A Phase 2/3 Trial to Evaluate Margetuximab in Combination With INCMGA00012 and Chemotherapy or MGD013 and Chemotherapy in Patients With Metastatic or Locally Advanced, Treatment-naïve, HER2-Positive Gastric or Gastroesophageal Junction Cancer
Phase: PHASE2
Conditions: Gastric Cancer, Gastroesophageal Junction Cancer, HER2-positive Gastric Cancer
Sponsor: MacroGenics

Margetuximab, INCMGA00012, MGD013
MacroGenics, Inc.
Clinical Trial Protocol: CP-MGAH22-06
Amendment 5, 06 June 2022
CLINICAL STUDY PROTOCOL: CP-MGAH22-06
PROTOCOL AMENDMENT 5 
Study Title:
A Phase 2/3 Trial to Evaluate Margetuximab in Combination with 
INCMGA00012 and Chemotherapy or MGD013 and 
Chemotherapy in Patients with Metastatic or Locally Advanced, 
Treatment-naïve, HER2-Positive Gastric or Gastroesophageal 
Junction Cancer
Study Number:
CP-MGAH22-06
Study Phase:
Phase 2/3
Product Name:
Margetuximab
Product Number:
INCMGA00012 (also known as MGA012 or retifanlimab), 
MGD013 (also known as tebotelimab)
IND Number:
EudraCT Number:
Indication:
Treatment-naïve (metastatic or locally advanced) HER2-positive 
gastric cancer or gastroesophageal junction cancer
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 contains proprietary information of MacroGenics, Inc. and is provided in 
confidence to the Recipient. The information may be used by the Recipient solely for the 
purposes authorized in writing by MacroGenics, Inc, or to the extent required by law. Any 
other use, viewing or disclosure of such information, in whole or in part, is strictly 
prohibited.
Confidential
Page
1
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
 
 
Confidential
Page
2
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ................................................................................................. 14 
1 
SYNOPSIS .................................................................................................................. 17 
2 
BACKGROUND INFORMATION ............................................................................ 23 
2.1 
Anti-HER2 Therapy in Gastric Cancer .............................................................. 23 
2.2 
Anti–PD-1 Therapy in Gastric Cancer ............................................................... 24 
2.3 
Anti-LAG-3 Therapy in Gastric Cancer ............................................................ 25 
2.4 
Rationale for Study Treatments ......................................................................... 26 
2.4.1 
Margetuximab .......................................................................................... 26 
2.4.2 
Margetuximab in Combination with Checkpoint Inhibitors .................... 27 
2.4.3 
Chemotherapy Backbone Treatment ........................................................ 32 
2.5 
Margetuximab Background Information ........................................................... 32 
2.5.1 
Margetuximab Clinical Experience ......................................................... 32 
2.5.2 
Margetuximab Clinical Pharmacokinetics ............................................... 33 
2.5.3 
Margetuximab Nonclinical Experience ................................................... 34 
2.6 
INCMGA00012 Background Information ......................................................... 35 
2.6.1 
INCMGA00012 Clinical Experience ....................................................... 35 
2.6.2 
INCMGA00012 Nonclinical Experience ................................................. 36 
2.7 
MGD013 Background Information .................................................................... 37 
2.7.1 
MGD013 Clinical Experience .................................................................. 37 
2.7.2 
MGD013 Nonclinical Experience ............................................................ 39 
2.8 
Dose Selection ................................................................................................... 40 
2.8.1 
Margetuximab Dose Selection ................................................................. 40 
2.8.2 
INCMGA00012 Dose Selection .............................................................. 41 
2.8.3 
MGD013 Dose Selection ......................................................................... 42 
2.8.4 
Chemotherapy .......................................................................................... 43 
2.9 
Risk and Benefit Assessment ............................................................................. 43 
2.9.1 
Risk Assessment ....................................................................................... 43 
2.9.2 
Potential Benefits ..................................................................................... 44 
2.9.3 
Overall Assessment .................................................................................. 45 
3 
STUDY PURPOSE AND OBJECTIVES ................................................................... 46 
3.1 
Primary Objective .............................................................................................. 46 
3.2 
Secondary Objectives......................................................................................... 46 
4 
OVERALL STUDY DESIGN AND PLAN ............................................................... 47 
4.1 
Guidelines for Dose Modification ..................................................................... 49 
4.1.1 
General Guidelines ................................................................................... 49 
4.1.2 
Modifications for SARS-CoV-2 Infection ............................................... 49 
Confidential
Page
3
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
4.1.3 
Margetuximab .......................................................................................... 50 
4.1.4 
INCMGA00012 and MGD013 ................................................................ 50 
4.1.5 
Trastuzumab (HERCEPTIN®) ................................................................. 51 
4.1.6 
Chemotherapy .......................................................................................... 52 
4.2 
Study Duration ................................................................................................... 54 
4.2.1 
Definition of End of Study ....................................................................... 54 
4.3 
Appropriateness of Measurements ..................................................................... 54 
4.3.1 
MSI Status ................................................................................................ 54 
4.3.2 
HER2 IHC Testing ................................................................................... 55 
4.3.3 
PD-L1 IHC Testing .................................................................................. 55 
4.3.4 
Fcγ Receptor ............................................................................................ 56 
4.3.5 
Clinical Laboratory Evaluations .............................................................. 56 
4.3.6 
Pharmacokinetic Assessments ................................................................. 56 
4.3.7 
Immunogenicity ....................................................................................... 56 
5 
SELECTION AND WITHDRAWAL OF PATIENTS ................................................ 57 
5.1 
Inclusion Criteria ............................................................................................... 57 
5.2 
Exclusion Criteria .............................................................................................. 58 
5.3 
Rules for Study Treatment Discontinuation ....................................................... 61 
5.4 
Guidelines for Discontinuation of Patient from Study ...................................... 62 
6 
STUDY TREATMENTS ............................................................................................ 63 
6.1 
Description of Treatments .................................................................................. 63 
6.1.1 
Method of Assigning Patients to Treatment Groups ................................ 64 
6.2 
Blinding.............................................................................................................. 64 
6.3 
Emergency Unblinding ...................................................................................... 64 
6.4 
Study Drug and Supplies ................................................................................... 64 
6.4.1 
Margetuximab .......................................................................................... 65 
6.4.2 
INCMGA00012 ....................................................................................... 65 
6.4.3 
MGD013 .................................................................................................. 65 
6.5 
Other Study Treatments ..................................................................................... 65 
6.5.1 
Trastuzumab ............................................................................................. 65 
6.5.2 
Chemotherapy .......................................................................................... 65 
6.6 
Study Treatment Preparation and Administration .............................................. 66 
6.7 
Treatment Compliance ....................................................................................... 66 
6.8 
Storage and Accountability ................................................................................ 66 
6.9 
Investigational Product Disposition at End of Study ......................................... 66 
7 
POTENTIAL ADVERSE EVENTS AND SUPPORTIVE CARE 
MEASURES ............................................................................................................... 68 
7.1 
Infusion Related Reactions Including Cytokine Release Syndrome ................. 68 
7.1.1 
Premedication and Prophylaxis ................................................................ 68 
Confidential
Page
4
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
7.1.2 
Management of Observed Infusion Reactions ......................................... 69 
7.2 
Immune-Related Adverse Events ....................................................................... 70 
8 
CONCOMITANT THERAPY AND RESTRICTIONS ............................................. 76 
8.1 
Concomitant Therapy ......................................................................................... 76 
8.1.1 
Prohibited Therapy ................................................................................... 76 
8.1.2 
Permitted Therapies ................................................................................. 77 
8.1.3 
Contraception ........................................................................................... 77 
8.2 
Restrictions ........................................................................................................ 78 
8.2.1 
Fluid and Food Intake .............................................................................. 78 
8.2.2 
Patient Activity Restrictions .................................................................... 78 
9 
STUDY PROCEDURES ............................................................................................ 79 
9.1 
Informed Consent............................................................................................... 79 
9.2 
Screening Period ................................................................................................ 79 
9.3 
Medical History ................................................................................................. 79 
9.4 
Prior and Concomitant Medications .................................................................. 79 
9.5 
Physical Examination......................................................................................... 79 
9.6 
Vital Signs .......................................................................................................... 80 
9.7 
Pulse Oximetry................................................................................................... 80 
9.8 
Clinical Laboratory Tests ................................................................................... 80 
9.8.1 
Local HER2 Testing ................................................................................. 80 
9.9 
Central Laboratory Assays ................................................................................. 81 
9.10 
Pharmacodynamics/Biomarkers ........................................................................ 81 
9.11 
Radiographic Assessments ................................................................................. 81 
9.12 
Electrocardiography ........................................................................................... 81 
9.13 
MUGA/Echocardiogram .................................................................................... 81 
9.14 
End of Treatment Visit ....................................................................................... 82 
9.15 
Post-Treatment Follow-up Visit ......................................................................... 82 
10 
ASSESSMENT OF PHARMACOKINETICS AND 
PHARMACODYNAMICS......................................................................................... 83 
10.1 
Pharmacokinetic Assessments ........................................................................... 83 
10.2 
Pharmacodynamic/Biomarker Assessments ...................................................... 83 
11 
ASSESSMENT OF EFFICACY ................................................................................. 84 
11.1 
Efficacy Assessments ......................................................................................... 84 
11.1.1 
Disease Response Assessments ................................................................ 84 
11.1.2 
Survival Assessments ............................................................................... 84 
11.2 
Immunogenicity Assessments ............................................................................ 84 
12 
ADVERSE EVENT REPORTING AND ASSESSMENT OF SAFETY ................... 85 
12.1 
Definitions.......................................................................................................... 85 
12.1.1 
Adverse Event .......................................................................................... 85 
Confidential
Page
5
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
12.1.2 
Adverse Drug Reaction ............................................................................ 85 
12.1.3 
Adverse Event of Special Interest ............................................................ 85 
12.1.4 
Serious Adverse Event ............................................................................. 85 
12.1.5 
Attribution/Assessment of Causality ....................................................... 86 
12.1.6 
Severity Criteria ....................................................................................... 86 
12.2 
Adverse Event Collection and Documentation .................................................. 87 
12.2.1 
All Adverse Events .................................................................................. 87 
12.2.2 
Serious Adverse Events ............................................................................ 88 
12.2.3 
Protocol-Specific Adverse Events of Special Interest ............................. 90 
12.2.4 
Pregnancy ................................................................................................. 90 
12.2.5 
Special Reporting Situations .................................................................... 91 
12.2.5.1 
Overdose......................................................................................... 91 
12.2.5.2 
Product Quality Issues .................................................................... 91 
12.2.5.3 
Discontinuation of Study Therapy Due to an Adverse 
Event............................................................................................... 91 
13 
PRODUCT QUALITY COMPLAINT HANDLING ................................................. 92 
13.1 
Procedures .......................................................................................................... 92 
13.2 
Contacting Sponsor Regarding Product Quality ................................................ 92 
14 
STATISTICAL ANALYSIS ........................................................................................ 93 
14.1 
Determination of Sample Size ........................................................................... 93 
14.2 
Independent Data Monitoring Committee ......................................................... 94 
14.3 
Analysis Populations .......................................................................................... 95 
14.4 
Demographics and Baseline Characteristics ...................................................... 95 
14.5 
Study Drug Exposures and Concomitant Medications ...................................... 96 
14.6 
PK/PD and Immunogenicity Analysis ............................................................... 96 
14.6.1 
Pharmacokinetics Analysis ...................................................................... 96 
14.6.2 
Immunogenicity Analysis ........................................................................ 96 
14.6.3 
Pharmacodynamic Analysis ..................................................................... 96 
14.7 
Efficacy and Endpoint Analyses ........................................................................ 96 
14.7.1 
Primary Efficacy Endpoints and Analyses for Cohort A ......................... 96 
14.7.2 
Secondary Efficacy Endpoints and Analyses for Cohort A ..................... 97 
14.7.3 
Efficacy Endpoints and Analyses for Cohort B Part 1 ............................. 98 
14.7.4 
Analysis of Tumor Size Change Over Time ............................................ 98 
14.8 
Safety Endpoints and Analyses .......................................................................... 98 
14.8.1 
Adverse Events ........................................................................................ 98 
14.8.2 
Laboratory Values .................................................................................... 99 
14.8.3 
Other Safety Endpoints ............................................................................ 99 
14.9 
Interim Analysis ................................................................................................. 99 
14.10 
Final Analysis..................................................................................................... 99 
Confidential
Page
6
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
14.11 
Other Assessments or Analyses ......................................................................... 99 
15 
QUALITY CONTROL AND ASSURANCE ........................................................... 100 
15.1 
Monitoring, Auditing and Inspections ............................................................. 100 
15.2 
Data Collection and Management .................................................................... 101 
16 
ADMINISTRATIVE CONSIDERATIONS.............................................................. 102 
16.1 
Institutional Review Board or Independent Ethics Committee 
Approval .......................................................................................................... 102 
16.2 
Ethical Conduct of the Study ........................................................................... 103 
16.3 
Patient Information and Consent ..................................................................... 103 
16.4 
Patient Confidentiality ..................................................................................... 103 
16.5 
Case Report Forms and Study Records ........................................................... 104 
16.6 
Access to Source Documentation .................................................................... 104 
16.7 
Retention of Data ............................................................................................. 104 
16.8 
Sample Retention ............................................................................................. 104 
16.9 
Financial Disclosure......................................................................................... 105 
16.10 
Publication and Disclosure Policy ................................................................... 105 
16.11 
Discontinuation of the Study or Study Sites .................................................... 105 
16.11.1 
Discontinuation of the Study ................................................................. 105 
16.11.2 
Discontinuation of Study Sites ............................................................... 106 
17 
REFERENCE LIST .................................................................................................. 107 
 
