 
Cycle 1 
Cycle 2 
Cycle 2 
Cycle X 
Cycle X 
Cycle X 
(pre-odd 
cycles 
only) 
Day (and window) 
-14 to 1 
1 
5 ± 2 
Within 1 
day of 
surgery 
 
Up to 3 
days from 
surgery 
surgery 
1 ± 2 
8 
15 ± 2 
1 ± 2 
15 ± 2 
1 ± 2 
15 ± 2 
1 ± 2 
 
Vital Signs: BP, 
HR, RR (Section 7) 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
ECG 
(Section 7) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight (Section 7) 
X 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
Height  (Section 7) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
(Section 7; within 
7d of first dose of 
study drug) 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Concomitant 
Medications 
(Section 7) 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
Clinical Laboratory 
Evaluation – non-
endocrine (CBC, 
CMP, Mag, Phos, 
LDH) 
(Section 7; within 
7d of first dose of 
study drug; Labs 
can be collected up 
to -3 days prior to 
treatment ) 
X 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 

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Study Week 
Screen 
Neo-  
adjuvant 
week 
Peri-op weeks 
W1 
W2 
W3 
W5 
W7 
 
Q 4 
weeks 
 
Q 8 
weeks 
EOT§ 
Cycle # (28-day 
cycles) 
  
Neo- adjuvant 
cycle 
Pre-Op 
Post-Op 
Cycle 
1 
Cycle 1 
Cycle 1 
Cycle 2 
Cycle 2 
Cycle X 
Cycle X 
Cycle X 
(pre-odd 
cycles 
only) 
Day (and window) 
-14 to 1 
1 
5 ± 2 
Within 1 
day of 
surgery 
 
Up to 3 
days from 
surgery 
1 ± 2 
8 
15 ± 2 
1 ± 2 
15 ± 2 
1 ± 2 
15 ± 2 
1 ± 2 
 
Clinical laboratory 
Evaluation – 
endocrine (TSH, 
T4) 
(Section 7) Labs can 
be collected up to -3 
days prior to 
treatment.  
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
Urinalysis  
(Section 7) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
HBV/HCV 
screening (Section 
7) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood collected for 
INCAGN01876 PK  
(Section 7) 
 
 
 
 
 
X*** 
X 
X 
 
X 
X† 
X***† 
 
 
Blood collected for 
INCAGN01876 
ADA (Section 7) 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
Blood collected for 
correlatives 
(Section 7) 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 

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Study Week 
Screen 
Neo-  
adjuvant 
week 
Peri-op weeks 
W1 
W2 
W3 
W5 
W7 
 
Q 4 
weeks 
 
Q 8 
weeks 
EOT§ 
Cycle # (28-day 
cycles) 
  
Neo- adjuvant 
cycle 
Pre-Op 
Post-Op 
Cycle 
1 
Cycle 1 
Cycle 1 
Cycle 2 
Cycle 2 
Cycle X 
Cycle X 
Cycle X 
(pre-odd 
cycles 
only) 
Day (and window) 
-14 to 1 
1 
5 ± 2 
Within 1 
day of 
surgery 
 
Up to 3 
days from 
surgery 
1 ± 2 
8 
15 ± 2 
1 ± 2 
15 ± 2 
1 ± 2 
15 ± 2 
1 ± 2 
 
Adverse Event / 
Unanticipated 
Problems 
Assessment 
(Section 7) 
X 
X 
 
X 
 
 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
INCMGA00012  
Administration 
(Section 5) 
 
X††   
 
 
 
X 
 
 
X 
 
X 
 
 
 
INCAGN01876 
Administration 
(Section 5) 
 
X††   
 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
MRI brain (tumor 
assessment by 
mRANO criteria) 
(Section 7) 
X 
  
  
 
 
 
 
 
  
  
 
 
X* 
 X††† 
SRS planning** 
(Section 5) 
 X 
 
  
 
 
 
 
 
  
  
 
 
  
  
SRS delivery** 
(Section 5) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Surgical Resection; 
tissue for 
correlatives 
(Section 7) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
* MRI scan should be performed within 7 days prior to the cycle start (and ideally within 3 days prior). Adjustments to this 7-day window 
are allowable per the treating physician’s discretion; however restaging scans MUST BE performed and reviewed before the subsequent 
cycle’s dose may be initiated  

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**SRS delivery: Total 24 Gy delivered over 3 consecutive days (8 Gy per day). Subjects may receive 3 fractions every other day (non-
consecutively) for logistical reasons relating to COVID-19. Must start between 3 and 7 days after first dose of study drugs 
*** PK samples for INCAGN01876 collected pre-dose and at end of infusion on Cycle 1 Day 1 and Cycle 3 Day 15. All other PK draws 
for INCAGN01876 are pre-dose.  
† After the first 2 cycles, PK samples for INCAGN01876 are drawn only on Cycle 3 Day 15, Cycle 4 Day 1, Cycle 4 Day 15, and then only 
on day 15 of each cycle starting with Cycle 5 
†† For the neoadjuvant dose(s) of study drugs INCMGA00012 and INCAGN01876, the subject will be assigned to receive the combination 
of INCMGA00012 and INCAGN01876, or the combination of INCMGA00012 and INCAGN01876 plus SRS.  After surgery ALL subjects 
will resume the combination of both INCMGA00012 and INCAGN01876 
††† MRI and mRANO assessment at EOT are only necessary if this has not already been performed within 28 days of the EOT visit 
§ EOT  visit occurs within 14 days from when the subject is taken off study

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Table 10: Schedule of study procedures, FOLLOW-UP 
Procedure 
Safety visit 
Safety follow-up  
Disease Status and 
Survival  
30 d after EOT  (+/- 
7 d) 
12 W (+/-14 d) after 
EOT 
Q12W after EOT (+/- 
14d) 
Karnofsky Performance Status 
(Section 7) 
X 
 
 
Targeted Physical Assessment 
(Section 7 
X 
 
 
Vital Signs: BP, HR, RR, weight 
(Section 7) 
X 
 
 
Prior/Concomitant Medications 
(Section 7) 
X 
X 
 
Clinical Laboratory Evaluation (CBC, 
CMP, Mag, Phos, LDH)  
(Section 7) 
X 
 
 
Urinalysis 
(Section 7) 
X 
 
 
Clinical laboratory Evaluation – 
endocrine (TSH, T4) 
(Section 7) 
X 
 
 
Urine Pregnancy Test 
(Section 7) 
X 
 
 
Adverse Event / Unanticipated 
Problems Assessment 
(Section 7) 
X 
X* 
 
MRI brain (tumor assessment) 
(Section 7) 
 
 
X 
Subject Vital Status  
(Collection of survival information 
every 3 months until death, lost to 
follow-up, or withdrawal of study 
consent) 
 
 
X 
* Only immune related Adverse Events are to be collected at the 12-week safety follow- up timepoint (see sections 
1.3.1.3 and 1.3.2.3). 
 
