A Phase 2 Open-Label Trial to Evaluate Enoblituzumab in Combination With Retifanlimab or Tebotelimab in the First-Line Treatment of Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck
Phase: PHASE2
Conditions: Head and Neck Cancer, Head and Neck Neoplasms, Head and Neck Squamous Cell Carcinoma
Sponsor: MacroGenics

Enoblituzumab, Retifanlimab, Tebotelimab 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGA271-06 
Amendment 1, 16 December 2020 
CLINICAL STUDY PROTOCOL: CP-MGA271-06
PROTOCOL AMENDMENT 1 
Study Title:
A Phase 2 Open-Label Trial to Evaluate Enoblituzumab in 
Combination with Retifanlimab or Tebotelimab in the First-Line 
Treatment of Patients with Recurrent or Metastatic Squamous Cell 
Carcinoma of the Head and Neck
Study Number:
CP-MGA271-06
Study Phase:
Phase 2 
Product Name:
Enoblituzumab (also known as MGA271)
Retifanlimab (also known as MGA012 or INCMGA00012)
Tebotelimab (also known as MGD013)
IND Number:
 
EudraCT Number:
NA 
Indication:
First-line treatment of patients with recurrent or metastatic SCCHN 
(squamous cell carcinoma of the head and neck) not curable by 
local therapy
Coordinating 
Principal 
Investigator:
TBD
Sponsor:
MacroGenics, Inc.
9704 Medical Center Drive
Rockville, MD 20850
301-251-5172
Sponsor’s Medical 
Monitor:
Refer to study contact list
Confidentiality Statement
This document is confidential. It contains proprietary information of MacroGenics, Inc. that 
can only be used for the purpose of reviewing or performing this study. Any use, viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly 
prohibited.
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NCT04634825

Enoblituzumab, Retifanlimab, Tebotelimab 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGA271-06 
Amendment 1, 16 December 2020 
 
TABLE OF CONTENTS 
SPONSOR SIGNATURES ....................................................................................................... 8 
 
LIST OF ABBREVIATIONS ..................................................................................................11 
1 
SYNOPSIS .................................................................................................................. 15 
2 
BACKGROUND INFORMATION ............................................................................ 21 
2.1 
Disease Background........................................................................................... 21 
2.2 
Rationale for Study ............................................................................................ 21 
2.3 
Background on Study Drugs .............................................................................. 27 
2.3.1 
Background on Study Drug Targets ......................................................... 27 
2.3.1.1 
Background on B7-H3 ................................................................... 27 
2.3.1.2 
Background on PD-1 ...................................................................... 28 
2.3.1.3 
Background on LAG-3 ................................................................... 29 
2.3.2 
Background on Enoblituzumab ................................................................ 30 
2.3.2.1 
General Information on Enoblituzumab ......................................... 30 
2.3.2.2 
Clinical Trial Experience with Enoblituzumab .............................. 33 
2.3.2.3 
Nonclinical Data for Enoblituzumab.............................................. 38 
2.3.3 
Background on Retifanlimab ................................................................... 39 
2.3.3.1 
General Information on Retifanlimab ............................................ 39 
2.3.3.2 
Clinical Trial Experience with Retifanlimab .................................. 39 
2.3.3.3 
Nonclinical Data for Retifanlimab ................................................. 40 
2.3.4 
Background on Tebotelimab .................................................................... 41 
2.3.4.1 
General Information on Tebotelimab ............................................. 41 
2.3.4.2 
Clinical Trial Experience with Tebotelimab ................................... 41 
2.3.4.3 
Nonclinical Data for Tebotelimab .................................................. 44 
2.4 
Dose Selection ................................................................................................... 44 
2.4.1 
Dose Selection for Enoblituzumab .......................................................... 44 
2.4.2 
Dose Selection for Retifanlimab .............................................................. 45 
2.4.3 
Dose Selection for Tebotelimab ............................................................... 46 
3 
STUDY PURPOSE AND OBJECTIVES ................................................................... 47 
3.1 
Primary Objective .............................................................................................. 47 
3.2 
Secondary Objectives......................................................................................... 47 
3.3 
Exploratory Objectives ...................................................................................... 48 
4 
STUDY DESIGN ........................................................................................................ 49 
4.1 
Overall Study Design ......................................................................................... 49 
4.2 
Dose Limiting Toxicity (Tebotelimab Cohort) .................................................. 51 
4.2.1 
Hematologic Dose Limiting Toxicity ...................................................... 52 
4.2.2 
Non-hematologic Dose Limiting Toxicity ............................................... 52 
4.2.3 
Hepatic Non-hematologic Dose Limiting Toxicity .................................. 53 
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4.3 
Guidelines for Dose Modification ..................................................................... 54 
4.3.1 
Dose Delays ............................................................................................. 54 
4.4 
Study Treatment Discontinuation ...................................................................... 54 
4.5 
Study Discontinuation ........................................................................................ 55 
4.6 
Definition of End of Study ................................................................................. 56 
5 
ELIGIBILITY CRITERIA .......................................................................................... 57 
5.1 
Inclusion Criteria ............................................................................................... 57 
5.2 
Exclusion Criteria .............................................................................................. 58 
6 
STUDY TREATMENTS ............................................................................................ 62 
6.1 
Description of Treatments .................................................................................. 62 
6.2 
Blinding.............................................................................................................. 62 
6.3 
Emergency Unblinding ...................................................................................... 62 
6.4 
Study Drug and Supplies ................................................................................... 62 
6.4.1 
Supply of Enoblituzumab ........................................................................ 62 
6.4.2 
Supply of Retifanlimab ............................................................................ 62 
6.4.3 
Supply of Tebotelimab ............................................................................. 63 
6.5 
Study Infusion Preparation ................................................................................ 63 
6.5.1 
General Guidelines and Precautions ........................................................ 63 
6.5.2 
Preparation and Administration of Enoblituzumab .................................. 64 
6.5.3 
Preparation and Administration of Retifanlimab ..................................... 65 
6.5.4 
Preparation and Administration of Tebotelimab ...................................... 65 
6.6 
Placebo or Active Comparator ........................................................................... 65 
6.7 
Treatment Compliance ....................................................................................... 65 
6.8 
Packaging and Labeling ..................................................................................... 65 
6.8.1 
Packaging and Labeling for Enoblituzumab ............................................ 65 
6.8.2 
Packaging and Labeling for Retifanlimab ............................................... 66 
6.8.3 
Packaging and Labeling for Tebotelimab ................................................ 66 
6.9 
Storage and Accountability ................................................................................ 66 
6.10 
Investigational Product Disposition at End of Study ......................................... 66 
7 
POTENTIAL ADVERSE EVENTS AND SUPPORTIVE CARE 
MEASURES ............................................................................................................... 67 
7.1 
Infusion Related Reactions Including Cytokine Release Syndrome ................. 67 
7.1.1 
Grading and Management of Infusion Reactions .................................... 67 
7.1.2 
Premedication and Prophylaxis ................................................................ 68 
7.1.3 
Management of Observed Infusion Reactions ......................................... 69 
7.2 
Immune-Related Adverse Events ....................................................................... 71 
7.2.1 
Diarrhea or Colitis .................................................................................... 72 
7.2.2 
Hepatic Toxicity ....................................................................................... 73 
7.2.2.1 
Elevations in Transaminases .......................................................... 73 
7.2.2.2 
Elevations in Total Bilirubin .......................................................... 74 
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7.2.3 
Pneumonitis .............................................................................................. 75 
7.2.4 
Dermatologic Toxicity ............................................................................. 76 
7.2.5 
Nephritis ................................................................................................... 76 
7.2.6 
Immune-Mediated Hypophysitis ............................................................. 77 
7.2.7 
Thyroid Toxicity ...................................................................................... 77 
8 
CONCOMITANT THERAPY AND RESTRICTIONS ............................................. 79 
8.1 
Concomitant Therapy ......................................................................................... 79 
8.1.1 
Prohibited Therapy ................................................................................... 79 
8.1.2 
Permitted Therapies ................................................................................. 80 
8.1.3 
Contraception ........................................................................................... 80 
8.2 
Restrictions ........................................................................................................ 81 
8.2.1 
Fluid and Food Intake .............................................................................. 81 
8.2.2 
Patient Activity Restrictions .................................................................... 81 
9 
STUDY PROCEDURES ............................................................................................ 82 
9.1 
Informed Consent............................................................................................... 82 
9.2 
Screening Period ................................................................................................ 82 
9.3 
Enrollment.......................................................................................................... 82 
9.4 
Medical History ................................................................................................. 82 
9.5 
Prior and Concomitant Medications and Procedures ......................................... 83 
9.6 
Physical Examination......................................................................................... 83 
9.6.1 
Vital Signs ................................................................................................ 83 
9.7 
ECOG Performance Status ................................................................................ 83 
9.8 
Clinical Laboratory Tests ................................................................................... 83 
9.9 
Pharmacokinetic, Immunogenicity, and Pharmacodynamic Biomarker 
Samples .............................................................................................................. 84 
9.9.1 
Blood Samples ......................................................................................... 84 
9.9.2 
Samples for HPV Status ........................................................................... 84 
9.9.3 
Biopsy Specimens .................................................................................... 84 
9.10 
Tumor Assessments ............................................................................................ 85 
9.11 
Electrocardiography ........................................................................................... 86 
9.12 
End of Treatment Visit ....................................................................................... 86 
9.13 
Post-Treatment Follow-up Visit ......................................................................... 86 
10 
ASSESSMENT OF PHARMACOKINETICS AND  
PHARMACODYNAMICS......................................................................................... 87 
10.1 
Pharmacokinetics Assessments .......................................................................... 87 
10.2 
Pharmacodynamic/Biomarker Assessments ...................................................... 87 
10.2.1 
PD-L1 Immunohistochemistry Testing .................................................... 87 
10.2.2 
B7-H3 Immunohistochemistry Testing .................................................... 87 
10.2.3 
PD-1/LAG-3 Immunohistochemistry Testing .......................................... 88 
10.2.4 
Additional Immunohistochemistry Testing .............................................. 88 
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10.3 
Gene Expression Profiling ................................................................................. 88 
10.4 
Immune-regulatory Activity Testing .................................................................. 88 
11 
ASSESSMENT OF EFFICACY ................................................................................. 89 
11.1 
Efficacy Assessments ......................................................................................... 89 
11.1.1 
Disease Response Assessments ................................................................ 89 
11.1.2 
Survival Assessments ............................................................................... 89 
11.2 
Immunogenicity Assessments ............................................................................ 89 
12 
ADVERSE EVENT REPORTING AND ASSESSMENT OF SAFETY ................... 90 
12.1 
Definitions.......................................................................................................... 90 
12.1.1 
Adverse Event .......................................................................................... 90 
12.1.2 
Adverse Drug Reaction ............................................................................ 90 
12.1.3 
Adverse Event of Special Interest ............................................................ 90 
12.1.4 
Serious Adverse Event ............................................................................. 90 
12.1.5 
Attribution/Assessment of Causality ....................................................... 91 
12.1.6 
Severity Criteria ....................................................................................... 92 
12.2 
Adverse Event Collection and Documentation .................................................. 92 
12.2.1 
All Adverse Events .................................................................................. 92 
12.2.2 
Serious Adverse Events ............................................................................ 94 
12.2.3 
Pregnancy ................................................................................................. 95 
12.2.4 
Special Reporting Situations .................................................................... 95 
12.2.4.1 
Sponsor Notification of Specific AEs ............................................ 95 
12.2.4.2 
Overdose......................................................................................... 96 
12.2.4.3 
Product Quality Issues .................................................................... 96 
12.2.4.4 
Discontinuation of Study Therapy Due to an Adverse Event ........ 96 
13 
PRODUCT QUALITY COMPLAINT HANDLING ................................................. 97 
13.1 
Procedures .......................................................................................................... 97 
13.2 
Contacting Sponsor Regarding Product Quality ................................................ 97 
14 
STATISTICAL ANALYSIS ........................................................................................ 98 
14.1 
Determination of Sample Size ........................................................................... 98 
14.2 
Analysis Populations .......................................................................................... 99 
14.3 
Demographics and Baseline Characteristics ...................................................... 99 
14.4 
Study Drug Exposures and Concomitant Medications ...................................... 99 
14.5 
Pharmacokinetic/Pharmacodynamic Analysis ................................................... 99 
14.5.1 
Pharmacokinetic Analysis ........................................................................ 99 
14.5.2 
Immunogenicity Analysis ........................................................................ 99 
14.5.3 
Pharmacodynamic Analysis ................................................................... 100 
14.6 
Efficacy and Endpoint Analyses ...................................................................... 100 
14.6.1 
Response Endpoints and Analyses ......................................................... 100 
14.6.2 
Analysis of Tumor Size Change Over Time .......................................... 100 
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Clinical Trial Protocol: CP-MGA271-06 
Amendment 1, 16 December 2020 
 
14.6.3 
Time-to-Event Endpoints and Analyses ................................................. 100 
14.7 
Safety Endpoints and Analyses ........................................................................ 101 
14.7.1 
Adverse Events ...................................................................................... 101 
14.7.2 
Laboratory Values .................................................................................. 102 
14.7.3 
Other Safety Endpoints .......................................................................... 102 
14.8 
Other Assessments or Analyses ....................................................................... 102 
15 
QUALITY CONTROL AND ASSURANCE ........................................................... 103 
15.1 
Monitoring, Auditing and Inspections ............................................................. 103 
15.2 
Data Collection and Management .................................................................... 104 
16 
ADMINISTRATIVE CONSIDERATIONS.............................................................. 105 
16.1 
Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) Approval................................................................................................. 105 
16.2 
Ethical Conduct of the Study ........................................................................... 105 
16.3 
Patient Information and Consent ..................................................................... 105 
16.4 
Patient Confidentiality ..................................................................................... 105 
16.5 
Source Documents ........................................................................................... 106 
16.6 
Retention of Data ............................................................................................. 106 
16.7 
Sample Retention and Further Testing ............................................................. 106 
16.8 
Financial Disclosure......................................................................................... 106 
16.9 
Publication and Disclosure Policy ................................................................... 107 
16.10 
Discontinuation of the Study or Study Sites .................................................... 107 
16.11 
Identification of the Coordinating Principal Investigator ................................ 107 
17 
REFERENCE LIST .................................................................................................. 108 
 
LIST OF TABLES  
Table 1 
LAG-3+ Tumor Infiltrating Lymphocyte Profile Across SCCHN ............... 30 
Table 2 
Enoblituzumab + Pembrolizumab Combination Data in SCCHN and 
NSCLC ......................................................................................................... 37 
Table 3 
Comparison of In Vitro Potencies of Retifanlimab and Nivolumab 
and Pembrolizumab Replicas ....................................................................... 41 
Table 4 
NCI CTCAE Version 5.0 Grading of Infusion-Related Reactions ............... 68 
Table 5 
Adverse Events of Special Interest ............................................................... 96 
Table 6 
Response Rates and 95% Confidence Intervals ........................................... 98 
Table 7 
 Censoring Rules for PFS ........................................................................... 101 
 
LIST OF FIGURES  
Figure 1 
Retifanlimab and Tebotelimab Sustain Enoblituzumab Mediated 
Immune Activation in Vitro .......................................................................... 24 
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Clinical Trial Protocol: CP-MGA271-06 
Amendment 1, 16 December 2020 
 
Figure 2 
Enoblituzumab (RES242) Mediates ADCC Activity Across a 
Spectrum of Cancer Types ............................................................................ 32 
Figure 3 
CP-MGA271-03 Anti-PD-1-Naïve SCCHN Waterfall Plot ......................... 37 
Figure 4 
CP-MGA271-03 Anti-PD-1-Naïve SCCHN Spider Plot ............................. 38 
Figure 5 
Study Schema ............................................................................................... 50 
Figure 6 
Treatment Cycles .......................................................................................... 51 
 
LIST OF APPENDICES  
APPENDIX 1 
TIME AND EVENTS SCHEDULE 
APPENDIX 2 
CLINICAL LABORATORY TESTS 
APPENDIX 3 
PHARMACOKINETICS, IMMUNOGENICITY, AND 
PHARMACODYNAMIC BIOMARKERS SCHEDULE 
APPENDIX 4 
RECIST 1.1 GUIDELINES 
APPENDIX 5 
PRINCIPAL INVESTIGATOR’S AGREEMENT 
 
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Clinical Trial Protocol: CP-MGA271-06 
Amendment 1, 16 December 2020 
 
SPONSOR SIGNATURES  
Study Title: 
A Phase 2 Open-Label Trial to Evaluate Enoblituzumab in 
Combination with Retifanlimab or Tebotelimab in the First-Line 
Treatment of Patients with Recurrent or Metastatic Squamous Cell 
Carcinoma of the Head and Neck 
Study Number: 
CP-MGA271-06 
 
This clinical study protocol has been approved by the Sponsor: 
Signed: 
See Appended Electronic Signature Page 
Date: 
 
 
 
Executive Director, Clinical Development 
MacroGenics, Inc. 
 
 
 
 
 
 
Signed: 
See Appended Electronic Signature Page 
Date: 
 
 
 
Director, Biostatistics 
MacroGenics, Inc. 
 
 
 
 
 
 
 
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Clinical Trial Protocol: CP-MGA271-06 
Amendment 1, 16 December 2020 
 
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Clinical Trial Protocol: CP-MGA271-06 
Amendment 1, 16 December 2020 
 
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MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGA271-06 
Amendment 1, 16 December 2020 
 
LIST OF ABBREVIATIONS  
The list of abbreviations of specialist terms does not include general scientific abbreviations 
of temperature, weight and volume. 
ADA 
anti-drug antibodies 
ADCC 
antibody-dependent cell-mediated cytotoxicity 
ADR 
adverse drug reaction 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase (SGPT) 
AST 
aspartate aminotransferase (SGOT) 
B7-H3 
B7 homolog 3 
BOR 
best overall response 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CNS 
central nervous system 
CPS 
combined positive score 
CR 
complete response 
CRS 
cytokine release syndrome 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
disease control rate 
DLT 
dose limiting toxicity 
DoR 
duration of response 
DSM 
Data Safety Monitor 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOTV 
End of Treatment Visit 
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MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGA271-06 
Amendment 1, 16 December 2020 
 
FACS 
fluorescence activated cell sorting 
Fc 
fragment crystallizable 
FcγR 
 
Fc gamma receptor 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
FU 
fluorouracil 
GC 
gastric cancer 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HBV 
hepatitis B virus 
HPV 
human papilloma virus 
HR 
hazard ratio 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ICF 
Informed Consent Form 
IEC 
Independent Ethics Committee 
IFN 
interferon 
IHC 
immunohistochemistry 
IL 
interleukin 
IgG 
immunoglobulin G 
irAE 
immune-related adverse event 
IRB 
Institutional Review Board 
IRR 
infusion related reaction 
IRT 
interactive response technology 
IV 
intravenous 
LAG-3 
lymphocyte-activation gene 3 
LTFU 
lost to follow up 
mAb 
monoclonal antibody 
MAD 
maximum administered dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
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Clinical Trial Protocol: CP-MGA271-06 
Amendment 1, 16 December 2020 
 
MTD 
maximum tolerated dose 
NE 
not evaluable 
NCI 
National Cancer Institute 
NK 
natural killer 
NSCLC 
non-small-cell lung cancer 
NT-proBNP 
N-terminal pro b-type natriuretic peptide 
ORR 
objective response rate 
OS 
overall survival 
Pap 
Papanicolaou 
PBMC 
peripheral blood mononuclear cells 
PD 
progressive disease 
PD-1 
programmed cell death protein 1 
PD-L1 
programmed death ligand 1 
PD-L2 
programmed death ligand 2 
PFS 
progression free survival 
PK 
pharmacokinetics 
PO 
orally 
PPK 
population pharmacokinetics 
PQC 
product quality complaint 
PR 
partial response 
PT 
Preferred Term 
QW 
weekly 
Q2W 
every 2 weeks 
Q3W 
every 3 weeks 
Q4W 
every 4 weeks 
RECIST 
response evaluation criteria in solid tumors 
RES242 
MGA271 with wild-type Fc 
R/M 
recurrent/metastatic 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
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Amendment 1, 16 December 2020 
 
SC 
subcutaneous 
SCC 
squamous cell cancer 
SCCHN 
squamous cell cancer of the head and neck 
SD 
stable disease 
SOC 
System Organ Class 
SPP 
statistical programming plan 
TCR 
T-cell receptor 
TEAE 
treatment-emergent adverse event 
TNBC 
triple negative breast cancer 
TRAE 
treatment-related adverse event 
TPS 
tumor proportion score 
ULN 
upper limit of normal 
US 
United States 
USP 
United States Pharmacopeia 
WOCBP 
women of child-bearing potential 
 
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1 
SYNOPSIS  
Sponsor: MacroGenics, Inc. 
IND Number: 143772 
Name of Products:  
Enoblituzumab (also known as MGA271) 
Retifanlimab (also known as MGA012 or INCMGA00012) 
Tebotelimab (also known as MGD013) 
Study Title: A Phase 2 Open-Label Trial to Evaluate Enoblituzumab in Combination with Retifanlimab or 
Tebotelimab in the First-Line Treatment of Patients with Recurrent or Metastatic Squamous Cell Carcinoma 
of the Head and Neck 
Study Number: CP-MGA271-06 
Study Phase: Phase 2 
Investigator(s)/Centers: 
The study will be conducted at approximately 35 centers in approximately 5 countries. 
Primary Objective(s): 
Retifanlimab Cohort: 
• 
To assess the efficacy of the combination of enoblituzumab + retifanlimab, based primarily upon 
evaluation of Investigator-assessed objective response rate (ORR) in the response evaluable 
patient population, in patients with recurrent or metastatic squamous cell carcinoma of the head 
and neck (SCCHN) not curable by local therapy, with no prior systemic therapy for SCCHN in 
the recurrent or metastatic setting (with the exception of systemic therapy completed > 6 months 
prior if given as part of multimodal treatment for locally advanced disease). 
Tebotelimab Cohort: 
• 
To assess the safety, tolerability, and preliminary efficacy of the combination of enoblituzumab + 
tebotelimab, based primarily upon evaluation of Investigator-assessed ORR in the response 
evaluable patient population, in patients with recurrent or metastatic SCCHN not curable by local 
therapy, with no prior systemic therapy for SCCHN in the recurrent or metastatic setting (with the 
exception of systemic therapy completed > 6 months prior if given as part of multimodal 
treatment for locally advanced disease). 
Secondary Objective(s): 
Retifanlimab Cohort: 
• 
To evaluate the Investigator-assessed progression free survival (PFS), disease control rate (DCR), 
duration of response (DoR), and overall survival (OS). 
• 
To evaluate safety and tolerability. 
• 
To assess the pharmacokinetics (PK) of enoblituzumab + retifanlimab. 
• 
To evaluate the immunogenicity of enoblituzumab + retifanlimab. 
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Clinical Trial Protocol: CP-MGA271-06 
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Tebotelimab Cohort: 
• 
To evaluate the Investigator-assessed PFS, DCR, DoR, and OS. 
• 
To assess the PK of enoblituzumab + tebotelimab. 
• 
To evaluate the immunogenicity of enoblituzumab + tebotelimab. 
Study Drug: 
• 
Enoblituzumab is a humanized IgG1κ monoclonal antibody (mAb) that binds B7 homolog 3 (B7-
H3), a member of the B7 family of ligands that bind to receptors on lymphocytes and regulate 
immune responses. 
• 
Retifanlimab is a humanized, hinge-stabilized, IgG4κ mAb that recognizes human PD-1. 
• 
Tebotelimab is an Fc-bearing bispecific tetravalent (bivalent for each antigen) DART® protein 
engineered as a hinge stabilized immunoglobulin G4 (IgG4) molecule designed to concomitantly 
bind programmed cell death protein 1 (PD-1) and lymphocyte-activation gene 3 (LAG-3) 
Study Design: 
This is a Phase 2, open label, non-randomized study in the first-line treatment of patients with recurrent or 
metastatic SCCHN not curable by local therapy, with no prior systemic therapy for SCCHN in the recurrent or 
metastatic setting (with the exception of systemic therapy completed > 6 months prior if given as part of 
multimodal treatment for locally advanced disease). The study will be conducted at approximately 35 centers 
in approximately 5 countries. 
Approximately 80 patients will be enrolled in 2 cohorts, to receive enoblituzumab in combination with either 
retifanlimab (Retifanlimab Cohort, programmed cell death ligand 1 [PD-L1] positive [combined positive score 
(CPS) ≥ 1] patients, N=50) or tebotelimab (Tebotelimab Cohort, PD-L1 negative [CPS < 1] patients, N=30; 
see figure below). Enrollment into each cohort will occur independently in a non-randomized fashion. Patients 
may not crossover between cohorts. PD-L1 expression will be prospectively collected and prospectively 
analyzed based on IHC staining using the FDA-approved 22C3 pharmDx assay. B7-H3 and LAG-3 
expression will be prospectively collected and retrospectively analyzed.  
An independent Data Safety Monitor (DSM), the Sponsor, and Investigators will maintain regular oversight of 
patient safety throughout the trial. In the Tebotelimab Cohort, toxicity will be evaluated by monitoring the 
occurrence and severity of dose limiting toxicities (DLTs) in the first 12 patients (2 mini-cohorts of 6 patients 
each) through Cycle 2 Day 7. If warranted, enrollment in the Tebotelimab Cohort will be paused and ad hoc 
meetings with the Principal Investigators (or designee), the Medical Monitor, and the independent DSM will 
be held to consider dose reduction of tebotelimab to 300 mg, Tebotelimab Cohort termination, or continuation 
at the pre-established 600 mg dose. 
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Clinical Trial Protocol: CP-MGA271-06 
Amendment 1, 16 December 2020 
 
Study Schema  
 
The data for each of the Retifanlimab and Tebotelimab Cohorts will be analyzed upon completion of 
enrollment of each cohort, and after all patients in the applicable cohort have at least one tumor assessment, to 
inform whether to proceed with the study and to determine any modifications to the trial design. 
Patients will receive the assigned study drugs (enoblituzumab 15 mg/kg and either retifanlimab 375 mg or 
tebotelimab 600 mg) on an every 3 week (Q3W) basis, in cycles of 3 weeks duration (see figure below). The 
initial tumor assessment will occur at the end of Cycle 2 (i.e., after approximately 6 weeks), and at the end of 
every 3 cycles thereafter (i.e., approximately every 9 weeks). After receipt of the last dose of study treatment, 
patients will enter an Efficacy Follow-up Period and will be followed for survival.  
 