LIST OF TABLES 
Table 1 
PD-L1 Status in Trials of Available Anti–PD-1/PD-L1 
Monotherapy Data in GC or GEJ Cancer ..................................................... 25 
Table 2 
LAG-3+ Tumor Infiltrating Lymphocyte Profile Across Gastric 
Adenocarcinoma ........................................................................................... 26 
Table 3 
Efficacy Results in Gastric Cancer Population by Biomarker 
Expression .................................................................................................... 28 
Table 4 
Comparison of In Vitro Potencies of INCMGA00012 and 
Nivolumab and Pembrolizumab Replicas .................................................... 29 
Table 5 
Margetuximab Pharmacokinetics at Steady State: 6 mg/kg, 
15 mg/kg, and 18 mg/kg – CP-MGAH22-01 ............................................... 34 
Table 6 
Summary of Disposition Parameters for Patients Administered 6 
to 18 mg/kg Margetuximab Doses................................................................ 34 
Table 7 
CP-MGAH22-04 Infusion Sub-study Cumulative Exposure 
(Safety Population) ....................................................................................... 41 
Table 8 
Dose Modification Recommendations for Chemotherapy ........................... 53 
Table 9 
Overview of Study Treatments ..................................................................... 63 
Confidential
Page
7
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
Table 10 
Toxicity Management Guidelines for Immune Related Adverse 
Events ........................................................................................................... 71 
Table 11 
Adverse Events of Special Interest ............................................................... 90 
Table 12 
Censoring Rules for PFS Analysis ............................................................... 97 
LIST OF FIGURES 
Figure 1 
Margetuximab-Dependent Induction of PD-1 and LAG-3 on NK 
NKT Cells ..................................................................................................... 30 
Figure 2 
CP-MGAH22-04 Sub-study Schema ........................................................... 40 
Figure 3 
Study Design for Cohort A: Margetuximab + INCMGA00012 
(Chemotherapy-free Regimen) ..................................................................... 47 
Figure 4 
Study Design for Cohort B: Margetuximab plus Chemotherapy 
plus Checkpoint Inhibitor (INCMGA00012 or MGD013) .......................... 48 
Figure 5 
Sequence of Study Drug Administration for Each Cohort/Arm ................... 64 
LIST OF APPENDICES 
APPENDIX 1 
TIME AND EVENTS SCHEDULES 
APPENDIX 2 
CLINICAL LABORATORY TESTS 
APPENDIX 3 
RECIST 1.1 GUIDELINES 
APPENDIX 4 
GASTRIC ADENOCARCINOMA SUB-TYPES 
APPENDIX 5 
PRINCIPAL INVESTIGATOR’S AGREEMENT 
 
Confidential
Page
8
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2020 
 
 
SPONSOR SIGNATURES  
Study Title: 
A Phase 2/3 Trial to Evaluate Margetuximab in Combination with 
INCMGA00012 and Chemotherapy or MGD013 and 
Chemotherapy in Patients with Metastatic or Locally Advanced, 
Treatment-naïve, HER2-Positive Gastric or Gastroesophageal 
Junction Cancer 
Study Number: 
CP-MGAH22-06 
 
This clinical study protocol has been approved by the Sponsor: 
Signed: 
See Appended Electronic Signature Page 
Date: 
 
 
 
Chief Medical Officer 
MacroGenics, Inc. 
 
 
 
Signed: 
See Appended Electronic Signature Page 
Date: 
 
 
 
 
Senior Director, Biostatistics 
MacroGenics, Inc. 
 
 
 
 
 
Confidential
Page
9
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
Confidential
Page
10
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
Confidential
Page
11
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
Confidential
Page
12
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
 
 
Confidential
Page
13
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
LIST OF ABBREVIATIONS  
The list of abbreviations of specialist terms does not include general scientific abbreviations 
of temperature, weight, and volume. 
Abbreviation  
Term 
5-FU 
5-fluorouracil 
ADA 
Anti-drug antibodies 
ADCC 
Antibody-dependent cell-mediated cytotoxicity 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
BOR 
Best overall response 
CI 
Confidence Interval 
CL 
Total body clearance 
Cmax 
Maximum concentration 
CPI 
Checkpoint inhibitor 
CPS 
Combined positive score 
CR 
Complete response 
CRF 
Case report form 
CRS 
Cytokine release syndrome 
CSR 
Clinical Study Report 
CT 
Computed tomography 
Ctrough 
Trough concentration 
DCR 
Disease control rate 
DoR 
Duration of response 
EAP 
Expanded access program 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EMA 
European Medicines Agency 
EOI 
End of infusion 
EOTV 
End of Treatment Visit 
ePPND 
Enhanced pre- and postnatal development 
FACT-Ga 
Functional Assessment of Cancer Therapy - Gastric 
FcRn 
Neonatal FcR 
FDA 
Food and Drug Administration 
FFPE 
Formalin-fixed paraffin-embedded 
FISH 
Fluorescent in situ hybridization 
Confidential
Page
14
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
Abbreviation  
Term 
GC 
Gastric cancer 
GEJ 
Gastroesophageal junction 
HBV 
Hepatitis B virus 
HCB 
Hepatitis C virus 
HR 
Hazard ratio 
HER2 
Human epidermal growth factor receptor 2 
ICF 
Informed consent form 
IDMC 
Independent data monitoring committee 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
IHC 
Immunohistochemistry 
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
ITT 
Intent-to-treat 
IV 
Intravenous 
irAE 
Immune-related adverse events 
LAG-3 
Lymphocyte-activation gene 3 
LVEF 
Left ventricular ejection fraction 
mAb 
Monoclonal Antibody 
MedDRA 
Medical dictionary for regulatory activities 
mFOLFOX-6 
Modified fluorouracil, leucovorin, and oxaliplatin regimen 6 
MHC-II 
Major histocompatibility complex class II 
MRI 
Magnetic resonance imaging 
MSI 
Microsatellite instability 
MSI-H 
Microsatellite instability-High 
MUGA 
Multigated acquisition ventriculography scanning 
NK 
Natural killer 
NE 
Not evaluable 
NSCLC 
Non-small cell lung carcinoma 
ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease  
PD-1 
Programmed death receptor 1 
PD-L1 
Programmed death ligand 1 
PD-L2 
Programmed death ligand 2 
PEP 
Primary efficacy population 
PFS 
Progression-free survival 
Confidential
Page
15
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
Abbreviation  
Term 
PK 
Pharmacokinetics 
PPK 
Population PK 
PQC 
Product Quality Complaint 
PR 
Partial response 
PREP 
Primary response evaluable population 
PRO 
Patient-reported outcome 
Q2W 
Every 2 weeks 
Q3W 
Every 3 weeks 
Q4W 
Every 4 weeks 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumours version 1.1 
REP 
Response Evaluable Population 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease  
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
ToGA 
Trastuzumab for Gastric Cancer 
TRAE 
Treatment-related adverse event 
US 
United States 
VD 
Volume of distribution at steady state 
WOCBP 
Women of child-bearing potential 
XELOX 
Capecitabine and oxaliplatin 
 
 
Confidential
Page
16
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
1 
SYNOPSIS  
Sponsor: MacroGenics, Inc. 
IND Number: 
 
Name of Product: Margetuximab, INCMGA00012 (also known as MGA012), MGD013 
Study Title: A Phase 2/3 Trial to Evaluate Margetuximab in Combination with INCMGA00012 and 
Chemotherapy or MGD013 and Chemotherapy in Patients with Metastatic or Locally Advanced, Treatment-
naïve, HER2-Positive Gastric or Gastroesophageal Junction Cancer 
Study Number: CP-MGAH22-06 
Study Phase: 2/3  
Investigator(s)/Centers: 
Cohort A Part 1 and Part 2 will be conducted in approximately 40-80 centers in approximately 10 countries.  
Cohort B Part 1 will be conducted at approximately 50-70 centers in approximately 10 countries. 
Primary Objective(s):  
Cohort A:  
• 
To evaluate the safety and tolerability of margetuximab + INCMGA00012 in patients with untreated 
locally advanced or metastatic gastric cancer (GC) or gastroesophageal junction (GEJ) cancer that is 
human epidermal growth factor 2 (HER2) immunohistochemistry (IHC) 3+ and PD-L1+ by IHC 
staining.  
• 
To evaluate the objective response rate (ORR) of margetuximab + INCMGA00012 for 
non-microsatellite instability-high (non-MSI-H) patients in the response evaluable population (REP) 
using Investigator-assessed radiology reviews.  
Secondary Objective(s):  
Cohort A: 
• 
To determine duration of response (DoR), disease control rate (DCR), progression-free survival 
(PFS) using Investigator-assessed radiology review for non-MSI-H patients.  
• 
To evaluate the number of patients with anti-drug antibodies (ADA) to margetuximab or 
INCMGA00012, or both.  
Cohort B, Part 1: 
• 
To evaluate ORR and DCR of each treatment arm. 
• 
To evaluate the number of patients with ADA to margetuximab, MGD013, and INCMGA00012. 
Study Drugs: 
Margetuximab is an Fc-optimized mouse-human chimeric anti-HER2 monoclonal antibody (mAb). 
INCMGA00012 is a hinge-stabilized, humanized immunoglobulin (Ig)G4κ anti-programmed death receptor 1 
(PD-1) mAb. 
MGD013 is a humanized Fc-bearing bispecific tetravalent (bivalent for each antigen) DART® molecule with 
specificity for PD-1 and LAG-3. 
I 
Confidential
Page
17
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
Study Design: 
This is a Phase 2/3, randomized, open-label study for the treatment of patients with HER2+ GC or GEJ cancer 
will determine the efficacy of margetuximab combined with a checkpoint inhibitor (CPI) INCMGA00012 in 
patients who are positive for both HER2 and PD-L1 (Cohort A), and a margetuximab plus CPI 
(INCMGA00012 or MGD013) plus chemotherapy compared to trastuzumab (marketed as HERCEPTIN®) 
plus chemotherapy in patients who are HER2 positive, irrespective of PD-L1 status (Cohort B). Patients will 
be treated in 3-week (21-day) cycles. Cohort A and Cohort B will not be opened simultaneously at the same 
institution.  
Cohort A (Single Arm):  
Cohort A was closed prior to completing enrollment target. 
INCMGA00012 plus margetuximab. The efficacy of INCMGA00012 plus margetuximab will be evaluated in 
up to approximately 100 patients that are HER2 IHC3+, PD-L1+, and non-MSI-H. Enrollment will occur 
without prior ascertainment of MSI status. If the MSI status is determined to be MSI-H, patients will be 
allowed to remain on treatment but will be removed from the efficacy analysis. It is expected that about 
110 patients will need to be enrolled to have approximately 100 non-MSI-H patients. Patients will receive 
375 mg of INCMGA00012 once every 3 weeks (Q3W) plus 15 mg/kg of margetuximab Q3W. In addition to 
regular Sponsor medical oversight, the independent data monitoring committee (IDMC) will review all 
accumulated safety data from all enrolled patients and provide a recommendation to the Sponsor. The first 
scheduled IDMC meeting will take place after the first 12 patients have completed at least 1 cycle of study 
treatment, or at 6 months from first enrollment, whichever comes first. Enrollment will continue during the 
evaluation. Reviews will continue in 6-month intervals (± 1 month). After approximately 40 patients have 
enrolled and are evaluable for response, data will be analyzed for ORR, as determined by central imaging 
review, and safety. Additional patients will be enrolled in Part 2 of the cohort if the threshold for study 
continuation is met. Decision rules that govern the analysis of the ORR from Part 1 and continuation of Part 2 
of Cohort A are outlined in Section 14.7.1.  
 
Cohort B Part 1 (Randomized, open-label):  
Cohort B was closed prior to completing enrollment target. 
Cohort B Part 1 consists of 4 arms: 1 control arm of trastuzumab plus chemotherapy and 3 experimental arms 
of margetuximab-containing regimens. Experimental Arms 1 and 2 will combine margetuximab plus a CPI 
plus chemotherapy. The CPI for Experimental Arm 1 is INCMGA00012, and the CPI for Experimental Arm 2 
is MGD013. Experimental Arm 3 will evaluate margetuximab alone in combination with chemotherapy. 
Chemotherapy will be capecitabine and oxaliplatin (XELOX) or modified 5-FU, leucovorin, and oxaliplatin 
regimen 6 (mFOLFOX-6), according to the investigator’s choice based on local approval and availability. The 
first safety evaluation by the IDMC will take place after 20 patients in each arm have enrolled and completed 
at least 1 cycle of treatment, or at approximately 6 months from first enrollment, whichever comes first. 
Reviews will continue in 6-month intervals (± 1 month). Once the first assessment in Cohort B is completed, 
to the extent possible, safety and efficacy data from Cohort A and Cohort B will be reviewed at the same 
meeting.  
Control arm: trastuzumab at an 8 mg/kg loading dose then 6 mg/kg Q3W, in combination with XELOX or 
mFOLFOX-6 chemotherapy.  
Experimental Arm 1: 375 mg of INCMGA00012 Q3W plus 15 mg/kg of margetuximab Q3W, in combination 
with XELOX or mFOLFOX-6 chemotherapy. 
Part 1 (n=40)* 
Margetuximab + INCMGA00012 
Confidential
Page
18
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
Experimental Arm 2: 600 mg MGD013 Q3W plus 15 mg/kg of margetuximab Q3W, in combination with 
XELOX or mFOLFOX-6 chemotherapy.  
Experimental Arm 3: margetuximab 15 mg/kg in combination with XELOX or mFOLFOX-6 chemotherapy. 
 