 
 

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6.1 Unscheduled Visits 
During the conduct of the study, there are multiple situations that may require the subject to 
come to the research site for an unscheduled visit.  Reasons for an unscheduled visit include but 
are not limited to the following: 
• Subject missed the visit window 
• Subject experienced an AE and needed to be seen for follow-up 
• Due to lab results, the investigator has determined that for the welfare of the subject, 
she or he should be seen sooner than previously scheduled  
 
The data from these visits will be recorded just as any study visit.  
6.2. Subject Withdrawal from the Study 
Subjects may withdraw consent for the study at any time for any reason without impact to their 
care. In addition, a subject may be withdrawn by the investigator or the sponsor if enrollment in 
the study is inappropriate, lack of adherence to the intervention or study procedures or visit 
schedules, the study plan is violated, or for administrative and/or other safety reasons. It is 
documented whether or not each subject completes the clinical study. If the subject actively 
withdraws consent for collection of follow-up data (i.e., subsequent anticancer treatments, safety 
follow-up, and survival), then no additional data collection occurs; however, all subjects are 
informed of the option to discontinue treatment and/or study assessments but allow collection of 
information in the follow-up period of the study. In the event that the latter occurs, the end-of-
treatment (EOT) visit should be conducted (see Table 8 and Table 9 for EOT visit procedures).  
Thereafter, the subject will return for follow-up visits for safety and disease/survival status, with 
procedures as outlined above in Table 10.  
 
If a subject withdraws from the study and has not yet received a dose of study drug, that subject 
is replaced according to the procedure outlined in Section 3.2; Replacement of Subjects.  
 
7   STUDY EVALUATIONS AND MEASUREMENTS  
7.1 Demographic and Medical Record Review 
The following variables will be collected at screening and abstracted from the electronic medical 
chart: 
• Date of birth 
• Height 
• Weight 
• Medical History, Prior and Concomitant Medications, and Allergies 
o All concomitant medications must be recorded, and any medication received within 
30 days before screening must be recorded. 
o Concomitant medications include any prescription, over-the-counter, or 
natural/herbal preparations taken or administered during the study period.   
• Karnofsky Performance Status, as defined in Table 11:   
 

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least 5-10 minutes. BP and pulse will be collected from subjects before, during, and after each 
infusion at the following times (based on a 60-minute infusion): 
• Prior to the beginning of the infusion (measured once from approximately 30 minutes before up 
to 0 minutes [ie, the beginning of the infusion]) 
• Approximately 30 minutes during 60-minute infusions (halfway through infusion). Vitals 
should be obtained at approximately 15 minutes during subsequent 30-minute infusions (halfway 
through infusion).  
• At the end of the infusion (approximately 60 or 30 minutes ±5 minutes) 
• A 1-hour observation period is recommended after the INCMGA00012 infusion prior to 
beginning the INCAGN01876 infusion. 
7.4 Electrocardiogram (ECG) 
A 12-lead electrocardiogram will be performed at screening only.  
7.5 Clinical Laboratory Evaluations 
Blood sampling will be performed for the following laboratory evaluations (Table 12) according 
to the schedule outlined in Table 8 and Table 9: 
 
• 
Hematology 
• 
Chemistry and Liver Function 
• 
Additional electrolytes 
• 
 Endocrine 
• 
 Hepatitis screening 
• 
 Urinalysis 
 
Table 12: Clinical Laboratory Tests 
Category 
Tests 
Hematology 
RBC, hemoglobin, hematocrit, platelet count, WBC with 
differential 
Chemistry and Liver 
function tests 
(comprehensive metabolic 
panel) 
Basic metabolic panel, LDH, AST, ALT, total Bilirubin (with 
direct and indirect components), alkaline phosphatase  
Additional electrolytes 
Magnesium, phosphorus 
Endocrine 
TSH, free T4 
Hepatitis screening 
HBV surface antigen (HBsAg), HCV viral load (RNA quant) 
Urine 
Microscopic Urinalysis 
7.6 Pregnancy Testing 
WOCBP are required to have a urine or serum pregnancy test performed during screening and 
this test must be completed within 7 days before the first dose of study drug. WOCBP must 
exhibit a negative serum or urine pregnancy (minimum sensitivity 25 IU/L or equivalent units of 
HCG) within 7 days prior to the start of study drug. Pregnancy testing will be performed as 
outlined in Table 8 and Table 9; this includes the EOT visit, although a pregnancy test is not 

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required if a subject is going to hospice. Urine pregnancy tests will be conducted during the 
intervention phase of the study only as medically indicated.  If a urine pregnancy test is positive 
or cannot be confirmed as negative, the results should be confirmed with a serum pregnancy test. 
If the serum pregnancy test is negative after a urine test was positive, the investigator will assess 
the potential benefit/risk to the subject and determine whether it is in the subject's best interest to 
resume study drug and continue participation in the study.  A serum pregnancy test should also 
be repeated at the EOT visit.  
 
7.7 Efficacy Evaluations 
7.7.1. Anti-Tumor Effect Definitions 
Modified Response Assessment in Neuro-Oncology (RANO) criteria (Ellingson et al, 
Neurotherapeutics 2017) will be used to assess for tumor response and progression, with 
definitions as outlined below. Radiologic response will be assessed by comparing the 
pretreatment baseline and on-treatment MRI scans. Radiologic progression will be determined by 
using the smallest tumor measurement at either the pretreatment baseline or after initiation of 
study medication.  MRI scans will be performed no less frequently than every 8 weeks. The MRI 
scan should be performed within 7 days prior to a cycle start (and ideally within 3 days prior). 
Adjustments to this 7 day window are allowable per the treating physician’s discretion; however 
restaging scans MUST BE performed and reviewed before the subsequent cycle’s dose may be 
initiated.  MRIs will be interpreted by the attending neuro-radiologist at the University of 
Pennsylvania assigned as a sub-investigator on this study. 
 