 
 
 
 
 
 
 
 
 
Recurrent/Metastatic
SCCHN
Not curable by 
local therapy
Retifanlimab Cohort, N=50
Enoblituzumab + Retifanlimab
Tebotelimab Cohort, N=30
Enoblituzumab + Tebotelimab
Safety evaluations at the end of Cycle 2 for first 
12 patients (2 mini-cohorts of 6 patients each)
PD-L1 Positive
(CPS ≥ 1)
PD-L1 Negative
(CPS < 1)
Efficacy Outcomes
Primary:
ORR
Secondary: PFS, DCR, DoR, OS
Dosing Regimens:
Enoblituzumab:  15 mg/kg Q3W
Retifanlimab:  375 mg Q3W
Tebotelimab: 600 mg Q3W
Enrollment in the 2 study cohorts will occur independently in a non-randomized fashion
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Treatment Cycles 
Dose Limiting Toxicity (Tebotelimab Cohort): 
For the purposes of safety management and defining DLTs, the combination of enoblituzumab + tebotelimab 
will be treated as one entity. If a DLT is considered related to study treatment, no distinction will be made as 
to which agent is the causative agent and administration of both agents will be stopped. 
Dose limiting toxicities will be based on treatment-emergent drug-related AEs (or laboratory abnormalities) 
occurring through Cycle 2 Day 7. 
Patients in the Tebotelimab Cohort who experience DLT will discontinue study treatment. 
Number of Patients Enrolled: 
The total sample size is planned to be approximately 80 patients, with approximately 50 and approximately 30 
patients in the Retifanlimab and Tebotelimab Cohorts, respectively. 
Patient Population/Key Entry Criteria: 
The patient population to be enrolled in this study will consist of adult patients with histologically proven, 
recurrent or metastatic SCCHN not curable by local therapy, and with no prior systemic therapy for SCCHN 
in the recurrent or metastatic setting (with the exception of systemic therapy completed > 6 months prior if 
given as part of multimodal treatment for locally advanced disease). Patients must have good performance 
status, adequate end organ function, radiographic evidence of measurable disease suitable for response 
monitoring, and no serious concurrent illnesses that would increase the risk to the patient or confound the 
study data. 
Duration of Treatment and Study Duration: 
Study treatment will continue in cycles of 3 weeks duration until confirmed complete response (CR; except as 
noted below), disease progression, unacceptable toxicity, withdrawal of consent, physician recommendation to 
Day
1
22
64
Cycle
Retifanlimab Cohort: enoblituzumab 15 mg/kg + retifanlimab 375 mg 
Tebotelimab Cohort: enoblituzumab 15 mg/kg + tebotelimab 600 mg
Tumor Assessment
85
106
127
148
169
Initial 
Tumor Assessment
(End of Cycle 2)
Subsequent 
Tumor Assessments
(Every 3 Cycles)
All patients will enter an Efficacy Follow-up Period after receipt of the 
last dose of study treatment to be followed for survival
2
3
4
5
6
7
8
1
The Principal Investigator, in consultation with the Sponsor, will waive requirement for biopsies 
depending on individual patient circumstances. This requirement will expire after an adequate number 
of samples have been collected, as determined by the Sponsor
Biopsy
(Screening)
Biopsy
(End of Cycle 2)
43
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discontinue therapy, death, or the maximum allowed treatment duration has been reached. The maximum 
allowed treatment duration is 35 cycles for each study drug. 
Discontinuation of study treatment may be considered for patients who have attained a confirmed CR. 
However, until Cycle 33, 2 additional cycles of study treatment may be completed beyond the date of 
confirmed CR (the total number of cycles of study treatment must not exceed 35). 
Patients who have radiographic progression may remain on study treatment until the next scheduled 
radiographic evaluation if the following conditions are met: absence of clinical symptoms or signs indicating 
clinically significant disease progression; no decline in ECOG performance status; absence of rapid disease 
progression or threat to vital organs or critical anatomical sites (e.g., central nervous system [CNS] metastasis, 
respiratory failure due to tumor compression, spinal cord compression) requiring urgent alternative medical 
intervention; and no significant, unacceptable, or irreversible toxicities related to study treatment. 
The end of study will occur after the last patient has met off-study criteria and the data collection process is 
completed (time of study database lock).  
End of study for each patient is defined as follows: Patient is lost to follow-up (LTFU) or discontinues from 
the study due to any reason. 
Criteria for Evaluation: 
Safety Assessments: 
The safety assessment will be based on the evaluation of adverse events (AEs) that occur from the time of 
initiation of administration of study drug until 30 days following the last dose of study drug or until the start 
of a subsequent systemic anticancer therapy, if earlier, and will be determined based on signs, symptoms, 
physical examination findings, and/or laboratory test results from enrolled patients as appropriate. The 
severity of AEs will be graded according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) v5.0.  
Disease progression or events deemed related to disease progression (including events resulting in 
hospitalization or death without other serious adverse event [SAE] criteria) will be documented as an 
antitumor activity outcome, not reported as an AE or SAE; they will be collected as efficacy endpoints. 
Conversely, AEs and SAEs should be reported if it is unclear if the event is due to PD. 
Response Assessments: 
Tumor assessments will be obtained using computed tomography (CT) and/or magnetic resonance imaging 
(MRI) scans and tumor response evaluated according to response evaluable criteria in solid tumors (RECIST) 
v1.1. Target and non-target lesions will be designated at screening and assessed at the end of Cycle 2 (i.e., 
after approximately 6 weeks, with a window of -3 days in relation to the beginning of the next cycle), and at 
the end of every 3 cycles thereafter (i.e., approximately every 9 weeks, with a window of -7 days in relation to 
the beginning of the next applicable cycle) until discontinuation of treatment. After receipt of the last dose of 
study treatment, all patients will enter an Efficacy Follow-up Period, during which tumor assessments will be 
obtained every 12 weeks (± 1 week) after the end of treatment visit (EOTV; or, if no EOTV is conducted, after 
the decision to end treatment), until evidence of disease progression, initiation of another anticancer therapy, 
withdrawal of consent, LTFU, death, or 36 weeks after the last patient’s EOTV. EOTV tumor assessment does 
not need to be conducted if prior tumor assessment was performed within 28 days of the EOTV and results are 
available for RECIST assessments. Patients who discontinue study treatment due to AEs are followed by 
radiographic evaluation until PD by RECIST v1.1, if the patients’ condition allows. If not, patients will be 
followed for OS without radiographic evaluation upon the discussion with the Sponsor’s Medical Monitor. 
The overall responses will be categorized as Complete Response (CR), Partial Response (PR), Stable Disease 
(SD), Progressive Disease (PD), or Not Evaluable (NE). At each on-treatment tumor assessment time point, 
the objective response status will be determined. In the context of the statistical analysis for this trial, 
objective response determination and the assessment of best overall response (BOR) will be defined using 
RECIST v1.1. 
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Survival Assessments: 
After discontinuation of treatment, patients will be followed for survival via telephone or other electronic 
contact at approximately 12-week (± 1 week) intervals after the EOTV (or, if no EOTV is conducted, after the 
decision to end treatment) until LTFU, withdrawal of consent, or death, or until 36 weeks after the last 
patient’s EOTV. Prior to the database lock for final OS analysis, all current survival data will be requested 
regardless of interval from the prior assessment to collect the most up-to-date survival information for the 
final OS analysis. 
Pharmacokinetic Assessments: 
Serum concentrations of enoblituzumab, retifanlimab, and tebotelimab will be analyzed using validated assay 
methods that will be carried out in the Sponsor’s designated central laboratory. Analysis of PK data will be 
carried out using industry standard software. Single and multiple dose PK parameters, including but not 
limited to Cmax and Ctrough, will be derived from serum concentration versus time data. Population PK (PPK) 
and exposure-response analyses will be conducted, using data from this study alone or combined with data 
from other studies. 
Immunogenicity Assessments: 
The generation of anti-drug antibodies (ADA) for enoblituzumab, retifanlimab, and tebotelimab will be 
monitored using validated analytical methods carried out in the Sponsor’s designated central laboratory. 
Analysis Populations:  
Safety Population: All patients who received at least one dose of any study drug. This population will be used 
for analyses of safety, PK, pharmacodynamics, and immunogenicity. It will also be used for summary of 
baseline data and analyses of PFS and OS. 
Response Evaluable Population: All patients who received at least one dose of any study drug and had 
baseline radiographic tumor assessment. This population will be used for summary of tumor assessment data 
and analyses of responses. 
Statistical Methods: 
A separate statistical analysis plan (SAP) and statistical programming plan (SPP) will further describe the 
details regarding statistical methods and will govern the analysis. 
Sample Size:  
The total sample size is planned to be approximately 80 patients, with approximately 50 and approximately 30 
patients in the Retifanlimab and Tebotelimab Cohorts, respectively. The sample size for each cohort is 
primarily based on providing preliminary estimation of ORR. In the Retifanlimab Cohort, 50 patients will 
distinguish a favorable true ORR of 36% from an unfavorable rate of 19% with 91% power and a 1-sided type 
1 error rate of 0.079. In the Tebotelimab Cohort, 3 responses out of 30 patients will have 80% confidence that 
the true ORR is > 5%. 
Safety: 
Adverse events (AEs) will be summarized in tables and in listings. AEs will be summarized by System Organ 
Class (SOC) and Preferred Term (PT), by relationship to study drugs, and by highest severity. Summaries of 
laboratory values will display descriptive statistics for numerically quantified labs.  
Efficacy: 
The primary efficacy endpoint is the Investigator-assessed ORR per RECIST v1.1, defined as the proportion 
of patients in the response evaluable population who achieve the BOR of CR or PR per RECIST v1.1. The 
BOR will be categorized as CR, PR, SD, PD, or NE. Number and percent of patients with their BOR will be 
summarized. The ORR and its 2-sided 95% exact binomial CI will be calculated for each cohort.  
DCR and its 2-sided 95% exact binomial CI will be calculated. Kaplan-Meier method will be applied to 
estimate PFS, DoR, and OS.  
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2 
BACKGROUND INFORMATION  
2.1 
Disease Background  
Head and neck cancer accounts for over 500,000 new cases and nearly 300,000 deaths 
annually worldwide as of 2012 (40, 72). Treatment options for patients with this disease vary 
according to the disease setting as well as other clinical characteristics. Patients with localized 
squamous cell carcinoma of the head and neck (SCCHN; American Joint Committee on 
Cancer stages I-IVB) are treated with potentially curative therapy using ≥ 1 treatment 
modality (surgery, radiation therapy, chemotherapy, and biologic therapy). However, many 
patients’ disease recurs; the recurrence rate in early-stage SCCHN is ≈ 10–20% (90), whereas 
the recurrence rate in locally advanced SCCHN is ≈ 50% with a predominance of locoregional 
failure (5, 9, 23). Patients with recurrent or metastatic (R/M) SCCHN have a poor prognosis 
with median overall survival (OS) of under 1 year (62). Thus, there remains a medical need 
for improved treatment in advanced cases.  
This population includes patients whose disease recurred locally or who developed distant 
metastasis after initial treatment for localized disease and patients with distant metastasis at 
first presentation. A small percentage of patients with localized recurrence can be treated with 
curative intent, but the vast majority receive palliative treatment with systemic therapy. 
Cancers of the head and neck constitute a collection of tumors that begin in the squamous 
cells lining the mucosal surfaces of the head and neck, referred to as SCCHN, and are 
categorized by the area of the head or neck in which they begin: oral cavity, pharynx (includes 
nasopharynx, oropharynx, and hypopharynx), paranasal sinuses, nasal cavity, and salivary 
glands. Although cancers originating in the salivary glands are usually classified as part of 
head and neck cancers, salivary gland cancers can arise from multiple types of cells within a 
gland and therefore have a heterogeneous histological pathology compared to the other head 
and neck cancers arising from a squamous cell lining. Therefore, patients with salivary gland 
cancers will not be evaluated in this planned study. 
Infection with human papilloma virus (HPV), specifically the cancer causing type, HPV-16, is 
considered a risk factor for certain head and neck cancers, particularly oropharyngeal cancers 
involving the tonsils or the base of the tongue (20, 39). In the US the incidence of 
oropharyngeal cancers caused by HPV infection is increasing, while the incidence of 
oropharyngeal cancers related to other causes is falling (20). 
2.2 
Rationale for Study  
The proposed study design will allow the assessment of the efficacy, safety, and tolerability of 
the combinations of enoblituzumab + retifanlimab and enoblituzumab + tebotelimab in 
patients with relapsed/metastatic SCCHN not curable by local therapy, with no prior systemic 
therapy for SCCHN in the recurrent or metastatic setting (with the exception of systemic 
therapy completed > 6 months prior if given as part of multimodal treatment for locally 
advanced disease). In this study, the enoblituzumab + retifanlimab combination will be given 
to programmed death ligand 1 (PD-L1) positive patients, and the enoblituzumab + tebotelimab 
combination will be given to PD-L1 negative patients. 
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According to National Comprehensive Cancer Network [NCCN] guidelines, relapsed 
metastatic PD-L1 positive SCCHN can be treated with single agent pembrolizumab, while 
PD-L1 negative patients should be treated with pembrolizumab + chemotherapy. However, 
most patients do not get cured and there is still an unmet need. Previous data for 
enoblituzumab monotherapy from MacroGenics study CP-MGA271-01 (NCT01391143; see 
Section 2.3.2.2), taken into consideration with results of the KEYNOTE-048 trial (see below 
in this section), indicate that modulation of B7 homolog 3 (B7-H3) with enoblituzumab might 
improve the response to programmed cell death protein 1 (PD-1) inhibitors such as 
retifanlimab, a drug with very similar characteristics to pembrolizumab and nivolumab (see 
below in this section). Preliminary data on enoblituzumab and other Fc-optimized antibodies 
(such as margetuximab) suggest elicitation of a coordinated engagement of both the innate 
and adaptive immune response, which could in turn enhance anti-tumor response. In PD-L1 
negative patients chemotherapy toxicity is not trivial, and many patients and practitioners 
choose not to administer chemotherapy upfront to preserve quality of life. Providing not only 
PD-L1 inhibition but also lymphocyte-activation gene 3 (LAG-3) inhibition in addition to B7-
H3 modulation (i.e., enoblituzumab + tebotelimab) might offer an efficacious therapeutic 
option to those patients who are not willing or not able to receive cytotoxic chemotherapy.  
The simultaneous targeting of PD-1 and B7-H3, and PD-1, LAG-3 and B7-H3 through the 
described combination strategies is supported by the complementary biology of these three 
molecules in modulating the immune response against tumor cells (63). 
Simultaneous targeting of LAG-3 and PD-L1 with monoclonal antibodies is a promising 
strategy in a number of solid tumors. Preclinical and early-phase trial data suggest that 
concomitant  inhibition of these pathways works synergistically to reactivate T-cells (60). 
Notably, a Phase 3 registrational trial of the anti-PD-1 antibody nivolumab (Opdivo®, Bristol-
Myers Squibb) and the anti-LAG-3 antibody relatlimab (Bristol-Meyers Squibb) is currently 
ongoing in patients with advanced melanoma (NCT03470922). Early phase data of this 
combination shows activity in heavily pretreated patients, particularly in those with positive 
LAG-3 expression (6). 
The simultaneous targeting of B7-H3 and PD-1 through combined enoblituzumab and 
retifanlimab administration potentially enhances the antitumor response compared to 
treatment with either molecule alone. The biology of B7-H3 and PD-1 (also called B7-H1) 
might be complementary in mediating tumor evasion. Enoblituzumab and retifanlimab have 
the ability to potentially engage adaptive and innate immunity, thus optimizing the anti-cancer 
response. Non-clinical and clinical observations to date supporting this are summarized below. 
Non-clinical studies have demonstrated that targeting B7-H3 through administration of an 
anti-B7-H3 antibody mediates anti-tumor activity in syngeneic mouse models including 
models of melanoma (50), SCCHN (52), pancreatic cancer and lung cancer (87). The anti-
tumor activity supported by anti-B7-H3 in these immune competent models appears 
dependent on immune mechanisms distinct from those mediated by PD-1 pathway blockade 
with dependence on natural killer (NK)-cells and CD8 T-cell infiltration (50, 87). Consistent 
with distinct mechanisms of immune-mediated tumor evasion, combined blockade of B7-H3 
and PD-1 through administration of anti-B7-H3 with either an anti-PD1 monoclonal antibody 
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(mAb) (50) or anti-PD-L1 mAb (87) provides more robust mouse tumor control than 
treatment with anti-B7-H3 or mAbs targeting the PD-1 axis alone.  
Clinically, it is well documented that therapeutic antibody blockade of the PD-1/PD-L1 
checkpoint pathway overcomes T-cell exhaustion resulting in anti-tumor responses; these 
responses however appear limited to CD8 T-cell infiltrated tumors (82). While preliminary, 
immunohistochemistry (IHC) analyses of post-treatment prostate cancer biopsies revealed that 
enoblituzumab (anti-B7-H3 mAb) mediates an increase in tumor T-cell infiltrate (71), 
providing a potential complementary immune mediated mechanism to overcome limitations to 
PD-1 intervention. Examination of peripheral T-cell receptor (TCR) repertoire demonstrates 
that administration of enoblituzumab also enhances peripheral T-cell clonality and clone 
abundance (61). While it is unclear whether this clonal expansion is also occurring in tumors, 
it is notable that PD-1 inhibitors have been reported to be more effective against tumors 
bearing increased tumor T-cell clonality, providing a possible additional mechanism by which 
enoblituzumab could enhance anti-PD-1 therapeutic response (4, 45, 59). The potential for 
B7-H3 targeting to overcome limitation to PD-1 blockade is also supported by the apparent 
inverse relationship of B7-H3 tumor expression and response to PD-1 inhibitors observed in a 
cohort of non-small-cell lung cancer (NSCLC) patients, where it has been demonstrated that 
responses to anti-PD-1 therapy are statistically greater in patients absent B7-H3 tumor 
expression (87). 
In addition to its potential T-cell modulatory properties, enoblituzumab is an Fc-enhanced 
monoclonal antibody modified to increase its Fc stimulatory activity by virtue of increased 
affinity for the activating receptor CD16A and reduced affinity for the inhibitory receptor 
CD32B (51). Biologically this supports enhanced antibody-dependent cell-mediated 
cytotoxicity (ADCC) directed against B7-H3 expressing tumor cells, which has been 
demonstrated in vitro (Section 2.3.2.1) and has yielded enhanced anti-tumor activity in mouse 
xenograft models (51). As shown in Figure 1, enoblituzumab mediated ADCC activity (in this 
example directed against a B7-H3 expressing head and neck cancer cell line) is accompanied 
with increased interferon (IFN)- expression and the upregulation of both co-stimulatory and 
co-inhibitory molecules, including CD137, LAG-3, and PDL-1 (Figure 1, panels A and B). 
Notably, combination of enoblituzumab with retifanlimab (anti-PD-1) or tebotelimab (PD-1 x 
LAG-3 bispecific DART molecule) sustained the ability of NK cells and CD8 T cells from 
peripheral blood mononuclear cells (PBMC) co-cultured with tumor cells to produce IFN- 
upon re-stimulation (Figure 1, panel C). Furthermore, both retifanlimab and tebotelimab 
enhanced enoblituzumab dependent cytotoxicity targeting B7-H3 expressing tumor cells 
(Figure 1, panel D). These in vitro data suggest that both retifanlimab and tebotelimab have 
potential to sustain enoblituzumab-mediated immune activation and anti-tumor activity. 
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Figure 1 
Retifanlimab and Tebotelimab Sustain Enoblituzumab Mediated 
Immune Activation in Vitro  
 
Retifanlimab (MGA012 or INCMGA00012) and tebotelimab (MGD013) sustain enoblituzumab mediated 
immune activation in vitro. Enoblituzumab mediated a dose dependent ADCC targeting SAS (B7-H3 
expressing head and neck cancer cell line) at E:T ratio of 30:1 (A), and upregulation of costimulatory and 
co-inhibitory molecules on NK cells from PBMCs co-cultured with SAS cells (B). The values in 
fluorescence activated cell sorting (FACS) plots represent the percent of positive cells within NK cell 
(CD3-CD56+) gate. (C, D) Both retifanlimab and tebotelimab promote the sustained enoblituzumab 
dependent immune activation. PBMCs were co-cultured with SAS tumor cells in the presence of 
0
10
20
30
10-2
10-1
100
101
102
103
104
0
10
20
30
40
Enoblituzumab
Control mAb
0
5
10
15
20
Control mAb
(-)
MGA012
MGD013
(-)
MGA012
MGD013
Enoblituzumab
CD8 T cell
NK cell
IFN-producing cell (%)
Enoblituzumab/control Ab Concentration  (mg/ml)
Enoblituzumab
0mg/ml
Enoblituzumab
0.05mg/ml
Enoblituzumab
5mg/ml
Control mAb
5mg/ml
PBMC 
only
PBMC+SAS
(-)
MGA 
012
MGD 
013
(-)
MGA 
012
MGD 
013
(-)
MGA 
012
MGD 
013
(-)
MGA 
012
MGD 
013
0
10000
20000
30000
40000
Luminescence (RLU)
Concentration  (ng/ml)
Cytotoxicity (%)
A
B
C
D
IFN
Enoblituzumab
Control mAb
CD137
PDL-1
Lag-3
PD-1
CD56
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enoblituzumab alone, or in combination with retifanlimab or tebotelimab for 6 days. (C) Cells were 
collected and re-stimulated with PMA/Ionomycin in the presence of Golgistop. Levels of NK cell and CD8 
cell specific intracellular IFN- were measured by FACS. (D) Alternatively, cells were collected and used 
as effector cells to measure the cytotoxicity targeting B7-H3 expressing tumor cell line (NCI H1975-luc) at 
E:T ratio of 15:1. The loss of luminescence signal was used to measure the target cell lysis. 
The potentially coordinated engagement of innate and adaptive immune responses is related to 
the polymorphisms observed in the Fcγ receptors (FcγR). CD16A and CD32A are activating 
receptors with ITAM signaling motifs. CD32B is an inhibitory receptor with an ITIM 
signaling motif. CD16 is GPI-linked decoy receptor homologous to CD16A. Polymorphisms 
at position 158 of CD16A and position 131 of CD32A influence their Fc binding properties. 
Homozygotes for the high-binding alleles of these receptors occur in a minority of the 
population (~15% in USA and Europe). Improved responses of breast cancer patients to 
trastuzumab are associated with homozygosity for CD16A-158V and, to a lesser extent, 
homozygosity for CD32A-131H (57). 
Monocytes, macrophages, and dendritic cells (DC) express all 3 FcγRs, while other 
circulating blood cells express a more limited repertoire of receptors. NK cells express only 
CD16A. Neutrophils express CD32A and CD16B, a GPI-linked decoy receptor homologous 
to CD16A. Platelets express CD32A, while B cells express only CD32B. Several pieces of 
evidence suggest that all these blood elements contribute to the antitumor activity of 
antibodies. An important role, however, is exerted by monocytes and macrophages, as 
indicated by experimental evidence in the mouse (83). Because these cells express the 
inhibitory receptor, these data support the notion that CD32B negatively impacts the in vivo 
therapeutic activity of monoclonal antibodies (24). 
There is evidence that tumor cell breakdown components may be delivered by therapeutic 
antibodies to antigen-presenting cells. Antigen delivery via immune complexes that bind both 
activating and inhibitory receptors has limited immune activating properties compared with 
delivery under condition of CD32B blockade (13, 30, 31). Therefore, exploitation of this 
phenomenon by Fc optimization may further contribute to the ability of immunotherapy to 
break tolerance in cancer and induce an adaptive response. Enoblituzumab comprises an 
engineered human immunoglobulin G1 (IgG1) fragment crystallizable (Fc) domain that 
imparts increased affinity for the human activating Fc receptor (FcR) IIIA (CD16A) and 
decreased affinity for the human inhibitory FcRIIB (CD32B) (74, 75). The engineered Fc 
domain imparted enoblituzumab with enhanced tumor-specific antibody-dependent cell 
cytotoxicity. 
When enoblituzumab is combined with single checkpoint blockade using anti-PD-1 antibody, 
both innate and adaptive immunity appear to mediate antitumor activity that substantially 
exceeds historical experience with either therapy alone. Enhanced ADCC activity and 
engagement with FcRIII on antigen presenting cells may also result in increased tumor 
antigen presentation and an improved adaptive immune response. Furthermore, as shown 
above (Figure 1), retifanlimab (anti-PD-1 mAb) or tebotelimab (PD-1 x LAG-3 DART 
molecule) can sustain enoblituzumab mediated NK-cell and CD8 T-cell activation and NK 
cell mediated anti-tumor cell cytolytic activity. 
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Preliminary clinical data evaluating the combination of tebotelimab and margetuximab (Fc-
optimized anti-HER2 antibody containing an identical Fc region to enoblituzumab) in the 
Phase 1 CP-MGD013-01 (NCT03219268) study suggest that the combination of this Fc-
optimized mAb with tebotelimab has acceptable tolerability, with early signs of activity. 
Notably PD-L1 expression in archival tumor biopsies collected was low (combined positive 
score [CPS] ≤ 1) in all patients responding to Fc-optimized margetuximab in combination 
with tebotelimab. Taken together these observations support the concept of evaluating 
enoblituzumab in combination with tebotelimab in PD-L1 negative SCCHN patients. 
The Phase 1 CP-MGA271-03 (NCT02475213) clinical study, evaluating enoblituzumab in 
combination with pembrolizumab in patients with advanced B7-H3-expressing solid tumors, 
has provided clinical data demonstrating an acceptable safety profile and significant efficacy, 
including long-term responses, in patients with PD-1-naïve SCCHN and NSCLC. In addition, 
this trial has provided data demonstrating that the safety and tolerability profile of 
enoblituzumab in combination with retifanlimab is highly comparable to the data yielded by 
the combination of pembrolizumab and enoblituzumab. Summaries of clinical safety and 
efficacy in CP-MGA271-03 are included in Section 2.3.2.2. 
The Phase 1 INCMGA 0012-101 (NCT03059823) clinical study, evaluating retifanlimab 
(INCMGA00012) in patients with advanced solid tumors, has provided clinical data 
demonstrating an acceptable safety profile and is comparable to other anti-PD-1 molecules, 
including pembrolizumab and nivolumab. Retifanlimab has been administered to 
approximately 200 patients in the ongoing trial, and data to date has demonstrated evidence of 
antitumor activity in several different tumor types, and an acceptable safety profile. See 
Section 2.3.3.2 for further details regarding the clinical experience with retifanlimab. 
Collectively, the evolving experience to date suggests that retifanlimab has comparable 
binding affinity, functional properties, receptor occupancy, pharmacokinetics (PK), clinical 
safety and patterns of clinical activity comparable to other anti-PD-1 molecules, including 
pembrolizumab and nivolumab (see also retifanlimab Investigator Brochure). 
First-line treatment of recurrent/metastatic SCCHN has been the combination of platinum 
chemotherapy, fluorouracil (5-FU), and cetuximab followed by cetuximab maintenance, 
commonly known as the EXTREME regimen. This regimen is associated with an OS of about 
10 months. While EXTREME incurs substantial toxicity, it is tolerable for fit patients. 
Immunotherapy with PD-1 inhibitors nivolumab and pembrolizumab has recently become 
standard of care for recurrent/metastatic disease after failure on platinum-based therapy based 
on durable responses, improved survival, favorable toxicity profile, and improved quality of 
life. 
The randomized Phase 3 KEYNOTE-048 trial compared first-line pembrolizumab as both 
monotherapy and in combination with platinum chemotherapy plus 5-FU to the current 
standard of care (EXTREME) in patients with recurrent/metastatic SCCHN (16, 65). Patients 
were randomized (1:1:1) to receive one of the following treatments: pembrolizumab as a 
single agent; pembrolizumab, carboplatin or cisplatin, and FU (pembrolizumab + platinum + 
5-FU); or cetuximab, carboplatin or cisplatin, and FU (EXTREME). Randomization was 
stratified by tumor PD-L1 expression (Tumor Proportion Score [TPS] ≥ 50% or < 50%), HPV 
status according to p16 IHC (positive or negative), and ECOG PS (0 vs. 1). PD-L1 expression 
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(TPS and CPS) was determined using the PD-L1 IHC 22C3 pharmDx kit. Overall survival 
(OS), sequentially tested in the subgroup of patients with CPS ≥ 20 SCCHN, the subgroup of 
patients with CPS ≥ 1 SCCHN and the overall population, was the major efficacy measure. 
Pembrolizumab + platinum + 5-FU significantly improved OS vs. EXTREME in the 
CPS ≥ 20 (hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.45-0.82, p = .0004; median 
14.7 vs. 11.0 months) and CPS ≥ 1 (HR 0.65, 95% CI 0.53-0.80, p < .0001; median 13.6 vs. 
10.4 months) populations. HR (95% CI) for progression free survival (PFS) was 0.76 (0.58-
1.01) for CPS ≥ 20 and 0.84 (0.69-1.02) for CPS ≥ 1. Objective response rate (ORR) 
(pembrolizumab + platinum + 5-FU vs. EXTREME) was 42.9% vs. 38.2% for CPS ≥ 20 and 
36.4% vs. 35.7% for CPS ≥ 1; median duration of response (DoR) was 7.1 vs. 4.2 months and 
6.7 vs. 4.3 months, respectively. Pembrolizumab did not significantly improve OS vs. 
EXTREME in the total population (HR 0.83, 95% CI 0.70-0.99, p = .0199; median 11.5 vs. 
10.7 months). HR (95% CI) for PFS was 1.29 (1.09-1.53). ORR (pembrolizumab vs. 
EXTREME) was 16.9% vs. 36.0%; median DoR was 22.6 vs. 4.5 months. Pembrolizumab 
monotherapy significantly improved OS vs. EXTREME in the CPS ≥ 1 population (HR 0.78, 
95% CI 0.64-0.96, p=.0086; median 12.3 vs. 10.3 months; HR (95% CI) for PFS was 1.16 
(0.96-1.39), median 3.2 vs. 5.0 months; ORR was 19% vs. 35%, median DoR 23.4 vs. 4.5 
months. ORR in pembrolizumab monotherapy for CPS < 1 was 5%. 
All-cause Grade 3-5 adverse event (AE) rates were 54.7% for pembrolizumab, 85.1% for 
pembrolizumab + platinum + 5-FU, and 83.3% for EXTREME. The most common adverse 
reactions reported in ≥ 20% of patients who received pembrolizumab in combination with 
chemotherapy in KEYNOTE-048 were nausea, fatigue, constipation, vomiting, mucosal 
inflammation, diarrhea, decreased appetite, stomatitis, and cough. 
Based on these results, pembrolizumab was approved for use in combination with platinum 
and FU for all patients and as a single agent for patients whose tumors express PD-L1 (CPS 
≥ 1) as determined by an FDA-approved test. 
2.3 
Background on Study Drugs  
2.3.1 
Background on Study Drug Targets  
2.3.1.1 
Background on B7-H3  
The B7 family of cell surface molecules consists of structurally related protein ligands that 
bind to receptors on lymphocytes and regulate immune responses. Activation of T and B 
lymphocytes is initiated by engagement of antigen-specific receptors, T cell antigen receptor 
(TcR) and membrane-bound immunoglobulin (mIg) respectively, but additional signals 
delivered simultaneously to members of the CD28 family of receptors by B7 ligands 
determine the ultimate immune response (26). B7 homolog 3 (B7-H3) is a novel member of 
the B7 family. B7-H3 has been implicated in the delivery of both co-stimulatory and co-
inhibitory signals (44). The apparent contrasting activities of B7-H3 may be attributed to 
multiple factors. While the murine B7-H3 molecule exists as a 2-Ig form, the human 
counterpart has undergone gene duplication and exists primarily as a 4-Ig molecule (77). 
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Further, as with other members of the B7 family, B7-H3 may bind, on different cells, to 
multiple receptors that remain to be identified. 
B7-H3 is an attractive target for tumor immunotherapy without regard to its immunological 
properties. Tissue expression studies have demonstrated that B7-H3 protein is not expressed in 
most normal tissues, rather its expression is inducible on certain antigen presenting cells (19, 
78) and vasculature, exists on certain endocrine tissues (most notably in the cytoplasm of 
epithelial cells of the adrenal cortex), and is over-expressed in a wide range of cancers 
(including cultured cancer stem-like cells). B7-H3 is broadly over-expressed on many 
malignant neoplasms, including SCCHN (MacroGenics unpublished observation); bladder 
cancer (11); prostate cancer (21, 81, 88), where expression of B7-H3 is associated with 
metastatic behavior and poor outcome; renal cell carcinoma (28), where B7-H3 is broadly 
expressed in tumor vasculature; ovarian cancer (89); colorectal cancer (78); gastric cancer 
(86); non-small cell lung cancer (68, 79) (MacroGenics unpublished observation); 
glioblastoma (56); melanoma (MacroGenics unpublished observation); and certain small 
round blue cell tumors of childhood, including neuroblastoma and rhabdomyosarcoma (18, 
41). 
B7-H3 has also been found to be expressed on a high percentage of SCCHN tumors 
(enoblituzumab Investigator’s Brochure) (46, 58). Based on IHC evaluation of SCCHN 
patient samples enrolled in the clinical program to date and complemented by an evaluation of 
SCCHN samples obtained outside the clinical program, MacroGenics has observed a B7-H3 
positivity rate of 90.3% (65/72). Furthermore, independent published studies evaluating 
primary tumor tissue samples obtained from either 165 SCCHN patients (52) or 37 
hypopharyngeal squamous cell carcinoma (SCC) patients (46) revealed a high percentage of 
B7-H3 positive specimens by IHC. In addition to the high percentage of SCCHN tumors 
expressing membranous B7-H3, the level of B7-H3 expression as determined by IHC staining 
on the tumor was inversely correlated with the number of tumor infiltrating CD8 + T-cells 
(46) and directly proportional to the development of distal metastases and decreased survival 
(46, 52). 
2.3.1.2 
Background on PD-1  
PD-1 is an immune-modulatory receptor expressed on activated T-cells. The physiological 
role of PD-1 is to limit the inflammatory response to infection and prevent autoimmunity by 
limiting the activity of T cells in the periphery (8, 36, 47). 
The basis for this physiology is that the ligands for PD-1, namely PD-L1 (B7-H1) and PD-L2 
(B7-DC), are up-regulated on many cell types — hematopoietic, endothelial, and epithelial — 
in response to pro-inflammatory cytokines, notably interferon gamma. In addition, B7-
DC/programmed death ligand 2 (PD-L2) is up-regulated on dendritic cells and macrophages 
in response to different pro-inflammatory cytokines such as IL-4 (76, 85). 
To avoid antitumor response, cancer cells co-opt the normal physiology of the PD-1 pathway 
used to prevent collateral normal tissue damage that would occur in an unchecked 
inflammatory immune response. Expression of B7-H1/ PD-L1 as an adaptive response to 
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antitumor immunity likely occurs because this ligand is induced on most epithelial cancers in 
response to interferon-gamma, similarly to epithelial and stromal cells in normal tissues (81). 
In addition, PD-1 is highly expressed on induced regulatory T-cells (T-regs), and PD-1: PD-L1 
interactions appear to promote the induction, conversion and maintenance of T-regs, 
suggesting an additional mechanism for immunosuppression in a tumor microenvironment 
rich in PD-1 ligands (3, 35). 
Monoclonal antibodies targeting the T-cell immune checkpoint inhibitors PD-1 and PD-L1 
have recently demonstrated antitumor activity in patients with advanced SCCHN. 
Pembrolizumab was evaluated in a cohort of 60 patients with both HPV-positive and 
HPV-negative SCCHN (70). Of the 56 evaluable patients, 51% had a reduction in tumor 
volume, with 19.6% having either a partial response (PR) or complete response (CR) that was 
equally distributed between the HPV-positive and negative patients. In addition, MEDI4736, a 
humanized monoclonal antibody targeting PD-L1, demonstrated a 32% objective response 
rate (ORR) in a cohort of 22 patients with advanced SCCHN (69). 
More recently, pembrolizumab was approved for use in the US in combination with platinum 
and fluorouracil (FU) for all patients, and as a single agent for patients whose tumors express 
PD‑L1 (Combined Positive Score [CPS] ≥ 1) as determined by an FDA‑approved test. 
Approval was based on KEYNOTE-048, a randomized, multicenter, 3-arm, open‑label, 
active‑controlled trial conducted in 882 patients with metastatic SCCHN, who had not 
previously received systemic therapy for metastatic disease, or with recurrent disease who 
were considered incurable by local therapies (65). Overall, KEYNOTE-048 showed that 
compared with the combination of platinum chemotherapy, 5-FU, and cetuximab followed by 
cetuximab maintenance (commonly known as the EXTREME regimen), pembrolizumab + 
platinum + 5-FU had superior OS in the PD-L1 CPS ≥ 20, CPS ≥ 1, and total populations with 
comparable safety, and pembrolizumab had superior OS in the CPS ≥ 20 and ≥ 1 populations, 
noninferior OS in the total population, and favorable safety. These results support 
pembrolizumab and pembrolizumab + platinum + 5-FU as new first line standards of care for 
R/M SCCHN in the US. 
2.3.1.3 
Background on LAG-3  
In addition to PD-1, another immune checkpoint molecule of growing interest is 
lymphocyte-activation gene 3 (LAG-3), a membrane protein that belongs to the 
immunoglobulin (Ig) superfamily and binds to major histocompatibility complex class II 
(MHC-II). LAG-3 engagement enhances regulatory T-cell activity and negatively regulates 
T-cell proliferation and differentiation (7). LAG-3 has been shown to be expressed on 
dysfunctional, “exhausted” T cells and is a marker for regulatory T cells, suggesting an 
immune suppressive role (73). Blockade of PD-1 and LAG-3 in animal tumor models 
generated enhanced antitumor immunity via distinct, nonredundant signaling pathways that 
fostered the accumulation of functionally competent CD8+ T cells in mice (42, 85).  
In gastric cancer (GC), several intrinsic factors, including LAG-3 and PD-1 have been 
recognized as negative regulatory proteins that block the expansion and suppress the effector 
function of antigen-specific CD8+ T cells (80). An IHC analysis conducted by the Sponsor of 
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tumor specimens from 39 SCCHN patients revealed the majority (34/39) contained 
lymphocyte infiltrates with detectable LAG-3 expression (Table 1). LAG-3 is believed to 
confer poor prognosis in SCCHN, and its blockade may reshape antitumor response (29). 
Table 1 
LAG-3+ Tumor Infiltrating Lymphocyte Profile Across SCCHN      
Any detectable  
LAG-3+ TIL  
Moderate or above  
LAG-3+ TIL  
Heavy 
LAG-3+ TIL  
34/39 (87.2%) 
28/39 (71.8%) 
22/39 (56.4%) 
LAG-3–positive tumor infiltrating lymphocyte prevalence rate determined by IHC analyses across 39 
independent SCCHN patient specimens. IHC was performed with anti–LAG-3 antibody EPR4392 (Abcam) 
using the Ventana Discovery Ultra Platform and the following scoring criteria applied within the area of highest 
observed density LAG-3 expressing lymphocytes by 40x magnification: negative scoring < 1 LAG-3+ 
lymphocyte; light: 1-5 LAG-3+ lymphocytes; moderate: 6-15 LAG-3+ lymphocytes; and heavy: > 15 LAG-3+ 
lymphocytes. 
 