 
IHC = immunohistochemistry; R = randomize,  
Number of Patients Enrolled: 
There were 48 patients enrolled in Cohort A (Parts 1 and 2). There were 34 patients randomized of which 33 
patients were treated Cohort B Part 1. No patients were enrolled in Cohort B Part 2.  
Patient Population/Key Entry Criteria: 
The patient population to be enrolled in this study will consist of adult patients with a histologically or 
cytologically confirmed diagnosis of previously untreated, locally advanced unresectable or metastatic 
HER2+ GC or GEJ adenocarcinoma. Patients will have Eastern Cooperative Oncology Group (ECOG) 
performance status of 0 or 1 and no clinically significant cardiovascular disease. For Cohort A, patients will 
be HER2+ (IHC 3+), PD-L1+ [combined positive score (CPS ≥ 1%)] by central review. Cohort B patients 
will be HER2+ [IHC 3+, or IHC 2+ and fluorescent in situ hybridization (FISH+)], irrespective of PD-L1 
status.  
Duration of Treatment and Study Duration:  
Study treatment will continue until completion of therapy, persistent CR, disease progression, unacceptable 
toxicity, withdrawal of consent, physician recommendation to discontinue therapy, or death. Patients will be 
evaluated at the end of every 3 cycles (± 7 days) for the first 9 months for radiographic evidence of disease 
progression. Beginning with Cycle 13, assessments will occur every 4 cycles (± 7 days).  
The maximum duration of protocol-specified study treatments are:  
Cohort A 
35 cycles of margetuximab and INCMGA00012 
Cohort B, 
Part 1 
Arm 
Chemotherapy 
Anti-HER2 Therapy 
Anti PD-1/PD-L1 Therapy
Control 
8 cycles XELOX or 
12 cycles mFOLFOX-6 
35 cycles trastuzumab 
N/A 
1 
35 cycles margetuximab 
35 cycles INCMGA00012 
2 
35 cycles margetuximab 
35 cycles MGD013 
3 
Until disease progression 
N/A 
Cohort B: HER2-positive (IHC3+ or IHC2+/FISH+), regardless of PD-L 1 status 
Part 1 (n=SO/arm)* 
Part 2 (n=250/arm) 
Study Part 2 Discontinued 
ControlArm 
Extension 
s SO patients 
* Each arm in Part 1 contains a 6 patient safety run-in 
Trastuzumab + 
Chemotherapy 
Margetuximab + 
Chemotherapy + CPI 
Confidential
Page
19
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
Discontinuation of study treatment may be considered for patients who have attained persistent CR. The 
criteria for persistent CR include:  
• 
confirmed CR and at least 8 complete cycles (approximately 6 months) of study treatments, and  
• 
an additional 2 cycles of study treatment must be completed beyond the date of initial CR.  
Patients in Cohort A only who have radiographic progression but are clinically stable may remain on study 
treatments until the next scheduled radiographic evaluation, upon Sponsor Medical Monitor consultation. 
There is no crossover in this study to a different treatment arm or different cohort. Following discontinuation 
of study treatment, each patient will be followed for safety for up to 30 days, or until initiation of subsequent 
anticancer therapy, whichever comes first. Patients currently in survival follow-up will be discontinued from 
the study.  
The end of study occurs after the last patient completes the safety follow-up period.   
Criteria for Evaluation:  
Safety Assessments: 
The safety assessment will be based on the evaluation of adverse events (AE) that occur from the time of 
initiation of study treatment through 30 days after the last dose of study treatment or until the start of a 
subsequent anticancer therapy. Determination of AEs are based on signs, symptoms, physical examination 
findings, and/or laboratory test results from enrolled patients as appropriate. Progression of the underlying 
neoplasm resulting in hospitalization or death [e.g., patient hospitalized for, or death from, PD only, without 
any other serious adverse events (SAE)] will be documented as an antitumor activity outcome and not as an 
SAE. 
Tumor Assessments: 
Tumor assessments will be obtained using computed tomography (CT) or magnetic resonance imaging (MRI) 
scans and evaluated using Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST v1.1) 
guideline. Assessments will be performed every 3 cycles (± 7 days) for the first 9 months, beginning at Cycle 
13 every 4 cycles (± 7 days) until treatment discontinuation. Measurement or assessment of individual lesions 
is not required. Overall response per assessment should be recorded per RECIST v1.1.  
Pharmacokinetic Assessments: 
Serum concentrations of margetuximab, INCMGA00012, and MGD013 will be monitored using validated 
assay methods.  
Immunogenicity Assessments: 
The generation of ADA for margetuximab, INCMGA00012, and MGD013 will be monitored using validated 
bioanalytical methods.  
Pharmacodynamics/Biomarker Assessments 
Biomarker assessments related to entry criteria will be performed prospectively prior to enrollment. Other 
biomarker assessments not related to entry criteria will be prospectively collected and retrospectively 
analyzed.  
Cohort A 
• 
MSI status performed by a central laboratory   
• 
PD-L1 and HER2 expression by IHC will be conducted with Food and Drug Administration (FDA)-
approved assays by a central laboratory for eligibility. 
Cohort B  
• 
Determination of MSI status by a central laboratory  
• 
LAG-3 expression based on FFPE tumor tissue  
Confidential
Page
20
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
• 
Determination of PD-L1 and HER2 expression will be conducted with FDA-approved assay for 
central confirmation. 
Analysis Populations:  
Safety Population: All patients who received at least one dose of study drug. The safety population will be 
used to summarize safety data for Cohort A and Cohort B of the study, respectively. Patients enrolled in 
Cohort B will be analyzed according to the actual treatment received rather than the treatment group they 
were assigned. This population will also be used to summarize baseline data for Cohort A. 
PK Evaluable Population: All patients who received at least one dose of study drug, date and time of dose 
administration and relative PK sample collection are known and have sufficient concentration data to derive at 
least one PK parameter.  
ADA Evaluable Population: All patients who received at least one dose of study treatment, date and time of 
dose administration and relative PK sample collection are known and have sufficient concentration data to 
derive at least one PK parameter. 
ITT Population: All patients who are assigned to treatment in Cohort A and all patients who are randomized 
into Cohort B of the study for each of the respective cohorts. Patients will be analyzed according to the 
treatment assigned. This population will be used to summarize baseline data and evaluate PFS. 
Response Evaluable Population (REP): All patients who received at least one dose of study drug and had 
baseline radiographic tumor assessment. This population will be used for response related efficacy analyses 
for Cohort A and Cohort B, respectively, and will be analyzed according to the actual treatment received. 
Statistical Methods:  
A separate statistical analysis plan (SAP) and statistical programming plan will further describe the details 
regarding statistical methods and will govern the analysis.  
Sample Size:  
The planned sample sizes are described below. The study enrollment was closed. There are 48 patients treated 
in Cohort A. There were 34 patients randomized of which 33 patients were treated in Cohort B Part 1. Cohort 
B Part 2 has never started.   
Cohort A: The sample size of approximately 100 non-MSI-H patients is based on a Simon two-stage design to 
provide approximately 83% power to test ORR of 
 at a 2-sided alpha level of 0.05. The first stage 
(Part 1) will enroll and treat response evaluable 40 non-MSI-H patients. If at least 21 (53%) responders 
[complete response (CR) or partial response (PR)] are observed, the study will move to the second stage 
(Part 2) with enrollment of approximately 60 additional response evaluable non-MSI-H patients. Other 
efficacy data such as DoR and PFS will be considered as well in enrollment decision-making. If the study 
continues to enroll an additional 60 patients, the null hypothesis H0: ORR = 
 would be rejected at 1-sided 
alpha level of 0.025 (or equivalently, 2-sided 0.05) if the observed ORR from all 100 response evaluable non-
MSI-H patients is ≥ 
. The totality of the data will be assessed to determine not only statistical significance 
but a clinically meaningful effect. The total number of patients to be enrolled in Cohort A is expected to be 
approximately 110 in order to obtain approximately 100 non-MSI-H patients. 
Cohort B: The sample size for Cohort B is determined based on a Phase 2/3 design. The sample size will 
consist of patients that are HER2+ by central confirmation. Entry criteria for HER2 may be based on a local 
test, however, enrollment will continue until the sample size is accrued based on central confirmation. The 
total planned sample size for Cohort B is approximately 750, consisting of two parts: 
Cohort B Part 1, approximately 200 patients will be randomized in a 1:1:1:1 ratio to 1 of 4 arms (one control 
arm and three margetuximab-containing arms). The randomization will be stratified by two stratification 
factors: chemotherapy regimen (XELOX vs mFOLFOX-6) and results of local HER2 testing (IHC 2+/FISH+ 
vs IHC 3+). Selection of which margetuximab and CPI-containing arm to move to the Phase 3 part of the 
study (Cohort B Part 2) for further testing will be primarily based on ORR but may also take into 
consideration PFS and safety.  
Confidential
Page
21
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
During the interim analysis, up to 50 additional patients will be added to Experimental Arm 3.  
Cohort B Part 2, approximately 500 additional patients will be randomized in a 1:1 ratio between the control 
arm and the selected margetuximab arm. The randomization will be stratified by two stratification factors: 
chemotherapy regimen (XELOX vs. mFOLFOX-6) and results of local HER2 testing (IHC 2+/FISH+ vs IHC 
3+).  
By applying the closed testing procedure and the inverse normal p-value combining method to test OS, 
respectively, at the end of the Cohort B Part 2 part of the study, the sample size of approximately 650 planned 
enrollment [Cohort B Part 1: control arm (50 patients) and 2 margetuximab and CPI-containing arms 
(100 patients)] and 500 patients from Cohort B Part 2] will provide approximately 80% power to detect OS 
hazard ratio (HR) = 
 (median OS increase from 
 months for control arm to 
months for either 
selected margetuximab and CPI-containing arm) at 1-sided 0.025 (or equivalently, 2-sided 0.05) alpha level. 
Safety:  
AEs will be coded to the Medical Dictionary for Regulatory Activities (MedDRA) dictionary. Only treatment-
emergent AEs will be summarized in tables. Events prior to treatment (e.g., due to study-related procedure) 
will be listed in an appendix to the final study report. 
Summaries of laboratory values will display descriptive statistics for numerically quantified labs. Summaries 
will be grouped by laboratory panel (e.g., hematology, blood chemistry, and urinalysis) and will be displayed 
by visit for each laboratory parameter. 
Efficacy:  
Primary Efficacy Endpoint and Analyses for Cohort A 
The primary efficacy endpoint for Cohort A is ORR per RECIST v1.1, defined as the proportion of 
non-MSI-H patients in the Response Evaluable Population who achieve the best overall response (BOR) of 
CR or PR (called responders) per RECIST v1.1. The 2-sided 95% exact binomial confidence interval (CI) of 
ORR will be calculated.  
For RECIST v1.1, the BOR will be categorized as CR, PR, stable disease (SD), PD, or not evaluable (NE). To 
be qualified as BOR, CR, and PR require confirmation at least 4 weeks after initial observation response. SD 
requires to be observed at least once after 6 weeks. BOR will be evaluated from the start of study treatment.  
The analysis of ORR will be based on investigator review determined response data.  
Secondary Efficacy Endpoints and Analyses for Cohort A 
The secondary efficacy endpoints for non-MSI-H patients in Cohort A are: 
• 
PFS, defined as the time from start of study treatment to the first documented disease progression per 
RECIST v1.1 or death due to any cause, whichever occurs first. 
• 
DoR, 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.  
• 
DCR, defined as the percentage of the REP who experienced response of CR, PR, or SD for at least 
3 months from start of study treatment. 
 
Efficacy Endpoints and Analyses for Cohort B Part I 
The efficacy endpoints for Cohort B Part I are ORR and DCR based on the response evaluable population. 
The analysis methods are same as those for Cohort A. 
 
 
 
Confidential
Page
22
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
2 
BACKGROUND INFORMATION  
Gastric cancer (GC) is the fifth most common malignancy, with half of all diagnoses 
occurring in Eastern Asia. It is the third leading cause of cancer death worldwide, 
with the highest estimated mortality rates occurring in Eastern Asia 
(http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx). In the United States (US) in 
2018, it is estimated that about 26,240 people will be diagnosed with GC and 
10,800 individuals will die from this disease (51, 57). Human epidermal growth factor 
receptor 2 (HER2) positivity has been observed in 7% to 35% of GC tumors (4). The 
introduction of targeted treatments for GC has improved overall survival (OS) rates for 
specific populations. 
2.1 
Anti-HER2 Therapy in Gastric Cancer  
In the Trastuzumab for Gastric Cancer (ToGA) trial (4), trastuzumab, a monoclonal antibody 
(mAb) against HER2, in combination with chemotherapy increased median OS by 
approximately 2.7 months and is now used for the first-line treatment of HER2+ advanced GC 
or gastroesophageal junction (GEJ) cancer. This trial established HER2 as a validated target in 
patients with GC or GEJ cancer and demonstrated that patients with overexpression of HER2 
benefit from receiving trastuzumab in addition to standard (frontline) 
fluoropyrimidine/cisplatin chemotherapy. Median OS and progression-free survival (PFS) in 
the chemotherapy plus trastuzumab-treated patients were 13.8 months and 6.7 months, 
respectively, compared to 11.1 months and 5.5 months, respectively, in patients treated with 
chemotherapy alone. An exploratory analysis conducted in patients whose tumors had high 
HER2 expression [as defined by HER2 3+ or 2+ by immunohistochemistry (IHC)] combined 
with amplification by in-situ hybridization (ISH), demonstrated a median OS of 16 months for 
patients treated with chemotherapy plus trastuzumab vs 11.8 months for patients treated with 
chemotherapy alone. These results have formed the basis for using trastuzumab as standard of 
care for frontline treatment of HER2+ GC or GEJ cancer patients (28). 
The US Food and Drug Administration (FDA) granted trastuzumab approval for use in 
patients with advanced GC with positive ISH results or an IHC score 3+ (21). The European 
Medicines Agency (EMA) limited the approval to patients with GC with HER2 
overexpression as defined by HER2 IHC score 2+, confirmed by a positive ISH result, or by 
HER2 IHC 3+ (15). Following publication of the results of the ToGA trial, trastuzumab in 
combination with fluoropyrimidine/cisplatin/ became a standard first-line treatment for 
patients with HER2+ advanced GC. Due to its more favorable toxicity profile, 
fluoropyrimidine in combination with oxaliplatin has become a preferred first-line treatment 
option for the management of advanced gastroesophageal cancers. Two Phase 2 studies have 
explored the combination of trastuzumab with capecitabine and oxaliplatin (XELOX) in 
patients with HER2+ advanced GC. Both studies demonstrated objective response rates 
(ORRs) of 67% and tolerability of this combination therapy (23, 48).  
A recent meta-analysis of studies comparing chemotherapy to trastuzumab plus chemotherapy 
in advanced HER2+ GC, reported that trastuzumab plus chemotherapy provides only 20% 
improvement of OS and 30% improvement in PFS over chemotherapy alone (64). 
Confidential
Page
23
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
2.2 
Anti–PD-1 Therapy in Gastric Cancer  
Programmed death receptor 1 (PD-1) and its ligand, programmed death ligand 1 (PD-L1), are 
expressed in up to 70% of GC or GEJ cancers (8, 50, 63). PD-L1 expression has been 
associated with a poor prognosis (13, 46), although occasional studies have found a reverse 
correlation (35). By overexpressing PD-L1 directly or inducing PD-1 expression on immune 
cells, cancer cells exploit the PD-1/PD-L1 pathway to promote an immunosuppressive 
environment and allow immune escape and tumor growth. The antitumor activity of various 
anti–PD-1 antibodies, including both nivolumab and pembrolizumab, has been investigated in 
various studies in patients with GC or GEJ cancer. 
In KEYNOTE-012, a Phase 1b study of pembrolizumab in 39 patients with recurrent or 
metastatic PD-L1+ (≥ 1% tumor cell cutoff; 22C3 assay) GC or GEJ cancer, the ORR by 
central review was 22% and the median OS was 11.4 months overall. Grade ≥ 3 treatment-
related adverse events (TRAEs) occurred in 13% of patients. In KEYNOTE-059 Cohort 1, 
259 patients received pembrolizumab monotherapy as third-line or later treatment (18). The 
ORR in this cohort was 12%, with a trend for higher ORR in PD-L1+ vs PD-L1 negative 
tumors (16% vs 6%, respectively). Median OS was 5.5 months. PD-L1 status was based on a 
combined positive score (CPS) of ≥ 1% PD-L1+ tumor or immune cells via the 22C3 assay. 
Grade ≥ 3 TRAEs occurred in 18% of patients. Results from this cohort led to the accelerated 
approval of pembrolizumab by the FDA as third-line treatment for patients with advanced PD-
L1+ GC or GEJ cancer. 
In KEYNOTE-061, 592 patients received pembrolizumab monotherapy as second-line 
treatment (50). Median OS was 9.1 months (95% confidence interval [CI] 6.2–10.7) with 
pembrolizumab and 8.3 months (7.6–9.0) with paclitaxel (hazard ratio [HR] 0.82, 95% CI 
0.66–1.03; one-sided p = 0.0421). Median PFS was 1.5 months (95% CI 1.4–2.0) with 
pembrolizumab and 4.1 months (3.1–4.2) with paclitaxel (HR 1.27, 95% CI 1.03–1.57). In the 
total population, Grade 3–5 TRAEs occurred in 42 (14%) of the 294 patients treated with 
pembrolizumab and 96 (35%) of the 276 patients treated with paclitaxel. 
Nivolumab was approved for the treatment of unresectable advanced or recurrent GC that has 
progressed after chemotherapy, based on the Phase 3 study ATTRACTION-2 (ONO-4538-12), 
in which nivolumab significantly reduced patients’ risk of death by 37% (HR 0.63; 95% CI 
0.51–0.78, P < 0.0001) when compared to placebo (33). Furthermore, nivolumab 
demonstrated a greater OS rate at 12 months vs placebo: 26.2% (95% CI 20.7–32.0) and 
10.9% (95% CI 6.2–17.0), respectively. TRAEs of any grade and Grade 3 or 4 occurred in 
42.7% vs 26.7% and 10.3% vs 4.3% of nivolumab-treated and placebo-treated patients, 
respectively. Grade 3 or 4 TRAEs reported in more than 2 patients were diarrhea, fatigue, 
decreased appetite, pyrexia, increased aspartate aminotransferase (AST), and alanine 
aminotransferase (ALT) in the nivolumab group. Fatigue and decreased appetite were reported 
in the placebo group. Nivolumab and placebo-treated patients had similar rates of TRAEs 
leading to discontinuation, 2.7% and 2.5%, respectively. 
A summary PD-L1 status in recent studies is provided in Table 1. 
Confidential
Page
24
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
Table 1 
PD-L1 Status in Trials of Available Anti–PD-1/PD-L1 
Monotherapy Data in GC or GEJ Cancer                                       
Study ID 
ATTRACTION-2  
KEYNOTE-059 
KEYNOTE-061  
PD-L1 status 
NR 
PD-L1 
CPS < 1 
CPS ≥ 1 
 