Measurable disease should be defined as contrast enhancing lesions with a minimum size of both 
perpendicular measurements greater than or equal to 10mm. For example, if the largest diameter 
is 15 mm but the perpendicular diameter is 8 mm, this would constitute non-measurable disease. 
Up to a total of five target measurable lesions should be defined and ranked from largest to 
smallest. Non-measurable disease should be defined as lesions that are too small to be measured 
(less than 1 cm in both perpendicular dimensions), lesions that lack contrast enhancement (non-
enhancing disease), or lesions that contain a poorly defined margin that cannot be measured or 
segmented with confidence.   
7.7.2. Response/Progression Categories  
 
The following definitions for disease response and progression will be used according to the 
following MRI and clinical criteria: 
Complete Response (CR): Requires all of the following: 
1. Disappearance of all enhancing measurable and non-measurable disease sustained for at 
least 4 weeks.  In the absence of a confirming scan at least 4 weeks later, this scan will be 
considered only stable disease.   
2. No new lesions 
3. Stable or improved non-enhancing (T2/FLAIR) lesions 
4. Patients must be off corticosteroids (or on physiologic replacement doses only). 
5. Stable or improved clinical assessments 

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Partial Response (PR): Requires all of the following: 
1. ≥50% decrease in sum of products of perpendicular diameters of all measurable enhancing 
lesions compared with baseline, sustained for at least 4 weeks. In the absence of a 
confirming scan at least 4 weeks later, this scan will be considered only stable disease.   
2. No progression of non-measurable disease 
3. No new lesions 
4. Stable or improved non-enhancing (T2/FLAIR) lesions 
5. Steroid dose should be the same or lower compared with baseline scan. 
6. Stable or improved clinical assessments. 
 
 Progressive Disease (PD) is defined by any of the following: 
 
1. ≥25% increase in sum of 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.  
2. Any new enhancing measurable lesion 
3. Clear clinical deterioration not attributable to other causes apart from tumor (e.g. seizures, 
medication adverse effects, therapy complications, stroke, infection) or attributable to 
changes in steroid dose.  The definition of clinical deterioration is left to the discretion of 
the investigator.  
4. Clear progression of non-measurable disease  
5. Failure to return for evaluation as a result of death or deteriorating condition. 
   
Stable Disease (SD): Requires all of the following: 
1. Does not qualify for CR, PR, or PD as defined above.  
2. Stable non-enhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids 
compared with baseline scan 
3. Clinically stable 
The response and progression criteria to be used in this study are summarized in Table 13: 
 
 
Table 13. Summary of the RANO response Criteria: 

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Of note, patients who require increased corticosteroids within 2 weeks of MRI assessment 
(relative to the dose taken at the time of the prior assessment) cannot be classified as CR, PR, or 
SD and should be classified as non-evaluable at that time point. Conversely, patients who 
decrease corticosteroids within 2 weeks of MRI assessment (relative to the dose taken at the time 
of the prior assessment) cannot be classified as PD and should be classified as non-evaluable.  
 
Unscheduled Assessments: 
If an unscheduled assessment was performed and the subject has not progressed, every attempt 
should be made to perform the subsequent assessments at their scheduled visits (relative to the 
date of first study drug infusion). 
7.7.3.  Study continuation beyond initial progressive disease   
Immunotherapeutic agents including PD-1 inhibitors such as INCMGA00012 may produce 
antitumor effects by potentiating endogenous cancer-specific immune response, which may 
manifest as initial worsening of enhancement on MRI (i.e., pseudoprogression).  In addition, the 
response patterns seen with immunotherapeutics may extend beyond the typical time course of 
responses seen with cytotoxic agents, and can manifest a clinical response after an initial 
increase in tumor burden or even the appearance of new lesions. For these reasons, the immune-
related response criteria (irRC) have endorsed continuation of study therapy beyond radiographic 
evidence of progression for clinically stable patients undergoing immune based therapies 
(Seymour et al, Lancet Oncol 2017).  
 
Therefore, the following adaptations of the RANO criteria, as reflected in the recently published 
Immunologic Response Assessment in Neuro-Oncology (iRANO) criteria (Okada et al, Lancet 
Oncol 2015), will be used to assess tumor progression for patients treated on this study: 
 
o Potential Pseudoprogression:  If radiologic imaging within the 
first 6 months from the first dose of immunotherapy shows 
confirmed PD by mRANO criteria, as defined in the above 
section, participants not experiencing significant clinical decline 

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may be allowed to continue study treatment for up to 3 months 
from the time of the scan showing confirmed PD. Patients who 
have radiographic evidence of further progression after 3 
months, or who decline significantly any time, will be classified 
as progressive disease with the date of disease progression back-
dated to the first date the participant met criteria for PD and such 
participants will be discontinued from study therapy.  In 
participants who have initial evidence of radiographic PD, it is 
at the discretion of the treating physician whether to continue a 
participant on study treatment for up to 3 months pending 
confirmation of PD on follow-up imaging.  This clinical 
judgment decision should be based on the participant’s overall 
clinical condition, including performance status, clinical 
symptoms, and laboratory data.  Subjects may receive study 
treatment while waiting for confirmation of PD if they are not 
experiencing significant clinical decline and if: 
o the subject is believed to demonstrate clinical benefit 
from the study regimen as determined by the treating 
physician; 
o the subject is adequately tolerating study therapy  
 
Subjects who have been on the study drugs for more than 6 months must come off study for 
disease progression at the first time that radiologic criteria for confirmed PD are met. 
7.7.4. MRI Procedures 
MRI of the brain is performed once every 8 weeks on study as per standard of care for the 
management of recurrent GBM. The MRIs performed for this study do not include experimental 
sequences or coils or any experimental contrast. These MRIs do require the use of an FDA-
approved gadolinium-based contrast agent. The gadolinium will be used in accordance with the 
FDA label for gadolinium-based contrast.   
 
 
 
IV Line Placement – This is required to administer the contrast agent. Multiple needle-
 
sticks may be necessary if a vein cannot be properly accessed and this will be carried out 
 
with the subjects’ permission.  
 