Laboratory studies suggest a role of LAG-3 in squamous cell carcinoma (SCC). Studies on 
mouse models with SCC derived from injection of tumor cells from SCC have shown that 
CD8+ tumor-infiltrating lymphocytes (TILs) exhibit phenotypes of chronic activation and 
exhaustion, including overexpression of activation markers, co-expression of PD-1 and 
LAG-3, as well as TCRβ downregulation. Dual blockade of PD-1 and LAG-3 inhibited tumor 
growth of SCC in these mice (55). Tebotelimab can achieve dual blockade of PD-1 and 
LAG-3 and may benefit patients with SCC. 
2.3.2 
Background on Enoblituzumab  
2.3.2.1 
General Information on Enoblituzumab  
Enoblituzumab (also known as MGA271) is a humanized IgG1κ monoclonal antibody (mAb) 
that binds the B7-H3 immunoligand with high affinity (51). The antibody has been engineered 
to have enhanced binding to the activating FcR, CD16A, and especially the low affinity 
allele of CD16A, CD16A-158F. The rationale for the incorporation of an engineered Fc 
domain in enoblituzumab stems from observations that the clinical outcome of 
immunotherapy with rituximab (17, 24, 67), cetuximab (10) and trastuzumab (57) can be 
predicted by the FcγR polymorphic variant expressed on the patient’s immune cells. Patients 
homozygous for the high-binding alleles of CD16A (158 V/V) or CD32A (131 H/H) 
demonstrate improved survival as compared to those carrying the low-binding alleles (131-F 
and 131-R carriers). Although homozygosity for either FcγR allele is an independent predictor 
of outcome, CD16A polymorphism is by far the stronger factor. These data indicated that 
FcγR-dependent events, such as ADCC, play an important role in the mechanisms of action 
for these monoclonal antibodies. 
Only approximately 15% of the patients are homozygous for the high-binding allele of 
CD16A; therefore, the Fc domain of enoblituzumab has been engineered to enhance the 
affinity for either CD16A allele but preferentially the low-binding form in order to enhance 
the overall activity and expand the benefit to the entire patient population. This approach has 
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resulted in enhanced tumor-specific ADCC in vitro (including activity against low-antigen 
density expressing cells) and improved anti-tumor activity in mice with a variety of cancer-
specific human IgG1 mAb, including enoblituzumab. Since most patients carry the low-
affinity allele of CD16A, the enhanced binding of the Fc-optimized version is expected to 
impart binding improvement that benefits the whole patient population, not just those patients 
who are homozygous for the high-binding allele of CD16A (valine/valine [V/V] genotype, 
approximately 15% of the population). Enoblituzumab Fc domain also exhibits reduced 
binding to the low-affinity inhibitory receptor, CD32B, a property that is expected to further 
enhance its anti-tumor activity based on evidence of improved responses to human IgG1 
immunotherapy in CD32B-deficient mice (24). 
ADCC has been shown to be an important mechanism of action for several monoclonal 
antibodies, including rituximab (24, 84) and trastuzumab (24, 57) and is likely an important 
mechanism of action for enoblituzumab. 
The ability of enoblituzumab to mediate ADCC activity was evaluated across multiple cancer 
types expressing varying levels of B7-H3 as determined by flow cytometry. The cancer types 
tested included: melanoma (A375, UACC-62), lung cancer (SK-MES-1, A549), prostate 
cancer (LnCAP), breast cancer (JIMT-1, MDA-MB-468), bladder cancer (SW780, HT-1197), 
and renal cancer (ACHN) cell lines (51). 
Enoblituzumab mediated ADCC activity against all tumor lines that express B7-H3 at 
detectable levels. Furthermore, enoblituzumab showed enhanced ADCC potency compared to 
the related version of the antibody with wild type Fc domains, chBRCA84D or RES240, 
against all the tumor cell lines examined (see Figure 2). Consistent with the studies described 
above, the greatest enhancement in ADCC activity against the B7-H3 expressing prostate 
cancer cell line LnCAP was observed with effector populations obtained from individuals 
homozygous for the weak binding allele of CD16A (phenylalanine/phenylalanine [F/F]). In 
contrast, enoblituzumab did not mediate ADCC against Raji B-cell lymphoma cells, which do 
not express detectable cell surface B7-H3. 
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Figure 2 
Enoblituzumab (RES242) Mediates ADCC Activity Across a 
Spectrum of Cancer Types  
 
The ability of enoblituzumab (referred to as RES242 in the figure keys) to mediate ADCC was evaluated 
on B7-H3 positive melanoma (A&B), lung (C&D), prostate (E&F), breast (G&H), bladder (I&J), and 
renal cancer (K) cell lines, as well as the B7-H3 negative Raji B cell lymphoma line (L). Enoblituzumab 
activity was compared to the indicated control molecules: humanized BRCA84D (hBRCA84D); chimeric 
BRCA84D (chBRCA84D), and mouse BRCA84D (mBRCA84D). Resting human PBMC from independent 
healthy donor were utilized and the effector cell to target cell (E:T) ratio is indicated in each panel. The 
percent cytotoxicity, as determined by lactate dehydrogenase (LDH) release, was calculated. 
UACC-62
E:T=30:1; D#48332 (F/F)
10-3
10-2
10-1
100
101
102
103
104
-10
0
10
20
30
40
50
60
RES240
RES242
mBRCA84D
Concentration (ng/mL)
% Cytotoxicity
SK-MES-1
E:T=25:1; D#46853 (F/V)
10-2
10-1
100
101
102
103
104
-10
0
10
20
30
40
50
60
RES242
RES240
chBRCA84D
Concentration (ng/mL)
% Cytotoxicity
A375
E:T=30:1; D#54070 (F/F)
10-3
10-2
10-1
100
101
102
103
-10
0
10
20
30
40
50
chBRCA84D
RES242
Concentration (ng/mL)
% Cytotoxicity
A549
E:T=25:1; D#46853 (F/V)
10-2
10-1
100
101
102
103
104
-10
0
10
20
30
40
50
60
RES242
RES240
chBRCA84D
Concentration (ng/mL)
% Cytotoxicity
LNCap
E:T=25:1 D#46853 (F/V)
10-2
10-1
100
101
102
103
104
-10
0
10
20
30
40
50
60
70
80
RES242
RES240
chBRCA84D
Concentration (ng/mL)
% Cytotoxicity
LNCap
E:T=25:1 D#50401 (F/F)
10-2
10-1
100
101
102
103
104
-10
0
10
20
30
40
50
60
70
80
RES242
RES240
chBRCA84D
Concentration (ng/mL)
Cytotoxicity (%)
JIMT-1
E:T=30:1; D#54070 (F/F)
10-3
10-2
10-1
100
101
102
103
-10
0
10
20
30
40
50
60
70
80
chBRCA84D
RES242
Concentration (ng/mL)
% Cytotoxicity
MDA-MB-468
E:T=30:1  D#31936  (F/F)
10-3
10-2
10-1
100
101
102
103
104
-10
0
10
20
30
40
50
60
chBRCA84D
RES242
Concentration (ng/mL)
Cytotoxicity (%)
SW780
E:T=30:1  D#51140 (F/V)
10-3
10-2
10-1
100
101
102
103
104
-10
0
10
20
30
40
50
60
ChBRCA84D
RES242
Concentration (ng/mL)
Cytotoxicity (%)
HT-1197
E:T=30:1 D#49480 (F/F)
10-3
10-2
10-1
100
101
102
103
104
-10
0
10
20
30
40
50
60
70
80
RES240
RES242
Concentration (ng/mL)
% Cytotoxicity
ACHN
E:T=30:1  D#31936  (F/F)
10-3
10-2
10-1
100
101
102
103
104
-10
0
10
20
30
40
50
60
chBRCA84D
RES242
Concentration (ng/mL)
Cytotoxicity (%)
Raji (B7-H3 negative)
E:T = 30:1 D#53560 (F/F)
10-2
10-1
100
101
102
103
104
-10
0
10
20
30
40
50
RES242
chBRCA84D
Rituximab
Concentration (ng/mL)
Cytotoxicity (%)
A.
D.
E.
B.
G.
J.
K.
H.
F.
C.
L.
I.
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A series of in vivo xenograft tumor efficacy studies were conducted to identify tumor cell 
lines that are sensitive to enoblituzumab as a single agent, establish dose response profiles for 
the antitumor activity of enoblituzumab, and identify cancer types that exhibit sensitivity to 
enoblituzumab. Weekly intravenous (IV) administration of enoblituzumab resulted in 
significant inhibition of growth of a variety of human tumor xenografts representing bladder, 
gastric, lung, melanoma, prostate, and kidney cancer. Enoblituzumab exhibited antitumor 
activity when administered approximately 1 week after tumor cell implantation or after 
tumors were allowed to become fully established (approximately 3 weeks after implantation 
when tumors were ~300 mm3 in volume). See enoblituzumab Investigator’s Brochure for 
additional details. 
2.3.2.2 
Clinical Trial Experience with Enoblituzumab  
Enoblituzumab is currently being evaluated in patients with cancer in 4 (1 ongoing fully 
enrolled, and 3 completed), Phase 1, MacroGenics-sponsored clinical studies. Clinical trial 
experience is presented for enoblituzumab + pembrolizumab combination therapy, and 
enoblituzumab + retifanlimab combination therapy, for study CP-MGA271-03 (1), and 
enoblituzumab monotherapy for study CP-MGA271-01 (NCT01391143). Data from the 
remaining 2 studies are not included, as 1 explores enoblituzumab treatment in a pediatric 
population and the other explores combination enoblituzumab and ipilimumab treatment.  
Safety of Enoblituzumab 
Safety data are available for 133 patients exposed to enoblituzumab + pembrolizumab in 
ongoing study CP-MGA271-03 (as of the cut-off date of 13 April 2020), and for 179 patients 
exposed to enoblituzumab in completed study CP-MGA271-01. In addition, safety data are 
available for 12 patients exposed to enoblituzumab + retifanlimab in ongoing study 
CP-MGA271-03 (as of the cut-off date of 13 April 2020). A discussion of safety for each 
study is presented below. 
Study CP-MGA271-03 – Enoblituzumab + Pembrolizumab Combination Therapy 
This open-label study is evaluating the safety, tolerability, dose limiting toxicities (DLTs), and 
maximum tolerated dose (MTD) or maximum administered dose (MAD) of enoblituzumab (3, 
10, or 15 mg/kg) administered IV weekly (QW) in combination with 2 mg/kg pembrolizumab 
administered IV every 3 weeks (Q3W) to patients with unresectable, locally advanced, or 
metastatic melanoma, SCCHN, NSCLC, urothelial cancer, and other cancers. Enrollment in 
the enoblituzumab + pembrolizumab cohorts is complete (N=133). Patients enrolled in the 
combination enoblituzumab and pembrolizumab dose escalation and expansion cohorts have 
completed combination treatment; no MTD was defined.  
Adverse events irrespective of grade and considered related to enoblituzumab + 
pembrolizumab treatment were reported in 117 patients (88.0%). The most common 
treatment-related adverse events (TRAEs) reported in ≥ 5% of patients exposed to 
enoblituzumab + pembrolizumab in decreasing order of frequency were as follows: infusion 
related reaction (IRR, 55.6%); fatigue (27.8%); nausea (9.8%); pyrexia (9.0%); lipase 
increased (8.3%); arthralgia (7.5%); events of diarrhea, hypothyroidism, rash maculo-papular, 
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and decreased appetite, pneumonitis (6.8%, each); lymphocyte count decreased (6.0%); and 
events of chills, anemia, and pruritus (5.3% each). Greater than or equal to Grade 3 TRAEs 
were reported in 38 patients (28.6%). Of these, the most commonly reported in ≥ 5% of 
patients were IRR (7.5%) and lipase increased (6.0%). The majority of ≥ Grade 3 AEs of 
lipase increased were isolated, reversible, and asymptomatic. The majority of IRR were Grade 
1 or 2 in severity. Observed IRR to date have been manageable and have resolved without 
sequelae. Patients who experienced Grade 3 IRR have fully recovered following brief 
interruption in dosing and after receiving treatment based upon symptomatology. Typically, 
these IRR occurred only with the first dose of enoblituzumab and did not recur with 
subsequent dosing. 
Twenty-three patients (17.3%) experienced serious adverse events (SAEs) considered related 
to enoblituzumab + pembrolizumab; for the majority of these patients (20/23, 87%), the 
events were ≤ Grade 3 in severity. The most common SAEs considered related were IRR 
(7.5%) and pneumonitis (4.5%). Fourteen patients (10.5%) experienced at least 1 ≥ Grade 3 
SAE that was considered related to enoblituzumab + pembrolizumab; with the exception of 
IRR (7 patients, 5.3%) and pneumonitis (3 patients, 2.3%), the events were singularly 
reported. 
Myocarditis and pneumonitis have been identified as important potential risks associated with 
enoblituzumab/pembrolizumab combination treatment. The cumulative safety data reviewed 
to date suggest the combination with enoblituzumab does not increase the risk of myocarditis 
or pneumonitis compared to anti-PD-1 inhibitors alone. Notably, both important potential 
risks are recognized, yet rare, adverse effects associated with the administration of PD-1 
inhibitors. Furthermore, pneumonitis and myocarditis have not been observed in 
MacroGenics-sponsored monotherapy trials of enoblituzumab to date. 
Study CP-MGA271-03 – Enoblituzumab + Retifanlimab Combination Therapy 
This open-label study is evaluating the safety, tolerability, and DLT of 15 mg/kg 
enoblituzumab in combination with a flat dose of 375 mg of retifanlimab, each administered 
IV Q3W. Enrollment in the enoblituzumab + retifanlimab cohort is complete (N=12). 
Adverse events irrespective of grade and considered related to enoblituzumab + retifanlimab 
treatment were reported in 10 (83.3%) patients. The most common TRAE reported in patients 
exposed to enoblituzumab + retifanlimab was IRR (50.0%). The remaining TRAEs of anemia, 
contusion, dysgeusia, eye irritation, fatigue, granulomatous lymphadenitis, influenza like 
illness, lipase increased, nausea, pruritus, pyrexia, rash maculo-papular, tumor pain, and 
weight increased were each reported in 1 (8.3%) patient.  
Greater than or equal to Grade 3 TRAEs were reported in 2 (16.7%) patients: granulomatous 
lymphadenitis, IRR, lipase increased, and weight increased, each in 1 (8.3%) patient, all of 
which were Grade 3. The majority of IRR were Grade 1 or 2 in severity, manageable, and 
resolved without sequelae. For the 1 patient with Grade 3 IRR, the event, was manageable and 
resolved within 2 days. IRR occurred only with the first dose of enoblituzumab and did not 
recur with subsequent dosing. One (8.3%) patient experienced SAEs considered related to 
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enoblituzumab + retifanlimab. These SAEs (granulomatous lymphadenitis and IRR) were 
both Grade 3 in severity. 
Study CP-MGA271-01 – Enoblituzumab Monotherapy  
This Phase 1, open-label study evaluated the safety, tolerability, DLTs, and MTD or MAD of 
enoblituzumab (from 0.01 to 15 mg/kg) administered IV QW to patients with unresectable or 
metastatic B7-H3-expressing neoplasms or neoplasms whose vasculature expresses B7-H3 for 
whom no standard therapy is available.  
Adverse events irrespective of grade and considered related to enoblituzumab monotherapy 
treatment were reported in 146 patients (81.6%). The most common related AEs reported in 
≥ 5% of patients exposed to enoblituzumab in decreasing order of frequency were as follows: 
IRR (39.7%), fatigue (31.8%), nausea (19.6%), chills (14.0%), vomiting (12.8%), pyrexia 
(9.5%), diarrhea (8.4%), decreased appetite (7.3%), pruritus (6.1%), influenza-like illness 
(5.6%), and headache (5.0%). These events were generally mild (Grade 1) or moderate (Grade 
2) in severity. Thirteen patients (7.3%) reported ≥ Grade 3 AEs considered related to 
enoblituzumab treatment.  
Eleven patients (6.1%) experienced SAEs considered related to enoblituzumab treatment. The 
most common SAEs considered related were IRR (6, 3.4%) and pyrexia (2, 1.1%). The SAEs 
considered related to enoblituzumab treatment were generally mild (Grade 1) or moderate 
(Grade 2) in severity; few patients (5, 2.8%) experienced at least 1 ≥ Grade 3 SAE considered 
to be related, with the most commonly reported as IRR (1.7%).  
Overall, enoblituzumab administration as a monotherapy was generally well tolerated, with 
IRR reactions, typically mild or moderate, being the primary safety concern. No MTD was 
identified, and the MAD was 15 mg/kg. Observed IRR were manageable, resolving without 
sequelae. Patients who experienced Grade 3 IRR fully recovered following brief interruption 
in dosing and after receiving treatment based upon symptomatology. Typically, these IRR 
occurred only with the first dose of enoblituzumab and did not recur with subsequent dosing. 
Safety Summary 
In conclusion, the data from the clinical studies CP-MGA271-03 and CP-MGA271-01 suggest 
that enoblituzumab, at doses up to 15 mg/kg combined with 2 mg/kg pembrolizumab weekly 
by IV and enoblituzumab monotherapy at doses up to 15 mg/kg administered weekly by IV, is 
generally well tolerated with toxicities manageable by standard medical therapy for patients 
with advanced cancer. See current enoblituzumab Investigator’s Brochure for more detailed 
safety information. In addition, the safety and tolerability profile of 15 mg/kg enoblituzumab 
in combination with a flat dose of 375 mg of retifanlimab, each administered IV Q3W, is 
highly comparable to the data yielded by enoblituzumab monotherapy. 
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Efficacy of Enoblituzumab 
Study CP-MGA271-03 – Enoblituzumab + Pembrolizumab Combination Therapy 
Objective efficacy responses have been observed in study CP-MGA271-03 in the following 
expansion cohorts, receiving enoblituzumab in combination with pembrolizumab:  
• melanoma (post PD-1/PD-L1 inhibitor),  
• urothelial cancer (post PD-1/PD-L1 inhibitor),  
• SCCHN without prior PD-1/PD-L1 inhibitor, and  
• NSCLC with and without prior PD-1/PD-L1 inhibitor. Patients with NSCLC who 
had no prior PD-1/PD-L1 inhibitor had tumors whose PD-L1 expression level was 
negative (< 1%). 
 
Durable objective responses were seen in PD-1/PD-L1 inhibitor-naïve SCCHN and NSCLC 
patients (1). The overall response rate of PD-1/PD-L1 inhibitor-naïve SCCHN patients (post 
platinum chemotherapy) was 33% (6 of 18 patients) including 1 confirmed complete response 
and 5 confirmed partial responses. The overall response rate of PD-1/PD-L1 inhibitor-naïve 
NSCLC patients (PD-L1 < 1%) was 36% with 5/14 PRs. In both instances, the observed 
response rate for patients treated with the combination of enoblituzumab and pembrolizumab 
represent increases of 2 to 3-fold over what would be expected in similar patients treated with 
checkpoint inhibitors alone (Table 2). 
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Table 2 
Enoblituzumab + Pembrolizumab Combination Data in SCCHN 
and NSCLC  
 
a 
Ferris et al, 2016 (34). 
b 
Keytruda® package insert (33). 
c 
Cohen et al, 2017 (25). 
d 
Borghaei et al, 2015 (12). 
e 
Brahmer et al. 2015 (14). 
f 
Garon et al. 2015 (38). 
 
The degree of tumor regression and the durability of objective responses of anti-PD1-naïve 
SCCHN patients treated on CP-MGA271-03 as of November 2018 are demonstrated on the 
waterfall and spider plots in Figure 3 and Figure 4, respectively.  
Figure 3 
CP-MGA271-03 Anti-PD-1-Naïve SCCHN Waterfall Plot  
 
Note that the waterfall plot shows target lesions only, while overall patient response is represented in the 
table. 
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Figure 4 
CP-MGA271-03 Anti-PD-1-Naïve SCCHN Spider Plot  
 
 
2.3.2.3 
Nonclinical Data for Enoblituzumab  
A repeat dose Good Laboratory Practice (GLP) toxicology study was conducted in 
cynomolgus monkeys to determine the potential toxicity and toxicokinetics of enoblituzumab 
when administered weekly for 4 weeks via IV infusion at doses of 1, 10, 30, or 150 mg/kg and 
to evaluate recovery from any effects of the enoblituzumab over a dose-free period of at least 
8 weeks. In this study, enoblituzumab was well tolerated at all dose levels evaluated. There 
were no test article-related mortalities and no test article-related changes in clinical 
observations, food consumption, body weight, clinical pathology parameters, gross pathology, 
and organ weights. The no observed adverse effect level (NOAEL) was considered to be 150 
mg/kg. A detailed summary of pathology, laboratory and IHC findings in the cynomolgus 
monkeys from the repeat-dose GLP toxicology study can be found in the enoblituzumab 
Investigator’s Brochure. 
The potential cross reactivity of enoblituzumab with cryosections of normal human tissues 
was evaluated in the GLP-MGA271-03 study. The observed staining was generally consistent 
with reported sites of B7-H3 expression. Membrane staining was only present in rare 
conjunctival epithelium, esophageal epithelium, prostate epithelium, mononuclear cells 
(including rare Kupffer cells and rare alveolar macrophages), and placental decidual cells. The 
remainder of the staining in this study was cytoplasmic in nature, and it is unlikely that 
cytoplasm and cytoplasm structures would be accessible to enoblituzumab following IV 
administration (enoblituzumab Investigator’s Brochure). 
In IHC studies, enoblituzumab was shown to recognize epithelial elements in the normal 
human adrenal cortex, and in tissue distribution studies enoblituzumab was found to distribute 
to the adrenal cortex in cynomolgus monkeys treated with a 150 mg/kg dose. However, no 
changes in hormone parameters were observed in cynomolgus monkeys treated with 
enoblituzumab. 
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A comprehensive immunohistochemical study using the 8H9 antibody (with specificity 
against B7-H3) was performed in frozen tumors from 330 patients with neuroectodermal, 
mesenchymal, and epithelial neoplasia; in addition to 15 normal human tissue samples and 
8 normal cynomolgus monkey tissue samples. This study clearly shows that the anti B7-H3 
antibody 8H9 recognizes this antigen in a tumor-specific manner, with broad distribution 
across a spectrum of tumors of varying lineage (neuroectodermal, mesenchymal, and 
epithelial), with restricted expression in normal tissues (2, 56). 
2.3.3 
Background on Retifanlimab  
2.3.3.1 
General Information on Retifanlimab  
Retifanlimab (also known as INCMGA00012 or MGA012) is a humanized, hinge-stabilized, 
IgG4κ mAb that recognizes human PD-1. Retifanlimab contains a hinge-stabilized human 
IgG4 Fc domain to limit effector function, while retaining neonatal FcR (FcRn) binding to 
extend circulating half-life. Retifanlimab binds to PD-1 expressing cells in a dose-dependent 
manner. Consistent with its specific binding properties and designed mechanism of action, 
retifanlimab blocks the binding of the ligands PD-L1 and programmed death ligand 2 (PD-L2) 
to cell surface-expressed PD-1 in a dose-dependent manner.  
2.3.3.2 
Clinical Trial Experience with Retifanlimab  
Retifanlimab 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 the 
data cutoff date of 23 September 2019, 382 unique participants with advanced malignancies 
have been exposed to retifanlimab as monotherapy (N = 322) or in combination with other 
agents (epacadostat in 31 participants, INCB050465 [also known as parsaclisib] in 22 
participants, and pemigatinib in 7 participants). 
Safety of Retifanlimab 
Phase 1 (Study INCMGA 0012-101) dose-finding results in participants with advanced solid 
tumors (N = 37) have been presented (49). Retifanlimab demonstrated acceptable tolerability 
with no dose-limiting toxicity observed at doses ranging from 1 to 10 mg/kg every 2 weeks 
(Q2W). Administration every 4 weeks (Q4W) was also studied. A maximum tolerated dose 
was not reached. A dose of 3 mg/kg Q2W was selected for further expansion in non-small-cell 
lung carcinoma (NSCLC), endometrial cancer, cervical cancer, and sarcoma cohorts, with 
subsequent evaluation of flat dosing in tumor-agnostic and microsatellite instability (MSI) 
high uterine cancer cohorts.  
As of 23 September 2019, 230 participants have been exposed to any dose of retifanlimab  
monotherapy in Study INCMGA0012-101. As of the data cutoff date, 11.7% of participants 
have received ≥ 1 year of continuous treatment with retifanlimab. Treatment-emergent adverse 
events (TEAEs) were reported in 212 participants (92.2%). TEAEs reported for ≥ 10% of 
participants included fatigue, anemia, diarrhea, nausea, and vomiting. The most frequently 
reported TEAEs (≥ 10%) in the 29 patients receiving the fixed dose of 500 mg Q4W were 
fatigue, blood alkaline phosphatase increased, anemia, back pain, diarrhea, and rash. Adverse 
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events of special interest (AESI) included ≥ Grade 2 immune-related adverse events (irAEs), 
≥ Grade 3 IRR or cytokine release syndrome (CRS), and abnormal liver enzymes that met the 
criteria for potential Hy’s law (defined as aspartate aminotransferase [AST] and/or alanine 
aminotransferase [ALT] > 3 × upper limit of normal [ULN] and total bilirubin > 2 × ULN and 
without any alternate etiology). A total of 32 participants (13.9%) experienced ≥ 1 AESI in 
Study INCMGA 0012-101. The most common AESI (> 1 participant) were IRR, 
hypothyroidism, hyperthyroidism, colitis, rash, and diarrhea. There were no fatal irAEs. 
Further details of clinical data can be found in the retifanlimab Investigator’s Brochure. 
Efficacy of Retifanlimab 
Preliminary efficacy in terms of confirmed response evaluation criteria in solid tumors 
(RECIST) overall response has been demonstrated in multiple tumor types in Study INCMGA 
0012-101, and is consistent with previous experience with other PD-(L)1 inhibitors. 
Specifically, Investigator-assessed ORR was 17.1% with partial responses observed in 6 of 35 
participants in the cervical cancer cohort (54), and Investigator-assessed responses were 
observed in 6/28 evaluable participants with NSCLC and 4/23 evaluable participants with 
endometrial cancer (53). Preliminary activity has also been demonstrated against squamous 
carcinoma of the anal canal (64). Early evidence of activity has also been seen in Study 
INCMGA 0012-201 (NCT03599713; Merkel cell carcinoma) and the soft tissue sarcoma 
cohort of Study INCMGA 0012-101.  
2.3.3.3 
Nonclinical Data for Retifanlimab  
In a single-dose PK study, administration of retifanlimab by intravenous (IV) infusion was 
well tolerated in cynomolgus monkeys at a dose level of 10 mg/kg. There were no changes in 
circulating immune cell subsets and no evidence of cytokine release. Binding profiles of 
retifanlimab to PD-1 on CD4+ and CD8+ T cells were similar to those exhibited by 
pembrolizumab but more durable than those exhibited by the nivolumab replica. 
In repeat-dose GLP toxicology studies, retifanlimab was administered at dose levels of 0 to 
150 mg/kg to cynomolgus monkeys. All the infusions were well tolerated. There were no 
deaths prior to study termination nor treatment-related toxicities. The only findings related to 
retifanlimab were modest decreases in lymphocytes after the first infusion, a mild-to-moderate 
increase in fibrinogen on Day 2 with no clear dose-response, and microscopic changes at the 
IV administration site consistent with effects of repeated injections. Further details of 
nonclinical data can be found in the retifanlimab Investigator’s Brochure. 
Consistent with its specific binding properties and designed mechanism of action, retifanlimab 
blocks the binding of the ligands PD-L1 and PD-L2 to cell surface-expressed PD-1 in a dose-
dependent manner. These properties of retifanlimab are comparable to those observed with 
replicas of the approved anti-PD-1 mAbs, nivolumab and pembrolizumab. Retifanlimab 
functionally blocks the PD-1/PD-L1 inhibitory axis in a dose-dependent manner in various 
cellular assays, including enhancement of antigen-driven cytokine secretion (SEB re-
stimulation), blockade of PD-L1 induced SHP-2 activation and reversal of PD-1 pathway 
blockade of T-cell receptor (TCR)-induced nuclear factor of activated T cells (NFAT) 
activation with activity that is again comparable to those observed with the nivolumab and 
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pembrolizumab replicas (48). Table 3 presents the in vitro potency of Retifanlimab in 
comparison to nivolumab and pembrolizumab replicas. 
Table 3 
Comparison of In Vitro Potencies of Retifanlimab and Nivolumab 
and Pembrolizumab Replicas                                                                    
Property 
EC50 (or IC50) Values (µg/mL) a 
Mean ± SEM 
 
Retifanlimab 
Nivolumab 
replica 
Pembrolizumab 
replica 
Binding to PD-1-expressing NS0/PDCD1 cells 
0.138 ± 0.046 
0.158 ± 0.058 
0.140 ± 0.048 
Inhibition of sPD-L1 binding to PD-1 
expressing NS0/PDCD1 cells 
0.010 ± 0.001 
0.016 ± 0.005 
0.014 ± 0.001 
Inhibition of sPD-L2 binding to PD-1 
expressing NS0/PDCD1 cells 
0.021 ± 0.001 
0.028 ± 0.004 
0.028 ± 0.003 
Inhibition of PD-1/PD-L1 Signaling in 
luciferase reporter assay 
0.090 ± 0.008 
0.171 ± 0.017 
0.103 ± 0.016 
a 
EC50, effective concentration at 50% of maximal activity; IC50, effective concentration at 50% inhibition of 
activity. 
 