plb 
Nivo 
+ 
- 
Total Pembr
o 
Ptx 
Pembr
o 
Ptx 
ORR 
0 
11.2 
15.5 
6.4 
11.6 
NR 
NR 
15.8 
13.6 
mPFS 
NR 
NR 
NR 
NR 
2.0 
NR 
NR 
1.5 
4.1 
mOS 
4.14 
5.26 
5.8 
4.9 
5.6 
4.8 
8.2 
9.1 
8.3 
CPS = combined positive score, Nivo = nivolumab, NR = not reported, PD-L1 = programmed death ligand 1, 
Pembro = pembrolizumab, plb = placebo, Ptx = Paclitaxel 
 
2.3 
Anti-LAG-3 Therapy in Gastric Cancer  
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 (3). 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 (52). 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 (26, 62). In 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 (56). An IHC analysis conducted by the Sponsor of tumor specimens 
from 34 GC patients revealed the majority (30/34) contained lymphocyte infiltrates with 
detectable LAG-3 expression (Table 2). Because PD-1 and LAG-3 expression on both CD4+ 
and CD8+ T cells are upregulated in GC, dual targeting PD-1 and LAG-3 may be an effective 
way to enhance the treatment of GC (38, 56). 
 
 
Confidential
Page
25
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
Table 2 
LAG-3+ Tumor Infiltrating Lymphocyte Profile Across Gastric 
Adenocarcinoma                                                    
Any detectable  
LAG-3+ TIL  
Moderate or above  
LAG-3+ TIL  
Heavy 
LAG-3+ TIL  
30/34 (88.2%) 
19/34 (55.9%) 
15/34 (44.1%) 
LAG-3–positive tumor infiltrating lymphocyte prevalence rate determined by IHC analyses across 34 
independent GC 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. 
 
2.4 
Rationale for Study Treatments  
2.4.1 
Margetuximab  
Increased clinical activity of the anti-HER2 mAb trastuzumab has been seen in patients with 
HER2+ breast cancer (20, 42) or HER2+ GC (59) who were homozygous for CD16A-158V, 
compared with CD16-A 158F allele carriers (F/F and V/F). The homozygous V/V genotype is 
present in approximately 15% of Caucasian, African American, and Asian populations, and 
the lower affinity F/F and intermediate affinity F/V carriers comprise the remainder of the 
population. Since most patients carry the lower affinity allele of CD16A, the engineered Fc 
domain of margetuximab is expected to confer benefit to the whole patient population and not 
disproportionately to the higher affinity CD16A V/V homozygotes. 
Margetuximab is an Fc-optimized mouse-human chimeric mAb that binds to the human 
HER2/neu antigen. Margetuximab was derived from the murine precursor to the humanized 
therapeutic antibody, trastuzumab, 4D5. Margetuximab is produced as a full-length 
glycosylated IgG1 ԟ immunoglobulin using a Chinese hamster ovary cell line. Margetuximab 
maintains the same direct anti-proliferative activity as trastuzumab but, in contrast to 
trastuzumab, margetuximab binds with increased affinity to both allotypes of the activating Fc 
receptor, CD16A, and decreased affinity to the inhibitory Fc receptor, CD32B, due to specific 
mutations introduced into its Fc region. 
Consistent with its enhanced binding to CD16A, margetuximab exhibits enhanced antibody-
dependent cell-mediated cytotoxicity (ADCC) activity in vitro against HER2-expressing 
tumor cell lines and enhanced antitumor activity against HER2+ xenografts in mice transgenic 
for human CD16A-158F. 
In studies with N87 (HER2 3+ GC) target cells and natural killer (NK) effector cells obtained 
from donors with differing CD16A-158 genotypes, margetuximab was 7- to 84-fold more 
potent in mediating ADCC than trastuzumab (37). A greater fold difference in potency was 
evident with NK cells that expressed the more common, lower affinity FF and VF genotypes 
than those that expressed the less common, high affinity VV genotype. 
Confidential
Page
26
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
When peripheral blood mononuclear cells (PBMCs) and HER2 3+ N87 cells are incubated 
with margetuximab, NK (CD56+CD3-) cells and NKT (CD56+CD3+) cells are induced to 
express markers of activation (CD137), cytolytic capability (granzyme B, perforin) and 
proliferation (Ki67) to levels that are greater than those induced by trastuzumab. By contrast, 
an Fc null variant of margetuximab was generally ineffective, indicating that the induced 
changes in NK and NKT cells were Fc-dependent (37). Thus, margetuximab with an 
engineered Fc domain induces NK and NKT responses more effectively than trastuzumab 
with a wild type Fc domain. These differential effector cell responses occurring in the 
presence of HER2-expressing target cells are consistent with the higher ADCC potency of 
margetuximab compared to trastuzumab.  
Enhanced ADCC activity may result in increased tumor antigen presentation and an improved 
adaptive immune response. Analysis of blood samples collected from patients in the Phase 1 
study (CP-MGAH22-01) demonstrated that single-agent margetuximab treatment of HER2+ 
cancer patients, who had received multiple prior treatments, was associated with enhanced 
HER2-specific T-cell and antibody responses together with increased T-cell receptor CR 
clonality, which is indicative of a more focused T-cell repertoire. The high frequency of 
HER2-specific immunity observed in the margetuximab-treated patients (> 95%) is consistent 
with the enhanced Fc region of margetuximab contributing to linkage of innate and adaptive 
immune responses. 
2.4.2 
Margetuximab in Combination with Checkpoint Inhibitors  
Combination with Anti–PD-1 
Enhanced ADCC activity mediated by margetuximab toward HER2-overexpressing tumor 
cells may facilitate cross-talk between innate and adaptive immune responses. The Sponsor 
hypothesizes that induction of ADCC against HER2+ tumor cells and facilitation of adaptive 
immunity by margetuximab may be further potentiated in combination with immune CPIs. 
Trastuzumab-mediated upregulation of PD-L1 through engagement of immune effector cells 
has been reported as a potential mechanism of trastuzumab resistance (12). Emerging 
evidence suggests that anti–PD-1 antibodies could potentiate the antitumor activity of anti-
HER2 antibodies (55, 60). 
Study CP-MGAH22-05 evaluates simultaneous targeting of HER2 with margetuximab and 
PD-1 with pembrolizumab as therapy for relapsed or refractory HER2+ GC. As of 10 July 
2019, 95 patients received the combination of margetuximab and pembrolizumab. TRAEs 
irrespective of grade were reported in 63.2% (60/95) of patients, and 20.0% (19/95) had a 
TRAE grade ≥3. The most common TRAEs occurring in ≥10% of patients were pruritus 
(n=16; 16.8%), diarrhea (n=14; 14.7%), infusion-related reaction (IRR; n=13; 13.7%), and 
fatigue (n=13; 13.7%). Serious grade 3 TRAEs were: autoimmune hepatitis (n=2), 
pneumonitis (n=1), hyponatremia (n=1), diabetic ketoacidosis (n=1), hypotension (n=1), IRR 
(n=1), and dehydration (n=1) and grade 2 dizziness (n=1). TRAEs of special interest were 
hyperthyroidism (n=3), adrenal insufficiency (n=3), autoimmune hepatitis (n=2), pneumonitis 
(n=2), left ventricular ejection fraction dysfunction (n=2), diabetes mellitus (n=1), 
hyperglycemia (n=1), and hypothyroidism (n=1). There were no grade 5 TRAEs reported. 
Confidential
Page
27
of
129

Margetuximab, INCMGA00012, MGD013
MacroGenics, Inc.
Clinical Trial Protocol: CP-MGAH22-06
Amendment 5, 06 June 2022
HER2 eligibility in CP-MGAH22-05 was based on archival tissue. Published data show loss 
of HER2 expression after trastuzumab therapy (44, 49). As an exploratory endpoint, HER2 
expression post-trastuzumab was evaluated by measuring ERBB2 amplification on cell-free 
tumor DNA; data showed retention of HER2 expression in approximately 60% of patients. 
GC had higher PD-L1 expression than GEJ cancer (43% vs 9%, respectively). This coincided 
with more responses in IHC 3+ GC than GEJ patients. Response to treatment is displayed in 
Table 3. In the HER2 3+ and PD-L1+ GC population (n=25), responses were observed in 11 
(44.0%) patients.
Table 3
Efficacy Results in Gastric Cancer Population by Biomarker 
Expression
N 
ORR (cCR+cPR), 
n (%) 
[95% CI] 
DCR (cCR+cPR+SD), 
n (%) 
[95% CI] 
Response evaluable population a, b 
92 
17c (18.48) 
[11.15−27.93] 
49 (53.26) 
[42.56−63.74] 
HER2 IHC3+ 
71 
17 (23.94) 
[14.61−35.54] 
44 (61.97) 
[49.67−73.24] 
HER2 IHC2+ 
21 
0 
5 (23.81) 
[8.22−47.17] 
PD-L1+ 
33 
11 (33.33) 
[17.96−51.83] 
22 (66.67) 
[48.17−82.04] 
PD-L1− 
43 
3 (6.98) 
[1.46−19.06] 
19 (44.19) 
[29.08−60.12] 
HER2 IHC3+ & PD-L1+ c
25 
11 (44.00) 
[24.40−65.07] 
18 (72.00) 
[50.61−87.93] 
HER2 IHC2+ & PD-L1− 
9 
0 
0 
HER2 IHC3+ & PD-L1− 
34 
3 (8.82) 
[1.86−23.68] 
19 (55.88) 
[37.89−72.81] 
HER2 IHC2+ & PD-L1+ 
8 
0 
4 (50·00) 
[15·70−84·30] 
ERBB2amp+ (by ctDNA) 
48 
15 (31.25) 
[18.66−46.25] 
31 (64.58) 
[49.46−77.84] 
ERBB2amp− (by ctDNA) 
34 
2 (5.88) 
[0.72−19.68] 
13 (38.24) 
[22.17−56.44] 
a.
Confirmed responses only are included in this table; there were 3 additional unconfirmed responses.
b.
Patients who received at least one dose of margetuximab at the 15 mg/kg IV q3w dose and had baseline
measurable disease.
c.
One cCR was observed in double-positive (HER2 IHC3+ & PD-L1+) subgroup.
BL=baseline; cCR=confirmed complete response; cPR=confirmed partial response; DCR=disease control 
rate; ctDNA=circulating tumor DNA; ERBB2amp=ERBB2 amplifications; HER2=human epidermal 
growth factor receptor 2; IHC=immunohistochemistry; ORR=objective response rate; PD-L1=programmed 
death-ligand 1; SD=stable disease. 
Based on efficacy results in the double-positive population from CP-MGAH22-05, combined 
INCMGA00012 (also known as retifanlimab) and margetuximab in double-positive first-line 
patients may be comparable to standard treatment with trastuzumab and chemotherapy. 
Patients in Cohort A (chemotherapy-free regimen) will be required to be HER2 ICH 3+, since 
Confidential
Page
28
of
129