 
IV Contrast Risks- As mention above, part of the MRI study will require the injection of 
 
a gadolinium contrast agent into the blood stream. There is a rare possibility that the 
 
subject could have an adverse reaction to the contrast agent such as rash, hives, itching, 
 
mild headache and nausea. The subject may also experience some minor discomfort and 
 
low risk of bleeding, infection and bruising associated with Intravenous catheter 
 
placement.  Recently, FDA has also required a new class warning for all gadolinium-
 
based contrast agents (GBCAs) for MRI concerning gadolinium remaining in patients’ 
 
bodies, including the brain, for months to years after receiving these drugs. The long-term 
 
risks of this retention are not well elucidated; Gadolinium retention has not been directly 
 
linked to adverse health effects in patients with normal kidney function, and the FDA has 
 
concluded that the benefit of all approved GBCAs continues to outweigh any potential 
 
risks.  Also, there is a possible risk of nephrogenic systemic fibrosis (NSF, also 

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referred to as nephrogenic fibrosing dermopathy or NFD) occurring following 
 
administration of a GBCA in subjects with known moderate to severe renal disease (with 
 
a glomerular filtration rate or GFR < 30 mL/min/1.73m2). However, such patients are not 
 
eligible for this trial (see Section 4; Eligibility Criteria). In addition, serial creatinine 
 
values will be  checked for each subject once monthly throughout the course of the trial. 
 
If at any point a subject’s GFR falls below 30 mL/min/1.73m2 or a rise in creatinine 
 
above baseline suggests an acute kidney injury, that subject must undergo a repeat serum 
 
creatinine test within 24 hours prior to the next planned MRI scan with contrast.  This 
 
MRI with contrast should not be performed until the GFR is above 30 mL/min/1.73m2 
 
and is stable improving on two additional tests each separated by 48 hours.  
 
 
Pregnancy Clause - Although there are no known risks related to MRI on pregnant  
 
 
women or a fetus, there is a possibility of yet undiscovered pregnancy related risks. Since 
 
there is potential danger to the fetus from participating in this protocol for a pregnant 
 
woman, we will exclude pregnant women. A negative urine or serum pregnancy test will 
 
be required before a woman of child-bearing potential can participate in this study. If the 
 
subject is post-menopausal for at least one year or has undergone a hysterectomy, the 
 
subject will not be required to undergo a pregnancy test prior to enrolling in this study 
 
and undergoing MRI scans. Gadolinium-based IV contrast agents are not approved 
 
in pregnant women (pregnant women will be excluded from this trial). 
 
 
Metallic Foreign Fragments/Flying Object Clause -The known risks associated with 
 
this study are minimal. Implanted medical devices and metallic foreign fragments inside 
 
the body may pose a risk if you were to enter the MRI magnet room. Therefore, questions 
 
regarding medical and work history will be asked prior to the exam. The greatest risk is a 
 
magnetic object flying through the air toward the magnet and hitting the subject. To 
 
reduce this risk, we require that all people involved with the study remove  all magnetic 
 
metal from their clothing and all magnetic metal objects from their pockets. No magnetic 
 
metal objects are allowed to be brought into the magnet room at any time except by 
 
approved personnel. In addition, once subject is in the magnet, the door to the room will 
 
be closed so that no one inadvertently walks into the room. 
 
 
Magnetic Fields Health Risks Statement--There is no known health risk associated 
 
with exposure to magnetic fields during an MRI. There are minimal risks from the loud 
 
noise associated with the MRI scanner and from the discomfort of lying on a hard 
 
surface. We shall provide the subject with protective earplugs as necessary and make 
 
every attempt to ensure comfort with blankets, etc. during time in the scanner. 
7.8 Safety Assessments  
Subjects are evaluated for safety according to the office visit and laboratory evaluation schedule 
outlined in Table 8 and Table 9 (Section 6). Safety and AE definitions, recording, and reporting 
are outlined in detail in Section 9. 
7.9 Tissue/Blood collection for correlative analyses, PK, and ADA 
For all subjects in this study (both Cohort A and Cohort B), informed consent will be obtained to 
collect a formalin-fixed, paraffin-embedded (FFPE) preserved component of tumor tissue from 
the subject’s initial surgical tumor resection for exploratory correlative analyses. This surgery 

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will have already been performed prior to their enrollment on this protocol as part of standard of 
care therapy for glioblastoma.   
 
For subject in the surgical arm only (Cohort B, N=16), both fresh frozen and FFPE preserved 
components of tumor tissue will also be collected from the surgery that subjects will undergo as 
part of this protocol (i.e., the subject’s surgery for recurrent GBM).   
 
In addition, in both Cohorts A and B 60 mL of peripheral blood will also be collected for future 
exploratory correlative analyses.  These 60 mL blood samples will be collected at the time points 
outlined in the SOE (Table 8 and Table 9).   
 
All subjects will be asked to consent to collection of an FFPE preserved component of tumor 
tissue from any surgical brain tumor resection or brain tumor biopsy that is performed (as 
clinically indicated) after the subject has discontinued the study treatment. If a subject comes off 
study for progressive disease, initiates another treatment regimen per standard of care, and then 
has another tumor resection, collection of FFPE preserved tissue will not occur.     
 
The exploratory endpoints of this study are outlined in Section 2. All correlative analyses will be 
performed in University of Pennsylvania laboratories with the following exceptions: 
pharmacokinetic (PK) and anti-drug antibody (ADA) measurements will be performed by 
Syneos Health, and GITR expression by IHC will be performed by Mosaic Laboratories.  In 
addition to the correlative assays listed in Section 2, other assays relevant to understanding 
mechanisms or predictors of clinical benefit and/or resistance to INCMGA00012 and 
INCAGN01876 in GBM may be performed on these tissue and blood samples in the future based 
upon emerging data and future hypotheses. The informed consent form reflects this flexibility for 
future research use of subject biospecimens collected during the course of this study.  
 