2.3.4 
Background on Tebotelimab  
2.3.4.1 
General Information on Tebotelimab  
Tebotelimab (also known as MGD013) is an Fc-bearing bispecific tetravalent (bivalent for 
each antigen) DART® protein engineered as a hinge stabilized immunoglobulin G4 (IgG4) 
molecule designed to concomitantly bind programmed cell death protein 1 (PD-1) and 
lymphocyte-activation gene 3 (LAG-3), 2 checkpoint molecules expressed by T lymphocytes 
following antigen-induced activation. See tebotelimab Investigator’s Brochure for 
additional details. 
2.3.4.2 
Clinical Trial Experience with Tebotelimab  
The first-in-human Phase 1 Study CP-MGD013-01 is ongoing in patients with unresectable or 
metastatic neoplasms. This trial characterizes safety, tolerability, PK, pharmacodynamic, 
immunogenicity, and preliminary antitumor activity of tebotelimab given by IV infusion on a 
Q2W or Q3W schedule, either as monotherapy or in combination with margetuximab. 
Safety of Tebotelimab Monotherapy 
As of the cut-off date of 16 May 2020, safety data are available for 263 patients exposed to 
tebotelimab monotherapy and 24 patients exposed to tebotelimab + margetuximab 
combination therapy in ongoing study CP-MGD013-01. A discussion of safety for 
monotherapy and combination therapy is presented below. 
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Study CP-MGD013-01 – Tebotelimab Monotherapy – Dose Escalation 
A total of 53 patients with diverse solid tumor types have been treated in Dose Escalation with 
tebotelimab at flat doses ranging from 1 mg to 1200 mg given Q2W. Patients were treated at 
escalating dose levels as follows: 1 patient at 1 mg, 1 patient at 3 mg, 4 patients at 10 mg, 5 
patients at 30 mg, 4 patients at 120 mg, 10 patients at 400 mg, 8 patients at 800 mg, and 7 
patients at 1200 mg. Patients who were not safety evaluable were replaced at various dose 
levels, and additional patients were enrolled in the 400 mg and 800 mg cohorts to gain 
additional clinical experience. Separately, escalating doses of tebotelimab (120 mg, 400 mg, 
and 600 mg) have been evaluated specifically in patients with advanced hepatocellular 
carcinoma (n = 13). 
All 53 (100%) patients treated with tebotelimab monotherapy in Dose Escalation experienced 
at least one AE, irrespective of attribution. Common AEs, reported in ≥ 15% of patients, 
include fatigue (28.3%); nausea (26.4%); abdominal pain (24.5%); pyrexia and vomiting 
(22.6% each); pruritus (20.8%); constipation and diarrhea (18.9%); hypothyroidism (17.0%); 
and aspartate aminotransferase increased, hyponatremia, and back pain (15.1% each). 
TRAEs have been reported in 43 of 53 (81.1%) patients treated in Dose Escalation. Common 
TRAEs, reported in ≥ 10% of patients, include fatigue (22.6%); nausea (18.9%); pruritus 
(15.1%); IRR and pyrexia (13.2%); and diarrhea and hypothyroidism (11.3%). Potential irAEs 
observed less commonly (in ≥ 5% of patients) include lipase increased and amylase increased 
(7.5% each); and AST increased (5.7% each). 
The majority of TRAEs observed in Dose Escalation have been mild-to-moderate in severity 
(i.e., Grade 1 or Grade 2). A total of 14 (26.4%) patients treated in Dose Escalation have had 
at least one ≥ Grade 3 TRAE. These events include lipase increased (n=3); fatigue and IRR 
(n = 2 each); and adrenal insufficiency, amylase increased, arthritis, colitis, diarrhea, 
hypophosphatemia, immune-mediated hepatitis, myalgia, pancreatitis, pruritus, rash, 
transaminases increased, and vomiting (n = 1 each). Additionally, 1 patient treated in the 
limited hepatocellular carcinoma dose escalation at 120 mg experienced Grade 4 
asymptomatic events of amylase and lipase increased with no clinical or radiographic 
evidence of pancreatitis. No patients have experienced a Grade 5 TRAE. 
A total of 13 (24.5%) patients experienced SAEs in Dose Escalation. Seven (13.2%) patients 
had at least 1 treatment-related SAE, including immune-mediated hepatitis (n = 2, 400 mg and 
1200 mg); adrenal insufficiency with resultant hypotension (n = 1, 400 mg), anemia (n = 1, 
400 mg), colitis (n = 1, 800 mg), hypophosphatemia (n = 1, 400 mg), pancreatitis (n=1, 1200 
mg), and thyroiditis (n=1, 600 mg). SAEs assessed not to be related to tebotelimab include 
abdominal pain, clostridium difficile colitis, diarrhea, dyspnea, hemobilia, hyponatremia, 
inappropriate antidiuretic hormone secretion, pneumonia, pulmonary hemorrhage, pyrexia, 
small intestinal obstruction, and urinary tract infection. These events were related to the 
respective patient’s underlying malignancy or comorbid condition(s). 
The dose of 600 mg, given Q2W or Q3W, was chosen for further development in the Cohort 
Expansion Phase. This decision was based on the totality of clinical, PK, and receptor 
occupancy data. Within Dose Escalation, tebotelimab demonstrated acceptable tolerability. 
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The MTD was not defined or exceeded, and 1200 mg represents the maximum dose level to 
be administered in Study CP-MGD013-01.  
Study CP-MGD013-01 – Tebotelimab Monotherapy – Cohort Expansion 
A total of 210 patients with advanced cancer have been treated with tebotelimab 600 mg Q2W 
or Q3W. Of these patients, 187 (89.0%) experienced at least one AE, irrespective of 
attribution. Common AEs, reported in ≥ 15% of patients, include fatigue (26.7%), anemia 
(15.7%), and nausea (15.2%).  
TRAEs have been observed in 125 (59.5%) patients treated with tebotelimab monotherapy in 
Cohort Expansion. The only TRAE occurring in ≥ 10% of patients is fatigue (16.2%). 
Potential irAEs observed less commonly (in ≥ 5% of patients.) include hypothyroidism 
(7.6%); AST increased (6.7%); ALT increased (5.7%); and amylase increased and lipase 
increased (5.2% each). The majority of irAEs were mild to moderate in severity. The majority 
of TRAEs have been mild to moderate in severity (i.e., Grade 1 or Grade 2). A total of 39 
(18.6%) patients had at least one Grade ≥ 3 TRAE. 
A total of 67 (31.9%) patients experienced SAEs in Cohort Expansion. Of these, 19 (9.0%) 
experienced a treatment-related SAE, including the following events: IRR (n=5); pyrexia 
(n=2); and colitis, confusional state, CRS, diarrhea, headache, hepatitis, hyperthyroidism, 
immune-mediated hepatitis, immune-mediated pneumonitis, pancytopenia, peripheral 
neuropathy, small intestinal hemorrhage, and transaminases increased (n = 1 each) 
Safety Summary – Tebotelimab Monotherapy 
Overall, the cumulative safety data continue to support an acceptable safety profile for the 
treatment of patients with unresectable or metastatic neoplasms. The safety observations are 
consistent with the mechanism of action of tebotelimab, and irAEs have been manageable 
with proactive surveillance to identify early symptoms, prompt and aggressive management 
with systemic immune-modulating agents, and adherence to protocol guidelines on treatment 
interruption or discontinuation. The safety profile has not clearly demonstrated synergistic 
toxicity between the blockade of the anti-PD-1 and anti-LAG-3 arms and is largely consistent 
with the safety demonstrated with established anti-PD-L1 monoclonal antibodies. 
Efficacy of Tebotelimab Monotherapy 
Although it is premature for definitive conclusions regarding the efficacy of tebotelimab in the 
multiple tumor types being evaluated, early signs of antitumor activity have been observed. 
Within Dose Escalation, 3 patients (triple negative breast cancer [TNBC], mesothelioma, and 
GC) experienced confirmed PRs, while 18 other patients with various tumor types (including 
1 patient with SCCHN) had stable disease (SD) as a best response. In Cohort Expansion, 
objective responses, including those unconfirmed at data cut, have been reported in 17 
(10.4%) response evaluable patients: epithelial ovarian cancer (n = 2), SCCHN (n=2), NSCLC 
(n = 5), TNBC (n = 4), cholangiocarcinoma (n=1), cervical cancer (n=1), and DLBCL (n = 2), 
and 61 (37.4%) response evaluable patients have experienced a best overall response of SD. 
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2.3.4.3 
Nonclinical Data for Tebotelimab  
Single- and multiple-dose studies with selected toxicological endpoints were conducted in 
cynomolgus monkeys. Tebotelimab was administered at 0 to 150 mg/kg by a 1-hour IV 
infusion. All the infusions were well tolerated. There were no deaths prior to study 
termination. Infusion of Tebotelimab did not induce an increase in serum concentrations of 
IFN-γ, IL-2, IL-4, IL-5, or TNF-α. Transient increases in IL-6 levels were observed. 
Tebotelimab occupancy is detectable in circulating T cells that express PD-1. 
Tebotelimab-related changes were limited to transient decline with subsequent rebound in 
circulating immune cell populations between 23 and 71 hours post end of infusion (EOI) at 
150 mg/kg. Clinical signs of emesis or vomitus and watery and/or green feces in males at 
≥ 40 mg/kg and watery and/or green feces in females at 100 mg/kg that occurred sporadically 
during the dosing phase. Microscopic observations of increased frequencies of minimal 
mononuclear cell infiltrates in several organs in males at ≥ 10 mg/kg and females at 
≥ 40 mg/kg at the end of the dosing phase. The observations showed a trend towards 
reversibility at the end of the 10-week recovery period. 
2.4 
Dose Selection  
2.4.1 
Dose Selection for Enoblituzumab  
Enoblituzumab will be administered at a dose of 15 mg/kg Q3W. 
Data from clinical studies CP-MGA271-03 and CP-MGA271-01 suggest that enoblituzumab 
at doses up to 15 mg/kg IV weekly in combination with pembrolizumab 2 mg/kg IV Q3W and 
enoblituzumab monotherapy at doses up to 15 mg/kg administered weekly by IV, is generally 
well tolerated with toxicities manageable by standard medical therapy for patients with 
advanced cancer (see Section 2.3.2.2 and current enoblituzumab Investigator’s Brochure 
for more detailed safety information).  
Based on population PK modeling and simulation of enoblituzumab, the estimated t1/2 was 
18.7 days and average Cmin_SS for the 15 mg/kg dose was 787.6 µg/mL (276.8-1548.1 µg/mL) 
when the doses were administered QW and 160.5 µg/mL (26.9-412.2 µg/mL) when the dose 
was administered Q3W. As expected, the decrease in dosing frequency would decrease the 
average Cmin_SS in subjects; however, based on preclinical PK-pharmacodynamic analysis, this 
concentration remains higher than the therapeutically active plasma concentration estimated in 
xenograft mouse models. As per the multi-dose anti-tumor activity studies of enoblituzumab 
against B7-H3-expressing tumors in mCD16-/-, hCD16A+ FOXN1 mice, in general, a 5 
mg/kg weekly dose was observed as the highest efficacious dose in mice. At the 5 mg/kg 
weekly dose of enoblituzumab, Cmin_SS was estimated as 35 µg/mL. Furthermore, based on 
PK-pharmacodynamic modeling of tumor growth inhibition data, the threshold concentration 
for tumor growth inhibition in mice was estimated between 2.6 to 45 µg/mL. These data 
indicate that at the clinical dose of 15 mg/kg Q3W, Cmin_SS would be at least ~4 fold higher 
than the tumor growth inhibitory concentrations in mice and ~160 fold higher than the 
concentrations corresponding to maximal in vitro ADCC activity (see Section 2.3.2.1). 
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2.4.2 
Dose Selection for Retifanlimab  
Retifanlimab will be administered as a flat dose of 375 mg, Q3W.  
Retifanlimab was administered in Study INCMGA 00012-101 as both a weight-based dose 
(ranging from 1 mg/kg to 10 mg/kg) and at fixed doses of 500 mg and 750 mg. Treatment has 
been well tolerated over the entire dosing range and a maximum tolerated dose has not been 
reached (49). 
The monotherapy recommended Phase 2 dose of 500 mg Q4W is based on clinical data from 
the ongoing first-in-human monotherapy study (INCMGA 00012-101). This dose-escalation 
study of retifanlimab was performed and evaluated in 37 patients at the following doses: 1, 3, 
and 10 mg/kg Q2W, and 3 and 10 mg/kg Q4W. While more than dose proportional increases 
were observed for area under the curve (AUC) and Cmax for the first dose over the dose range 
of  1  to 10 mg/kg, linear PK was shown from 3 to 10 mg/kg.  
A population PK (PPK) analysis was performed on patients in the INCMGA 00012-101 study 
to characterize the effect of body weight on the PK of retifanlimab. The plasma concentrations 
of retifanlimab were adequately described by a 2-compartment model with first-order 
elimination. Higher clearance of retifanlimab was estimated for the 1 mg/kg dose than for 
other dose groups. Body weight dependence of clearance was characterized by a power 
relationship with an exponent of 0.911.  
A simulation was conducted to investigate the use of weight-based dosing and flat dosing for 
retifanlimab, with the aim of targeting a steady-state trough concentration of approximately 
21 µg/mL, the median trough concentration for pembrolizumab (37) providing flexibility for 
combinations with different schedules. The median retifanlimab exposure and its distribution 
around the median at 500 mg Q4W were similar to 7 mg/kg Q4W in the simulated population, 
which justified clinical exploration in an expansion cohort of the study. The median steady-
state concentration at 500 mg Q4W was 24.8 µg/mL, and 54% of participants had trough 
concentrations greater than the target concentration. The median steady-state concentration at 
350 mg Q3W was 27.6 µg/mL. The 375 mg Q3W dose was selected based on the trough 
concentration.  
Fifteen patients are enrolled in an additional expansion cohort of Study INCMGA 00012-101 
to test the 375 mg Q3W regimen. Preliminary safety experience with this dosing regimen is 
also favorable (Incyte Corporation, data on file). Pharmacokinetic data were obtained from 14 
participants who received retifanlimab 375 mg Q3W in the cohort expansion portion of Study 
INCMGA 0012-101. Following a first dose of 375 mg Q3W, retifanlimab had t½ (276 hours 
[11.5 days]) and CL (14.8 mL/min) values comparable to those of the 500 mg Q4W and 
750 mg Q4W doses. Furthermore, simulated Cmin at steady-state PK following a 375 mg Q3W 
infusion was 24.3 µg/mL with the accumulation ratio at approximately 1.4, making this a 
comparable dose to 500 mg Q4W. Based on these observations, a flat dose regimen of 
retifanlimab 375 mg Q3W is considered an acceptable alternative where flexibility in dosing 
is needed. Receptor occupancy analysis for patients dosed with retifanlimab demonstrated full 
occupancy in all cohorts assessed, with average receptor occupancy for both CD4+ and CD8+ 
T cells above 90% at all time points assessed (retifanlimab Investigator’s Brochure). In 
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addition, population PK and modeling and simulation analyses indicate that a retifanlimab 
dose of 375 mg administered by IV Q3W is appropriate based on PK and receptor occupancy 
findings from the INCMGA 0012-101 study (22). 
The Q3W recommended dose of retifanlimab is 375 mg, based on population PK and 
modeling, and a demonstration of clinical safety and favorable pharmacology in the dose-
finding INCMGA 00012-101 study (22, 27, 53). 
2.4.3 
Dose Selection for Tebotelimab  
Tebotelimab will be administered as a flat dose of 600 mg, Q3W.  
Within Dose Escalation in the MacroGenics-sponsored trial CP-MGD013-01 in patients with 
unresectable or metastatic neoplasms, tebotelimab monotherapy demonstrated antitumor 
activity with acceptable tolerability up to a dose of 1200 mg without exceeding the MTD. 
Based on receptor occupancy data, a dose of 600 mg Q2W was selected for further study in 
monotherapy; and a dose of 600 mg Q3W was selected for further study in combination with 
margetuximab, an anti HER2 Fc-optimized mAb. Mean t1/2 was 8.5 days, and peripheral blood 
flow cytometry analyses confirmed full and sustained on-target binding during treatment at 
doses ≥ 120 mg. 
PK simulations were performed for different dose regimens (600 mg Q2W, Q3W, Q4W; and 
800 mg Q2W) (Huang L, Liu L, Sun Q, Kaul S, and Sumrow B, unpublished data, 2020). 
Tebotelimab PK after IV infusion in cancer patients was nonlinear and was described by a 
two-compartment PK model with parallel linear and MM (target-mediated non-linear) 
elimination. Typical values of central volume and peripheral volume were 3.54 L and 4.07 L, 
respectively. The clearance and inter-compartment clearance were 7.99 mL/hr and 15.6 mL/hr, 
respectively. The maximum target-mediated elimination rate and MM constant were estimated 
at 88.0 μg/hr and 0.327 μg/mL, respectively. The CVs of all estimated PK parameters were no 
more than 30%. Based on simulation results using the final model, the PK curves of all tested 
dose regimens were above the pembrolizumab efficacious threshold (23.1 μg/mL). 
Based on the PK modeling results, tebotelimab has a PK profile similar to other immune 
checkpoint inhibitors, and a dose regimen of 600 mg administered Q2W or Q3W maintains 
sufficient exposure. These data support the selection of a 600 mg Q3W dose in the present 
study. See tebotelimab Investigator’s Brochure for additional details. 
 
 
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3 
STUDY PURPOSE AND OBJECTIVES  
3.1 
Primary Objective  
Retifanlimab Cohort 
• To assess the efficacy of the combination of enoblituzumab + retifanlimab, based 
primarily upon evaluation of Investigator-assessed ORR in the response evaluable 
patient population, in patients with recurrent or metastatic SCCHN not curable by 
local therapy, with no prior systemic therapy for SCCHN in the recurrent or 
metastatic setting (with the exception of systemic therapy completed > 6 months 
prior if given as part of multimodal treatment for locally advanced disease). 
 
Tebotelimab Cohort 
• To assess the safety, tolerability, and preliminary efficacy of the combination of 
enoblituzumab + tebotelimab, based primarily upon evaluation of Investigator-
assessed ORR in the response evaluable patient population, in patients with 
recurrent or metastatic SCCHN not curable by local therapy, with no prior systemic 
therapy for SCCHN in the recurrent or metastatic setting (with the exception of 
systemic therapy completed > 6 months prior if given as part of multimodal 
treatment for locally advanced disease). 
 
3.2 
Secondary Objectives  
Retifanlimab Cohort 
• To evaluate the Investigator-assessed PFS, disease control rate (DCR), DoR, and 
OS. 
• To evaluate safety and tolerability. 
• To assess the PK of enoblituzumab + retifanlimab. 
• To evaluate the immunogenicity of enoblituzumab + retifanlimab. 
 
Tebotelimab Cohort 
• To evaluate the Investigator-assessed PFS, DCR, DoR, and OS. 
• To assess the PK of enoblituzumab + tebotelimab. 
• To evaluate the immunogenicity of enoblituzumab + tebotelimab. 
  
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3.3 
Exploratory Objectives  
Retifanlimab and Tebotelimab Cohorts 
• To explore the relationships between PK, pharmacodynamics, patient safety, and 
antitumor activity. 
• To explore PPK and exposure-response analyses. 
• To explore the relationships between PD-1, PD-L1, B7-H3, and LAG-3 expression 
on tumor cells and response. 
• To investigate the immune-regulatory activity in vivo, including various measures 
of T-cell and NK-cell activation/exhaustion in peripheral blood and/or tumor biopsy 
specimens. 
• To assess circulating immune cells and effect of treatment. 
• To evaluate peripheral biomarkers and correlate with potential clinical response. 
• To explore gene expression profiles and Fc receptor polymorphism in PBMCs 
and/or pre-treatment tumor biopsies and correlate with clinical response (when 
applicable). 
 
The results of the exploratory objectives may not be included in the Clinical Study Report or 
database lock unless they represent meaningful findings.  
 
 
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4 
STUDY DESIGN  
4.1 
Overall Study Design  
This is a Phase 2, open label, non-randomized study in the first-line treatment of patients with 
recurrent or metastatic SCCHN not curable by local therapy, with no prior systemic therapy 
for SCCHN in the recurrent or metastatic setting (with the exception of systemic therapy 
completed > 6 months prior if given as part of multimodal treatment for locally advanced 
disease). The study will be conducted at approximately 35 centers in approximately 5 
countries. 
Approximately 80 patients will be enrolled in 2 cohorts, to receive enoblituzumab in 
combination with either retifanlimab (Retifanlimab Cohort, PD-L1 positive [CPS ≥ 1] 
patients, N=50) or tebotelimab (Tebotelimab Cohort, PD-L1 negative [CPS < 1] patients, 
N=30; see Figure 5). Enrollment into each cohort will occur independently in a non-
randomized fashion. Patients may not crossover between cohorts. PD-L1 expression will be 
prospectively collected and prospectively analyzed as described in Section 10.2.1. B7-H3 and 
LAG-3 expression will be prospectively collected and retrospectively analyzed.  
An independent Data Safety Monitor (DSM), the Sponsor, and Investigators will maintain 
regular oversight of patient safety throughout the trial. In the Tebotelimab Cohort, toxicity will 
be evaluated by monitoring the occurrence and severity of DLTs (see Section 4.2) in the first 
12 patients (2 mini-cohorts of 6 patients each) through Cycle 2 Day 7. If warranted, 
enrollment in the Tebotelimab Cohort will be paused and ad hoc meetings with the Principal 
Investigators (or designee), the Medical Monitor, and the independent DSM will be held to 
consider dose reduction of tebotelimab to 300 mg, Tebotelimab Cohort termination, or 
continuation at the pre-established 600 mg dose. 
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Figure 5 
Study Schema  
 
 
 
The data for each of the Retifanlimab and Tebotelimab Cohorts will be analyzed upon 
completion of enrollment of each cohort, and after all patients in the applicable cohort have at 
least one tumor assessment, to inform whether to proceed with the study and to determine any 
modifications to the trial design. 
Patients will receive the assigned study drugs (enoblituzumab 15 mg/kg and either 
retifanlimab 375 mg or tebotelimab 600 mg) on a Q3W basis, in cycles of 3 weeks duration 
(see Figure 6). The initial tumor assessment will occur at the end of Cycle 2 (i.e., after 
approximately 6 weeks), and at the end of every 3 cycles thereafter (i.e., approximately every 
9 weeks). After receipt of the last dose of study treatment, patients will enter an Efficacy 
Follow-up Period and will be followed for survival.  
Recurrent/Metastatic
SCCHN
Not curable by 
local therapy
Retifanlimab Cohort, N=50
Enoblituzumab + Retifanlimab
Tebotelimab Cohort, N=30
Enoblituzumab + Tebotelimab
Safety evaluations at the end of Cycle 2 for first 
12 patients (2 mini-cohorts of 6 patients each)
PD-L1 Positive
(CPS ≥ 1)
PD-L1 Negative
(CPS < 1)
Efficacy Outcomes
Primary:
ORR
Secondary: PFS, DCR, DoR, OS
Dosing Regimens:
Enoblituzumab:  15 mg/kg Q3W
Retifanlimab:  375 mg Q3W
Tebotelimab: 600 mg Q3W
Enrollment in the 2 study cohorts will occur independently in a non-randomized fashion
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Figure 6 
Treatment Cycles  
 
Study treatment will continue in cycles of 3 weeks duration until confirmed CR (except as 
noted below), disease progression, unacceptable toxicity, withdrawal of consent, physician 
recommendation to discontinue therapy, death, or the maximum allowed treatment duration 
has been reached (see Section 4.4 for a complete list of reasons for discontinuation of 
treatment). The maximum allowed treatment duration is 35 cycles for each study drug. 
Discontinuation of study treatment may be considered for patients who have attained a 
confirmed CR. However, until Cycle 33, 2 additional cycles of study treatment may be 
completed beyond the date of confirmed CR (the total number of cycles of study treatment 
must not exceed 35). 
Patients who have radiographic progression may remain on study treatment until the next 
scheduled radiographic evaluation if the following conditions are met: absence of clinical 
symptoms or signs indicating clinically significant disease progression; no decline in ECOG 
performance status; absence of rapid disease progression or threat to vital organs or critical 
anatomical sites (e.g., central nervous system [CNS] metastasis, respiratory failure due to 
tumor compression, spinal cord compression) requiring urgent alternative medical 
intervention; and no significant, unacceptable, or irreversible toxicities related to study 
treatment. 
4.2 
Dose Limiting Toxicity (Tebotelimab Cohort)  
For the purposes of safety management and defining DLTs, the combination of enoblituzumab 
+ tebotelimab will be treated as one entity. If a DLT is considered related to study treatment, 
no distinction will be made as to which agent is the causative agent and administration of both 
agents will be stopped. 
Day
1
22
64
Cycle
Retifanlimab Cohort: enoblituzumab 15 mg/kg + retifanlimab 375 mg 
Tebotelimab Cohort: enoblituzumab 15 mg/kg + tebotelimab 600 mg
Tumor Assessment
85
106
127
148
169
Initial 
Tumor Assessment
(End of Cycle 2)
Subsequent 
Tumor Assessments
(Every 3 Cycles)
All patients will enter an Efficacy Follow-up Period after receipt of the 
last dose of study treatment to be followed for survival
2
3
4
5
6
7
8
1
The Principal Investigator, in consultation with the Sponsor, will waive requirement for biopsies 
depending on individual patient circumstances. This requirement will expire after an adequate number 
of samples have been collected, as determined by the Sponsor
Biopsy
(Screening)
Biopsy
(End of Cycle 2)
43
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Dose limiting toxicities will be based on treatment-emergent drug-related AEs (or laboratory 
abnormalities) occurring through Cycle 2 Day 7. 
Patients in the Tebotelimab Cohort who experience DLT will discontinue study treatment. 
4.2.1 
Hematologic Dose Limiting Toxicity  
Hematologic DLT is defined as follows: 
• Grade 4 neutropenia lasting > 5 days 
• ≥ Grade 3 febrile neutropenia 
• Grade 4 thrombocytopenia, irrespective of duration 
• Grade 3 thrombocytopenia associated with clinically significant bleeding 
• ≥ Grade 3 hemolysis 
 
The following events will be specifically excluded from the definition of hematologic DLT: 
• ≥ Grade 3 lymphopenia 
• Grade 3 anemia that is not associated with other clinically significant 
complications. 
 
4.2.2 
Non-hematologic Dose Limiting Toxicity  
• Any intolerable Grade 2 toxicity that results in dose interruption lasting more than 
20 days, or requires drug withdrawal. 
• Non-hematologic DLT is defined as any ≥ Grade 3 non-hematologic event with the 
following exceptions:  
o Grade 3 electrolyte abnormality that lasts less than 72 hours, that is not 
otherwise associated with clinical complications, and responds to medical 
intervention 
o Grade 3 fever that lasts < 72 hours and is not associated with hemodynamic 
compromise 
o Grade 3 nausea or vomiting that lasts < 72 hours and responds to medical 
intervention 
o Grade 3 amylase and/or lipase elevation that is not associated with either 
clinical or radiographic evidence suggestive of pancreatitis. 
o Grade 3 gastrointestinal AEs of diarrhea, constipation, abdominal pain, 
cramping, dyspepsia or dysphagia that resolves to ≤ Grade 1 within 14 days 
with medical therapy 
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o Grade 3 fatigue that lasts < 7 days 
o Grade 3 infusion related reaction or cytokine release syndrome that lasts 
< 12 hours and responds to medical intervention. 
o Grade 3 or 4 endocrinopathy that is adequately controlled with hormone 
supplementation 
o Grade 3 skin toxicity that resolves to ≤ Grade 2 within 14 days of initiation 
of corticosteroids 
o Grade 3 inflammatory reaction (e.g., with associated pain, swelling) 
attributed to a local antitumor response (e.g., inflammatory reaction at sites 
of metastatic disease, lymph nodes, etc.) that resolves to ≤ Grade 2 within 7 
days. 
 
4.2.3 
Hepatic Non-hematologic Dose Limiting Toxicity  
Hepatic non-hematologic DLT will be defined as follows: 
• Any elevation of one or more transaminases > 8 × the institutional upper limit of 
normal (ULN) irrespective of duration. 
• Any Grade 3 elevation of one or more transaminases > 5.0 – 8.0 × the ULN that 
does not resolve to Grade 2 within 7 days, and Grade 1 or baseline within 14 days. 
If steroids are administered, they must be tapered to ≤ 10 mg of prednisone or 
equivalent per day by Day 14. Please see Section 7.2.2 for further management 
guidelines.  
o For patients with Grade 1 or 2 elevations of transaminases at baseline, a 
doubling of transaminases will be considered dose limiting, if not resolved 
to baseline within 14 days. 
• Any Grade 3 elevation of total bilirubin that is > 5 × the ULN irrespective of 
duration. 
• Any elevation of total bilirubin > 3.0 – 5.0 × ULN that does not resolve to Grade 2 
within 7 days and Grade 1 or baseline within 14 days. If steroids are administered, 
they must be tapered to ≤ 10 mg of prednisone or equivalent per day by Day 14. 
Please see Section 7.2.2 for further management guidelines. 
• Any event meeting the criteria for Hy’s law as follows (all three features): 
o Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
> 3 × ULN, or doubling of AST and/or ALT for patient having Grade 2 
transaminase levels at baseline. 
o Concurrent elevation of total bilirubin > 2 × ULN without initial evidence 
of cholestasis 
o No alternative etiology can be identified. 
 