Margetuximab, INCMGA00012, MGD013
MacroGenics, Inc.
Clinical Trial Protocol: CP-MGAH22-06
Amendment 5, 06 June 2022
this was identified as the population with the highest disease control rate (DCR) in Study CP-
MGAH22-05.
Recent data from a study of trastuzumab plus pembrolizumab plus XELOX chemotherapy in 
the first-line setting was published (32). All of the 24 evaluable patients had tumor regression 
(ranging from -22% to -100%). The Response Evaluation Criteria in Solid Tumours version 
1.1 (RECIST v1.1) ORR was 83% (95% CI 63%-95%) (17 PR, 3 CRs), and median PFS 11.4 
(95% CI 6-15) months. A Phase 3 clinical trial to evaluate pembrolizumab vs placebo in 
combination with trastuzumab and chemotherapy has been initiated. 
INCMGA00012 is a humanized, hinge-stabilized, IgG4κ mAb that recognizes human PD-1. 
INCMGA00012 contains a hinge-stabilized human IgG4 Fc domain to limit effector function, 
while retaining neonatal FcR (FcRn) binding to extend circulating half-life. INCMGA00012 
binds to PD-1 expressing cells in a dose-dependent manner. Consistent with its specific 
binding properties and designed mechanism of action, INCMGA00012 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. These properties of INCMGA00012 are comparable to those 
observed with replicas of the approved anti–PD-1 mAbs, nivolumab and pembrolizumab 
(Table 4). INCMGA00012 also blocks the PD-1/PD-L1 inhibitory axis (measured with a 
luciferase reporter assay system) in a dose-dependent manner that is comparable to those 
observed with the nivolumab and pembrolizumab replicas (Table 4).
Table 4
Comparison of In Vitro Potencies of INCMGA00012 and Nivolumab 
and Pembrolizumab Replicas
Property
EC50 (or IC50) Values (µg/mL) 1 
Mean ± SEM
INCMGA00012
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 
EC50 = effective concentration at 50% of maximal activity; IC50 = effective concentration at 50% inhibition of 
activity. 
In vitro studies revealed that margetuximab, incubated with human PBMCs and HER2+ 
gastric tumor cells, enhances PD-1/PD-L1 axis expression and LAG-3 on NK and NKT cells 
(Figure 1). Moreover, blockade of PD-1 by INCMGA00012 enhances margetuximab-
dependent induction of NK cell activation, proliferation, and cytolytic potential.
The safety, tolerability, and preliminary efficacy of INCMGA00012 has been explored in a 
Phase 1 study, CP-MGA012-01 as described in Section 2.6.1.
Confidential
Page
29
of
129

Margetuximab, INCMGA00012, MGD013
MacroGenics, Inc.
Clinical Trial Protocol: CP-MGAH22-06
Amendment 5, 06 June 2022
Combination with Anti–PD-1 and Anti–LAG-3
In mice bearing HER2+ tumors (CT26-HER2 tumors), the antitumor activity mediated by a 
poxvirus-based HER2 vaccine (MVA-BN-HER2: poxvirus vaccine with an engineered HER2 
tumor-associated antigen vector) was accompanied by upregulation of PD-L1 expression in 
the tumor microenvironment. The antitumor activity mediated by the HER2 vaccine was 
enhanced when combined with PD-1 blockade. Additional administration of anti–LAG-3 and 
anti–PD-L1 mAbs led to complete regression of CT26-HER2 tumors (16). In other models, 
LAG-3 expression was upregulated with anti–PD-L1 therapy, possibly as a compensatory 
measure (1, 29, 62).
When PBMCs and HER2 IHC 3+ N87 cells are incubated with margetuximab, NK cells and 
NKT cells are induced to express elevated levels of PD-1 and LAG-3 (Figure 1). By 
contrast, an Fc null variant of margetuximab was much less effective, indicating that PD-1 
and LAG-3 induction is Fc-dependent. Blockade of PD-1 and LAG-3 by MGD013 may 
enhance the Fc-dependent, effector cell-mediated activities of margetuximab, such as ADCC.
Figure 1
Margetuximab-Dependent Induction of PD-1 and LAG-3 on NK 
NKT Cells
Human PBMC and N87 (HER2 3+ GC) cells were incubated (E:T ratio 15:1) with margetuximab or an Fc 
null variant of margetuximab at 50-100 ng/mL for the indicated number of days and percentages of NK 
cells (CD56+CD3+) or NKT cells (CD56+CD3+) that were positive for PD-1 or LAG-3 were determined.
NK Cells: PD-1 
NK Cells: LAG-3 
20 
60 
/ 
!I> 
.... Marge1wdma 
.~ 
1 / 
.~ 
.. ;:~r~~:tima!} 
:= 
:= 
"' 
<10 
"' 
C 
0 
CL 
CL 
10 
M 
0 20 
ct 
5 
..I 
,!!. 
--------
* 
0 
0 
,0 
2 
3 
4 
0 
;i 
Days 
Days 
NKT Cells: P0-1 
NKT Cells: AG-3 
60 
40 
!I> 
!I> 
.2: 
.2: 
30 
i 
40 
i 
C 
C 
CL 
CL 
M 
20 
... 
0 
20 
ct 
CL 
..I 
10 
0 
0 
0 
2 
3 
4 
5 
0 
2 
3 
d 
5 
1Days 
Days 
Confidential
Page
30
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
In an initial efficacy study of the combination of nivolumab and the LAG-3 inhibitor BMS-
986016 was evaluated in 55 heavily pretreated patients with melanoma. Patients had either 
relapsed while receiving anti–PD-1/PD-L1 directed therapy or had disease progression while 
receiving an anti–PD-1/PD-L1 directed therapy. In the 41 patients with radiographically 
evaluable efficacy, 15 patients experienced a reduction in tumor burden. The ORR was 13% 
(confirmed and unconfirmed) and DCR was 54%, with benefit observed in some patients 
refractory to prior anti–PD-1. The safety profile of the combined treatment is similar to 
nivolumab monotherapy (2). 
MGD013 (also known as tebotelimab) is a humanized Fc-bearing bispecific tetravalent 
(bivalent for each antigen) DART® protein engineered as a hinge-stabilized IgG4 molecule 
and is designed to concomitantly bind PD-1 and LAG-3. MGD013 is derived from the 
humanized murine proprietary mAb clones, MG13.78 (anti–PD-1) and MG14.99 (anti–
LAG-3), which were generated using standard hybridoma technology from mice immunized 
with a His-tagged, human PD-1 extracellular domain molecular and human LAG-3 
extracellular domain molecule. MGD013 contains a hinge-stabilized IgG4 molecule to limit 
effector function, while retaining FcRn binding to extend circulating half-life. MGD013 is 
produced in Chinese hamster ovary cells. The molecular weight of the molecule is 
approximately 166.7 kDa. MGD013 is cross-reactive with both human and cynomolgus 
monkey PD-1 and LAG-3 proteins. 
MGD013 is designed to bind concomitantly to PD-1 and LAG-3, 2 checkpoint molecules 
expressed by T (CD4+ and CD8+) lymphocytes, and to inhibit their interaction with their 
respective ligands, PD-L1 or PD-L2 and MHC-II. Upon interaction with their respective 
ligands, PD-1 and LAG-3 act as negative regulators of T-cell function. PD-1 and LAG-3 
expression on tumor infiltrating lymphocytes (TILs) or chronically viral-infected T cells have 
been correlated with immune dysfunction, also known as “T cell exhaustion.” Thus, by 
inhibiting PD-1 and LAG-3 interaction with their ligands, MGD013 can potentially reverse 
T cell inhibitory effects mediated by PD-1 and LAG-3, leading to restoration of the function 
of exhausted T cell and enhanced antitumor immunity. 
Consistent with its specific binding properties, MGD013 blocked the binding of 
PD-L1 and PD-L2 to cell surface–expressed PD-1 and blocked the binding of LAG-3 to 
cell surface–expressed MHC-II. MGD013 directly blocked the PD-1/PD-L1 inhibitory axis, 
as measured by a co-culture reporter assay system, in which disruption of PD-1/PD-L1 
interactions between the 2 cell lines resulted in enhanced TCR-mediated NFAT-driven 
luciferase signaling by the PD-1 expressing cell line. MGD013 also demonstrated the ability 
to enhance interferon-gamma (IFN-γ) secretion by human PBMCs stimulated with 
staphylococcal enterotoxin B (SEB) or memory T cells stimulated with tetanus toxoid (TTd) 
beyond that observed with an equimolar combination of replicas for nivolumab (anti–PD-1) 
and BMS-986016 (anti–LAG-3). The nivolumab and BMS-986016 replicas were constructed 
as IgG4κ molecules by MacroGenics based on published sequences. 
Thus, MGD013 is functionally active in interfering with the PD-1 – PD-L1/PD-L2 and 
LAG-3/MHC-II inhibitory signaling pathways. Although the binding properties of MGD013 
were comparable to those of the replicas of nivolumab and BMS-986016, the functional 
properties of MGD013 were greater than those achieved by the combination of the nivolumab 
Confidential
Page
31
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
and BMS-986016 replicas, suggesting that MGD013 may offer additional effects beyond 
those observed with the combination of antibodies. 
Safety, tolerability, and preliminary efficacy of MGD013 has been explored in a Phase 1 
study, CP-MGD013-01, as described in Section 2.7.1. 
We hypothesize that dual blockade targeting of PD-1 and LAG-3 will increase effectiveness of 
margetuximab by enhancing innate and adaptive immune responses against HER2 
overexpressing tumor cells. 
2.4.3 
Chemotherapy Backbone Treatment  
Based on the ToGA study, trastuzumab has been approved for use in combination with 
fluoropyrimidine plus cisplatin for the treatment of HER2+ advanced GC (4). Combination 
therapy of trastuzumab and XELOX showed comparable efficacy and tolerability to the ToGA 
regimen of 5-fluorouracil (5-FU) and cisplatin (FP) or capecitabine and cisplatin (XP) in 
multicenter Phase 2 study (48). Modified fluorouracil, leucovorin, and oxaliplatin 
(mFOLFOX-6) and XELOX are commonly used regimen for first-line HER2 positive GC and 
GEJ cancer patients worldwide (39, 61). The previous studies showed similar efficacy and 
safety profile in trastuzumab combination with mFOLFOX-6 or XELOX regimen (48, 54). 
2.5 
Margetuximab Background Information  
2.5.1 
Margetuximab Clinical Experience  
Margetuximab has been, or is currently being, evaluated in 4 clinical studies. As of 23 
February 2019, 763 patients have been enrolled in trials investigating margetuximab. 
Overall, most adverse effects noted in patients participating in clinical investigations of 
margetuximab (single-agent and combination studies combined, excluding the EAP [n=758]) 
have been mild (Grade 1) to moderate (Grade 2) in severity. Cumulatively, in the single-agent 
studies, the most frequently reported AEs, regardless of causality, include nausea (24.2%), 
fatigue (23.1%), vomiting (19.8%), infusion-related reaction (18.7%), diarrhea (17.6%), and 
anemia (17.6%). The most frequently reported AEs in the ongoing randomized portion of the 
study CP-MGAH22-04 in patients treated with margetuximab plus chemotherapy include 
fatigue (39.8%), nausea (31.8%), neutropenia (28.4%), diarrhea (24.2%), and anemia (18.6%). 
Adverse events occurring with a ≥5% higher incidence among patients treated with 
margetuximab plus chemotherapy compared with those treated with trastuzumab plus 
chemotherapy include neutropenia (28.4% vs 19.5%), vomiting (19.7% vs 14.3%), asthenia 
(17.05% vs 11.7%), and infusion related reaction (12.9% vs 3.8%). Infusion-related reactions 
(including the terms infusion related reaction and cytokine release syndrome [CRS]) have 
occurred in 76 of 492 (15.4%) patients administered margetuximab in MacroGenics-
sponsored clinical studies.   
The combination of margetuximab with immune CPI pembrolizumab is being evaluated in 
ongoing Study CP-MGAH22-05, where safety data are available through 10 July 2019. 
TRAEs irrespective of grade were reported in 63.2% (60/95) of patients, and 20.0% (19/95) 
Confidential
Page
32
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
had a TRAE grade ≥3. The most common TRAEs occurring in ≥10% of patients were pruritus 
(n=16; 16.8%), diarrhea (n=14; 14.7%), infusion-related reaction (IRR; n=13; 13.7%), and 
fatigue (n=13; 13.7%). Serious grade 3 TRAEs were: autoimmune hepatitis (n=2), 
pneumonitis (n=1), hyponatremia (n=1), diabetic ketoacidosis (n=1), hypotension (n=1), IRR 
(n=1), and dehydration (n=1) and grade 2 dizziness (n=1). TRAEs of special interest were 
hyperthyroidism (n=3), adrenal insufficiency (n=3), autoimmune hepatitis (n=2), pneumonitis 
(n=2), left ventricular ejection fraction dysfunction (n=2), diabetes mellitus (n=1), 
hyperglycemia (n=1), and hypothyroidism (n=1). There were no grade 5 TRAEs reported. 
Margetuximab has demonstrated an acceptable safety profile as monotherapy and in 
combination with chemotherapeutic agents or an anti–PD-1 antibody (pembrolizumab). Refer 
to the currently effective version of the Margetuximab Investigator’s Brochure for details 
on its safety profile. 
2.5.2 
Margetuximab Clinical Pharmacokinetics  
Steady-state exposure estimates are shown in Table 5 for margetuximab when dosed at 
6.0 mg/kg weekly for 3 of every 4 weeks (Q4W) (n = 19), 15.0 mg/kg every 3 weeks (Q3W) 
(n = 6), and 18.0 mg/kg Q3W (n = 6) in Study CP-MGAH22-01. At steady state, these doses 
and regimens are estimated to have very similar exposure. Serum trough concentrations 
(Ctrough) for all 3 doses are nearly identical, are at or above those reported for trastuzumab in 
patients with breast cancer (22), and are above that required for inhibition of HER2 signaling 
as demonstrated for trastuzumab in published reports (11). Similarly, area under the 
concentration-time curve (AUC) values are also very similar, with the 15.0 mg/kg slightly 
lower than either 6.0 mg/kg or 18.0 mg/kg. Maximum concentration (Cmax) differs among the 
3 doses, as would be expected with higher maximal concentrations seen in the 15.0 mg/kg and 
18.0 mg/kg doses compared with 6 mg/kg. 
 