No results of tissue or blood correlatives will be recorded in the subject’s electronic medical 
record and will not be used in any way to guide treatment or clinical decision making.  
7.10 Protocol exceptions (prospective action) 
An exception is defined as a one-time, intentional action or process that departs from the 
approved study protocol, intended for one occurrence.  If the action disrupts the study progress, 
such that the study design or outcomes may be compromised, or the action compromises the 
safety and/or welfare of study subjects, advance documented approval from the Regulatory 
Sponsor and local regulatory review committees, per institutional guidelines, is required.  
Approval from the Regulatory Sponsor must be received prior to submission to the local 
regulatory review committees. 
7.11 Protocol Deviations (retrospective action) 
A deviation is defined as a one-time, unintentional action or process that departs from the approved 
study protocol, involving one incident and identified retrospectively.  If the deviation disrupts 
study progress, such that the study design or outcomes may be compromised, or the deviation 
compromises the safety and/or welfare of study subjects, the deviation must be reported to the 
Regulatory Sponsor within 24 hours of PI knowledge and to local regulatory review committees 
per institutional guidelines.  

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Report the following information on the Sponsor’s exception/deviation form:  
• Protocol number 
• Subject number 
• Description of the exception or deviation 
• Impact on subject safety 
• Impact on data integrity  
Deviations that are assessed by the PI to not disrupt the study progress, such as not affecting the 
study design or outcome, or compromising the safety and/or welfare of study subjects, should be 
documented in site records and contain documentation of the PI’s assessment. 
 
8   STATISTICAL PLAN 
8.1 Definition of Primary Endpoint 
The primary efficacy endpoint of this study is objective radiographic response (ORR), as defined 
by modified Response Assessment in Neuro-Oncology (mRANO) criteria (Ellingson et al, 
Neurotherapeutics 2017). Per mRANO criteria, ORR is defined as the presence or absence of an 
objective radiographic tumor response, either a) partial or complete response; OR b) absence of 
partial or complete response, i.e., a binary endpoint. A two-sided 95% confidence interval for 
ORR will be calculated. 
 
Only subjects enrolled on Cohort A who have (1) not been replaced AND (2) received SRS and 
at least one dose of both study drugs are evaluable for the primary endpoint. 
 
8.2 Statistical Methods 
8.2.1 Primary Endpoint Analysis (Efficacy of Regimen) 
The primary efficacy hypothesis of this study is that the proportion of subjects who experience 
an objective radiographic response will be 25% or higher. We will test this hypothesis against the 
null hypothesis of 5% of subjects experiencing an objective response using an exact single-stage 
phase II design for the primary study cohort (Cohort A; Non-surgical). A sample size of 16 
evaluable subjects is required for 80% power. A one-sided significance level has been set at 0.05. 
A subject is considered evaluable for the primary endpoint if (a) the subject is one of the 16 
subjects enrolled onto Cohort A at the same dose and schedule of study drugs that is determined 
to be the final dose/schedule based on the safety run-in phase, AND (b) the subject has received 
at least one dose of BOTH study drugs AND has received at least one fraction of SRS.  
 
In one of the largest series of patients with recurrent high-grade glioma treated with 
hypofractionated stereotactic radiation therapy alone, ~10% of patients experienced a minimal 
response of the irradiated tumor by MacDonald Criteria; no patients experienced a partial 
response (Fogh, J Clin Oncol 2010).  For patients who have one tumor site irradiated while other 
sites of tumor are not irradiated, such as some of the subjects who will be enrolled in the current 
protocol, no responses would be expected in non-irradiated tumor. With these data in mind, 

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coupled with the historic overall response rate of ~10% to single-agent lomustine (a standard of 
care) in recurrent GBM (Batchelor TT, et al. J Clin Oncol 2013), we have designated ORR=5% 
as the null hypothesis. 
 
The alternative hypothesis, a 25% ORR, would be a clinically significant difference that would 
suggest this regimen is worthy of further investigation.  
  
8.2.2 Analysis of Secondary and Exploratory endpoints 
Descriptive analyses will be conducted to summarize subject characteristics and detect potential 
selection bias as a result of missing data or dropout.  
 
All subjects who sign informed consent will be included in safety analyses and in calculation of 
the rate of AEs, regardless of whether and how much study drug was received.  Safety and 
tolerability will be assessed by clinical review of all relevant parameters including AEs, 
laboratory tests, and vital signs. Safety summaries will be provided for both cohorts. Immune-
related adverse events (irAEs, as defined in Section 9), are prespecified events of interest.  These 
events will be summarized in separate tables from other AEs by toxicity grade and will include 
the counts, percentages, and 95% CI. AEs (specific terms as well as system organ class terms) 
that are not pre-specified as events of interest will be summarized with descriptive statistics 
(counts, percentage, mean, standard deviation, etc).   
 
 
Progression-free survival (PFS) and overall survival (OS) will be estimated using the Kaplan-
Meier product-limit method, with subjects censored at their last known date alive. Standard error 
for the Kaplan-Meier estimate will be calculated according to the formula of Peto, et al (Br J 
Cancer 1977) and a two-sided 95% confidence intervals for the median PFS and median OS, 
respectively, will also be calculated.  
 
Comparisons of PFS and OS in subjects on Cohort A (nonsurgical) vs. PFS and OS in subjects 
on Cohort B (neoadjuvant therapy) will be exploratory in nature, as the study is not adequately 
powered for these comparisons. Log-rank tests will be used to explore differences in PFS/OS 
between these two groups. 
 
For analysis of correlative data, variable distributions will be presented graphically and 
descriptively at each time point; if needed, appropriate transformations will be performed. Paired 
t-tests will be used to assess change from pre- to post-treatment for exploratory endpoints that 
are normally distributed. Wilcoxon signed-rank tests will be used to assess change from pre- to 
post-treatment for exploratory endpoints that are not normally distributed. Multiple comparison 
adjustment using false discovery rate (FDR) will be used. The sample size of 16 subjects in the 
surgical arm of the study (Cohort B), with N=8 per sub-arm provides 85% power with one-sided 
alpha of 0.05 to detect the difference between the null hypothesis of a CD8+ tumor-infiltrating 
lymphocyte score of 1 and the alternative hypothesis of a CD8+ tumor-infiltrating lymphocyte 
score of 1.85.  These numbers are based on the pre- and post- CD8+ tumor-infiltrating 
lymphocyte scoring system (scored 0 to 3, least to most CD8+ T cell infiltration) used in our 
prior CAR T cell trial in recurrent GBM (O’Rourke, Sci Transl Med 2017), which is one of the 
few immunotherapies shown to increase tumor T cell infiltration in this disease. In that study, 

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pre-CAR T cell GBM specimens had a mean score of 1 (standard deviation 0.1) and post-CAR T 
cell GBM specimens had a mean score of 1.85 (standard deviation 0.80).   
 