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4.3 
Guidelines for Dose Modification   
No intrapatient reductions in the dose of enoblituzumab, retifanlimab, or tebotelimab are 
allowed. Dose interruption or discontinuation should be used for the management of drug-
related toxicity. The management of IRR is specified in Section 7.1.3. The management of 
immune-related AEs (irAEs) is specified in Section 7.2. 
4.3.1 
Dose Delays  
Tebotelimab Cohort 
Patients who experience a Grade 2 to 4 AE that is potentially dose-limiting should have study 
drug held pending assessment, management, and resolution of the AE. If the AE is assessed as 
unrelated to study drug or does not meet DLT criteria, therapy may be restarted at the previous 
dose and schedule, after appropriate recovery.  
Retifanlimab and Tebotelimab Cohorts 
A dose delay of up to 20 days is allowed for patients experiencing AEs. In the case of 
abnormal troponins or N-terminal pro b-type natriuretic peptide (NT-proBNP) values, study 
drug must be withheld and a thorough cardiac assessment performed promptly to diagnose 
myocarditis or other cardiovascular diseases; the patient may resume study drugs if 
myocarditis is not confirmed. Refer to Section 7 for specific guidance on restarting study 
therapy for IRR and irAEs. A dose delay of up to 20 days may also be permitted for reasons 
other than AEs. All procedures at the missed dosing visit should be performed and treatment 
reinstituted as if the delay had not occurred. 
Patients with infusion delays > 20 days will discontinue the study drug, complete the End of 
Treatment visit, and then enter the Post-treatment Follow-up Period. 
4.4 
Study Treatment Discontinuation  
Patients who tolerate treatment may continue to receive treatment with the study drug(s) as 
specified in the protocol until any one of the following conditions are met: 
• Adverse Event Requiring Treatment Discontinuation 
o Patients who discontinue study treatment due to AEs are followed by 
radiographic evaluation until disease progression by RECIST v1.1, if the 
patients’ condition allows. If not, patients will be followed for OS without 
radiographic evaluation upon the discussion with the Sponsor’s Medical 
Monitor. 
• Completed Treatment per Protocol 
• Death 
• Physician Decision (should occur only after discussion with the Sponsor’s Medical 
Monitor) 
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• Lost to Follow-up 
• Pregnancy 
• Progressive Disease-Clinical Progression 
• Progressive Disease-Objective Progression 
o Patients who have radiographic progression according to RECIST v1.1 may 
remain on study treatment until the next scheduled radiographic evaluation 
if the following conditions are met: 
 Absence of clinical symptoms or signs indicating clinically 
significant disease progression. 
 No decline in ECOG performance status. 
 Absence of rapid disease progression or threat to vital organs or 
critical anatomical sites (e.g., CNS metastasis, respiratory failure 
due to tumor compression, spinal cord compression) requiring 
urgent alternative medical intervention. 
 No significant, unacceptable, or irreversible toxicities related to 
study treatment. 
• Major Protocol Deviation Requiring Treatment Discontinuation 
• Study Terminated (patients might be offered enrollment in a follow-up/roll over 
protocol if in place at the time of study termination) 
• Patient Decision 
• Patient Withdrew Consent for Study 
 
If the Investigator decides that the patient should be withdrawn from the study or from dosing 
for any reason other than disease progression, the Sponsor or its designee must be alerted 
within 24 hours). 
A patient may be determined to be lost to follow up (LTFU) after there have been 3 
documented phone contact attempts. If this fails, a certified letter should be sent to the patient. 
Only after these attempts have failed can a patient be determined to be LTFU. 
4.5 
Study Discontinuation  
Patients who are no longer on treatment but are still followed on the study can be terminated 
from the study for the following reasons: 
• 
Completed Protocol-Defined Follow-up Period 
• Death 
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• Lost to Follow-up 
• Study Terminated by Sponsor 
• Patient withdrew from Study 
 
4.6 
Definition of End of Study  
The end of study will occur after the last patient has met off-study criteria and the data 
collection process is completed (time of study database lock).  
End of study for each patient is defined as follows: Patient is LTFU or discontinues from the 
study due to any reason. Each patient’s end of study status will be recorded in the End of 
Study CRF page.  
 
 
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5 
ELIGIBILITY CRITERIA  
To be eligible for study participation, patients must meet all the inclusion criteria. Patients will 
be excluded from the study if they meet any exclusion criteria. No exceptions to these criteria 
will be granted by the Sponsor. 
5.1 
Inclusion Criteria  
1. Ability to provide informed consent and documentation of informed consent prior 
to initiation of any study-related tests or procedures that are not part of standard of 
care for the patient’s disease.  
2. Age ≥ 18 years old. 
3. Histologically proven, recurrent or metastatic SCCHN not curable by local therapy.  
4. No prior systemic therapy for SCCHN in the recurrent or metastatic setting (with 
the exception of systemic therapy completed > 6 months prior if given as part of 
multimodal treatment for locally advanced disease). 
5. Primary tumor locations of oropharynx, oral cavity, hypopharynx, or larynx. 
Patients may not have a primary tumor site of upper esophagus, salivary gland, or 
nasopharynx (any histology). 
6. All patients enrolled in this study must have an identified formalin-fixed, paraffin 
embedded (FFPE) tumor specimen for immunohistochemical evaluation of 
pharmacodynamic markers of interest. If no archival specimen is available, tissue 
from a contemporaneous core or excisional biopsy is acceptable (fine needle 
aspirate is not sufficient; refer to Section 9.9.3 for details).  
Patients must also be willing to provide consent for a baseline and on-treatment 
tumor biopsy, if tumor lesions are accessible for biopsy with acceptable risk in the 
judgment of the Investigator and after discussion with the Sponsor (refer to 
Section 9.9.3 for details). This requirement will expire after an adequate number of 
samples have been collected, as determined by the Sponsor. 
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, 
verified within 3 days before Day 1. 
8. Life expectancy ≥ 6 months. 
9. Has adequate end organ function as determined by the site Investigator. 
10. Has at least one radiographically measurable lesion (target lesion), as defined in 
RECIST v1.1 and documented by computed tomography (CT) or magnetic 
resonance imaging (MRI), suitable for response monitoring. 
11. Has PD-L1 expression level that is either: 
a. Positive (CPS ≥ 1) for the Retifanlimab Cohort, or 
b. Negative (CPS < 1) for the Tebotelimab Cohort 
12. Has results from testing of HPV p16 status for oropharyngeal cancer. 
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13. Acceptable laboratory parameters as follows: 
a. Platelet count  100 × 103/µL without transfusion within 28 days prior to 
the initiation of study drug. 
b. Absolute neutrophil count  1.5 × 103/µL in the absence of any growth 
factor support within 28 days prior to the initiation of study drug. 
c. ALT/AST  2.5 × ULN; for patients with hepatic metastases, ALT and 
AST ≤ 5 × ULN. 
d. Total bilirubin < 1.5 × ULN, except patients with Gilbert’s syndrome, who 
may enroll if the conjugated bilirubin is within normal limits. 
e. Creatinine < 2 mg/dL, or a calculated or measured creatinine clearance 
> 50 mL/min. 
f. Negative serum pregnancy test, if applicable. 
14. Women patients of child-bearing potential (WOCBP), defined as not surgically 
sterilized (hysterectomy, bilateral salpingectomy, and bilateral oophorectomy) and 
between menarche and 1-year post menopause, must have a negative serum 
pregnancy test performed within 72 hours prior to the initiation of study drug 
administration. Female patients must agree to abstain from egg donation during the 
course of the study. 
15. WOCBP and male patients with partners of WOCBP must agree to use highly 
effective methods of contraception according to Section 8.1.3 from the time of 
consent through 120 days after discontinuation of study drug administration. Male 
patients must agree to abstain from sperm donation during the course of the study. 
16. WOCBP is not pregnant or breastfeeding or male patient is not expecting to father 
children within the projected duration of the study, starting with screening visit 
through 120 days after the last dose of study drug. 
 
5.2 
Exclusion Criteria  
1. Disease suitable for local therapy administered with curative intent. 
2. Has progressive disease within 6 months of completion of curatively intended 
systemic treatment for locoregionally advanced SCCHN. 
3. Radiation therapy (or other non-systemic therapy) within 2 weeks prior to the first 
dose of study drug. Patients must have recovered from all radiation-related 
toxicities, not require corticosteroids for this purpose, and not have had radiation 
pneumonitis. 
4. Toxicity of prior therapy that has not recovered to ≤ Grade 1 or baseline, with the 
exception of any grade of alopecia and anemia not requiring transfusion support. 
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5. Diagnosis of immunodeficiency or receiving systemic steroid therapy 
corticosteroids (≥ 10 mg per day prednisone or equivalent) or any other form of 
immunosuppressive therapy within 14 days prior to the first dose of study 
medication (physiologic doses of corticosteroids may be approved after 
consultation with the Sponsor). 
6. Currently participating in a study of an investigational agent and receiving study 
therapy, participated in a study of an investigational agent and received study 
therapy, or used an investigational drug or device within 4 weeks of the first dose of 
study drug administration. 
7. Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the patient’s 
participation for the full duration of the trial, or is not in the best interest of the 
patient, in the opinion of the treating Investigator and/or the Sponsor, including: 
a. Participants who are known to be HIV-positive, unless all the following 
criteria are met: 
 CD4+ count ≥ 300/μL, 
 Undetectable viral load, and 
 Receiving highly active antiretroviral therapy. 
b. Known history of or current acute or chronic hepatitis B virus (HBV) 
infection (as evidenced by detectable HBV surface antigen and HBV DNA 
≥ 500 IU/ml).  
c. Patients with a history of hepatitis C virus (HCV) infection, unless the 
infection has been treated and cured. 
d. Has had an allogeneic stem cell or tissue/solid organ transplant. 
e. Patients with central nervous system metastases and/or carcinomatous 
meningitis. 
f. Patients with a history of psoriatic arthritis.  
g. Patients with any history of known or suspected autoimmune disease with 
the specific exceptions of vitiligo, resolved childhood atopic dermatitis, 
psoriasis not requiring systemic treatment within the past 2 years and 
patients with a history of autoimmune disease who are now clinically stable 
with replacement therapy and by laboratory testing. 
h. Evidence of active viral, bacterial, or systemic fungal infection requiring 
systemic treatment within 7 days prior to the initiation of study treatment. 
Patients requiring any systemic antiviral, antifungal, or antibacterial 
therapy for active infection must have completed treatment no less than 
1 week prior to the initiation of study treatment. 
i. Known hypersensitivity to recombinant proteins, 
, or any 
excipient contained in the enoblituzumab, retifanlimab, or tebotelimab drug 
formulation (Section 6.4). 
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j. Any serious underlying medical or psychiatric condition that would impair 
the ability of the patient to receive or tolerate the planned treatment at the 
investigational site. 
k. History of uncontrolled seizures within 6 months prior to the first dose of 
study drug. 
l. Active or history of alcohol or other substance abuse within 1 year prior to 
the first dose of study drug. 
8. Clinically significant cardiovascular disease including but not limited to: 
a. Myocardial infarction or unstable angina within the 6 months prior to the 
initiation of study drug. 
b. Stroke or transient ischemic attack within 6 months prior to the initiation of 
study drug. 
c. Clinically significant cardiac arrhythmias. 
d. Uncontrolled hypertension: systolic blood pressure > 160 mmHg or 
diastolic blood pressure > 100 mmHg. 
e. Congestive heart failure (New York Heart Association class III-IV). 
f. Pericarditis or clinically significant pericardial effusion. 
g. Myocarditis. 
h. QTcF > 480 milliseconds as the average of 3 repeat examinations. 
9. Clinically significant gastrointestinal disorders including but not limited to: 
a. Any history of gastrointestinal perforation unless the affected area has been 
deemed by the Investigator to no longer be a risk for perforation. 
b. History of clinically significant gastrointestinal bleeding within 4 weeks 
prior to the initiation of study drug. 
c. History of acute pancreatitis within 4 weeks prior to the initiation of study 
drug.  
d. Diverticulitis that is clinically significant in the opinion of the Investigator 
based on the extent or severity of known disease and/or the occurrence of 
clinically significant disease flares within 4 weeks prior to the initiation of 
study drug administration. 
10. Vaccination with any live virus vaccine within 4 weeks prior to the initiation of 
study drug administration. Inactivated annual influenza vaccination is allowed. 
a. If an immunization strategy for SARS-CoV-2 was available prior to 
enrollment, potential exclusion from the study based on history of receipt 
of SARS-CoV-2 prophylaxis will be discussed with the Sponsor. 
11. Major surgical procedure or trauma within the 4 weeks prior to the initiation of 
study treatment. 
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12. A history of (non-infectious) pneumonitis or interstitial lung disease that required 
steroids, or current pneumonitis or interstitial lung disease. 
13. Prior therapy with an anti-B7-H3, anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-LAG-
3 agent. 
14. Severe dyspnea at rest due to complications of advanced malignancy or requiring 
supplemental oxygen therapy. 
15. Clinically significant pulmonary compromise, including but not limited to 
pneumonia or a requirement for supplemental oxygen use to maintain adequate 
oxygenation. 
16. Second primary invasive malignancy that has not been in remission for greater than 
2 years; except non-melanoma skin cancer; cervical carcinoma in situ on biopsy; or 
squamous intraepithelial lesion on Pap smear; localized prostate cancer (Gleason 
score < 6); or resected melanoma in situ. 
17. Known psychiatric or substance abuse disorders, including but not limited to 
dementia or altered mental status that would preclude understanding and rendering 
of informed consent and cooperation with the requirements of the trial. 
18. Employees of MacroGenics, Inc., or Incyte Corporation, unless approved by 
institutional review board (IRB) and principal Investigator. 
19. Prisoners or other individuals who are involuntarily detained. 
20. Any investigative site personnel directly affiliated with this study. 
21. Any issue that in the opinion of the Investigator or the Sponsor would 
contraindicate the patient’s participation in the study or confound the results of the 
study. 
 
 
 
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6 
STUDY TREATMENTS  
6.1 
Description of Treatments  
Patients in the Retifanlimab Cohort will receive enoblituzumab at a dose of 15 mg/kg and 
retifanlimab at a dose of 375 mg.  
Patients in the Tebotelimab Cohort will receive enoblituzumab at a dose of 15 mg/kg and 
tebotelimab at a dose of 600 mg.  
Patients in both cohorts will receive each study drug on a Q3W basis, in cycles of 3 weeks 
duration, for a maximum of 35 cycles. 
All changes in study drug infusions, including interruptions and their duration, as well as 
reductions in rate and duration, must be recorded. The actual date, and infusion start time and 
end time will be recorded on the electronic case report form (eCRF). 
6.2 
Blinding  
Not applicable. This is an open-label study. 
6.3 
Emergency Unblinding  
Not applicable. This is an open-label study. 
6.4 
Study Drug and Supplies  
Requests for additional study drug should be made to MacroGenics, Inc., via interactive 
response technology (IRT) at least 2 weeks in advance. 
6.4.1 
Supply of Enoblituzumab  
Enoblituzumab (MGA271) drug product is a sterile, preservative-free, clear to slightly 
opalescent, colorless to pale yellow or pale brown solution 
 
 Some 
visible, proteinaceous enoblituzumab particles may be present. 
 
 
 
 
6.4.2 
Supply of Retifanlimab  
Retifanlimab (INCMGA00012 or MGA012) drug product is a sterile, preservative-free, clear 
to slightly opalescent, colorless to pale yellow solution, practically free from visible particles. 
 
 
 
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6.4.3 
Supply of Tebotelimab  
Tebotelimab (MGD013) drug product is a sterile, preservative-free, clear to slightly 
opalescent, colorless to pale yellow or pale brown solution, essentially free from foreign 
visible particles. 
 
 
 
 
 
6.5 
Study Infusion Preparation  
6.5.1 
General Guidelines and Precautions  
Under no circumstances is the Investigator allowed to release these clinical supplies for use by 
another physician not named on Form FDA 1572 (or equivalent form) or to administer study 
drug to a patient who is not enrolled in this study. Study drug must be dispensed at an 
institution specified on Form FDA 1572 (or equivalent form). 
Infusion or allergic reactions may occur with the infusion of monoclonal antibodies and other 
protein-based therapeutics. Precautions for anaphylaxis should be observed during 
administration. Supportive measures may include, but are not limited to, epinephrine, 
antihistamines, corticosteroids, IV fluids, vasopressors, oxygen, bronchodilators, 
diphenhydramine, and acetaminophen (or equivalent). Please refer to Section 7.1 for specific 
guidelines regarding the management of infusion reactions. Supportive care measures 
consistent with optimal patient care will be provided throughout the study according to 
institutional standards. 
Visual inspection of drug product vials for solution clarity, foreign particulate matter, and 
discoloration is required prior to use. If solution cloudiness or foreign particulate matter or 
pronounced discoloration (noting that a pale yellow or pale brown color is acceptable for 
enoblituzumab and tebotelimab, and a pale yellow color is acceptable for retifanlimab) is 
observed, the drug product should not be used for dose preparation. Enoblituzumab, 
retifanlimab, and tebotelimab drug product vials are single-dose containers. Any partially used 
vials or unused diluted dosing solutions should be discarded using appropriate drug disposal 
procedures (see Pharmacy Manual).  
Instructions on the preparation of each study drug are detailed in the Pharmacy Manual. 
Standard laboratory practices should be used for avoidance of contact. 
All IV infusions of study-agents must be administered separately. Do not mix 
enoblituzumab, retifanlimab, or tebotelimab in the same infusion with each other or with 
other medicinal products. Do not infuse enoblituzumab, retifanlimab, or tebotelimab as 
an IV push or bolus. A sterile, non-pyrogenic, low protein binding polyethersulfone 
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0.2 micron in-line filter administration set must always be used for IV administration of 
enoblituzumab, retifanlimab, and tebotelimab. Study treatments are administered Q3W 
± 3 days. An interval of at least 18 days should occur since the previous administration. 
Enoblituzumab, retifanlimab, and tebotelimab do not contain preservatives; once diluted in 
normal saline, the dose solution contained in the IV bag is stable up to 4 hours at room 
temperature or 24 hours refrigerated at 2° to 8°C with minimal exposure to light. If the dose 
solution is stored at 2° to 8°C, it should be removed from the refrigerator at least 30 to 
60 minutes prior to administration, to allow the dose solution to reach room temperature. 
Precautions should be taken to minimize the time between dose preparation and IV infusion 
administration.  
If there is a delay in administration of study drug such that it will not be administered on the 
day of preparation, the Medical Monitor should be notified immediately. Instructions on how 
to proceed will be provided. 
Study treatments are administered in the following order: 
• Retifanlimab Cohort: (1) retifanlimab and (2) enoblituzumab.  
• Tebotelimab Cohort: (1) tebotelimab and (2) enoblituzumab.   
 
An effort should be made to begin the enoblituzumab infusion between 30 minutes and 120 
minutes after the completion of the retifanlimab or tebotelimab infusion.  It is understood that 
this window may not always be attainable but is the preferred window of time to administer 
enoblituzumab. 
6.5.2 
Preparation and Administration of Enoblituzumab  
Enoblituzumab will be administered at a dose of 15 mg/kg, initially calculated based on the 
patient’s actual weight at Cycle 1 Day 1 (baseline) measurement. Significant (≥ 10%) change 
in body weight from baseline should prompt recalculation of the dose. Refer to the Pharmacy 
Manual for further instructions on allowable parameters for dose rounding of enoblituzumab. 
Only in patients with body mass index (BMI) greater than or equal to 30 kg/m2, the 
enoblituzumab dose will be calculated using ideal body weight (IBW). Refer to the Pharmacy 
Manual for further instructions on calculation of the enoblituzumab dose to be administered. 
The desired amount of enoblituzumab should be withdrawn from the vial(s) and diluted to the 
appropriate final concentration with 0.9% Sodium Chloride Injection, USP (normal saline), 
according to the instructions provided in the Pharmacy Manual. The infusion bag containing 
enoblituzumab should be gently inverted to mix the solution. The dose solution should be 
administered via IV infusion over 120 minutes with a commercially available infusion pump. 
Up to 10 additional minutes of infusion time (i.e., up to a total of 130 minutes) are permitted 
to allow for flushing the line. 
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6.5.3 
Preparation and Administration of Retifanlimab  
Retifanlimab will be administered at a flat dose of 375 mg, regardless of body weight or body 
surface area. 
Retifanlimab must be diluted in 0.9% Sodium Chloride Injection, USP (normal saline), prior 
to dose administration. Retifanlimab dose solution diluted in normal saline must be at a final 
concentration range of 0.3 mg/mL to 12 mg/mL. The infusion bag containing retifanlimab 
should be gently inverted to mix the solution. The dose solution should be administered via IV 
infusion over 60 minutes with a commercially available infusion pump. Up to 10 additional 
minutes of infusion time (i.e., up to a total of 70 minutes) are permitted to allow for flushing 
the line. 
6.5.4 
Preparation and Administration of Tebotelimab  
Tebotelimab will be administered initially at a flat dose of 600 mg, regardless of body weight 
or body surface area. 
Tebotelimab must be diluted in 0.9% Sodium Chloride Injection, USP (normal saline), prior to 
dose administration. Tebotelimab dose solution diluted in normal saline must be at a final 
concentration range of 0.12 mg/mL to 6.4 mg/mL. The dose solution should be administered 
via infusion over 60 minutes with a commercially available infusion pump. Up to 10 
additional minutes of infusion time (i.e., up to a total of 70 minutes) are permitted to allow for 
flushing the line. 
6.6 
Placebo or Active Comparator  
There will be neither placebo nor active control drug for this study. 
6.7 
Treatment Compliance  
The study drugs will be administered by healthcare professionals under the supervision of the 
Investigator. Records of dose calculation, administration, and dosing regimen will be 
accurately maintained by site staff. The monitor will review dose calculation, administration, 
and regimen as well as medication accountability during study site visits and at the 
completion of the study. 
6.8 
Packaging and Labeling  
All study drugs will be labeled according to local regulatory health authority requirements. 
Please see the Pharmacy Manual for detailed information about packaging and labeling. 
6.8.1 
Packaging and Labeling for Enoblituzumab  
Enoblituzumab is supplied in a USP and Ph. Eur. conforming Type I borosilicate, 20 mL clear 
glass vial with a 20 mm FluroTec-coated 4432/50 gray butyl rubber serum stopper. The vial is 
sealed with a 20 mm TruEdge aluminum closure with a plastic overseal. 
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6.8.2 
Packaging and Labeling for Retifanlimab  
Retifanlimab is supplied in a single-dose vial packaged in a USP and Ph. Eur. conforming 
Type I borosilicate, 10 mL clear glass vial with a 20 mm FluroTec-coated 4432/50 gray butyl 
rubber serum stopper. The vial is sealed with a 20 mm aluminum closure with a plastic 
overseal.  
6.8.3 
Packaging and Labeling for Tebotelimab  
Tebotelimab is supplied in a single-dose vial packaged in a USP and Ph. Eur. conforming 
Type I borosilicate, 20 mL clear glass vial with a 20 mm FluroTec-coated 4023/50 gray butyl 
rubber serum stopper. The vial is sealed with a 20 mm aluminum closure with a plastic 
overseal. 
6.9 
Storage and Accountability  
Vials containing enoblituzumab, retifanlimab, or tebotelimab should be stored upright under 
monitored refrigeration at 2°–8°C (36°–46°F) in a room accessible only to pharmacy 
personnel, the Investigator, or duly designated personnel. Vials should be protected from light 
during storage and should not be shaken or frozen. 
Accurate accounting of all study drug must be maintained. The Investigator agrees to keep an 
inventory of study drugs using the institution’s drug accountability logs or logs provided by 
MacroGenics. The Investigator will maintain records of temperature monitoring of study drug. 
Drug disposition records must be kept in compliance with applicable guidelines and 
regulations. 
A Pharmacy Manual will be provided to the Investigator or designee. When the study is 
completed, copies of all study drug accountability records must be provided to the Sponsor. 
Original drug accountability records must be maintained with the rest of the documentation 
for inspection by the study monitors.  
6.10 
Investigational Product Disposition at End of Study  
All unopened vials of study drug must be returned to MacroGenics or its representative, 
unless the site has received written authorization from MacroGenics to destroy study drug at 
the site. All drug returns to MacroGenics or its representative must be accompanied by the 
appropriate documentation and be clearly identified by protocol number and study site 
number on the outermost shipping container. If MacroGenics approves the destruction of drug 
at the site, the Investigator must ensure arrangements are made for proper disposal and that 
appropriate records of disposal are documented and maintained, and copies provided to the 
Sponsor. 
Additional details regarding storage, handling, and accountability can be found in the 
Pharmacy Manual. 
 
 
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7 
POTENTIAL ADVERSE EVENTS AND SUPPORTIVE CARE 
MEASURES  
7.1 
Infusion Related Reactions Including Cytokine Release Syndrome  
Infusion reactions (including cytokine release syndrome [CRS]) associated with study drugs 
administration should be managed according to the standard practice of medicine. General 
guidelines for the management of such reactions are provided in this section. However, severe 
reactions may require more intensive interventions (e.g., steroids, anti-TNF antibodies, 
and/or IL-6 inhibitors). 
Patients should be monitored closely for the development of infusion related reactions during 
infusions. Medications and supportive measures for the treatment of severe hypersensitivity 
reactions should be available for immediate use for an infusion reaction during study drug 
administration and may include, but are not limited to: subcutaneous (SC) epinephrine (0.3 to 
0.5 mL of a 1:1000 solution), antihistamines (e.g., diphenhydramine 25 to 50 mg IV), 
corticosteroids (e.g., hydrocortisone 20-40 mg IV push or equivalent), IV fluids, vasopressors, 
oxygen, bronchodilators, and antipyretics. Resuscitation equipment and other supplies for the 
emergency management of an allergic/toxic reaction must be available. The patient should be 
treated according to the best available local practices and procedures. All supportive measures 
consistent with optimal patient care will be provided throughout the study according to 
institutional standards. 
Should symptoms of fever or chills develop, it may be difficult to distinguish among potential 
causes including emerging infection, and infusion reaction. Patients should be evaluated 
carefully for presence of infection, with acquisition of cultures and/or implementation of 
empiric antibiotic therapy as appropriate based on the Investigator’s assessment. Please refer 
to Section 7.1.3 for guidance regarding the management of infusion reactions. 
7.1.1 
Grading and Management of Infusion Reactions  
IRR, CRS and allergic reactions should be graded according to the criteria in Table 4. 
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Table 4 
NCI CTCAE Version 5.0 Grading of Infusion-Related Reactions     
System 
Organ Class 
Injury, poisoning and procedural 
complications 
Immune System Disorders 
Preferred 
Term 
Infusion–related Reaction 
Allergic Reaction 
Cytokine Release 
Syndrome 
Grade 1 
Mild transient reaction; infusion 
interruption not indicated; intervention 
not indicated 
Systemic intervention 
not indicated 
Fever with or without 
constitutional symptoms 
Grade 2 
Therapy or infusion interruption 
indicated but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, non-steroidal anti-
inflammatory drugs, narcotics, IV 
fluids); prophylactic medications 
indicated for ≤ 24 hrs. 
Oral intervention 
indicated 
Hypotension responding 
to fluids; hypoxia 
responding to <40% O2 
Grade 3 
Prolonged (e.g., not rapidly responsive 
to symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial 
improvement; hospitalization indicated 
for clinical sequelae 
Bronchospasm; 
hospitalization 
indicated for clinical 
sequelae; intravenous 
intervention indicated 
Hypotension managed 
with one pressor; 
hypoxia requiring ≥ 
40% O2 
Grade 4 
Life-threatening consequences; urgent intervention indicated 
Grade 5 
Death due to AE 
 
7.1.2 
Premedication and Prophylaxis  
The following are suggested guidelines for the Investigator regarding prophylactic 
pre-infusion measures to be followed to mitigate the occurrence or severity of potential 
infusion reactions. Equivalent medications may be substituted based on the local practice of 
medicine and availability. 
Cycle 1, Day 1: required prior to first infusion of study treatment: 
• Acetaminophen 650-1000 mg orally (PO) or ibuprofen 400 mg PO 
• H1 antagonist: Diphenhydramine 50 mg PO or IV   
• H2 antagonist: Famotidine 40 mg PO or 20 mg IV  
• Dexamethasone 10-20 mg IV, IV steroid 
 
No pre-infusion prophylactic steroids administration is required for subsequent infusions. 
Non-steroidal pre-medications may be administered prior to the subsequent infusion, 
if warranted. 
For patients who had infusion reactions following the first dose of enoblituzumab, 
retifanlimab, or tebotelimab that were not adequately or only moderately controlled with 
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acetaminophen, diphenhydramine, or famotidine, IV corticosteroids may be added to the pre-
medication for subsequent administration of the applicable study drug. Dexamethasone (10 to 
20 mg IV), may be used as premedication in addition to acetaminophen, diphenhydramine, 
and famotidine if patient experiences a ≥ Grade 2 infusion reaction with the first infusion. 
Premedication with steroids should be reduced by 50% with subsequent dose and stopped 
thereafter, if there are no reactions. 
If a dose delay is greater than 11 days (i.e., > 35 days since the last dose) then the 
premedication and prophylaxis procedures should be the same as those done on Cycle 1, Day 
1. 
7.1.3 
Management of Observed Infusion Reactions  
≥ Grade 3 infusion reactions should be reported as AESIs and/or SAEs, as applicable. 
The following are suggested treatment guidelines for the Investigator regarding the 
management of infusion reactions. Equivalent medications may be substituted based on the 
local practice of medicine and availability. 
Grade 1: 
• Slow the infusion rate by 50%. 
• Monitor the patient for worsening of condition. 
• Continue rate at 50% reduction and increase dose rate to the original rate by 
doubling the infusion rate after 30 minutes, as tolerated to the initial rate. 
Consideration can be given to beginning subsequent infusions at 50% rate and 
increasing as tolerated. 
• The following prophylactic pre-infusion medications are recommended prior to 
future infusions of study treatment for patients who experience Grade 1 infusion 
reactions:  
o Diphenhydramine 25 to 50 mg PO/IV. 
o Acetaminophen 650 mg PO and/or ibuprofen 400 mg PO at least 
30 minutes before additional study drug administrations. 
o Famotidine 40 mg PO or 20 mg IV before additional study drug 
administrations. 
 