 
Confidential
Page
33
of
129

Margetuximab, INCMGA00012, MGD013
MacroGenics, Inc.
Clinical Trial Protocol: CP-MGAH22-06
Amendment 5, 06 June 2022
Table 5
Margetuximab Pharmacokinetics at Steady State: 6 mg/kg, 
15 mg/kg, and 18 mg/kg – CP-MGAH22-01
Parameter 
(unit)
Margetuximab Dose and Schedule
6 mg/kg QW a
N = 19
15 mg/kg Q3W b 
N = 6
18 mg/kg Q3W b 
N = 6
Ctrough 
(µg/mL) 
Mean 
(SD) 
73.0 
(38.2) 
69.9 
(42.9) 
86.1 
(47.9) 
Median 
(95% CI) 
66.9 
(20.5 - 169) 
61 
(15.8 - 180) 
77.6 
(20.8 - 207) 
Cmax 
(µg/mL) 
Mean 
(SD) 
217 
(58.1) 
360 
(93.9) 
429 
(103) 
Median 
(SD) 
211 
(125 - 355) 
345 
(222 - 590) 
417 
(263 - 660) 
AUC 
(µg/mL*h) 
Mean 
(SD) 
84700 
(30000) 
72200 
(27200) 
87500 
(30300) 
Median 
(95% CI) 
80500  
(40700 - 15800) 
66800 
(35300 - 139000) 
82200 
(43600 - 160000) 
a.
Dosed once weekly (QW) for 3 weeks in 4-week (28-day) cycles
b.
Dosed once every 3 weeks (Q3W) in 3-week (21-day) cycles.
SD = standard deviation 
Clinical pharmacokinetics (PK) of margetuximab was also investigated by tumor type. 
Median total body clearance (CL), volume of distribution at steady state (VD), and t1/2 values 
and associated percentile intervals suggested that the PK of margetuximab was similar in 
patients with gastric, breast, and other tumor types (Table 6).
Table 6
Summary of Disposition Parameters for Patients Administered 6 to 
18 mg/kg Margetuximab Doses
Tumor Type
Median BW
(kg)
Statistic
CL
(mL/h/kg)
VD 
(mL/kg)
t1.2
(h)
Gastric 
67.3 
Median 
0.18 
94.5 
387.1 
Q05-Q95 
0.13-0.26 
59.0-144.2 
262.7-481.6 
Q10-Q90 
0.14-0.24 
75.0-128.8 
264.2-467.0 
Breast 
59.9 
Median 
0.15 
77.4 
389.4 
Q05-Q95 
0.12-0.31 
58.8-127.7 
173.5-629.4 
Q10-Q90 
0.12-0.25 
61.2-120.3 
303.2-537.7 
Other 
63.0 
Median 
0.17 
88.1 
348.1 
Q05-Q95 
0.13-0.35 
62.6-110.3 
211.6-546.6 
Q10-Q90 
0.14-0.33 
66.9-108.4 
239.5-478.1 
Source: Population PK Report for CP-MGAH22-01
Abbreviations: BW = body weight; CL = total body clearance; Qx = x percentile of the distribution; 
t1/2 = terminal elimination half-life; VD = volume of distribution at steady state
NOTE: Median BWs are estimations
2.5.3 
Margetuximab Nonclinical Experience 
Margetuximab was well tolerated in male and female cynomolgus monkeys when 
administered by intravenous (IV) infusion at a single dose of 50 mg/kg and at 6-weekly doses 
of 0, 15, 50, or 150 mg/kg and supports a no-observed-adverse-effect level of 150 mg/kg. 
Confidential
Page
34
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
Thirteen weeks of margetuximab dosing (0, 15, 50, and 100 mg/kg) was well tolerated with 
the exception of 1 moribund animal (100 mg/kg). Findings suggested decreased red cell 
production and/or hemolysis; however, a clear mechanism could not be determined and 
similar findings were not observed for any other animals receiving margetuximab. There have 
been no cardiac-related toxicities, including no margetuximab-related changes in serum 
concentrations of troponin I, electrocardiogram (ECG) assessments, or gross or microscopic 
findings in heart tissue. 
No carcinogenicity, mutagenicity, or fertility studies have been conducted for margetuximab. 
In an enhanced pre- and postnatal development (ePPND) toxicology study, pregnant 
cynomolgus monkeys received 0, 50, or 100 mg/kg margetuximab by IV infusion starting on 
gestational day (GD) 20, Q3W until infant delivery. Consistent with other biologics in this 
pharmacological class, treatment with margetuximab during pregnancy resulted in 
oligohydramnios beginning on GD 75 in maternal animals administered 50 mg/kg (44% 
incidence) or 100 mg/kg (82% incidence). The majority of infants had decreased kidney 
weights and microscopic findings of immature nephrons that frequently correlated with 
increased concentrations of serum urea nitrogen and creatinine. One female infant (mother 
received 100 mg/kg) was sacrificed in moribund condition on maturation phase Day 63, 
which was attributed to margetuximab-related kidney degeneration.  
Please refer to the currently effective version of the Margetuximab Investigator’s Brochure 
for additional details. 
2.6 
INCMGA00012 Background Information  
2.6.1 
INCMGA00012 Clinical Experience  
Retifanlimab (INCMGA00012) is a humanized, hinge-stabilized, IgG4κ monoclonal antibody 
that recognizes human PD-1. Retifanlimab contains a human IgG4 Fc domain to limit effector 
function while retaining neonatal Fc receptor binding to extend circulating half-life. 
Retifanlimab is designed to target PD-1–expressing cells, including T cells, and sustain or 
restore their effector function by blocking checkpoint inhibitory interactions between PD-1 
and its 2 ligands, PD-L1 and PD-L2. 
In vitro studies with retifanlimab have demonstrated high affinity binding to both recombinant 
human and cynomolgus monkey PD-1 as well as to PD-1 expressed on the cell surface. 
Consistent with its intended mechanism of action and functional properties, retifanlimab has 
been shown to inhibit the binding of PD-L1 and PD-L2 to PD-1, to disrupt the PD-1–PD-L1 
inhibitory axis, and to enhance IFN-γ secretion in SEB-stimulated human PBMCs with 
activity comparable to pembrolizumab and nivolumab replicas (generated by MacroGenics, 
Inc. based on the published sequences of these antibodies). Retifanlimab does not induce 
ADCC or CDC, mitogenic activity, hemolysis, or cytokine release. 
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. 
Confidential
Page
35
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
As of 23 Sep 2021, 818 unique participants have been exposed to retifanlimab as 
monotherapy (660 participants), in combination with epacadostat (97 participants), in 
combination with pemigatinib (19 participants), in combination with parsaclisib (22 
participants), in combination with INCB001158 (6 participants), in combination with 
INCB081776 (3 participants), or in combination with INCAGN02385 and INCAGN02390 (11 
participants). Additionally, 427 participants have been exposed to retifanlimab or placebo in 
blinded studies (INCMGA 0012-303 [57 participants] and INCMGA 0012-304 [370 
participants]). Retifanlimab was administered as a monotherapy in 6 ongoing clinical trials at 
doses of 1 mg/kg Q2W, 3 mg/kg Q2W, 3 mg/kg Q4W, 10 mg/kg Q2W, 10 mg/kg Q4W, 375 
mg Q3W, 500 mg Q4W, and 750 mg Q4W. The most frequently reported TEAEs were 
asthenia (17.3%), fatigue (16.1%), and diarrhea (15.9%). The most frequently reported serious 
TEAEs were urinary tract infection (2.1%), pneumonia (1.8%), and abdominal pain (1.5%). 
None of the serious TEAEs with a fatal outcome occurred in more than 1 participant. Fatal 
TEAEs that were considered related to retifanlimab by the investigator were lymphangiosis 
carcinomatosa, concomitant disease progression, tumor hyperprogression, and nephritis. 
Immune-related AEs occurred in 181 participants, including in 130 participants (28.3%) 
receiving 500 mg Q4W retifanlimab monotherapy. The most frequent irAE was 
hypothyroidism (9.2%). The most frequent nonendocrine irAE was skin reactions (7.1%). 
Most irAEs were Grade 1 or 2 in severity. The most frequent Grade 3 or higher irAEs were 
acute kidney injury and pneumonitis (0.9% each). Infusion-related reactions were infrequent 
(7.0%). All infusion-related reactions were Grade 1 or 2 in severity with the exception of 2 
Grade 3 events in 2 participants (0.3%). The overall safety profile of retifanlimab is as 
expected for a PD-L1 inhibitor. 
Retifanlimab has shown clinical activity as monotherapy against a variety of solid tumors, 
including lung, urothelial, renal, Merkel cell, anal squamous, cervical, and endometrial 
carcinomas, as well as melanoma (6, 7, 24, 25, 40, 47). This activity is representative of the 
PD-(L)1 inhibitor class. 
2.6.2 
INCMGA00012 Nonclinical Experience  
In a single-dose PK study, administration of INCMGA00012 by 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 
INCMGA00012 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, INCMGA00012 was administered at dose levels of 0 -
150 mg/kg to cynomolgus monkeys. All the infusions were well tolerated. There were no 
preterm deaths nor treatment-related toxicities. The only findings related to INCMGA00012 
were modest decreases in lymphocytes after the first infusion and microscopic changes at the 
IV administration site consistent with effects of repeated injections. 
Please refer to the currently effective version of the INCMGA00012 Investigator’s 
Brochure for additional details. 
Confidential
Page
36
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
2.7 
MGD013 Background Information  
2.7.1 
MGD013 Clinical Experience  
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 MGD013 given by IV infusion on a 
Q2W schedule. 
Dose Escalation 
As of a data-cutoff date of 01 October 2019, 49 patients with diverse solid tumor types have 
been treated in Dose Escalation with MGD013 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 MGD013 (120 mg, 400 mg, and 600 mg) have been evaluated specifically in patients with 
advanced hepatocellular carcinoma (n=9). 
Forty-eight of 49 (98.0%) patients treated with MGD013 monotherapy in Dose Escalation 
experienced at least one AE, irrespective of attribution. Common AEs, reported in > 15% 
of patients, include fatigue (n=13 [26.5%]); nausea, vomiting, and abdominal pain 
(n=11 [22.5%] each); constipation, pyrexia, and pruritus (n = 10 [20.4%] each); diarrhea 
(n=9 [18.4%]); and chills (n=8 [16.3%]). 
TRAEs have been reported in 39 of 49 patients (79.6%) treated in Dose Escalation. Common 
TRAEs include fatigue (n=9 [18.4%]); nausea (n=8 [16.3%]); pruritus (n=7 [14.3%]); IRR 
and rash (n=6 [12.2%] each); and diarrhea, vomiting, pyrexia, and chills (n=5 [10.2%] each). 
Other potential irAEs observed less commonly include hypothyroidism (n=4 [8.2%]); 
arthralgia, AST increased, and lipase increased (n=3 [6.1%] each); immune-mediated 
hepatitis, hyponatremia, and myalgia (n=2 [4.1%] each); and hyperthyroidism, adrenal 
insufficiency, colitis, stomatitis, ALT increased, and transaminases increased (n=1 [2.0%] 
each). 
The majority of TRAEs observed in Dose Escalation have been mild-to-moderate in severity 
(i.e., Grade 1 or Grade 2). Eleven of 49 patients (22.4%) treated in Dose Escalation have had 
at least one Grade 3 TRAE. These events include IRR and lipase increased (n=2, each) and 
anemia, adrenal insufficiency, diarrhea, colitis, vomiting, fatigue, immune-mediated hepatitis, 
amylase increased, transaminases increased, hypophosphatemia, arthritis, myalgia, rash, and 
pruritus (n=1, each). Additionally, 1 other patient treated in the limited HCC dose escalation at 
120 mg experienced Grade 4 elevations of amylase and lipase with no clinical or radiographic 
signs or symptoms of pancreatitis. No patients have experienced a Grade 5 TRAE. 
SAEs were limited to 10 of 49 patients (20.4%) treated with MGD013 in Dose Escalation. 
Five patients (10.2%) had a treatment-related SAE, including immune-mediated hepatitis 
Confidential
Page
37
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
(n = 2, 400 mg and 1200 mg); colitis (n = 1, 800 mg); adrenal insufficiency (n = 1, 400 mg); 
hypophosphatemia (n = 1, 400 mg), and anemia (n=1, 400 mg). SAEs assessed not to be 
related to MGD013 include abdominal pain, pyrexia, lung infection, urinary tract infection, 
small intestinal obstruction, dyspnea, inappropriate antidiuretic hormone secretion, and 
pulmonary hemorrhage. These events were related to the respective patients’ underlying 
malignancies or comorbid conditions. 
The dose of 600 mg Q2W was chosen to carry forward in the Cohort Expansion Phase. This 
decision was based on the totality of clinical, PK, and receptor occupancy data. Within 
Dose Escalation, MGD013 demonstrated antitumor activity with acceptable tolerability. The 
MTD was not defined or exceeded, and 1200 mg represents the maximum dose level to be 
administered in Study CP-MGD013-01. Three patients (TNBC, mesothelioma, and GC) 
experienced confirmed partial responses (PRs), while 18 other patients with various tumor 
types had stable disease as a best response.  
Cohort Expansion 
As of 01 October 2019, 150 patients with advanced cancer have been treated with MGD013 
600 mg Q2W. One hundred thirty-two of the 150 patients (88.0%) experienced at least one 
AE, irrespective of attribution. Common AEs, reported in > 10% of patients, include fatigue 
(n=36 [24.0%]); anemia, nausea, and decreased appetite (n=20 [13.3%] each); dyspnea (n=18 
[12.0%]), vomiting, and AST increased (n=16 [10.7%] each); and abdominal pain, 
constipation, and pyrexia (n=15 [10.0%] each). 
TRAEs have been observed in 94 of 150 patients (62.7%) treated with MGD013 monotherapy 
in Cohort Expansion. The only TRAE occurring in > 10% of patients is fatigue (n=27 
[18.0%]). Potential irAEs and other notable TRAEs observed less commonly include rash 
(n=13 [8.7%]); IRR and AST increased (n=10 [6.7%] each); hyperthyroidism and lipase 
increased (n=9 [6.0%] each); ALT increased (n=8 [5.3%]); amylase increased, arthralgia, and 
hypothyroidism (n=7 [4.7%] each); headache (n=5 [3.3%]); hyponatremia, myalgia, 
confusional state, and hyperbilirubinemia (n=3 [2.0%] each); and pancytopenia, CRS, 
immune-mediated hepatitis, and pneumonitis (n=1 [0.7%] each). The majority of TRAEs have 
been mild to moderate in severity (i.e., Grade 1 or Grade 2), and 31 of the 150 patients 
(20.7%) have had at least one Grade ≥ 3 TRAE. 
SAEs have been limited to 47 of 150 patients (31.3%) treated with MGD013 monotherapy in 
Cohort Expansion. Fifteen patients (10.0%) experienced a treatment-related SAE, including 
the following events:  diarrhea and IRR (n=2, each) and anemia, pancytopenia, 
hyperthyroidism, small intestinal hemorrhage, pyrexia, immune-mediated hepatitis, CRS, 
headache, confusional state, immune-mediated pneumonitis, and hypotension (n=1, each). 
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 
observed are consistent with the mechanism of action of MGD013, 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 
Confidential
Page
38
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
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. 
Although it is premature for definitive conclusions regarding the efficacy of MGD013 in the 
multiple tumor types being evaluated, early signs of antitumor activity have been observed in 
Cohort Expansion. Objective responses have been reported in epithelial ovarian cancer (n=2), 
NSCLC (n=3), TNBC (n=1), and DLBCL (n=2), and a substantial proportion of response 
evaluable patients (46.9%) have experienced stable disease as a best response. 
HER2+ Combination Cohort 
Within CP-MGD013-01, a separate cohort of patients with HER2+ solid tumors is being 
treated with margetuximab (anti-HER2 mAb) 15 mg/kg in combination with escalating doses 
of MGD013 (300 mg and 600 mg) on a Q3W schedule. As of 10 January 2020, 10 patients 
have been treated with this combination, including 3 at the first dose level (MGD013 300 mg) 
and 7 patients at the top dose level (MGD013 600 mg).  
The MGD013 plus margetuximab combination has been well tolerated among patients treated 
to date. Both dose levels were cleared in a 3+3 dose escalation scheme with no observed 
DLTs, and additional patients are currently being treated at the top dose level. No treatment-
related SAEs have occurred, and the solitary Grade ≥ 3 TRAE occurred in one patient at the 
300 mg dose level who experienced Grade 3 AST elevation which occurred in the setting of 
liver metastasis, and the transaminitis recovered to baseline with oral corticosteroid treatment. 
Although the data are immature, initial tumor assessments of the response-evaluable 
population (n=6) have demonstrated early signs of antitumor activity. Two breast cancer 
patients have had partial responses (PRs), one confirmed. One of these patients, with 
extensive chest wall involvement, experienced dramatic disease regression 2 weeks after a 
single administration of the combination, with a confirmed PR demonstrated at subsequent 
disease assessments. Other patients have had stable disease (n=2) and progressive disease 
(n=2) as best response.  
2.7.2 
MGD013 Nonclinical Experience  
MGD013-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. 
Single- and multiple-dose studies with selected toxicological endpoints were conducted in 
cynomolgus monkeys. MGD013 was administered at 0 to 150 mg/kg by a 1-hour IV infusion. 
All the infusions were well tolerated. There were no preterm deaths. Infusion of MGD013 did 
not induce an increase in serum concentrations of IFN-γ, IL-2, IL-4, IL-5, or TNF-α. Transient 
Confidential
Page
39
of
129