9    SAFETY AND ADVERSE EVENTS 
9.1 Definitions 
9.1.1. Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in 
severity during the course of the study, whether or not considered drug related.  This study will 
utilize the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 for assessing 
the severity of AEs, as follows in Table 14: 
 
 
Table 14: CTCAE version 5.0 for assessment of the severity of AEs 
Grade 1  Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.  
Grade 2  Moderate; minimal, local, or noninvasive intervention indicated; limiting age-
appropriate activities of daily living.  
Grade 3  Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care activities of daily living.  
Grade 4  Life-threatening consequences; urgent intervention indicated.  
Grade 5  Death 
 
The CTCAE severity grades 1 through 5 provide unique clinical descriptions of severity of each 
adverse event. The CTCAE v5.0 is available on the NCI/NIH website. 
 
Abnormal laboratory values or test results occurring after informed consent constitute AEs only 
if they induce clinical signs or symptoms, are considered clinically meaningful, require therapy, 
or require changes in the study drug(s). Whenever possible, a diagnosis rather than a symptom 
should be provided (eg, "anemia" instead of "low hemoglobin").  Laboratory abnormalities that 
meet the criteria for AEs should be followed until they have returned to normal or an adequate 
explanation of the abnormality is found. When an abnormal laboratory test result corresponds to 
a sign or symptom of a previously reported AE, it is not necessary to separately record the 
laboratory test result as an additional event.  
 
A preexisting condition is one that is present at the start of the study.  A preexisting condition 
should be recorded as an adverse event if the frequency, intensity, or the character of the 
condition worsens during the study period.  
9.1.2 Immune-Related Adverse Events  
Immune-related AEs (irAEs)may be defined as an AE of unknown etiology, associated with drug 
exposure and consistent with an immune phenomenon. irAEs may be predicted based on the 
nature of the INCMGA00012 and INCAGN01876 compounds, their mechanism of action, and 
extensive reported experience with immunotherapies that have a similar mechanism of action. 

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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.  
 
Of note, intratumoral/peritumoral edema and any resultant AEs (seizure, e.g.), even if attributed 
to the study drug(s), are NOT considered irAEs in this study. Such edema may be a desired 
effect of the treatment, as it may represent immune infiltration of the tumor.  
 9.1.3 Serious Adverse Events  
Serious Adverse Event (SAE): 
Adverse events are classified as serious or non-serious.  An SAE is any AE that is at least one of 
the following:  
• fatal 
• life-threatening 
• requires hospitalization or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• is considered to be an important medical event, which are those that may not be immediately 
life threatening but are clearly of major clinical significance.   These may jeopardize the 
subject and may require intervention to prevent one of the other serious outcomes noted 
above.  
 
Events not considered to be SAEs in this trial are: 
• Progression of the cancer under study (GBM) 
• A visit to the emergency room or another hospital department that does not result in a 
hospitalization of >24 hours (unless considered an important medical or life-threatening 
event) 
• Hospitalization for any of the following: 
o Elective procedures, including routine health assessment (e.g. routine colonoscopy) 
or elective/pre-planned treatment for a pre-existing condition that did not worsen 
while on study 
o Seizure, if felt related to subject’s underlying disease 
o Scheduled tumor debulking surgery 
 
9.1.4 Unanticipated problem 
Any incident, experience, or outcome that meets all of the following  
 
 
criteria 
is defined as an unanticipated problem:  
• Unexpected in nature, severity, or frequency (i.e., not described in protocol or 
consent form, the drug package insert, or the investigators brochure; a summary 
of expected AEs related to INCMGA00012/INCAGN01876 can be found in the 
Investigator’s Brochure) 
• Related or possibly related to participation in the research (i.e. possibly related 
means there is a reasonable possibility that the incident experience, or outcome 
may have been caused by the procedures involved in the research) 
• Suggests that the research places subjects or others at greater risk of harm 
(including physical, psychological, economic, or social harm). 

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9.2 Collecting and recording of Adverse Events 
Adverse event collection will occur from signing of the informed consent form until the 12-week 
safety follow-up visit.  At screening, any clinically significant abnormality should be recorded as 
a preexisting condition.  At the 12-week safety follow-up, any new clinically significant 
findings/abnormalities that meet the definition of an immune related adverse event must also be 
recorded and documented as an adverse event (see sections 1.3.1.3 and 1.3.2.3). 
 
At each contact with the subject, the investigator will seek information on adverse events by 
specific questioning and, as appropriate, by examination. AEs may also be volunteered 
spontaneously by the study patient.  Information on all adverse events will be recorded 
immediately in the source document, and also in the appropriate adverse event module of the 
electronic case report form (eCRF).   
 
Each AE should be evaluated to determine:  
•    The severity grade (CTCAE Grade 1 to 5).  
•    The start and end dates, unless unresolved at final follow-up.  
•    The action taken with regard to study drug(s)  
• The event outcome (e.g, not recovered/not resolved, recovered/resolved,   recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown).  
•   The seriousness, as per serious adverse event (SAE) definition provided in Section   9.1.2 
•    Per the Investigator, whether the event is definitely related, probably related, possibly 
related, unlikely related, or unrelated to the study drug(s) and/or SRS. In order to be 
unrelated, a causal relationship between the drug(s)/SRS and the AE is not a reasonable 
possibility: there is no temporal relationship between the medicinal product and event, or 
an alternative etiology is more reasonable.  
 
All adverse events occurring between the time the informed consent form is signed and the end 
of the safety follow up phase will be recorded.  The clinical course of each event will be 
followed until resolution, stabilization, or until it has been determined that the study intervention 
or participation is not the cause.  Serious adverse events that are still ongoing at the 12-week 
safety follow-up period will continue to be followed to determine the final outcome.   
 
When the severity of an AE changes over time for a reporting period (eg, between visits), each 
change in severity will be reported as a separate AE until the event resolves. For example, 2 
separate AEs will be reported if a subject has Grade 1 diarrhea, meeting the definition of an AE, 
that lasts for 3 days before worsening to a Grade 3 severity. The Grade 1 event will be reported 
as an AE with a start date equal to the day the event met the Grade 1 AE definition and a stop 
date equal to the day that the event increased in severity from Grade 1 to Grade 3. The Grade 3 
event will also be reported as an AE, with the start date equal to the day the event changed in 
intensity from Grade 1 to Grade 3 and a stop date equal to the day that the event either changed 
severity again or resolved.  
 