Grade 2: 
• Stop the infusion. 
o Administer diphenhydramine hydrochloride 25 to 50 mg IV.  
o Acetaminophen 650 mg PO or ibuprofen 400 mg PO for fever.  
o Oxygen and bronchodilators for mild bronchospasm.  
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• Resume the infusion at 50% of the prior rate once the infusion reaction has resolved 
or decreased to Grade 1. The rate may then be escalated to the original rate after 30 
minutes, as tolerated. Consideration can be given to beginning all subsequent 
infusions at 50% rate and increasing as tolerated.  
• Monitor for worsening condition. If symptoms recur, discontinue the infusion; no 
further study drug will be administered at that visit.  
• Prophylactic pre-infusion medications should be given prior to subsequent study 
treatment infusions. Patients who experience Grade 2 infusion reaction, for 
subsequent doses of study treatment, pre-medicate with diphenhydramine 
hydrochloride 25 to 50 mg IV/PO and acetaminophen 650 mg PO and/or ibuprofen 
400 mg PO at least 30 minutes before additional study drug administrations. For 
patients with Grade 2 infusion reactions, despite premedication with 
diphenhydramine and acetaminophen and/or ibuprofen, corticosteroids (10 to 
20 mg dexamethasone IV) may be added to the premedication regimen for the next 
dosing of study treatment. Reduce corticosteroid dosing by 50% for the subsequent 
dose and hold thereafter, if there are no reactions. 
 
Grade 3: 
• STOP THE INFUSION AND DISCONNECT THE INFUSION TUBING FROM 
THE PATIENT. 
• TO AVOID EXACERBATION OF INFUSION REACTION OR CRS: DO NOT 
FLUSH THE TUBING – ASPIRATE RESIDUAL DRUG FROM THE PORT 
LUMEN. 
• Administer diphenhydramine hydrochloride 25 to 50 mg IV, dexamethasone 20 mg 
IV, and other medications/treatment as medically indicated. Higher doses of 
corticosteroids (e.g., methylprednisolone 2 to 4 mg/kg IV) may also be considered 
for acute management. 
• Consider administering tocilizumab (an IL6 receptor antagonist) 4-8 mg/kg IV. 
• IV fluids, supplemental oxygen, H2 blockers such as famotidine, and 
bronchodilators should be considered, as appropriate.  
• If the Grade 3 infusion reaction occurs with any study treatment, it will be 
discontinued for that day. If symptoms have resolved to baseline within 12 hours, 
study treatment may be infused at the next scheduled dose, with a 50% reduction of 
infusion rate. In addition, patients should be pre-medicated for this re-challenge and 
for any subsequent doses of study treatment with the following: diphenhydramine 
hydrochloride 25 to 50 mg IV, acetaminophen 650 mg PO and/or ibuprofen 400 mg 
PO; corticosteroids may be considered as well (dexamethasone 10 to 20 mg IV). 
Reduce corticosteroid dosing by 50% for the subsequent dose and hold thereafter, if 
there are no reactions. 
• Patients who have a Grade 3 infusion reaction that does not resolve within 12 hours 
despite medical management should not receive further study treatment. 
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• Patients who experience a second Grade 3 infusion reaction at the time of 
re-challenge of study treatment (the same study treatment for which the first Grade 
3 infusion reaction was seen) will permanently discontinue study treatment.  
 
Grade 4: 
• STOP THE INFUSION AND DISCONNECT THE INFUSION TUBING FROM 
THE PATIENT. 
• TO AVOID EXACERBATION OF INFUSION REACTION OR CRS: DO NOT 
FLUSH THE TUBING. 
• Administer diphenhydramine hydrochloride 50 mg IV, dexamethasone 20 mg IV 
(or higher doses of steroids, e.g., methylprednisolone 2 to 4 mg/kg IV or the 
equivalent, as considered appropriate). 
• Consider administering tocilizumab (an IL6 receptor antagonist) 4-8 mg/kg IV. 
• Give epinephrine or bronchodilators as indicated. 
• Support ventilation and blood pressure as indicated. 
• Patients who have a Grade 4 infusion reaction should not receive further study 
treatment. 
 
All changes in the infusion of any of the study drugs, including interruption of the infusion 
and its duration as well as reductions in infusion rate and duration, must be recorded. 
7.2 
Immune-Related Adverse Events  
Blockade of immune checkpoints is associated with immune mediated adverse events (irAEs) 
due to disruption of normal immune tolerance (43, 66, 79). These irAEs include but are not 
limited to autoimmune diarrhea, colitis, hepatitis, pneumonitis, encephalitis, nephritis, 
myositis, autoimmune endocrinopathies, myocarditis, and Stevens Johnson Syndrome/Toxic 
Epidermal Necrolysis. Occurrence of such events may call for interruption and/or 
discontinuation of study drug pending further evaluation and reporting to the Sponsor as 
AESIs. Most low-grade irAEs can be managed symptomatically. Persistent low grade or 
moderate toxicities may require treatment with corticosteroids or in refractory cases other 
immune suppressing agents such as mycophenolate or infliximab. High-grade immune-related 
toxicities in most cases require treatment with high-dose corticosteroids. 
Temporary interruptions of study drugs may be required in the event of treatment-related, 
immune-related toxicity. General guidelines for specific toxicity regarding dosing and 
treatment are provided below. Unless otherwise specified Grade 1 immune-related toxicities 
may be monitored without administering specific interventions. Guideline principles may be 
adapted to local standard of care at the Investigator’s discretion. 
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7.2.1 
Diarrhea or Colitis  
Diarrhea that develops in patients while receiving study drugs may reflect immune reactivity 
against normal colonic epithelium and careful monitoring for potential immune-related colitis 
should be instituted. Patients who develop signs or symptoms including abdominal pain, 
bloating, nausea, vomiting, diarrhea, or blood in the stools should be evaluated carefully for 
potential colitis. 
• Grade 1 diarrhea - Closely monitor the diarrhea until resolution. 
• Grade 2 diarrhea - Increase frequency of monitoring until resolution. For 
management of symptoms: 
o Loperamide/diphenoxylate. 
o Low-dose steroids if clinically indicated. 
o Consider management of prolonged Grade 2 event lasting more than 5 to 
7 days or relapsed diarrhea as Grade 3 diarrhea (see below). 
• Grade 3 diarrhea - Hold study treatment. Hospitalize patient promptly for further 
evaluation and management, including the following: 
o Bowel rest. 
o Supplemental IV fluids with close monitoring of fluid and electrolyte 
status. 
o Monitor frequency of bowel movements. 
o Consider imaging to rule out bowel obstruction or perforation. 
o Consideration of colonoscopy as appropriate. 
o Implementation of initial empiric immune suppression consisting of IV 
corticosteroids using methylprednisolone at a dosage of 2 mg/kg/day (or 
equivalent) divided twice daily. As tolerated, patients may be converted to 
oral corticosteroids (i.e., prednisone 2 mg/kg/day divided twice daily) and 
tapered as appropriate guided by the patients’ clinical status. 
o Taper corticosteroids as clinically indicated. 
o For patients with severe colitis, or those who do not respond to 
corticosteroids, additional immune suppression with anti–TNF-α antibodies 
(i.e., infliximab) should be considered early in the course. 
o Consider restarting study treatment if: 
 It is determined there is no colitis and an alternative cause of 
diarrhea is found, and 
 Diarrhea resolves to ≤ Grade 1 within 14 days. 
• Grade 4 diarrhea - discontinue study treatment and treat as for Grade 3. 
 
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7.2.2 
Hepatic Toxicity  
7.2.2.1 
Elevations in Transaminases  
• Grade 1 elevations - No specific therapy required. 
• Grade 2 elevations - For elevations in transaminases 3 to 5 × ULN, rule out viral 
and other etiologies. Consider imaging studies such as ultrasound or CT scan and 
liver biopsy to ascertain etiology of liver dysfunction. Consider starting oral 
prednisone 60 mg/day divided twice daily, and hold study treatment. 
o If improvement to ≤ Grade 1 does not occur within 48 hours consider IV 
steroids such as methylprednisolone at 2 mg/kg/day divided twice daily or 
oral steroids such as prednisone 60 to 120 mg per day, divided twice daily. 
o Monitor liver function tests at least twice weekly (or more frequently as 
clinically appropriate in the judgment of the Investigator) until 
transaminases have returned to Grade 1 or baseline. 
o Taper oral steroids as clinically indicated with improvement in liver 
function. 
o Resume study treatment at the next scheduled dose if no more than two 
doses were missed. 
o If improvement to ≤ Grade 1 does not occur within 14 days, discontinue 
study treatment.  
• Grade 3 elevations - Hold study treatment. 
o For elevations in transaminases > 8 × ULN, permanently discontinue study 
treatment. 
 Begin immediate IV steroids; suggest methylprednisolone at a 
dosage of 2 mg/kg/day divided twice daily. 
 Consider additional immune suppression with mycophenolate for 
patients who do not respond to corticosteroid therapy within 3 to 
5 days.  
 Monitor liver function tests at least twice weekly (or more 
frequently as clinically appropriate in the judgment of the 
Investigator) until transaminases have returned to Grade 1 or 
baseline. 
o For elevations in transaminases > 5 but ≤ 8 × ULN: 
 Begin immediate IV steroids; suggest methylprednisolone at a 
dosage of 2 mg/kg/day divided twice daily. 
 Consider additional immune suppression as above for patients who 
do not respond to corticosteroid therapy within 3 to 5 days. 
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 Monitor liver function tests at least twice weekly (or more 
frequently as clinically appropriate in the judgment of the 
Investigator) until transaminases have returned to Grade 1 or 
baseline. 
 If the elevation does not improve to Grade 2 within 7 days and to 
Grade 1 within 14 days, discontinue study treatment. 
o Resume study treatment administration if following conditions are met: 
 Laboratory elevations improved to ≤ Grade 2 within 7 days and 
improve to ≤ Grade 1 or baseline within 14 days. 
 Steroids have been tapered to ≤ 10 mg per day of prednisone or 
equivalent. 
 On resuming study treatment, AST, ALT, and total and direct 
bilirubin laboratory test values will be evaluated at least once per 
week for 3 consecutive weeks. 
o Permanently discontinue study treatment in the case of a second increase of 
AST or ALT to ≥ Grade 3. 
• Grade 4 elevation - Discontinue study treatment and treat as for Grade 3 elevation. 
 
7.2.2.2 
Elevations in Total Bilirubin  
• Grade 1 elevations - No specific therapy required. 
• Grade 2 elevations - Hold study treatment until improvement to ≤ Grade 1. 
o Rule out viral and other etiologies. Consider imaging studies such as 
ultrasound or CT scan and liver biopsy to ascertain etiology of liver 
dysfunction. Consider oral steroids. 
o If improvement to ≤ Grade 1 does not occur within 14 days, discontinue 
study treatment and begin oral steroids. 
• Grade 3 elevations - Hold study treatment. 
o For elevations in total bilirubin > 5 × ULN, permanently discontinue study 
treatment and initiate IV steroids, suggest methylprednisolone at a dosage 
of 2 mg/kg/day divided twice daily, and, 
 If no response to corticosteroid therapy within 3 to 5 days is 
observed, consider adding immune suppression therapy with 
mycophenolate. 
 Monitor liver function testing at least twice weekly (or more 
frequently as clinically appropriate in the judgment of the 
Investigator) until total bilirubin has returned to Grade 1 or 
baseline. 
o For elevations in total bilirubin > 3.0 but ≤ 5 × ULN: 
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 Begin immediate IV steroids, suggest methylprednisolone at a 
dosage of 2 mg/kg/day divided twice daily. Consider additional 
immune suppression as above for patients who do not respond to 
corticosteroid therapy within 3 to 5 days. 
 Monitor liver function including total bilirubin testing at least twice 
weekly (or more frequently as clinically appropriate in the judgment 
of the Investigator) until total bilirubin has returned to Grade 1 or 
baseline. 
 If the elevation does not improve to Grade 2 within 7 days and to 
Grade 1 within 14 days, discontinue study treatment. 
o Resume study treatment administration if: 
 Laboratory elevations downgrade to ≤ Grade 2 within 7 days and 
improve to ≤ Grade 1 or baseline within 14 days. 
 Steroids have been tapered to ≤ 10 mg per day of prednisone or 
equivalent 
 On resuming study treatment, AST, ALT, and total bilirubin 
laboratory test values will be evaluated at least once per week for 
3 consecutive weeks. 
o Permanently discontinue study treatment in the case of a second increase of 
total bilirubin to ≥ Grade 3. 
• Grade 4 elevations - Discontinue study treatment and treat as for Grade 3 elevation. 
 
7.2.3 
Pneumonitis  
• Grade 1 pneumonitis - No specific therapy required; close monitoring of lung 
function and imaging.  
• Grade 2 pneumonitis - Hold study treatment. 
o Consider corticosteroids: 1 to 2 mg/kg of oral prednisone or equivalent per 
day divided twice daily. 
o Taper over 4 weeks as clinically indicated.  
o Resume study treatment administration at next scheduled dose if 
pneumonitis resolves to ≤ Grade 1 within 5 days with or without treatment. 
• Grade 3 and 4 pneumonitis - Permanently discontinue study treatment. 
o Hospitalize.  
o Recommend a pulmonary consult/diagnostic evaluation including chest 
X-ray and CT scan. 
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o Initiate maximal supportive care including IV corticosteroids, suggest 
methylprednisolone at 2 to 4 mg/kg/day divided twice daily. Higher doses 
may be used in consultation with the Sponsor’s Medical Monitor. 
o If no response to corticosteroid therapy is observed within 3 to 5 days, 
consider adding immune suppression therapy (i.e., infliximab, etc.). 
 
7.2.4 
Dermatologic Toxicity  
• Grade 1 or 2 skin reactions 
o Symptomatic treatment with low-dose topical corticosteroids 
(betamethasone 0.1% or hydrocortisone 1%) or antihistamines 
(diphenhydramine). 
o Persistent Grade 1 or 2 rash should be managed with higher dose topical 
corticosteroids and/or oral prednisone (1 to 2 mg/kg/day) if there is not 
improvement with topical therapies or the rash is associated with other 
dermal toxicities such as pruritus. 
• Grade 3 skin reactions – Hold study treatment. 
o Initiate oral corticosteroids (oral prednisone 1 to 2 mg/kg/day). 
o Study treatment administration may be restarted at the next scheduled 
dosing if symptoms resolve to ≤ Grade 2 within 14 days. 
o Grade 3 skin toxicity that does not resolve to ≤ Grade 2 within 14 days of 
initiation of oral corticosteroids requires permanent discontinuation of 
study treatment. 
• Grade 4 skin reactions - Discontinue study treatment. 
o Initiate oral corticosteroids (oral prednisone 1 to 2 mg/kg/day). 
o Consideration should be given to start IV corticosteroids 
(methylprednisolone 1-2 mg/kg/day) for Grade 4 dermatologic toxicities 
with tapering on resolution to < Grade 2 over 30 days. 
 
7.2.5 
Nephritis  
• Grade 1 nephritis - No specific therapy required; close monitoring of renal function. 
• Grade 2 nephritis - Hold study treatment. 
o Consider nephrology consultation and renal biopsy to confirm interstitial 
nephritis. 
o Begin corticosteroids: 1 to 2 mg/kg of oral prednisone or equivalent per 
day divided twice daily. Taper over 4 weeks as clinically indicated. 
o Resume study treatment administration at next scheduled dose if: 
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 Nephritis resolves to ≤ Grade 1 within 14 days with or without 
treatment 
• Grade 3 and 4 nephritis - Permanently discontinue study treatment. 
o Consider hospitalization, nephrology consultation, and renal biopsy to 
confirm interstitial nephritis 
o Begin corticosteroids: 2 to 4 mg/kg of oral or IV methylprednisolone or 
equivalent per day divided twice daily. Taper over 4 weeks as clinically 
indicated. 
 
7.2.6 
Immune-Mediated Hypophysitis  
• Grade 1 hypophysitis - No specific therapy required. 
• Grade ≥ 2 hypophysitis - Hold study treatment. 
o Consult endocrinologist. 
o Consider hospitalization.  
o Consider short course of high dose IV 
corticosteroids: e.g., methylprednisolone 2-4 mg/kg IV (or 
equivalent) divided twice daily. 
o Initiate hormonal replacement as indicated. 
o Study treatment may be resumed as allowed by protocol when: 
 Endocrinopathy is controlled with appropriate replacement therapy. 
 Corticosteroid dose reduced to ≤ 10 mg prednisone or equivalent 
per day. 
o  Brain MRI recommended. 
 
7.2.7 
Thyroid Toxicity  
Thyroid disorders may occur at any time during treatment with study drugs. Monitor patients 
for changes in thyroid function per protocol and as indicated based on clinical evaluation and 
for clinical signs and symptoms of thyroid disorders. Isolated hypothyroidism may generally 
be managed with replacement therapy without treatment interruption and without 
corticosteroids, and a suggested treatment guideline for hyperthyroidism is described below: 
• Grade 1 hyperthyroidism - No specific therapy required. 
• Grade 2 hyperthyroidism - Hold study treatment. 
o Consider starting oral corticosteroid therapy. 
o Short course of corticosteroid such as methylprednisolone 1 to 2 mg/kg IV 
(or equivalent) divided twice daily. 
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o Resume study treatment if corticosteroid dose is reduced to ≤ 10 mg 
prednisone or equivalent per day and stable on hormone replacement 
therapy (if necessary). 
• Grade 3 or 4 hyperthyroidism - Hold study treatment. 
o Consider hospitalization and consulting endocrinologist. 
o Begin IV corticosteroids such as methylprednisolone 2 to 4 mg/kg IV (or 
equivalent) divided twice daily. 
o Initiate hormonal replacement as necessary. 
o Consider restarting study treatment with complete resolution, or if stable on 
hormone replacement therapy within 14 days, and if corticosteroid dose is 
reduced to ≤ 10 mg prednisone or equivalent per day. 
 
 
 
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8 
CONCOMITANT THERAPY AND RESTRICTIONS  
8.1 
Concomitant Therapy  
All concomitant medications, including prophylactic pre-infusion medications, and blood 
products administered during the patient’s participation in the study until 30 days following 
the last dose of study drug or until the start of a subsequent systemic anticancer therapy, if 
earlier, must be recorded in the source document and on the electronic Case Report Form 
(eCRF). All changes in infusions, including interruptions and their duration as well as 
reductions in rate and duration, must be recorded.  
8.1.1 
Prohibited Therapy  
The following rules concerning concurrent treatment(s) will apply in this study: 
• Any other anti-neoplastic therapies, other than the assigned study treatment, 
including but not limited to chemotherapy, small molecules, biologics, or 
radiotherapy are not allowed.  
• Patients may not receive other investigational drugs during the period of study 
participation. 
• The use of immuno-suppressive agents is prohibited, unless they are being used to 
treat an AE. 
• Probiotics are not allowed. 
• Live vaccines within 4 weeks prior to the first dose of study treatment and while 
participating in the study are prohibited. Examples of live vaccines include, but are 
not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, 
rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection 
are generally killed virus vaccines and are allowed. However, intranasal influenza 
vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed. 
o If an immunization strategy for SARS-CoV-2 becomes available during the 
study, permissibility of administration of SARS-CoV-2 prophylaxis during 
the study will be discussed with the Sponsor. 
• The use of corticosteroids should be limited to the extent possible. Chronic doses of 
corticosteroids more than 10 mg/day prednisone or equivalent are prohibited other 
than for the management of drug-related adverse experiences. Steroids may be 
employed in the treatment of suspected study treatment-associated irAEs in 
consultation with the Sponsor’s Medical Monitor. Steroids for topical, ophthalmic, 
inhaled, or nasal administration are allowed. 
 
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8.1.2 
Permitted Therapies  
Patients may receive the following concurrent therapy: 
• Antiemetics, antidiarrheal, anticholinergics, antispasmodics, antipyretics, 
antihistamines, analgesics, antibiotics and other antimicrobials, histamine receptor 
antagonists or proton pump inhibitors, and other medications intended to treat 
symptoms or signs of disease. 
• Transfusions such as red blood cells and platelets are permitted to treat symptoms 
or signs of anemia or thrombocytopenia. 
• Bisphosphonates or receptor activator of nuclear factor Kappa-B ligand (RANK-L) 
inhibitors provided treatment with the agent is begun before the start of study 
treatment.  
• Use of granulocyte colony stimulating factor, granulocyte-macrophage colony 
stimulating factor, or other growth factors is permitted. 
 
8.1.3 
Contraception  
Male and female patients are required to use highly effective contraceptive measures as 
specified below. Male patients are required to use a condom regardless of his WOCBP 
partner’s method of contraception. 
• Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation: 
o Oral  
o Intravaginal  
o Transdermal  
• Progestogen-only hormonal contraception associated with inhibition of ovulation:  
o Oral  
o Injectable 
o Implantable   
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized partner is a highly effective birth control method provided that the 
vasectomized partner is the sole sexual partner of the WOCBP trial participant and 
that the vasectomized partner has received medical assessment of the surgical 
success. 
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• Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study treatments. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the clinical trial and the preferred and usual lifestyle of 
the patient. 
 
8.2 
Restrictions  
8.2.1 
Fluid and Food Intake  
There are no requirements for fasting and no restrictions for fluid and food intake by the 
patients during the study, although it is recommended that, to the extent possible, patients 
have a fluid intake of  2 liters on days associated with PK sampling, and that 
electrocardiograms will be obtained pre-meal. 
8.2.2 
Patient Activity Restrictions  
There are no restrictions on patient activities and no requirement for patient confinement 
during the study. 
 
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9 
STUDY PROCEDURES  
This section provides a general description of the procedures and assessments associated with 
this study. The timing of the study procedures is presented in Appendix 1. All data should be 
recorded in source documents and entered into the eCRF.  
9.1 
Informed Consent  
The Investigator is responsible for ensuring that the patient or his/her legal representative 
provides informed consent prior to performing any study-related assessments, evaluations, or 
procedures that are not part of standard of care for the patient’s disease. Informed consent for 
this study must be provided by signing an Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC)-approved informed consent document. A copy of the relevant signed 
informed consent document must be provided to the patient and the original maintained 
according to institutional procedures. The patient’s medical records will include 
documentation of the informed consent process.  
9.2 
Screening Period  
At the screening visit, patients will enter the study upon signing the informed consent 
document. No screening activities outside of usual standard of care should be performed prior 
to obtaining informed consent from the patient. However, medical testing that is performed 
according to local standard of care may be used to qualify patients for participation in the 
study. Screening procedures, with the exception of obtaining the tumor biopsy specimen, 
should be performed within 28 days prior to Cycle 1 Day 1. 
Patients who sign the informed consent form but fail to meet the inclusion and/or exclusion 
criteria are defined as screen failures. An eCRF with a minimum of the following information 
must be completed for patients who fail screening: demographics, reason for screen failure, 
and serious adverse events related to study procedures. 
9.3 
Enrollment  
Only those patients who meet all inclusion/exclusion criteria specified in Section 5 will be 
enrolled into this study. 
Instructions for enrollment will be provided via IRT. 
9.4 
Medical History  
A complete medical history should be obtained during the screening visit, including history of 
use of tobacco and other nicotine-containing products, and history of alcohol use. All 
concurrent medical conditions in the last 60 days and any significant past medical conditions 
(e.g., hospitalizations, surgeries, chronic conditions, prior cancer history, etc.) should be 
collected. Any untoward event that occurs prior to the first dose of study drug should be 
recorded as medical history and not as an AE, unless it is due to a protocol-related procedure. 
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9.5 
Prior and Concomitant Medications and Procedures  
All concomitant medications, blood products, and procedures administered for 30 days prior 
to study drug administration through the End of Treatment Visit must be recorded in the 
source document and on the eCRF. 
All prior regimens of systemic anti-cancer therapy will be documented in the medical records 
and on the eCRF. 
9.6 
Physical Examination  
The Investigator will perform physical examination of all patients. Full physical examination 
will be performed at screening and at the End of treatment visit, and it will include height 
(screening only), weight, and examination of skin, HEENT (head, eyes, ears, nose, and 
throat), lymph nodes, heart, chest, lungs, abdomen, extremities, and neurologic system. All 
other physical examinations will be directed physical examinations based on patient signs, 
symptoms, tumor location, and as clinically indicated. Directed physical examinations will 
include weight. 
9.6.1 
Vital Signs  
Vital signs include temperature, pulse, blood pressure, and respiratory rate. It is recommended 
vital signs are obtained in a seated, semi-recumbent, or supine position after an appropriate 
rest.  
9.7 
ECOG Performance Status  
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity, but ambulatory and able to carry out work of 
a light or sedentary nature (e.g., light house work or office work) 
2 
Ambulatory and capable of all self-care, but unable to carry out any work activities. Up 
and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled. Cannot carry-on any self-care. Totally confined to bed or chair. 
5 
Dead 
 
9.8 
Clinical Laboratory Tests  
Blood and urine samples will be collected. Both local and central laboratory testing will be 
used. 
Local laboratories should be used for all clinical decision-making, including but not limited to 
decisions regarding dose adjustments, if needed. Necessary laboratory testing should be 
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performed as required by the clinical situation. Local laboratory testing will be used for 
confirmation of pregnancy status prior to dosing as indicated. 
Central laboratory testing should be used to determine patient eligibility and assess overall 
safety in the study, unless the Medical Monitor approves the use of a local laboratory in place 
of an unanalyzable central laboratory sample. Central laboratory test results need not be 
reviewed prior to dosing on study if local testing is available. 
Protocol-specific clinical laboratory requirements are presented in Appendix 2. Safety 
laboratory tests should be performed and reviewed before study drug administration. 
9.9 
Pharmacokinetic, Immunogenicity, and Pharmacodynamic 
Biomarker Samples  
Unless otherwise stated, PK, immunogenicity, pharmacodynamic, and biomarker assays will 
be carried out in a central laboratory designated by the Sponsor. Additional details on 
collection, processing, storage, and shipping of central laboratory samples will be provided in 
the Laboratory Manual. PK, anti-drug antibodies (ADA), pharmacodynamic, and biomarker 
specimens will be collected according to the schedules in Appendix 3. PK, 
pharmacodynamic, and biomarker assessments are described in Section 10. 
9.9.1 
Blood Samples  
Blood samples will be collected from the arm contralateral to the site of IV infusion. If an 
indwelling catheter is used, the fluid in the catheter will be removed and discarded prior to the 
collection of blood sample for PK, ADA, or biomarker assessment. PBMCs, serum, and 
plasma will be collected according to the schedules in Appendix 3 for assessment of 
immunomodulatory activity. 
9.9.2 
Samples for HPV Status  
Local laboratory results are acceptable for evaluation of HPV p16 status. If local laboratory 
results are not available, evaluation of HPV p16 status will be conducted at a central 
laboratory designated by the Sponsor.  
For evaluation of HPV p16 status, if local laboratory results are not available, patients are 
required to have an identified tumor specimen (FFPE) or 5 unstained slides.  
9.9.3 
Biopsy Specimens  
Per Inclusion Criterion 6, all patients enrolled in this study must have an identified FFPE 
tumor specimen for immunohistochemical evaluation of pharmacodynamic markers of 
interest. If no archival specimen is available, tissue from a contemporaneous core or 
excisional biopsy is acceptable (fine needle aspirate is not sufficient).  
Patients must also be willing to provide consent for a baseline and on-treatment (end of Cycle 
2) tumor biopsy, if tumor lesions are accessible for biopsy with acceptable risk in the 
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judgment of the Investigator and after discussion with the Sponsor. This requirement will 
expire after an adequate number of samples have been collected, as determined by the 
Sponsor. Submission of an archival sample is highly encouraged but not mandatory for 
patients that provide a fresh biopsy sample. 
Tumor lesions used for biopsy should be lesions that are felt to be accessible with acceptable 
clinical risk in the judgment of the Investigator, and should not be lesions used as RECIST 
target lesions unless there are no other lesions suitable for biopsy. If a RECIST target lesion is 
used for biopsy, the lesion must be ≥ 2 cm in longest diameter. Previously irradiated lesions 
should not be biopsied unless the lesion has grown in size after at least 14 days from the last 
dose of radiation. Multiple lesions may be used to obtain the biopsy sample. Lesions to be 
biopsied should be of sufficient size to enable acquisition of at least 2 tumor biopsy cores 
using a 16-gauge biopsy needle. Exceptions to the gauge of the needle may be considered 
after consultation with the Sponsor. Up to 3 additional biopsy cores may be obtained if this 
can be performed with acceptable clinical risk in the judgment of the Investigator. Excisional 
biopsies are allowed if these can be performed with acceptable clinical risk in the judgment of 
the Investigator. Immediate confirmation of the adequacy of the biopsy specimen and the 
presence of malignant cells in the tumor biopsy are strongly encouraged. Cores may be 
obtained if this can be performed with acceptable clinical risk in the judgment of the 
Investigator. Additional instructions for the processing and storage of tumor biopsy specimens 
will be provided in the Laboratory Manual.  
If any new tissue acquisition is performed during the study course, submission of this new 
sample to the laboratories designated by the Sponsor is highly encouraged (but not 
mandatory). 
9.10 
Tumor Assessments  
Baseline tumor imaging consists of a CT/MRI scan for all patients. The subsequent tumor 
assessments on treatment should use the same imaging modality as that for the baseline 
assessment. Target and non-target lesions will be designated at screening and re-evaluated 
according to Appendix 1. 
A CT or MRI scan of the brain will be performed in cases in which it is clinically indicated 
(e.g., suspicion of brain metastases). 
If bone metastases are suspected or present, a bone scintigraphy may be performed at baseline 
and as clinically indicated on study. Bone scan, positron emission tomography (PET) scan, or 
plain films are not considered adequate imaging techniques for the measurement of bone 
lesions. However, these techniques can be used to confirm the presence or disappearance of 
bone lesions. Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as CT or MRI 
can be considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. Blastic bone lesions are non-measurable. 
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9.11 
Electrocardiography  
Twelve-lead electrocardiograms will be obtained to evaluate the potential cardiac effect, 
including QTc interval prolongation. Screening and Cycle 1 Day 1 ECGs are performed in 
triplicate. Subsequent ECGs are obtained as clinically indicated. 
Actual times of the ECG assessments will be recorded on the eCRFs. 
9.12 
End of Treatment Visit  
The end of treatment visit (EOTV) should be performed within 30 days after the patient has 
met study treatment discontinuation criteria, and before initiation of any subsequent 
anticancer therapies.  
It is recognized that patients may go to other facilities for continuing care, or may elect not to 
return to the study site. Therefore, failure to return for an EOTV will not be considered a 
protocol deviation. Whenever possible all required procedures and tests should be performed, 
with the following exception: the EOTV tumor assessment does not need to be conducted if 
prior tumor assessment was performed within 28 days of the EOTV and results are available 
for RECIST assessments. 
9.13 
Post-Treatment Follow-up Visit  
The post-treatment follow-up period includes the following: 
• Survival follow-up: Patients will be followed via telephone or other electronic 
contact at approximately 12-week (± 1 week) intervals after the EOTV (or, if no 
EOTV is conducted, after the decision to end treatment) until LTFU, withdrawal of 
consent, or death, or until 36 weeks after the last patient’s EOTV. Prior to the 
database lock for final OS analysis, all current survival data will be requested 
regardless of interval from the prior assessment to collect the most up-to-date 
survival information for the final OS analysis. 
• Tumor assessments: Will be collected every 12 weeks (± 1 week) after the EOTV 
(or, if no EOTV is conducted, after the decision to end treatment) until evidence of 
progressive disease (PD), initiation of another anticancer therapy, withdrawal of 
consent, LTFU, death, or 36 weeks after the last patient’s EOTV. Patients who 
discontinue study treatment due to AEs are followed by radiographic evaluation 
until PD by RECIST v1.1, if the patients’ condition allows. If not, patients will be 
followed for OS without radiographic evaluation upon the discussion with the 
Sponsor’s Medical Monitor.  
• PK and ADA: For patients with evidence of ADA from any prior visit, samples will 
be collected for PK and ADA at 12 and 24 weeks after the EOTV (or, if no EOTV is 
conducted, after the decision to end treatment). 
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10 
ASSESSMENT OF PHARMACOKINETICS AND  
PHARMACODYNAMICS  
10.1 
Pharmacokinetics Assessments  
Serum concentrations of enoblituzumab, retifanlimab, and tebotelimab will be analyzed using 
validated assay methods that will be carried out in the Sponsor’s designated central laboratory. 
Analysis of PK data will be carried out using industry standard software.  
Single and multiple dose PK parameters, including but not limited to Cmax and Ctrough, will be 
derived from serum concentration versus time data. PPK and exposure-response analyses will 
be conducted, using data from this study alone or combined with data from other studies. PPK 
and exposure-response modeling will be performed, and appropriate models and model 
parameters will be described. The influence of intrinsic and extrinsic covariates on model 
parameters will be investigated. The PPK and exposure-response analyses will be the subject 
of separate reports. 
10.2 
Pharmacodynamic/Biomarker Assessments  
Assessment of PD-L1 must be performed prospectively prior to enrollment. Other biomarker 
assessments will be prospectively collected and retrospectively analyzed. 
Pharmacodynamic/biomarker assessments will each be carried out in a central laboratory 
designated by the Sponsor. Assessments will use an archival tumor specimen block (FFPE) or 
up to 20 unstained slides from an archival tumor specimen as noted below. 
10.2.1 
PD-L1 Immunohistochemistry Testing  
Prospective PD-L1 testing will be performed for all patients, and should be performed on 
archival tissue if this is available. PD-L1 testing may also be carried out using fresh baseline 
and on-treatment tumor biopsy specimens, depending on sample availability. Anti–PD-1 
agents have demonstrated improved efficacy in SCCHN patients with tumors that express PD-
L1 as determined by immunohistochemistry (IHC) (65). PD-L1 protein expression is 
determined by using CPS, which is the number of PD-L1 staining cells (tumor cells, 
lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 
100. The specimen should be considered to have PD-L1 expression if CPS ≥ 1. PD-L1 
expression will be assessed based on IHC staining using the FDA-approved 22C3 pharmDx 
assay. 
10.2.2 
B7-H3 Immunohistochemistry Testing  
As enoblituzumab is an Fc-optimized antibody targeting B7-H3, IHC to assess B7-H3 
expression will be performed in all patients. Testing may be carried out on both archival and 
fresh baseline and on-treatment tumor biopsy specimens, depending on sample availability.  
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10.2.3 
PD-1/LAG-3 Immunohistochemistry Testing  
PD-1/LAG-3 testing will be performed by PD-1 and LAG-3 dual IHC staining. Testing may 
be carried out on both archival and fresh baseline and on-treatment tumor biopsy specimens, 
depending on sample availability. Tebotelimab is a dual-affinity targeting agent that binds 
both PD-1 and LAG-3. While LAG-3 expression is documented in SCCHN, its correlation 
with response to immunotherapy agents is not completely understood. The selected study 
antibodies for the IHC staining will include rabbit anti LAG-3 Ab clone EPR4392(2) (Abcam) 
and mouse anti PD-1 Ab clone NAT105 (Ventana). The dual IHC assay will be carried out on 
Ventana Discovery Ultra platform according to sponsor established Standard Operating 
Procedures (SOPs) and controls to ensure validity of the results generated. 
10.2.4 
Additional Immunohistochemistry Testing  
Additional IHC testing may be carried out on fresh baseline and on-treatment tumor biopsy 
tissue, depending on sample availability. These markers include but are not limited to: MHC 
class II, Granzyme, Ki67, T-cell infiltrate (e.g., CD3, CD8), immune cell activation markers, 
and natural killer (NK) cell markers. 
10.3 
Gene Expression Profiling  
Gene expression profiling using Nanostring and tumor mutational burden may be determined 
retrospectively based on response, and prioritized according to the availability of archival and 
fresh tumor biopsy specimens. 
10.4 
Immune-regulatory Activity Testing  
Immune-regulatory activity may be assessed at a Sponsor’s designated laboratory by such 
assays as: peripheral multi-parameter flow cytometry, Fc receptor genotyping, TCR 
spectratyping, ELISpot analyses, ex-vivo ADCC and CTL activity, IHC analyses, tumor 
mutation burden, and/or transcript profiling of any post-treatment biopsy samples obtained, 
and soluble biomarker analyses by ELISA or equivalent detection method. 
 