Margetuximab, INCMGA00012, MGD013
MacroGenics, Inc.
Clinical Trial Protocol: CP-MGAH22-06
Amendment 5, 06 June 2022
increases in IL-6 levels were observed. MGD013 occupancy is detectable in circulating 
T cells that express PD-1. 
Please refer to the currently effective version of the MGD013 Investigator’s Brochure for 
additional details.
2.8 
Dose Selection 
2.8.1 
Margetuximab Dose Selection 
The margetuximab dose and schedule selected, 15.0 mg/kg, infused over 120 minutes Q3W, is 
based on the observed safety and efficacy profile of margetuximab at all doses tested to date 
and the predictable PK characteristics. A dose of 15 mg/kg is the recommended Phase 3 dose 
in the ongoing breast cancer study (CP-MGAH22-04) and the recommended dose for an 
ongoing study in combination with pembrolizumab (CP-MGAH22-05). 
The feasibility of a reduced infusion duration of margetuximab at Cycle 2 and thereafter was 
explored in a sub-study of CP-MGAH22-04. Patients were enrolled into the study in 3 stages, 
as depicted in Figure 2. Margetuximab was administered at a dose of 15 mg/kg after 
receiving an Investigator’s choice of chemotherapy. Patients, initially dosed with a Cycle 2 
60-minute infusion, were eligible for further reduction in infusion duration to 30 minutes at 
the end of Stage A2.
Figure 2
CP-MGAH22-04 Sub-study Schema
No patients experienced ≥ Grade 3 infusion-related reactions (IRRs) in Stages A1 and A2. The 
Stage B Cycle 2 target infusion duration was confirmed at 30 minutes. As of the 17-Jun-2019 
cutoff date, 88 subjects enrolled to the CP-MGAH22-04 Infusion Substudy, and 79 received 
accelerated infusions at or after Cycle 2. Of 88 enrolled, 37 subjects remained on the study, 14 
died, 13 had SAEs, and 3 discontinued due to adverse events (AEs). Of 88 enrolled, 18 had a 
first-cycle IRR, none of which were ≥ Grade 3. One patient had an IRR in Cycle 2. This 
nonrandomized cohort study remains ongoing. Summary information on cumulative exposure 
is displayed in Table 7.
S t.O:!!C B . cenario I 
Cycl; I : 120 minutes: 
Cycle 2: 30 minutes 
m~e 
yclc I : 120 min,11e : 
Cycle 2: 60 minutes 
,:; ? GrndeJ+ IRI! 
ilt C)<le 2 
,:; 2 Grs <l c J+ 11!1! • • Cydt 2 
Srngc B Sccn:lrio 2 
Cyc le I: 120 minutes: 
yclt 2: 60 minutes 
Sub-s1udy 
stoppod 
Confidential
Page
40
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
Table 7 
CP-MGAH22-04 Infusion Sub-study Cumulative Exposure 
(Safety Population) 
Number (%) of Patients with an Observation 
Total 
(N=88) 
Enrolled Study Stage A1 
8 (9.1) 
Enrolled Study Stage A2 
9 (10.2) 
Enrolled Study Stage B 
71 (80.7)a 
Subject Exposure 
 
Stage A1 
 
Cycle 1 (120 minutes) 
8 (9.1) 
Cycle 2 (60 minutes) 
7 (8.0) 
Stage A2 
 
Cycle 1 (120 minutes) 
9 (10.2) 
Cycle 2 (30 minutes) 
8 (9.1) 
Stage B 
 
Cycle 1 (120 minutes) 
69 (78.4) a 
Cycle 2 (30 minutes) 
68 (77.3) 
Data cutoff: 17-Jun-2019 
a 
Although 71 patients enrolled in Stage B, 2 did not complete Cycle 1 due to IRR, but did complete Cycle 2. Three 
patients did not complete Cycle 2, including 1 due to non-radiologic disease progression, 1 due to patient decision, 
and 1 due to septic shock.  
Abbreviations IRR: infusion related reaction; N: number of patients in dataset. 
The 30-minute infusion resulted in comparable PK to the 120-minute infusion in the 
randomized study. Based on median Ctrough, margetuximab is at steady-state by the end of 
Cycle 3 or in Cycle 4. Median Ctrough remains consistently above the putative threshold target 
concentration (30 mcg/mL) for margetuximab efficacy. Chemotherapy coadministration with 
margetuximab has no clinically meaningful effects on margetuximab PK (Ctrough and Cmax). 
Exposure was comparable across Stages A1, A2, and B. 
Two of 80 evaluable subjects (2.5%) developed anti-drug antibodies (ADA) on or after 
margetuximab therapy. No subjects developed neutralizing antibodies. ADA induction by 
margetuximab is modest. Accelerated 30-minute margetuximab infusions demonstrated 
acceptable safety and tolerability. There were no Grade 3 or higher IRRs in this Infusion 
Substudy. Starting from Cycle 2, IRRs during 30-minute infusions had similar incidence and 
character when compared to 120-minute infusions. Reduction of infusion duration to 30 
minutes for Cycle 2 and beyond does not adversely affect margetuximab safety or increase 
IRR risk or severity. 
Margetuximab can be safely administrated, alone or with chemotherapy, as a 120-minute 
infusion for Cycle 1 then 30-minute infusion for Cycle 2 and beyond. 
2.8.2 
INCMGA00012 Dose Selection  
Retifanlimab will be administered at 375 mg Q3W. The selection of this dose regimen was 
based on modeling of clinical PK data from 219 participants enrolled in the first in human 
monotherapy study, INCMGA 0012-101 (NCT03059823). Participants were treated with both 
Confidential
Page
41
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
body weight–based and flat doses of 1 mg/kg Q2W, 3 mg/kg Q2W, 3 mg/kg Q4W, 10 mg/kg 
Q2W, 10 mg/kg Q4W, 375 mg Q3W, 500 mg Q4W, and 750 mg Q4W. 
Pharmacokinetic data from Study INCMGA 0012-101 suggested that retifanlimab exposure 
increased in a dose-dependent manner with doses ranging from 1 to 10 mg/kg (including flat 
doses of 375 to 750 mg). Full and sustained PD-1 receptor occupancy was observed with all 
doses studied on both PD-1 expressing CD4+ and CD8+ cells. The PK of retifanlimab 
following IV administration was well characterized by a 2-compartment linear disposition 
model with time-dependent elimination. A population PK model estimated typical 
retifanlimab CL as 0.0127 L/h with a steady-state t½ of 18.4 days. Similar PK profiles were 
observed for the 3 mg/kg Q2W and 500 mg Q4W doses. 
Simulations demonstrated that the median steady-state trough concentration of retifanlimab 
500 mg Q4W and 375 mg Q3W was approximately 21.1 μg/mL, which is the median trough 
concentration for pembrolizumab 2 mg/kg Q3W (17). The 500 mg Q4W and 375 mg Q3W 
regimens also resulted in steady-state exposure that was similar to the 3 mg/kg Q2W regimen 
(Ctrough). In addition, full PD-1 receptor occupancy was observed on PD-1 expressing CD4+ 
and CD8+ cells with effects on circulating cytokines that are typical for a PD-1 inhibitor in all 
dose regimens of Study INCMGA 0012-101. Therefore, the 500 mg Q4W dose regimen was 
selected for further development in monotherapy treatments, and the 375 mg Q3W dose 
regimen was selected to facilitate the development of combination regimens, such as 
chemotherapy treatments, with a shorter cycle length. No meaningful exposure-response 
relationships have been demonstrated for either safety or efficacy. 
Pharmacokinetic data were obtained from 15 participants who received retifanlimab 375 mg 
Q3W in the cohort-expansion portion of Study INCMGA 0012-101. Following the first dose 
of the 375 mg Q3W regimen, retifanlimab had mean t½ (12.9 days) and CL (0.366 L/day) 
values comparable to those of the 500 mg Q4W and 750 mg Q4W doses. Furthermore, 
Ctrough at steady state following a 375 mg Q3W infusion was 43.0 ± 15.0 mg/L with the 
accumulation ratio at approximately 1.5, making this a comparable dose to 500 mg Q4W 
(Ctrough at steady state 58.7 ± 26.8 mg/L with the accumulation ratio at approximately 1.3). 
For more information, refer to the retifanlimab IB 
2.8.3 
MGD013 Dose Selection  
Within Dose Escalation, MGD013 demonstrated antitumor activity with acceptable 
tolerability up to a dose of 1200 mg without exceeding the MTD. Based on receptor 
occupancy data and other clinical data, a dose of 600 mg was selected for further study in 
monotherapy. MGD013 in combination with margetuximab was evaluated in a HER2+ solid 
tumor cohort in Study CP-MGD013-01. The safety and tolerability of the combination of 
MGD013 and margetuximab Q3W was confirmed and a dose of 600 mg of MGD013 will be 
used for combination treatment. 
Confidential
Page
42
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
2.8.4 
Chemotherapy  
Preferred chemotherapeutic treatments for first-line metastatic GC are a fluoropyrimidine 
(infusional 5-FU or oral 5-FU prodrug) in combination with cisplatin or oxaliplatin (41, 43, 
53). Modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX-6) and XELOX are 
commonly used regimen for first-line HER2 positive GC and GEJ cancer patients worldwide 
(39, 61). The previous studies showed similar efficacy and safety profile in trastuzumab 
combination with mFOLFOX-6 or XELOX regimen (48, 54). Table 9, in Section 6.1, 
describes the protocol-specific chemotherapy dose and schedule combinations with the 
standard dose of trastuzumab. 
2.9 
Risk and Benefit Assessment  
2.9.1 
Risk Assessment  
Study Risks 
Infusion-related reaction (IRR) is a known identified risk for margetuximab. As of 10 Jan 
2022, the IRR incidence rate for the combination of INCMGA00012/margetuximab with or 
without chemotherapy (across Cohorts A and B), the combination of 
MGD013/margetuximab+chemotherapy, and margetuximab+chemotherapy was: 12/56 
subjects (21.4%), 2/5 subjects (40.0%) and 3/8 subjects (37.5%), respectively. All IRRs were 
either Grade 1 or 2 except for one Grade 3 event reported with margetuximab+chemotherapy.  
The combination of margetuximab and INCMGA00012 or MGD013 can potentially increase 
the risk of cardiac toxicities. Decreased left ventricular ejection fraction (LVEF) is an 
important potential risk for margetuximab. As of 10 Jan 2022, the incidence rate of decreased 
LVEF for the combination of INCMGA00012/margetuximab with or without chemotherapy 
(across Cohorts A and B), the combination of MGD013/margetuximab+chemotherapy, and 
margetuximab+chemotherapy was: 3/56 subjects (5.3%), 0/5 subjects (0.0%) and 1/8 subjects 
(12.5%), respectively. One Grade 2 cardiac failure event (1/56 subjects; 1.8%) was reported 
with the combination of INCMGA00012/margetuximab therapy (across Cohorts A and B). 
The cardiac failure event occurred in Cohort A. No cardiac failure events have been reported 
with the combination of MGD013/margetuximab+chemotherapy or 
margetuximab+chemotherapy.  
Immune-related adverse events (irAEs) are important identified risks for INCMGA00012 and 
MGD013. Thus far, the incidence rate of irAEs in the combination of margetuximab and 
INCMGA00012 or MGD013 is comparable with other anti-PD-1 targeted therapies.   
The combination of margetuximab and INCMGA00012 or MGD013 did not show any 
synergistic toxicity between investigational drugs in both combination and is largely 
consistent with the safety profile of each monotherapy.  
SARS-cov-2 (COVID-19) infection 
Confidential
Page
43
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
Investigators must ensure that their institution can provide the protocol-specified safety and 
efficacy assessments during the pandemic period.  All procedures should continue as per 
protocol and study manuals. Prospective protocol waivers remain unacceptable and that 
patients should not be included in trials without proper eligibility assessment, including 
performance of planned tests, and written informed consent according to national laws and 
regulations. Enrollment and continuing participation in the study should follow any national 
or local guidance related to COVID-19.  
Telemedicine visits may be considered, in alignment with national and local guidance, to 
monitor adverse events and any other medical issues as necessary. 
The risk of treatment delays associated with the COVID-19 pandemic is not increased by 
participation in the clinical trial. If patients are unable to receive study treatments at the 
enrolling site, continuing participation at another open site should be considered in 
consultation with the MacroGenics and in accordance with local and national guidance.  
Remote monitoring of clinical data using electronic medical records will follow all local and 
regional guidelines regarding the access to and protection of patient’s identifiable medical 
information. 
As with any infection, confirmed cases of COVID-19 infection or suspected infection should 
be reported as AEs or SAEs (if seriousness criteria are met) within 24 hours. All 
medications/treatment administered for these respective events and corresponding 
unscheduled visits must be entered in EDC. 
2.9.2 
Potential Benefits  
The investigation of margetuximab in combination with INCMGA00012 or MGD013 may 
potentially yield a novel therapeutic option with an acceptable benefit-risk profile. The 
simultaneous targeting of HER2 and PD-1 (by margetuximab plus INCMGA00012) or HER2 
and PD-1 plus LAG3 (by margetuximab plus MGD013) provides an opportunity to focus the 
immune system and potentially enhance the antitumor response compared to treatment with 
either molecule alone. The rationale for this is supported by the complementary biology of 
HER2, PD-1 and LAG3 in mediating tumor evasion and the ability of margetuximab and 
INCMGA00012 or MGD013 to coordinately leverage both innate and adaptive immune 
responses by virtue of their respective functional properties. The Phase 1/2 evaluation of 
margetuximab in combination with anti-PD-1 therapy has demonstrated efficacy and tolerable 
safety in gastric cancer patients that benchmarks favorably to historical experience with 
standard of care.  
Additionally, Cohort A, may provide a chemotherapy-free treatment option with a potentially 
favorable safety profile. In Cohort B, all patients will receive an anti-HER2 agent in 
combination with chemotherapy. Based on recently published clinical data (31), there is 
synergy of anti-tumor effect with combination of an anti- HER2 agent (trastuzumab) + anti- 
PD-1 agent (pembrolizumab) + chemotherapy.  Further, as seen in emerging preliminary data 
regarding the margetuximab + MGD013 combination therapy in study CP-MGD013-01 
Confidential
Page
44
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
margetuximab +MGD013 + chemotherapy could potentially bring similar efficacy to PD-L1 
negative patients to PD-L1 positive patients.   
2.9.3 
Overall Assessment  
The patients expected to enroll in the study have metastatic or locally advanced, unresectable, 
treatment-naïve, HER2-positive gastric or gastroesophageal junction cancer. The 
administration of study drugs in patients with advanced cancer in the CP-MGAH22-06 could 
potentially prevent disease progression, which may result in longer survival.  
In reference to safety concerns for COVID-19, there is currently no evidence of increased risk 
for COVID-19 infection or its exacerbation during treatment with margetuximab, 
INCMGA00012 or MGD013, or a combination of either INCMGA00012 or MGD013 with 
margetuximab.  
In conclusion, the currently available data for margetuximab in combination with 
INCMGA00012 or MGD013 indicate that there is an acceptable benefit-risk profile which 
supports the conduct of the CP-MGAH22-06 trial.  MacroGenics’ medical team will continue 
to review and monitor patient data and ensure patient safety at all times. 
 