For AEs associated with disease progression, the relevant signs and symptoms should be 
reported using a diagnosis whenever possible rather than individual underlying signs and 
symptoms. When a clear diagnosis cannot be identified, each sign or symptom should be 
reported as a separate AE. If the events resulting from disease progression meet the criteria for 
an SAE (eg, resulted in hospitalization, a life-threatening event, or death), the specific event(s) 

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should be reported as an SAE(s).  In both cases (ie, AEs or SAEs related to disease progression), 
it should be indicated that each event (reported as a diagnosis or as signs and symptoms) is 
related to disease progression on the Adverse Events form of the eCRF.  
 
The study’s principal investigator is ultimately responsible for the recording, and reporting, 
unanticipated problems related to the research, which occur during the study. 
9.3 Reporting of Adverse Events  
The study period during which adverse events must be reported is defined as the period from the 
signing of the informed consent form to the 12-week safety follow-up visit.  
9.3.1 Follow-up reporting for SAEs  
If an SAE has not resolved at the time of the initial report and new information arises that 
changes the investigator’s or Sponsor’s assessment of the event, a follow-up report including all 
relevant new or reassessed information (e.g., concomitant medication, medical history) should be 
submitted to the FDA and IRB. The PI and Sponsor are responsible for ensuring that all SAEs 
are followed until either resolved or stable. 
9.3.2 Investigator Reporting: Notifying the Study Sponsor  
All investigators should report all AEs to the study PI. The PI must report all AEs to the Sponsor 
(University of Pennsylvania) regardless of whether they are serious or not, as well as all 
unanticipated problems.   
 
Any SAEs are notified to the study Sponsor and Medical Director by email or phone within 24 
hours of the event. The PI will keep a copy of the SAE reporting form on file.   
 
The PI then provides further information on the SAE as information becomes available in a SAE 
form. This includes the following: 
 
• Study identifier 
• Study Center 
• Subject number 
• A description of the event 
• Date of onset 
• Current status 
• Whether study intervention was discontinued 
• The reason why the event is classified as 
serious 
• Investigator assessment of the association 
between the event and study intervention 
 
Significant new information on ongoing SAEs should be provided promptly to the Principal 
Investigator and Sponsor. 
 9.3.3 Investigator Reporting: Notifying the Penn IRB  
The investigator will report to the IRB following institutional policies requirements.  
9.3.4 Reporting to Incyte 
All SAEs and follow up information must be notified by phone or e-mail to Incyte within one (1) 
business day of Sponsor becoming aware of the initial event or follow-up information. 

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spontaneous or voluntary termination, details of the birth, and the presence or absence of any birth 
defects, congenital abnormalities, or maternal and/or newborn complications, by following until 
the first well-baby visit.  
An elective abortion without complications should not be regarded as an AE. Therapeutic 
abortions should be reported as a treatment procedure and as an AE. Hospitalization for normal 
delivery of a healthy newborn should not be considered an SAE. 
The Sponsor Institution must report all pregnancies associated with Incyte products including 
follow up outcomes to Incyte within one (1) business day of awareness.  
9.7 Special Situations: Misuse, Medication Errors, Overdose, and Accidental or 
Occupational Exposure 
• Misuse: medicinal product is intentionally and inappropriately used not in accordance with 
the authorized/approved product information. 
• Medication error:  is any preventable incident that may cause or lead to inappropriate 
study treatment use or patient harm while the study treatment is in the control of the health 
care professionals or patients. Such incident may be due to health care professional 
practice, product labeling, packaging and preparation, procedures for administration, and 
systems, including the following: prescribing, order communication, nomenclature, 
compounding, dispensing, distribution, administration, education, monitoring, and use. 
• Overdose:  is a deliberate or accidental administration of study treatment to a study patient, 
at a dose greater than that which was assigned to that patient per the study protocol and 
under the direction of the Investigator.  If an overdose with a Incyte product, the Sponsor 
Institution and Incyte should be notified immediately, and the patient should be observed 
closely for AEs. Associated AEs should be treated and monitored by the Investigator. The 
dosage of study drug administered, any associated AEs, and/or treatment provided to the 
patient because of the overdose, should be reported.  
• Accidental /Occupational exposure:  is the unintentional exposure to a study treatment 
as a result of one’s professional or non-professional occupation, or accidental exposure to 
a non-professional to whom exposure was not intended (i.e., study product given to wrong 
patient).  
Reporting Special Situations:  All occurrences of misuse, medication error, overdose, and 
accidental or occupational exposure associated with an Incyte product must be reported on a 
Special Situations Report Form to the Sponsor and from Sponsor to Incyte within 5 business days 
of awareness regardless of whether or not an AE or SAE has occurred. If the misuse, medication 
error, overdose, or accidental / occupational exposure is associated with an AE, a safety form must 
also be submitted to the Sponsor Institution and from Sponsor to Incyte within one (1) business 
day of awareness.  
10 STUDY ADMINISTRATION, DATA HANDLING, AND RECORD 
KEEPING 

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10.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.   
10.2 Data Collection and Management  
Data will be managed using the clinical trial data management system Clinical Trial 
Management Systems (CTMS).  Access to the trial project in CTMS is granted by the Penn 
Office of Clinical Research (OCR) to all persons with the appropriate roles in the study. 
 
The study case report form (CRF) is the primary data collection instrument for the study. All 
data requested on the eCRF must be recorded.  All missing data must be explained.  If a space on 
the eCRF is left blank because the procedure was not done or the question was not asked, type 
“N/D”.  If the item is not applicable to the individual case, type “N/A”.  Source data is all 
information, original records of clinical findings, observations, or other activities in a clinical 
trial necessary for the reconstruction and evaluation of the trial.  Source data are contained in 
source documents.   
 