 
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11 
ASSESSMENT OF EFFICACY  
11.1 
Efficacy Assessments  
11.1.1 
Disease Response Assessments  
Tumor assessments will be obtained using CT and/or MRI scans and tumor response 
evaluated according to RECIST v1.1. Target and non-target lesions will be designated at 
screening and assessed at the end of Cycle 2 (i.e., after approximately 6 weeks, with a window 
of -3 days in relation to the beginning of the next cycle), and at the end of every 3 cycles 
thereafter (i.e., approximately every 9 weeks, with a window of -7 days in relation to the 
beginning of the next applicable cycle) until discontinuation of treatment. After receipt of the 
last dose of study treatment, all patients will enter an Efficacy Follow-up Period, during which 
tumor assessments will be obtained as described in Section 9.13. 
The overall responses will be categorized as Complete Response (CR), Partial Response (PR), 
Stable Disease (SD), Progressive Disease (PD), or Not Evaluable (NE). At each on-treatment 
tumor assessment time point, the objective response status will be determined. In the context 
of the statistical analysis for this trial, objective response determination and the assessment of 
best overall response (BOR) will be defined using RECIST v1.1 (Appendix 4). 
11.1.2 
Survival Assessments  
Patients who are discontinued from study treatment will be assessed for survival status as 
described in Section 9.13. Prior to the final OS analysis, all current survival data will be 
requested regardless of interval from the prior assessment to collect the most up-to-date 
survival data for the final OS analysis.  
11.2 
Immunogenicity Assessments  
The generation of ADA for enoblituzumab, retifanlimab, and tebotelimab will be monitored 
using validated analytical methods carried out in the Sponsor’s designated central laboratory. 
 
 
 
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12 
ADVERSE EVENT REPORTING AND ASSESSMENT OF 
SAFETY  
The safety assessment will be based on the evaluation of AEs that occur from the time of 
initiation of administration of study drug until 30 days following the last dose of study drug or 
until the start of a subsequent systemic anticancer therapy, if earlier, and will be determined 
based on signs, symptoms, physical examination findings, and/or laboratory test results from 
enrolled patients, as appropriate. 
12.1 
Definitions  
12.1.1 
Adverse Event  
Adverse event (AE) means any untoward medical occurrence in a patient or clinical trial 
patient associated with the use of a drug in humans, whether or not considered drug related. 
An AE can be:  
• any unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
• any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including 
laboratory test abnormalities. 
 
12.1.2 
Adverse Drug Reaction  
Adverse drug reaction (ADR) is a noxious and unintended response to the medicinal product 
related to any dose. As used herein, the phrase “response to a medicinal product” means that a 
causal relationship between a medicinal product and an AE is at least a reasonable possibility. 
12.1.3 
Adverse Event of Special Interest  
An adverse event of special interest (AESI) is an event of scientific and medical interest or 
concern to the Sponsor’s product or program, for which ongoing monitoring and rapid 
communication to the Sponsor could be appropriate. It may be a serious or non-serious AE, 
which may require further investigation in order to characterize and understand it.  
12.1.4 
Serious Adverse Event  
A serious AE (SAE) is any AE that results in any of the following outcomes: 
• Death 
• Life-threatening (immediate risk of death) 
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• Inpatient hospitalization for longer than 24 hours or prolongation of existing 
hospitalization (even if the event is Grade 1) 
• Persistent or significant disability or incapacity  
• Congenital anomaly/birth defect  
• Important medical events 
 
12.1.5 
Attribution/Assessment of Causality  
Attribution/Assessment of Causality is a determination that describes the relationship or 
association of the study product with an AE.  
This assessment of causality or relationship of AEs to the study drug is provided by the 
Investigator and is determined by 1) temporal relationship of the event to the administration of 
study drug; 2) whether an alternative etiology has been identified, and 3) biological 
plausibility. Causality must be assessed separately for each study drug.  
Causality assessments that are considered not related to study drug: 
• None: The event is related to an etiology other than the study drug (the alternative 
etiology should be documented in the patient’s medical record). 
• Unlikely: The event is unlikely to be related to the study drug and likely to be 
related to factors other than study drug. An alternative explanation is more likely 
(e.g., concomitant drugs, concomitant disease), or the relationship in time suggests 
that a causal relationship is unlikely. 
 
If an SAE is considered “unlikely” or “unrelated” to study drug, the Investigator should offer 
his/her clinical opinion as to what factor(s), agent(s), or process(es) were the likely causative 
mechanism for the event. 
Causality assessments that are considered related to study drug: 
• Possible: There is an association between the event and the administration of the 
study drug and there is a plausible mechanism for the event to be related to study 
drug; but there may also be alternative etiology, such as characteristics of the 
patient’s clinical status or underlying disease. 
• Probable: There is an association between the event and the administration of study 
drug; there is a plausible mechanism for the event to be related to the study drug 
and the event could not be reasonably explained by known characteristics of the 
patient’s clinical status or an alternative etiology is not apparent. 
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• Definite: There is an association between the event and the administration of study 
drug; there is a plausible mechanism for the event to be related to the study drug, 
causes other than the study drug are ruled out, and/or the event re-appeared on re-
exposure to the study drug. 
 
12.1.6 
Severity Criteria  
Assessment of severity grade will be made using the NCI-CTCAE Version 5.0.  
For events not contained in CTCAE, the Investigator may assign intensity according to the 
following generic CTCAE grading scale: 
• 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 instrumental activities of daily living (ADL). 
• Grade 3 = Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.  
• Grade 4 = Life-threatening consequences; urgent intervention indicated. 
• Grade 5 = Death related to AE. 
 
12.2 
Adverse Event Collection and Documentation  
12.2.1 
All Adverse Events  
All patients who receive at least one dose of study drug will be considered evaluable for 
safety. AEs will be determined based on signs, symptoms, physical examination findings, 
and/or laboratory test results from enrolled patients as appropriate. 
All adverse events whether serious or non-serious, will be reported from the time a signed and 
dated informed consent form (ICF) is obtained until 30 days following the last dose of study 
drug or until the start of a subsequent systemic anticancer therapy, if earlier.  
Both protocol-related AEs and SAEs will be collected from the time the patient has consented 
to study participation. AEs and SAEs reported between the time the patient signs the ICF and 
the administration of the first dose of study drug will be captured as concurrent medical 
history unless the events are attributed to protocol-specified procedures.  
Disease progression or events deemed related to disease progression will be documented as an 
antitumor activity outcome, not reported as an AE; they will be collected as efficacy 
endpoints. Conversely, AEs should be reported if it is unclear if the event is due to PD. 
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Events attributed to protocol-specified procedures will be collected on the Adverse Event 
eCRFs and SAE Report Form, as appropriate.  
AEs, regardless of seriousness, severity, or relationship to study drug, are documented in the 
source and the eCRF, including:  
• duration, severity, and seriousness of each adverse event, 
• the action taken with respect to the study drug(s), 
• the Investigator’s attribution/causality assessment, 
• the outcome of the event. 
 
Whenever possible, diagnoses should be given when signs and symptoms are due to a 
common etiology (e.g. cough, runny nose, sneezing, sore throat, and head congestion should 
be reported as "upper respiratory infection"). All treatment measures for AE management will 
be recorded. All non-serious AEs should be entered into the eCRFs within 10 days of study 
site awareness. 
Clinical Laboratory Changes: Safety laboratory assessments will be evaluated by the 
Investigator to ensure patient safety. The Investigator is responsible for reviewing the results 
of all laboratory tests as they become available: 
• Laboratory values that fall outside of a clinically accepted reference range or values 
that differ significantly from previous values must be evaluated by the Investigator 
for clinical significance. The Investigator may repeat the laboratory test or request 
additional tests to verify the results of the original laboratory tests.  
 
A laboratory abnormality is reported as an AE if any criterion for an SAE is fulfilled, or the 
event is associated with an intervention including, but not limited to, discontinuation or 
interruption of treatment, dose reduction/delay, or required initiation of concomitant therapy. 
Also, any laboratory abnormality may be reported as an AE at the Investigator’s discretion, 
based on clinical significance. Examples include abnormalities for which there are no 
interventions yet abnormal value(s) suggest(s) disease or organ toxicity. If clinical sequelae 
are associated with a laboratory abnormality, diagnosis or medical condition should be 
reported (e.g., renal failure, hematuria) not the laboratory abnormality (e.g., elevated 
creatinine, urine red blood cells [RBC] increased). 
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory 
authorities. The sponsor will also report to the Investigator all suspected unexpected serious 
adverse reactions. The Investigator must report suspected unexpected serious adverse 
reactions to the appropriate Independent Ethics Committee/Institutional Review Board 
(IEC/IRB) that approved the protocol, unless otherwise required and documented by the 
IEC/IRB. 
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12.2.2 
Serious Adverse Events  
All SAEs occurring during the study must be reported to the Sponsor. SAEs considered 
related to study drug may be reported at any time, even after the patient’s final visit. 
• Within 24 hours of becoming aware of an SAE, the Investigator should send the 
Sponsor a completed SAE Report form by email, SAEReports@macrogenics.com, 
or fax, (301) 354-3800. The SAE Report Form and Completion Guidelines, and 
Contact Information for Reporting SAEs, are found in the Study Procedures 
Manual. Upon receipt of SAE follow-up information, a follow-up SAE Report form 
should be submitted within 24 hours of becoming aware of the follow-up 
information. SAEs should be entered into the eCRFs within 5 calendar days of the 
site’s awareness.  
• SAEs related to study drug may be reported at any time, through 30 days after the 
last dose of study drug or until start of a subsequent anticancer therapy, if earlier. 
o In those cases in which the SAE is considered related to study drug, the 
study drug may be discontinued, and the patient will continue participation 
in the study for observational safety and analysis (except for cases where 
the patient is withdrawn from the study by the Investigator or withdrew the 
consent). 
• After 30 days following the last dose of study drug administration, if an 
Investigator becomes aware of a SAE that s/he suspects is related to study drug, the 
Investigator should report the event to the Sponsor. Grade 3 or Grade 4 SAEs 
considered related to study drug are followed until recovery to ≤ Grade 1. 
• The Investigator must follow all SAEs until resolution and record the date of 
resolution. Resolution of an event is defined as the return to pre-treatment status or 
stabilization of the condition with the expectation that it will remain chronic. 
Unresolved SAEs must be followed until: 
o The event resolves. 
o The event stabilizes. 
o The event returns to baseline, if a baseline value/status is available. 
o The event can be attributed to etiology other than the study drug or to 
factors unrelated to study conduct. 
o It becomes unlikely that any additional information can be obtained 
(patient or health care practitioner refusal to provide additional 
information, lost to follow-up after demonstration of due diligence with 
follow-up efforts). 
 
• Any event requiring hospitalization (or prolongation of hospitalization) that occurs 
during the study must be reported as a SAE, except hospitalizations for the 
following: 
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o A standard hospitalization for administration of study drug therapy will not 
be reported as a serious adverse event. 
o A procedure for protocol/disease-related investigations (e.g., surgery, scans, 
endoscopy, sampling for laboratory tests, bone marrow sampling, 
pharmacokinetic or biomarker blood sampling).  
o Hospitalizations not intended to treat an acute illness or AE (e.g., social 
reasons such as pending placement in long-term care or hospice facility). 
o Surgery or procedure planned before entry into the study (must be 
documented in the eCRF). 
• Any SAE of suspected transmission of an infectious agent via a medicinal product 
will be reported. 
 
Disease progression or events deemed related to disease progression resulting in 
hospitalization or death without other SAE criteria will be documented as an antitumor 
activity outcome, not reported as a SAE; they will be collected as efficacy endpoints. 
Conversely, SAEs should be reported if it is unclear if the event is due to PD. 
12.2.3 
Pregnancy  
All initial reports of pregnancy in female patient s or partners of male patient s must be 
reported to the sponsor on the Pregnancy Exposure Form (from the Study Procedures manual)  
within 24 hours of study site awareness. The reporting period is from consent through 120 
days after the last dose of study drug, or initiation of another anticancer therapy. Abnormal 
pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth, congenital anomalies, 
ectopic pregnancy) are considered SAEs, to be reported on the SAE Report Form by email, 
SAEReports@macrogenics.com, or by fax, (301) 354-3800. SAEs should be entered into the 
eCRFs within 5 calendar days of the site’s awareness. Patients becoming pregnant during the 
study must discontinue study drug.  
The Investigator must attempt to follow the pregnancy to term or termination in order to 
report the outcome and health status of the mother and child. The Investigator should discuss 
with and encourage the pregnant partner to allow collection of follow up information. The 
Pregnant Partner Consent Form must be signed prior to collecting follow-up information. 
Follow-up information will be collected for all live newborns at birth and 6 months after birth. 
Information will be collected to assess study drug effects on the newborn. If appropriate, 
follow-up will be extended. 
12.2.4 
Special Reporting Situations  
12.2.4.1 
Sponsor Notification of Specific AEs  
Specific AEs or groups of AEs will be followed as part of standard safety monitoring activities 
by the Sponsor. The Sponsor must be notified of these events regardless of seriousness 
(i.e., serious and nonserious AEs). Some AESIs must be reported immediately to 
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MacroGenics within 24 hours of the study site’s awareness of the event. A list of protocol-
specific AESIs, with reporting requirements (i.e., timeframe within which events are entered 
on the eCRF), are displayed in Table 5. 
Table 5 
Adverse Events of Special Interest                                                        
AESI 
Reporting Requirement 
Potential Hy’s Law: AST or ALT > 3 × ULN and total bilirubin > 2 
× ULN and without any alternate etiology 
Within 24 hours of the study site’s 
awareness of the event 
All IRR or CRS events 
For ≤ Grade 2 IRRs or CRS events: 
Within 10 days of the study site’s 
awareness of the event. 
For ≥ Grade 3 IRRs or CRS events: 
Within 24 hours of the study site’s 
awareness of the event 
All immune-related AEs including colitis, pneumonitis, myocarditis, 
hepatitis, dermatologic toxicity, nephritis, hypophysitis, and 
hypo/hyperthyroidism, which are considered immune-mediated 
events (see Section 7.2) 
For ≥ Grade 2 events:  
Within 24 hours of the study site’s 
awareness of the event 
 
12.2.4.2 
Overdose  
Overdose is any accidental administration of study drug ≥ 20% more than the assigned dose. 
In the event of an overdose, the patient should be closely monitored for potential AEs.  
If an event of clinical consequence occurs due to the overdose an AE and needs to be reported 
to MacroGenics within 24 hours of awareness. All AEs associated with an overdose should be 
recorded in the eCRF. 
12.2.4.3 
Product Quality Issues  
Any suspected transmission of an infectious agent via a medicinal product, or other product 
quality issue that results in an event of clinical consequence are considered AEs. The AE 
resulting from a product quality issue should be reported within 24 hours of awareness of the 
event. 
12.2.4.4 
Discontinuation of Study Therapy Due to an Adverse Event  
Any AE not related to disease progression that results in the discontinuation of the patient 
from study therapy must be reported to MacroGenics within 24 hours of the discontinuation. 
Follow up of the AE will continue until resolution or stabilization of the AE unless the patient 
withdraws consent for further follow up. 
 
 
 
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13 
PRODUCT QUALITY COMPLAINT HANDLING  
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, i.e., any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may 
have an impact on the safety and efficacy of the product. Timely, accurate, and complete 
reporting and analysis of PQC information from studies are crucial for the protection of 
patients, Investigators, and the Sponsor, and are mandated by regulatory agencies worldwide. 
The Sponsor has established procedures in conformity with regulatory requirements 
worldwide to ensure appropriate reporting of PQC information; all studies conducted by the 
sponsor or its affiliates will be conducted in accordance with those procedures. 
13.1 
Procedures  
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours 
after being made aware of the event. 
If the defect is combined with a SAE, the study-site personnel must report the PQC to the 
sponsor according to the SAE reporting timelines (refer to Section 12.2.2, Serious Adverse 
Events). A sample of the suspected product should be maintained for further investigation if 
requested by the sponsor. 
13.2 
Contacting Sponsor Regarding Product Quality  
The name(s) (and corresponding telephone numbers) of the individuals who should be 
contacted regarding product quality issues are listed on the Contact Information page(s), 
which will be provided as a separate document. 
 
 
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14 
STATISTICAL ANALYSIS  
This section outlines the statistical methodology and principles which will be used for data 
analysis in this study. A separate statistical analysis plan (SAP) and statistical programming 
plan (SPP) will further describe the details regarding statistical methods and will govern the 
analysis.  
14.1 
Determination of Sample Size  
The total sample size is planned to be approximately 80 patients, with approximately 50 and 
approximately 30 patients in the Retifanlimab and Tebotelimab Cohorts, respectively. 
Enrollment into the Retifanlimab and Tebotelimab Cohorts will occur independently in a non-
randomized fashion.  
The sample size for each cohort is primarily based on providing preliminary estimation of 
ORR. Table 6 provides 2-sided 95% confidence intervals (CI) for a number of potential 
responses.  
Table 6 
Response Rates and 95% Confidence Intervals                                   
Sample Size 
Number of Responses 
Response Rate (%) 
95% Confidence Interval 
(%) 
30 
2 
6.7 
0.8 – 22.1 
30 
3 
10.0 
2.1 – 26.5 
30 
4 
13.3 
3.8 – 30.7 
50 
10 
20.0 
10.0 – 33.7 
50 
14 
28.0 
16.2 – 42.5 
50 
16 
32.0 
19.5 – 46.7 
 
ORRs of 19% and 5% were observed in first-line SCCHN patients with CPS ≥ 1 and CPS < 1, 
respectively, in pembrolizumab monotherapy (Section 2.2). In the Retifanlimab Cohort, based 
on an exact binomial test, 50 patients will distinguish a favorable true ORR of 36% from an 
unfavorable rate of 19% with 91% power and a 1-sided type 1 error rate of 0.079. Thus, at 
least 14 responses out of 50 patients are to be achieved. In the Tebotelimab Cohort, 3 
responses out of 30 patients will have 80% confidence that the true ORR is > 5% (the lower 
limit of 1-sided 80% CI for the response rate is > 5%).  
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14.2 
Analysis Populations  
The study analyses will be performed on the following populations: 
• Safety Population: All patients who received at least one dose of any study drug. 
This population will be used for analyses of safety, PK, pharmacodynamics, and 
immunogenicity. It will also be used for summary of baseline data and analyses of 
PFS and OS. 
• Response Evaluable Population: All patients who received at least one dose of 
any study drug and had baseline radiographic tumor assessment. This population 
will be used for summary of tumor assessment data and analyses of responses. 
 
14.3 
Demographics and Baseline Characteristics  
Patient disposition, demographics, baseline characteristics, disease history, medical history, 
and prior cancer treatment will be summarized using descriptive statistics. 
14.4 
Study Drug Exposures and Concomitant Medications  
Study drug exposures and concomitant medications will be summarized by descriptive 
statistics. The summary of study drug exposure will include descriptive statistics as well as 
frequency counts for the number of doses or cycles received, the total dose actually 
administrated as well as the total dose intended, and the dose intensity which is calculated as 
percentage of total dose actually administrated divided by total dose intended during whole 
treatment period. 
14.5 
Pharmacokinetic/Pharmacodynamic Analysis  
14.5.1 
Pharmacokinetic Analysis  
Summary statistics will be tabulated for PK parameters by study drug. Population PK analyses 
may be conducted using data from this study alone or combined with data from other studies. 
Analysis will be conducted separately for enoblituzumab, retifanlimab, and tebotelimab. 
14.5.2 
Immunogenicity Analysis  
The proportion of patients who are negative for ADA at baseline and become positive in this 
assay, the proportion of patients who are negative at baseline and remain negative, and those 
who have positive ADA at baseline that increase or decrease in titer over the course of 
treatment will be summarized. Analysis will be conducted separately for enoblituzumab, 
retifanlimab, and tebotelimab. 
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14.5.3 
Pharmacodynamic Analysis  
Summary statistics for pharmacodynamic parameters, such as, but not limited to, those listed 
under in Section 10.2 and corresponding changes from baseline, will be summarized and/or 
may also be presented graphically. Possible associations between changes in 
pharmacodynamic measures of interest and enoblituzumab, retifanlimab, and tebotelimab 
dose and exposure may be explored. 
14.6 
Efficacy and Endpoint Analyses  
14.6.1 
Response Endpoints and Analyses  
The primary efficacy endpoint is the Investigator-assessed ORR per RECIST v1.1, defined as 
the proportion of patients in the response evaluable population who achieve the BOR of CR or 
PR (called responders) per RECIST v1.1. The BOR will be categorized as CR, PR, SD, PD, or 
NE. To be qualified as an objective response, CR and PR require confirmation at least 4 weeks 
after initial observation of such response, and SD requires an observation at least once after 6 
weeks. BOR will be evaluated from the start of study treatment. Number and percent of 
patients with their BOR will be summarized. The ORR and its 2-sided 95% exact binomial CI 
will be calculated for each cohort. 
DCR is defined as the percentage of response evaluable patients who experienced response of 
CR, PR, or SD for at least 3 months. The 2-sided 95% exact binomial CI of DCR will be 
calculated. 
14.6.2 
Analysis of Tumor Size Change Over Time  
The tumor size is defined as the sum of diameters of the target lesions. The tumor size change 
from baseline over time will be summarized and presented by spider plot. The best tumor size 
change from baseline will be presented by waterfall plot.  
14.6.3 
Time-to-Event Endpoints and Analyses  
The time-to-event efficacy endpoints include the Investigator-assessed PFS, DoR, and OS as 
defined below. 
Progression-free survival (PFS) will be defined as the time from the first dose date to the date 
of first documented progression or death from any cause, whichever occurs first. The 
documented progression is determined by objective assessment of disease per RECIST v1.1. 
For patients who are not known to be dead or progressed at the time of data cut-off for PFS 
analysis, the PFS will be censored at the date of the last tumor assessment. Specifically, the 
following censoring rules will be applied (Table 7).  
 
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Table 7 
 Censoring Rules for PFS  
Situation 
Date 
Outcome 
No baseline tumor assessments  
First dose date 
Censored 
Death prior to first scheduled 
tumor assessment 
Date of death 
Progressed 
No post-baseline tumor 
assessments in absence of death 
prior to first scheduled tumor 
assessment 
First dose date 
Censored 
Documented progression 
Date of progression 
Progressed 
Initiation of alternative anti-
cancer treatments in absence of 
documented progression 
Date of last tumor assessment prior 
to initiation of such treatment 
Censored 
Death or documented progression 
immediately after missing 2 or 
more consecutive scheduled 
tumor assessments 
Date of last tumor assessment prior 
to missed assessments 
Censored 
 
Duration of Response (DoR) is defined as the time from the date of initial response (CR or 
PR) to the date of first documented progression or death from any cause, whichever occurs 
first. The DoR is calculated only for the responders. For responders who are not known to be 
dead or progressed at the time of data cut-off for DoR analysis, the DoR will be censored at 
the date of the last tumor assessment. Specifically, the last 3 situations described in Table 7 
will be applied. The DoR analyses will be performed only if there are enough responders to 
render the analyses meaningful. 
Overall survival (OS) is defined as the time from the first dose date to the date of death from 
any cause. For patients who are not known to be dead at the time of data cut-off for 
OS analysis, the OS will be censored at the time they are last known to be alive. 
The Kaplan-Meier method will be applied to estimate PFS, DoR and OS curves, their median 
times, PFS rates at 6 and 12 months, and OS rates 12 and 24 months, respectively. The 
method of Brookmeyer and Crowley (15) will be used to construct 95% CI for median time of 
each time-to-event endpoint. The 95% CIs for PFS and OS rates at each time point of interest 
will be calculated by normal approximation after log(-log) transformation. 
The above PFS and DoR analyses will be performed with the documented progression 
determined by RECIST v1.1. 
14.7 
Safety Endpoints and Analyses  
14.7.1 
Adverse Events  
Only TEAEs will be summarized. The following AEs will be provided in summary tables as 
well as displayed in listings:  
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• All AEs  
• AEs with CTCAE severity ≥ Grade 3  
• Study drug related AEs 
• Study drug related AEs with CTCAE severity ≥ Grade 3  
• SAEs  
• Study drug related SAEs 
• AEs that resulted in discontinuation of study treatment 
• AEs that led to interruption of individual study drug 
• Fatal AEs 
• AEs of special interest 
 
All of these tables will display the number and percent of patients that experience the given 
event and will display events by MedDRA System Organ Class (SOC) and Preferred Term 
(PT). Events will be displayed alphabetically for SOC and in descending order of PT 
incidence within each SOC. An overall summary of AEs will display the number and percent 
of patients who experience at least one event of each of the above types. 
14.7.2 
Laboratory Values  
Summaries of laboratory values will display descriptive statistics for numerically quantified 
labs. Summaries will be grouped by lab panel (hematology, blood chemistry, and urinalysis) 
and will be displayed by visit for each lab parameter. Shift tables may be produced.  
14.7.3 
Other Safety Endpoints  
ECGs will be collected and analyzed for evidence of cardiac toxicity, especially prolongation 
of QT interval. Vital signs will be summarized with descriptive statistics at each visit and time 
point where they are collected. Shift tables may be performed. 
14.8 
Other Assessments or Analyses  
Additional analyses, if any, will be defined in the SAP. 
 
 
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15 
QUALITY CONTROL AND ASSURANCE  
Quality review activities will be undertaken to ensure accurate, complete, and reliable data. 
MacroGenics and/or its representatives will do the following: 
• Provide instructional material to the study sites, as appropriate. 
• Sponsor a start-up training session (Investigator Meeting or Study Initiation Visit) 
to instruct the Investigators and study coordinators. This session will give 
instruction on the protocol, the completion of the eCRFs, and study procedures. 
• Make periodic visits to the study site to monitor protocol compliance and general 
Good Clinical Practice (GCP) compliance. 
• Be available for consultation and stay in contact with the study site personnel by 
mail, e-mail, telephone, and/or fax. 
• Review and evaluate eCRF data and use standard computer checks to detect and 
query errors in data collection. 
• Conduct a quality review of the database. 
 