Each subject will be assigned a unique study ID number (unique for this project) in CTMS   
To ensure that strict confidentiality is maintained, password-protected access to the CTMS 
project and a file linking medical record numbers (MRNs) to study ID number will be granted 
only to the clinical research coordinators and research nurses/assistants assigned to this study.   
10.3. Records Retention  
HIPAA Retention Period (45 CFR164.530(j):  
Protected Health Information (PHI) Research Requests (HIPAA1-008): Records documenting 
research requests, privacy board review or privacy officer expedited review, background 
material, and acceptance or denial of request. Retain until Sponsor provides approval to destroy.  
 
Protected Health Information Disclosure Records (HIPAA1-009): Documenting the release of 
PHI, including both authorized and unauthorized releases. Should include the date of release, 
to whom the information was released, and the circumstances of the release. Retain until Sponsor 
provides approval to destroy.  
 
Maintenance of HIPAA records is independent of the regulations for clinical study records. All 
records of PHI research requests and any type of release will be maintained until Sponsor 
provides approval to destroy.  
 

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11 STUDY MONITORING, AUDITING, and INSPECTING  
11.1 Study Monitoring Plan 
This study will be monitored by the Sponsor according to the monitoring plan.   
11.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the Sponsor, 
government regulatory bodies, and University compliance and quality assurance groups of all 
study related documents (e.g. source documents, regulatory documents, data collection 
instruments, study data etc.).  The investigator will ensure the capability for inspections of 
applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
12   ETHICAL CONSIDERATIONS  
This study is to be conducted in accordance with applicable US government regulations and 
international standards of Good Clinical Practice, and applicable institutional research policies 
and procedures. 
 
This protocol and any amendments will be submitted to the University of Pennsylvania 
Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal 
approval of the study conduct.  The decision of the IRB concerning the conduct of the study will 
be made in writing to the investigator and a copy of this decision will be provided to the sponsor 
before commencement of this study and throughout the study.  
 
12.1 Risks 
The primary risks to subjects enrolled on this protocol include the following: 
• 
That the experimental regimen will be ineffective against glioblastoma, thus permitting the 
tumor to continue to grow  
• 
Study drug-related adverse events, which, in the worst case, could lead to permanent 
toxicity/injury or death. Detailed descriptions of the types and rates adverse reactions 
previously reported with INCMGA00012 and INCAGN01876 are outlined in detailed in 
the Investigator’s Brochure. The risk that is most likely to result in an SAE related to the 
study drug(s) is cerebral edema (and resultant neurologic toxicity), which is outlined in 
detail in both this protocol (Section 5.8.3).  
• Serious harm or death due to an unexpected adverse event that occurs due to the 
combination of INCMGA00012 and INCAGN01876 with stereotactic radiosurgery. 
The risk that is most likely to result in an SAE related to the study drug(s) is cerebral 
edema (and resultant neurologic toxicity), which is outlined in detail in both this 
protocol (Section 5.8.3). 
 
12.2 Benefits 
Although no benefit can be guaranteed to subjects as a result of enrolling on this protocol, the 
investigational regimen has strong preclinical rationale for being studied in subjects with GBM. 
Therefore, there is a reasonable possibility that subjects enrolled on this study will receive 
therapy that is more efficacious than current standard of care for recurrent GBM; at present, there 

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is no systemic therapy that has been proven to prolong overall survival in recurrent GBM. In 
addition, even if the study is negative and does not reach its primary endpoint, there is benefit to 
medical knowledge and society as a whole from the correlative studies that accompany this trial.  
These studies are designed to improve our understanding of mechanisms of response and 
resistance to immunotherapy in GBM.  
12.3 Risk Benefit Assessment 
There continues to be a significant unmet need for patients with recurrent GBM. The potential 
benefit to subjects in this study is that the combination regimen of INCMGA00012, 
INCAGN01876, and SRS may be clinically active and would add additional progression-free 
and/or overall survival time compared to if the subject did not enroll on the trial.   The primary 
risk to subjects is of adverse events occurring related to the individual use or the combination of 
the study drugs.  
 
Overall, the current lack of any available systemic therapy that has been shown to improve OS in 
recurrent GBM, in combination with the relatively high level of safety and tolerability of 
INCMGA00012,  INCAGN01876, and SRS in prior studies, the risk benefit assessment for 
enrolling in this clinical trial is in favor of benefit.  
12.4 Informed Consent Process/HIPAA Authorization  
Subjects will be recruited from the Radiation Oncology, Neurosurgery, and Medical Oncology 
practices at the University of Pennsylvania Health Systems. The treating physician will 
determine if the patient is a potential research candidate. The treating physician will approach 
and inform the patient about the study, thereby initiating the informed consent process. If the 
patient expresses interest in the study, the treating physician will contact a qualified member of 
the research team in the Neurosurgery Clinical Research Division at the University of 
Pennsylvania and request availability for enrollment. A sub-investigator of the research team will 
continue the formal consent process. This person will explain the requirements of the study and 
provide a copy of the Informed Consent Form. The person obtaining consent will state the 
volunteer nature of research and advise the subject to take sufficient time to discuss the study 
before making her decision to sign the informed consent document. If a decision to participate is 
made, the informed consent form is signed after which screening procedures will be performed. 
Subject eligibility will be evaluated based upon the criteria outlined in the protocol. After 
eligibility is established, a subject study number will be issued. Eligibility is confirmed with the 
study PI.  
 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA) and 
the Sponsor. Those regulations require a signed subject authorization informing the subject of the 
following:  
 
o What protected health information (PHI) will be collected from subjects in this study  
o Who will have access to that information and why  
o Who will use or disclose that information  
o The rights of a research subject to revoke their authorization for use of their PHI.  
 

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13   STUDY FINANCES 
13.1 Funding Source 
This clinical trial is financed through a grant from Incyte.  
13.2 Conflict of Interest 
All University of Pennsylvania Investigators will follow the University of Pennsylvania Policy 
on Conflicts of Interest Related to Research.  
 
14   PUBLICATION PLAN 
This is an investigator-initiated trial and Penn holds the IND.  The Sponsor holds the primary 
responsibility for publication of the results of the study.  
 
 

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Ellingson BM, et al. Modified criteria for radiographic response assessment in glioblastoma 
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APPENDIX 1. Management guidelines for Immune-Related Adverse 
Events (irAEs)* 
 
*ICPi = immune checkpoint inhibitor; in this protocol, this refers to BOTH study drugs 
INCMGA00012 and INCAGN01876.  
*These tables are copied directly from the original publication for convenience (Brahmer et al, J 
Clin Oncol 2018).  

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