15.1 
Monitoring, Auditing and Inspections  
To ensure the safety of patients in the study, compliance with applicable regulations, and 
ensure accurate, complete, and reliable data, the Investigator will keep records of laboratory 
tests, clinical notes, and patient medical records in the patient files as source documents for 
the study. 
MacroGenics or its designee will monitor the study on a regular basis throughout the study 
period according to the study Monitoring Plan. The Investigator will allocate adequate time 
for such monitoring activities. The study monitor periodically will conduct a cross-check of 
the patient data recorded on eCRFs against source documents at the study site. The 
Investigator will also ensure that the monitor is given access to all the above noted study-
related documents, source documents (regardless of media) and study-related facilities (e.g., 
investigational pharmacy, etc.), and has adequate space to conduct the monitoring visit. 
Queries may be raised if any datum is unclear or contradictory. The Investigator and study site 
personnel must address all queries in a timely manner. 
Participation as an Investigator in this study implies acceptance of the potential for inspection 
by the study Sponsor/Representatives, US or non-US government regulatory authorities, 
IRB/IEC and applicable compliance and quality assurance offices. The Investigator will 
permit study-related audits and inspections and will provide access to 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.).  
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15.2 
Data Collection and Management  
Site personnel record all data for each patient through electronic case report forms (eCRFs) 
using the Medidata RAVE™, an Electronic Data Capture (EDC) system provided and 
approved by the Sponsor. Refer to the Study Procedures Manual for additional information 
regarding eCRFs, if any that will be used as source documentation. Study sites must complete 
eCRFs for each patient in a timely manner shortly after each patient visit. The Investigator 
must sign the Investigator’s Statement in each patients eCRF. 
The EDC system automatically generates queries resulting from the computer checks 
embedded into the system to ensure data accuracy, quality, consistency, and completeness. 
Manual queries resulting from review by monitors, medical coders, and Data Management 
staff are also generated from within the EDC system. Study sites are expected to resolve the 
queries and correct the entered data accordingly. Every change to data is captured in the EDC 
system audit trail. Adverse events are coded using MedDRA, and concomitant medications 
are coded using the WHO Drug Dictionary. Upon completion of the study, or after reaching a 
pre-specified point in the study, Data Management will lock the database and generate the 
SAS datasets necessary for analysis and reporting. Each study site will receive the eCRFs for 
each of their patients.  
 
 
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16 
ADMINISTRATIVE CONSIDERATIONS  
16.1 
Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) Approval  
The study protocol, any related documents, and patient-facing materials will be submitted to 
the IRB/IEC for review and approval. Written approval of the study protocol and the informed 
consent forms (ICFs) will be in the possession of the Investigator and the Sponsor before the 
study drug is shipped to the Investigator’s site. This approval must include the date of review, 
the protocol title and/or study number and version number, and ICF version number or date. A 
stamped version of the IRB-approved consent is acceptable. If the IRB/IEC or institution uses 
its own unique number for the protocol instead of the Sponsor’s number, that unique number 
should be noted on the approval statement. The Investigator should provide the Sponsor with 
a statement of compliance from the IRB/IEC indicating compliance with the applicable 
regulations in the region and ICH. 
Protocol modifications or changes may not be initiated without approval from the Sponsor and 
prior written IRB/IEC approval (when required), except when necessary to eliminate 
immediate hazards to the patients. Such modifications will be submitted to the IRB/IEC; and 
written verification that the modification was submitted should be obtained. The Investigator 
must submit all changes and updates to required documents to the IRB/IEC. 
16.2 
Ethical Conduct of the Study  
The investigational study will be conducted according to the Protection of Human Subjects 
(21 CFR [Code of Federal Regulations] 50), Institutional Review Boards (21 CFR 56), 
Obligations of Clinical Investigators (21 CFR 312.60 − 312.69), the current ICH Guideline for 
Good Clinical Practice (ICH E6), and all other applicable regulations. 
16.3 
Patient Information and Consent  
The Investigator will obtain, document and retain IRB/IEC-approved written informed 
consent from the patient, as specified in Section 9.1. Where required, the Investigator will use 
an appropriately translated and IRB/IEC-approved version. The Sponsor reserves the right to 
delay initiation of the study at a site where ICFs do not meet the standards of applicable local 
regulations or ICH E6. 
Information should be given to the patient in both oral and written form, and patients must be 
given ample opportunity to inquire about details of the study. The ICF must be signed and 
dated by the patient, and by the person who conducted the discussion of the informed consent.  
16.4 
Patient Confidentiality  
All laboratory specimens, evaluation forms, reports, and other records will be identified by a 
coded number. Clinical information will not be released without written permission of the 
patient, or the patient’s legally authorized representation, except as necessary for monitoring 
by the relevant regulatory authorities, the Sponsor, or the Sponsor’s representative. The 
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Investigator must comply with all local applicable privacy regulations regarding the protection 
of patient data.  
16.5 
Source Documents  
Source data in a clinical study are the original records or certified copies where clinical 
observations are first recorded, which may include, but are not limited to, the patient’s 
medical file, original laboratory reports, histology, and pathology reports (as applicable). The 
Investigator is responsible for maintaining adequate and accurate medical records from which 
accurate information will be entered into the eCRFs 
16.6 
Retention of Data  
All essential documents, including eCRFs, source documents (regardless of media), and 
signed ICFs, should be retained by the Investigator, per the guidance in ICH E6 or other 
regulatory retention requirement. There may be other circumstances for which MacroGenics is 
required to maintain study records for longer periods; therefore, MacroGenics should be 
contacted before study records are removed from the control of the study site for any reason. 
The Investigator must obtain written permission from MacroGenics prior to destruction of 
study documents. 
16.7 
Sample Retention and Further Testing  
Samples acquired for protocol-specified assays are retained for  
• at least 1 year following the end of the study, and may be retained for  
• up to 2 years after last approval of a marketing application in an ICH region or  
• until there are no pending or contemplated marketing applications in an ICH region 
or  
• until at least 2 years have elapsed since formal discontinuation of clinical 
development of the investigational product.  
 
If the patient consents, or the patient’s legal representative consents, to the use of their study 
samples for non-study research purposes, these samples may also be used for exploratory 
testing (including assay development) and may be retained up to 15 years from the end of 
study. 
16.8 
Financial Disclosure  
The Investigator and Sub-Investigators will be required to disclose in writing any applicable 
financial arrangement as defined in US regulation. The Principal Investigator’s disclosure will 
be signed and dated prior to participating in the study. 
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The information, as defined in 21 CFR 54, will be collected about the Investigators, their 
spouse and each dependent child. Investigators must update the Sponsor with any changes in 
reported information up to 1 year following the end of the study. 
In accordance with Securities and Exchange Commission regulation (17 CFR 229.404), 
Investigators and Sub-Investigators must disclose if they are employees of MacroGenics, or if 
an immediate family member of a MacroGenics employee, officer, or director. 
16.9 
Publication and Disclosure Policy  
Data collected in this clinical study belong to the study Sponsor. The publication terms 
regarding use of the study data will be noted in the Clinical Trial Agreement. This includes 
authorship: scheduling and prioritizing analyses for reports, publications, and presentations; 
and developing a review and approval process. 
16.10 
Discontinuation of the Study or Study Sites  
Site participation may be discontinued by MacroGenics, the Investigator, a regulatory 
authority, or an IRB/IEC. The study may be discontinued by a regulatory authority or at the 
discretion of the Sponsor. 
16.11 
Identification of the Coordinating Principal Investigator  
A Coordinating Principal Investigator will be appointed by the Sponsor Medical Monitor prior 
to the end of the study. 
As part of his or her responsibilities, the Coordinating Principal Investigator will review the 
final clinical study report (CSR). Agreement with the final CSR will be documented by the 
dated signature of the Coordinating Principal Investigator. 
 
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17 
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Appendix 1 
Time and Events Schedule  
EVALUATION/ 
PROCEDURE 
Screening 
D (-28 to -1) 
Cycle 1 
Subsequent Cycles  
 
EOTV b 
Follow-
Up 
D1 
D2 
D3 
D8 
(± 1d) 
D15 
(± 1d) 
D1  
(± 3d) a 
End of 
Cycle 
Enoblituzumab +  
retifanlimab or tebotelimab 
 
X 
In clinic visit for 
PK/ADA/biomarker 
assessments only 
X 
 
 
 
Informed Consent (no time constraint) 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical/Cancer History 
X 
 
 
 
 
 
Tumor biopsy c 
X 
 
 
X 
 
 
Archival tumor specimen (no time 
constraint) c 
X 
 
 
 
 
 
HPV p16 Status (no time constraint) d 
X 
 
 
 
 
 
Enrollment  
X 
 
 
 
 
 
Physical Examination e 
X 
X 
X 
 
X 
 
Height 
X 
 
 
 
 
 
Weight 
X 
X 
X 
 
X 
 
ECOG Performance Status 
X 
X 
X 
 
X 
 
ECG (12-lead) f 
X 
X 
 
 
 
 
Vital Signs g 
X 
X 
X 
 
X 
 
Clinical Laboratory Tests h 
X 
X 
X 
 
X 
 
Coagulation i 
X 
X 
 
 
 
 
Urinalysis j 
X 
X 
X 
 
 
 
Pregnancy Test k 
X 
X 
X 
 
X 
 
Tumor Assessment l 
X 
 
 
X 
X 
X 
Pharmacokinetics  
See Appendix 3 
ADA 
See Appendix 3 
PBMCs, Serum, and Plasma for PD 
and Exploratory Biomarkers 
See Appendix 3 
Concomitant Medications 
Continuous 
 
Concomitant Procedures 
Continuous 
 
Adverse Events 
Continuous 
 
Survival  
 
X m 
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EVALUATION/ 
PROCEDURE 
Screening 
D (-28 to -1) 
Cycle 1 
Subsequent Cycles  
 
EOTV b 
Follow-
Up 
D1 
D2 
D3 
D8 
(± 1d) 
D15 
(± 1d) 
D1  
(± 3d) a 
End of 
Cycle 
a 
A cycle is 21 days ± 3 days from the previous dosing day. There should be at least 18 days between administrations. 
b 
The EOTV, if conducted, should be performed within 30 days after the patient has met study treatment discontinuation criteria 
specified in Section 4.4, and before initiation of any subsequent anticancer therapies. 
c 
All patients enrolled in this study must have an identified formalin-fixed, FFPE tumor specimen for assessment of PD-L1 status 
prior to study entry. If no archival specimen is available, tissue from a contemporaneous core or excisional biopsy is acceptable 
(fine needle aspirate is not sufficient). Patients must also be willing to provide consent for a baseline and on-treatment tumor 
biopsy (end of Cycle 2), if tumor lesions are accessible for biopsy with acceptable risk in the judgment of the Investigator and 
after discussion with the Sponsor. This requirement will expire after an adequate number of samples have been collected, as 
determined by the Sponsor. Submission of an archival sample is highly encouraged but not mandatory for patients that provide a 
fresh biopsy sample. Baseline biopsy to be obtained after confirmation of eligibility and before Cycle 1 Day 1. End of Cycle 2 
biopsy to be obtained between 20 and 34 days after Cycle 2 dosing, and preferably before Cycle 3 Day 1 dosing. Cycle 3 Day 1 
dosing should not be delayed beyond the window of 21 ± 3 days from the previous dosing day, unless there is another reason to 
delay dosing per Section 4.3.1. 
d 
See Section 9.9.2 for details. 
e 
Full physical examination at screening and EOTV, directed physical examination at other time points. 
f 
Cycle 1 Day 1 ECG is conducted prior to the first infusion of any study treatment and at the end (± 15 minutes) of the last study 
treatment infusion (retifanlimab, tebotelimab, or enoblituzumab, as applicable). Subsequent ECGs are obtained as clinically 
indicated. Screening and Cycle 1 Day 1 ECGs are performed in triplicate. 
g 
Vital signs are obtained within 15 minutes before the first infusion and within 10 minutes after the end of infusion of each study 
treatment (retifanlimab, tebotelimab, or enoblituzumab, as applicable), and as clinically indicated. 
h 
Includes hematology, serum chemistry, endocrine tests, and cardiovascular disease markers (see Appendix 2). Laboratory 
assessment samples may be collected up to 3 days in advance of Day 1 of all cycles. If the screening samples are collected within 
3 days before Cycle 1 Day 1 these laboratory assessments do not need to be repeated on Cycle 1 Day 1. 
i 
Coagulation tests (see Appendix 2) performed at screening and Cycle 1 Day 1 (with a window of -3 days in relation to Day 1), 
then as clinically indicated. 
j 
Urinalysis (see Appendix 2) performed at screening, Day 1 of each cycle (with a window of -3 days in relation to the beginning 
of each cycle), and as clinically indicated. 
k 
Serum or urine pregnancy test for women of child-bearing potential (with a window of -3 days in relation to the beginning of each 
cycle). 
l 
Tumor assessments are performed at the end of Cycle 2 (with a window of -3 days in relation to the beginning of the next cycle), 
and at the end of every 3 cycles (Cycles 5, 8, 11, etc.) thereafter (with a window of -7 days in relation to the beginning of the next 
applicable cycle) until treatment discontinuation. Patients who discontinue from study treatment should be assessed every 12 
weeks (± 1 week) after the EOTV (or, if no EOTV is conducted, after the decision to end treatment) until evidence of PD, 
initiation of another anticancer therapy, withdrawal of consent, LTFU, death, or 36 weeks after the last patient’s EOTV. EOTV 
tumor assessment does not need to be conducted if prior tumor assessment was performed within 28 days of the EOTV and results 
are available for RECIST assessments. Patients who discontinue study treatment due to AEs are followed by radiographic 
evaluation until PD by RECIST v1.1, if the patients’ condition allows. If not, patients will be followed for OS without 
radiographic evaluation upon the discussion with the Sponsor’s Medical Monitor. 
m 
Survival follow-up occurs every 12 weeks (± 1 week) after the EOTV (or, if no EOTV is conducted, after the decision to end 
treatment) until withdrawal of consent, LTFU, death, or 36 weeks after the last patient’s EOTV. 
 
 
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Appendix 2 
Clinical Laboratory Tests  
Pregnancy test: 
Blood or Urine Human chorionic gonadotropin (hCG) 
 
Hematology: 
Hemoglobin  
Platelet count 
White blood cell count 
Absolute neutrophils, lymphocytes, eosinophils 
 
Serum chemistry: 
Albumin  
Alkaline phosphatase 
Alanine aminotransferase  
Amylase 
Aspartate aminotransferase 
Bicarbonate 
 
Bilirubin (Total and Direct) 
Blood urea nitrogen 
Calcium 
Chloride  
Creatinine 
Gamma glutamyl transferase 
Glucose 
Lipase 
Magnesium 
Phosphate 
Potassium 
Sodium 
Uric Acid 
Coagulation: 
Prothrombin time (PT) 
Activated Partial Thromboplastin Time (aPTT) 
INR 
Fibrinogen 
 
Endocrine tests: 
Free thyroxine (T4) 
Thyroid-stimulating hormone  
 
Urinalysis: 
Protein 
Occult blood 
 
Cardiovascular disease markers 
Creatine phosphokinase 
N-terminal pro b-type natriuretic peptide 
Troponins 
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Appendix 3 
Pharmacokinetics, Immunogenicity, and Pharmacodynamic Biomarkers Schedule  
Cycle 
Day 
Time Points 
Windows PK a 
ADA a Cytokines 
PD 
Biomarker a,b 
Serum 
Biomarker a,b 
Fc Gamma 
Receptor 
Genotyping 
Cycle 1 
1 
Pre retifanlimab or tebotelimab infusion 
n/a 
X 
X 
X 
X 
X 
X 
End of retifanlimab or tebotelimab infusion 
+15 min 
X 
 
 
 
 
 
Pre enoblituzumab infusion c 
n/a 
X 
 
 
 
 
 
End of enoblituzumab infusion 
+15 min 
X 
 
X 
X  
X 
 
4 hours after end of enoblituzumab infusion 
±10 min 
X 
 
X 
 
X 
 
2 
No specific time 
n/a 
X 
 
X 
X 
X 
 
3 
No specific time 
n/a 
X 
 
X 
X 
X 
 
8 
No specific time 
n/a 
X 
 
X 
X 
X 
 
15 
No specific time 
n/a 
X 
 
X 
X 
X 
 
Cycle 2 
Odd Cycles ≥3 
1 
Pre retifanlimab or tebotelimab infusion 
n/a 
X 
X 
X 
X 
X 
 
End of retifanlimab or tebotelimab infusion 
+15 min 
X 
 
 
 
 
 
Pre enoblituzumab infusion c 
n/a 
X 
 
 
 
 
 
End of enoblituzumab infusion 
+15 min 
X 
 
X 
X  
X 
 
Cycle 4 
Cycle 6 
1 
Pre retifanlimab or tebotelimab infusion 
n/a 
X 
X 
 
X 
X 
 
End of retifanlimab or tebotelimab infusion 
+15 min 
X 
 
 
 
 
 
Pre enoblituzumab infusion c 
n/a 
X 
 
 
 
 
 
End of enoblituzumab infusion 
+15 min 
X 
 
 
 
 
 
IRR-CRS d 
n/a 
No specific time 
n/a 
X 
 
X 
 
 
 
End of Treatment e n/a 
No specific time 
n/a 
X 
X 
 
X 
X 
 
Follow-up 
n/a 
12 weeks after end of treatment f 
n/a 
X  
X 
 
 
 
 
n/a 
24 weeks after end of treatment f 
n/a 
X  
X 
 
 
 
 
a 
Do not collect PK, ADA, or biomarker samples from the infusion port. Blood samples will be collected from the arm contralateral to the site of IV infusion. If an indwelling 
catheter is used, the fluid in the catheter will be removed and discarded prior to the collection of blood sample for PK, ADA, or biomarker assessments. Obtain PK samples as 
follows: Pre-infusion: Before start of first infusion on visit day (dosing day). When collecting multiple samples, collect the PK sample first. 
b 
PD biomarker and serum biomarker samples to be collected only up to and including Cycle 6. 
c 
Only to be collected if enoblituzumab is not administered on the same day as retifanlimab or tebotelimab. 
d 
Additional samples may be obtained selectively at additional time points in patients who experience signs and symptoms of infusion related reaction or cytokine release 
syndrome. 
e 
Sample to be collected at EOTV or, if no EOTV is conducted, when the decision is made to end treatment. 
f 
For patients with evidence of ADA from any prior visit. End of treatment refers to EOTV or, if no EOTV is conducted, when the decision is made to end treatment. 
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Cycle 
Day 
Time Points 
Windows PK a 
ADA a Cytokines 
PD 
Biomarker a,b 
Serum 
Biomarker a,b 
Fc Gamma 
Receptor 
Genotyping 
Notes:  
• 
Actual start and end of infusion times, PK, and ADA sample collection times will be recorded on the CRFs.  
• 
Pre-infusion samples should be collected before the start of infusion on visit day (dosing day). 
• 
End of infusion (EOI) is defined in the Pharmacy Manual.  
• 
Samples required at EOI can be drawn up to 15 minutes after the infusion is complete. For each study drug, up to 10 additional minutes of infusion time are permitted to 
allow for flushing the line: 
o 
Retifanlimab infusion duration = 60 minutes. 
o 
Tebotelimab infusion duration = 60 minutes.  
o 
Enoblituzumab infusion duration = 120 minutes. 
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Appendix 4 
RECIST 1.1 Guidelines  
Adapted from Eisenhauer 2009 (32).  
All patients with be required to have at least 1 measurable lesion to be considered as having 
measurable disease at baseline for the determination of eligibility for this study. Measurable 
lesions are defined below. 
1 
Measurability of Tumor at Baseline 
1.1 
Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
1.1.1 
Measurable 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
• 10 mm by CT scan (CT scan slice thickness no greater than 5 mm). 
• 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable). 
• 20 mm by chest X-ray. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed. See also notes below on ‘Baseline documentation of target and non-target lesions’ 
for information on lymph node measurement. 
1.1.2 
Non-measurable 
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with ≥ 10 to < 15 mm short axis) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
1.1.3 
Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
Bone lesions: 
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• Bone scan, PET scan or plain films are not considered adequate imaging techniques 
to measure bone lesions. However, these techniques can be used to confirm the 
presence or disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT 
or MRI can be considered as measurable lesions if the soft tissue component meets 
the definition of measurability described above. 
• Blastic bone lesions are non-measurable. 
Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
• ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred for 
selection as target lesions. 
Lesions with prior local treatment: 
• Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are not considered measurable unless there has been 
demonstrated progression in the lesion prior to study enrollment. 
1.2 
Specifications by methods of measurements 
1.2.1 
Measurement of lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
1.2.2 
Method of assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesions(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
and ≥ 10 mm diameter as assessed using calipers (e.g. skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken since it is more objective and may also be reviewed at 
the end of the study. 
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Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. 
MRI is also acceptable in certain situations (e.g., for body scans). 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of 
CT in selected instances. 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised. 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. 
2 
Tumor Response Evaluation 
2.1 
Assessment of overall tumor burden and measurable disease 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. Only patients with 
measurable disease at baseline should be included. Measurable disease is defined by the presence 
of at least one measurable lesion (as detailed above). 
2.2 
Baseline documentation of ‘target’ and ‘non-target’ lesions 
Where more than one measurable lesion is present at baseline all lesions up to a maximum of 
five lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. For 
example, in instances where patients have only one or two organ sites involved, a maximum of 
two and four lesions respectively will be recorded). Target lesions should be selected on the basis 
of their size (lesions with the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated measurements. It may be 
the case that, on occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesions which can be measured reproducibly should be 
selected. 
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Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. As noted above, pathological nodes which are 
defined as measurable and may be identified as target lesions must meet criterion of a short axis 
of ≥ 15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. 
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as two dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal or coronal). The smaller of these measures is the short axis. For 
example, an abdominal node which is reported as being 20 mm x30 mm has a short axis of 20 
mm and qualifies as a malignant, measurable node. In this example, 20 mm should be recorded 
as the node measurement. All other pathological nodes (those with short axis ≥ 10 mm but 
< 15 mm) should be considered non-target lesions. Nodes that have a short axis < 10 mm are 
considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression. 
In addition, it is possible to record multiple non-target lesions involving the same organ as a 
single item on the case record form (e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple 
liver metastases’). 
2.3 
Response criteria 
This section provides the definitions of the criteria used to determine objective tumor response 
for target lesions. 
2.3.1 
Evaluation of target lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm. 
Partial Response (PR): at least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters. 
Progressive Disease (PD): at least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression). 
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Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
2.3.2 
Special notes on the assessment of target lesions 
Lymph nodes. Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to below 10 mm on study. This means that when lymph nodes are 
included as target lesions, the ‘sum’ of lesions may not be zero even if complete response criteria 
are met, since a normal lymph node is defined as having a short axis of < 10 mm. In order to 
qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD and PD, the actual 
short axis measurement of the nodes is to be included in the sum of target lesions. 
Target lesions that become ‘too small to measure’. While on study, all lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g. 2 mm). However, sometimes lesions or lymph nodes 
which are recorded as target lesions at baseline become so faint on CT scan that the radiologist 
may not feel comfortable assigning an exact measure and may report them as being ‘too small to 
measure’. When this occurs it is important that a value be recorded on the case report form. If it 
is the opinion of the radiologist that the lesion has likely disappeared, the measurement should be 
recorded as 0 mm. If the lesion is believed to be present and is faintly seen but too small to 
measure, a default value of 5 mm should be assigned (Note: It is less likely that this rule will be 
used for lymph nodes since they usually have a definable size when normal and are frequently 
surrounded by fat such as in the retroperitoneum; however, if a lymph node is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should be assigned 
in this circumstance as well). This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness). The measurement of these lesions is 
potentially non-reproducible, therefore providing this default value will prevent false responses 
or progressions based upon measurement error. However, if the radiologist is able to provide an 
actual measure, that should be recorded, even if it is below 5 mm. 
Lesions that split or coalesce on treatment. When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesions. If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the ‘coalesced lesion’. 
2.3.3 
Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they 
need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol. 
Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be non-
pathological in size (< 10 mm short axis). 
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Non-CR/Non-PD: Persistence of one or more non-target lesions(s). 
Progressive Disease (PD): Unequivocal progression (see comments below) of existing non-
target lesions. (Note: the appearance of one or more new lesions is also considered progression). 
2.3.4 
Special notes on assessment of progression of non-target disease 
The concept of progression of non-target disease requires additional explanation as follows: 
When a patient also has measurable disease. In this setting, to achieve ‘unequivocal progression; 
on the basis of the non-target disease, there must be an overall level of substantial worsening in 
non-target disease such that, even in presence of SD or PR in target disease, the overall tumor 
burden has increased sufficiently to merit discontinuation of therapy. A modest ‘increase’ in the 
size of one or more non-target lesions is usually not sufficient to quality for unequivocal 
progression status. The designation of overall progression solely on the basis of change in non-
target disease in the face of SD or PR of target disease will therefore be extremely rare. 
When the patient has only non-measurable disease. The same general concepts apply here as 
noted above, however, in this instance there is no measurable disease assessment to factor into 
the interpretation of an increase in non-measurable disease burden. Because worsening in non-
target disease cannot be easily quantified (by definition: if all lesions are truly non-measurable) a 
useful test that can be applied when assessing patients for unequivocal progression is to consider 
if the increase in overall disease burden based on the change in non-measurable disease is 
comparable in magnitude to the increase that would be required to declare PD for measurable 
disease: i.e. an increase in tumor burden representing an additional 73% increase in ‘volume’ 
(which is equivalent to a 20% increase diameter in a measurable lesion). Examples include an 
increase in a pleural effusion from ‘trace’ to ‘large’, an increase in lymphangitic disease from 
localized to widespread, or may be described in protocols as ‘sufficient to require a change in 
therapy’. If ‘unequivocal progression’ is seen, the patient should be considered to have had 
overall PD at that point. While it would be ideal to have objective criteria to apply to non-
measurable disease, the very nature of that disease makes it impossible to do so; therefore, the 
increase must be substantial. 
2.3.5 
New Lesions 
The appearance of new malignant lesions denotes disease progression. There are no specific 
criteria for the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal: i.e. not attributable to differences in scanning technique, change in 
imaging modality or findings thought to represent something other than tumor (for example, 
some ‘new’ bone lesions may be simply healing or flare of pre-existing lesions). This is 
particularly important when the patient’s baseline lesions show partial or complete response. For 
example, necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, 
which it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this is 
the patient who has visceral disease at baseline and while on study has a CT or MRI brain 
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ordered which reveals metastases. The patient’s brain metastases are considered to be evidence 
of PD even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-
up evaluation will clarify if it represents truly new disease. If repeat scans confirm there is 
definitely a new lesion, then progression should be declared using the date of the initial scan. 
2.4 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the study treatment until 
the end of treatment taking into account any requirement for confirmation. The patient’s best 
overall response assignment will depend on the findings of both target and non-target disease and 
will also take into consideration the appearance of new lesions. 
2.4.1 
Time point response 
It is assumed that at each protocol specified time point, a response assessment occurs. Table A-1 
on the next page provides a summary of the overall response status calculation at each time point 
for patients who have measurable disease at baseline. 
2.4.2 
Missing assessments and inevaluable designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. If only a subset of lesion measurements is made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not change 
the assigned time point response. This would be most likely to happen in the case of PD. For 
example, if a patient had a baseline sum of 50 mm with three measured lesions and at follow-up 
only two lesions were assessed, but those gave a sum of 80 mm, the patient will have achieved 
PD status, regardless of the contribution of the missing lesion. 
2.4.3 
Best overall response: all time points 
The best overall response is determined once all the data for the patient is known. 
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Table A-1 
Time point response: patients with target (+/- non-target) disease        
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = 
inevaluable. 
 
Best response determination in trials where confirmation of complete or partial response IS 
required: Complete or partial responses may be claimed only if the objective response is 
confirmed on a follow-up scan obtained no less than 4 weeks after the initial scan demonstrating 
an objective response. In this circumstance, the best overall response can be interpreted as in 
Table A-2. 
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Table A-2 
Best overall response when confirmation of CR and PR required         
Overall response 
First time point 
Overall response 
Subsequent time point 
BEST overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PR a 
CR 
SD 
SD  
CR 
PD 
SD  
CR 
NE 
SD  
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise, NE 
NE 
NE 
NE 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = 
inevaluable. 
a. 
If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting 
PR criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after 
CR). Best response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ 
may be claimed when subsequent scans suggest small lesions were likely still present and in fact the patient 
had PR, not CR at the first time point. Under these circumstances, the original CR should be changed to PR 
and the best response is PR. 
 
Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ 
size (< 10 mm), they may still have a measurement reported on scans This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes. As noted earlier, this means that patients with CR may not 
have a total sum of ‘zero’ on the case report form (CRF). 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration”. Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy. The objective response status of 
such patients is to be determined by evaluation of target and non-target disease as shown in 
Table A-1 and Table A-2. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at 
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the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 
2.5 
Confirmation/Duration of response 
2.5.1 
Confirmation 
Objective responses should be confirmed by CT and/or MRI scans obtained no less than 4 weeks 
after the original scan. 
2.5.2 
Duration of overall response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded on study). The duration of overall complete response is measured from the time 
measurement criteria are first met for CR until the first date that recurrent disease is objectively 
documented. 
2.5.3 
Duration of stable disease 
Stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest sum on study (if the baseline sum is the smallest, this is the 
reference for calculation of PD). 
 
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Appendix 5 
Principal Investigator’s Agreement  
Study Title: 
A Phase 2 Open-Label Trial to Evaluate Enoblituzumab in 
Combination with Retifanlimab or Tebotelimab in the First-Line 
Treatment of Patients with Recurrent or Metastatic Squamous Cell 
Carcinoma of the Head and Neck 
Study Number: 
CP-MGA271-06 
 
I have read the protocol described above. 
I have fully discussed the objectives of this study and the contents of this protocol with the 
Sponsor’s representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution of the ethical review of the study, without 
written authorization from MacroGenics, Inc. It is, however, permissible to provide information 
to a patient in order to obtain consent. 
I agree to conduct this trial according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with ICH guidelines on GCP and with the applicable regulatory requirements. 
I understand that the Sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study, I will communicate my intention 
immediately in writing to the Sponsor. 
Signed: 
 
 
 
 
 
 
 
Date:  
 
 
 
 
 
 
 
Name (printed): 
 
 
 
 
 
 
 
 
 
 
 
 
Title:  
 
 
 
 
 
 
 
 
 
 
 
 
 
Affiliation: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Address: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phone number: 
 
 
 
 
 
 
 
 
 
 
 
 
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CP-MGA271-06 Protocol Amendment 1 (16-Dec-2020)
This is the electronic signature page for the above referenced document.
User Task: eSignatories Approval
roval (Intended or Designee)
17-Dec-2020 16:34:09 GMT+0000
User Task: eSignatories Approval
Data Management/Statistics Approval
(Intended or Designee)
17-Dec-2020 16:35:43 GMT+0000
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