 
 
Confidential
Page
45
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
3 
STUDY PURPOSE AND OBJECTIVES  
3.1 
Primary Objective  
Cohort A:  
• To evaluate the safety and tolerability of margetuximab + INCMGA00012 in 
patients with untreated locally advanced or metastatic GC or gastroesophageal 
junction (GEJ) cancer that is HER2 IHC 3+ and PD-L1+ by IHC staining.  
• To evaluate the ORR of margetuximab plus INCMGA00012 for non-MSI-H 
patients in the response evaluable population (REP) using Investigator-assessed 
radiology reviews. 
3.2 
Secondary Objectives  
Cohort A: 
• To determine DoR, DCR, PFS, using Investigator-assessed radiology review and 
for non-MSI-H patients.  
• To evaluate the number of patients with ADA to margetuximab or INCMGA00012, 
or both.  
Cohort B, Part 1: 
• To evaluate ORR and DCR of each treatment arm. 
• To evaluate the number of patients with ADA to margetuximab, MGD013, or 
INCMGA00012. 
 
 
 
 
Confidential
Page
46
of
129

Margetuximab, INCMGA00012, MGD013
MacroGenics, Inc.
Clinical Trial Protocol: CP-MGAH22-06
Amendment 5, 06 June 2022
4 
OVERALL STUDY DESIGN AND PLAN 
This is a Phase 2/3, randomized, open-label study for treatment of patients with HER2+ GC or 
GEJ cancer. The study will be conducted in 2 cohorts. Cohort A will determine efficacy of 
margetuximab combined with CPI INCMGA00012 in patients who are positive for both 
HER2 IHC 3+ and PD-L1+ and are non-MSI-H (as determined by a central laboratory). 
Cohort B will determine the efficacy of a margetuximab plus CPI (INCMGA00012 or 
MGD013) plus chemotherapy compared to trastuzumab plus chemotherapy in patients who 
are HER2+ [IHC 3+, or IHC 2+ and fluorescent in situ hybridization (FISH)+], irrespective of 
PD-L1 status. Formalin-fixed, paraffin-embedded (FFPE) tumor tissue for analysis of PD-L1 
and MSI status will be prospectively collected during the study and retrospectively analyzed 
by a central laboratory. Patients will be treated Q3W.
The study population consists of patients with previously untreated locally advanced, 
unresectable or metastatic, HER2+ (IHC 3+, or IHC2+ and FISH+) GC or GEJ cancer. Prior 
systemic treatment in the perioperative setting is allowed.  However, the patient must have 
had a disease-free interval of at least 6 months from complete surgical resection or from the 
initiation of adjuvant chemotherapy, whichever is later. Patients receiving perioperative anti-
HER2 therapy require repeat testing of HER2 status for eligibility. No perioperative 
immunotherapy is allowed. 
Cohort A (Single Arm)
Cohort A was closed prior to completing enrollment target. There were 48 patients 
enrolled in Cohort A. 
The efficacy of INCMGA00012 plus margetuximab will be evaluated in approximately 
100 patients that are HER2 IHC3+, PD-L1+, and non-MSI-H (Figure 3). Enrollment will 
occur without prior ascertainment of MSI status. If the MSI status is determined to be MSI-H, 
patients will be allowed to remain on treatment but will be removed from the efficacy 
analysis. It is expected that about 110 patients will need to be enrolled to have 100 non-MSI-H 
patients. 
Figure 3
Study Design for Cohort A: Margetuximab + INCMGA00012 
(Chemotherapy-free Regimen)
Patients will receive 375 mg of INCMGA00012 Q3W plus 15 mg/kg of margetuximab Q3W. 
In additions to regular Sponsor medical oversight, the independent data monitoring committee 
(IDMC) will review all accumulated safety data from all enrolled patients and provide a 
recommendation to the Sponsor. The first scheduled IDMC meeting will take place after the 
Cohort A: HER2+ (IHC3+), PD-LI+ (CPS~ 1%) 
I 
Part 1 (n;;;;40)* 
Margetuximab + INCMGA00012 
"The 40 pati nt in Part 1 are inclu iv or th 
-
Confidential
Page
47
of
129

Margetuximab, INCMGA00012, MGD013
MacroGenics, Inc.
Clinical Trial Protocol: CP-MGAH22-06
Amendment 5, 06 June 2022
first 12 patients have completed at least 1 cycle of study treatment, or at 6 months from first 
enrollment, whichever comes first. Enrollment will continue during the evaluation. Reviews 
will continue in 6-month intervals (± 1 month). After approximately 40 patients have enrolled 
and are evaluable for response, data will be analyzed for ORR, as determined by independent 
imaging review, and safety. Additional patients will be enrolled in Part 2 of the cohort if the 
threshold for study continuation is met. Decision rules that govern the analysis of the ORR 
from Part 1 and continuation of Part 2 of Cohort A are outlined in Section 14.7.1.
Cohort B (Randomized, Open-label)
Cohort B was closed prior to completing enrollment target. There were 34 patients 
randomized of which 33 were treated in Cohort B, Part 1. No patients were enrolled in 
Cohort B, Part 2.
Cohort B Part 1 consists of 4 arms: 1 control arm of trastuzumab plus chemotherapy and 
3 experimental arms of margetuximab-containing regimens. Experimental Arms 1 and 2 will 
combine margetuximab plus a CPI plus chemotherapy. The CPI for Experimental Arm 1 is 
INCMGA00012, and the CPI for Experimental Arm 2 is MGD013. Experimental Arm 3 will 
evaluate margetuximab alone in combination with chemotherapy. Entry criteria for HER2 may 
be based on a local test, however, enrollment will continue until the sample size is accrued 
based on central confirmation. Chemotherapy will be XELOX or mFOLFOX-6, according to 
the Investigator’s choice based local approval and availability. The study schema is displayed 
in Figure 4.
Figure 4
Study Design for Cohort B: Margetuximab plus Chemotherapy 
plus Checkpoint Inhibitor (INCMGA00012 or MGD013)
IHC = immunohistochemistry; R = randomize
The first safety evaluation by the IDMC will take place after 20 patients in each arm have 
enrolled and completed at least 1 cycle of treatment, or at approximately 6 months from first 
enrollment, whichever comes first.  The IDMC may meet at any time if evolving safety data 
Cohort B: HER2-positive (IHC3+ or IHC2+/FISH+), regardless of PD-L 7 status 
Part 1 (n=SO/arm)* 
Part 2 (n =250/arm) 
Study Part 2 Discontinued 
ControlArm 
Extension 
~50 patients 
* Each arm in Part 1 contains a 6 patient safety run-in 
Trastuzumab + 
Chemotherapy 
Ex e ·mental A 
Margetuximab + 
Chemotherapy + CPI 
Confidential
Page
48
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
warrant a safety review. Reviews will continue in 6-month intervals (± 1 month). Once the 
first assessment in Cohort B is completed, to the extent possible, safety and efficacy data from 
Cohort A and Cohort B will be reviewed at the same meeting. However, frequency of IDMC 
meetings may be adjusted in accordance with the consensus of the IDMC and reflected in the 
IDMC Charter. 
Chemotherapy treatment will be capped at approximately 6 months (8 cycles of XELOX and 
12 cycles of mFOLFOX-6). INCMGA00012, MGD013, and trastuzumab will be capped at 35 
cycles (approximately 2 years). 
• Control arm: trastuzumab at an 8 mg/kg loading dose then 6 mg/kg Q3W, in 
combination with XELOX or mFOLFOX-6 chemotherapy 
• Experimental Arm 1: 375 mg of INCMGA00012 Q3W plus 15 mg/kg of 
margetuximab Q3W, in combination with XELOX or mFOLFOX-6 chemotherapy. 
• Experimental Arm 2: 600 mg of MGD013 Q3W plus 15 mg/kg of margetuximab 
Q3W, in combination with XELOX or mFOLFOX-6 chemotherapy. 
• Experimental Arm 3: margetuximab 15 mg/kg in combination with XELOX or 
mFOLFOX-6 chemotherapy. 
 
4.1 
Guidelines for Dose Modification  
4.1.1 
General Guidelines  
No dose modification will be allowed for margetuximab, INCMGA00012, MGD013, or 
trastuzumab, with the exception of reduction of infusion rate during re-challenge for patients 
experiencing an infusion reaction (see Section 7.1) for any of the antibodies or decreased 
cardiac function (see Section 4.1.3) for margetuximab. If a patient experiences an irAE, the 
Investigator should follow the management guidelines outlined in Section 7.2. For patients in 
whom the toxicity is assessed as related to chemotherapy, other components of study 
treatment (i.e., margetuximab, INCMGA00012, or MGD013) may be continued upon 
consultation with the Sponsor’s Medical Monitor.  
Please refer to the respective Investigator’s Brochures for information on special warnings 
and precautions for use, interaction with other medicinal products and other forms of 
interaction, and undesirable effects associated with margetuximab, INCMGA00012, or 
MGD013. 
4.1.2 
Modifications for SARS-CoV-2 Infection  
The following guidelines apply to patients actively on study treatment with confirmed 
(positive by regulatory authority approved/authorized test) or presumed (test pending/clinical 
suspicion) COVID-19/SARS-CoV-2 infection: 
Confidential
Page
49
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
• For patients with confirmed or presumed SARS-CoV-2 infection, study drug 
should be delayed for at least 14 days from the start of symptoms. Consideration 
for study treatment continuation will be made on a case-by-case basis with the 
Medical Monitor and the Principal Investigator.   
• Prior to restarting study drug, patients should be afebrile for at least 72 hours and 
SARS-CoV-2–related symptoms should have recovered to ≤ Grade 1 or baseline 
for a minimum of 72 hours. 
• The Sponsor should be informed when resuming study drug. 
The Sponsor must be informed within 24 hours of awareness of a participant with confirmed 
or presumed COVID-19/ SARS-CoV-2 infection. Suspected COVID 19/SARS-CoV-2 cases 
should be tested per local practice/institutional guidelines with an approved/authorized test. 
At the discretion of the investigator, non-live COVID-19 vaccines may be administered per 
local practice. Patients may have study drug held to allow for COVID-19 vaccination. 
4.1.3 
Margetuximab  
No reductions in the dose of margetuximab are allowed. The rate of margetuximab infusion or 
dose schedule may be modified for IRRs or decreased cardiac function, respectively, that are 
determined to be associated with margetuximab based on the following parameters: 
• Infusion-related reactions: Follow the guidelines described in Section 7.1 
• Decreased cardiac function: Withhold margetuximab for at least 4 weeks if either  
of the following criteria are met:  
≥ 16 % absolute decrease in left ventricular ejection fraction (LVEF) 
from pre-treatment value, or  
LVEF below institutional normal limits (or 50% if no limits are 
available) and ≥ 10% absolute decrease in LVEF from 
pre-treatment values. 
 
LVEF will be monitored at regular intervals during the study. If a decrease in cardiac function 
is suspected, LVEF should be determined using the same method as used prior to treatment. 
Margetuximab may be resumed if, within 8 weeks, the LVEF returns to within normal 
limits and the decrease from baseline is ≤ 15%. Margetuximab should be permanently 
discontinued if a decline in LVEF persists for > 8 weeks or if dosing is interrupted for more 
than 3 occasions due to cardiomyopathy. 
4.1.4 
INCMGA00012 and MGD013  
No reductions in the dose of INCMGA00012 or MGD013 are allowed. Dose interruption or 
discontinuation should be used for the management of drug-related toxicity. The management 
Confidential
Page
50
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
of IRR is specified in Section 7.1.2. The dose interruption and overall management of irAEs 
is specified in Section 7.2.  
For other Grade 3 and higher drug-related AEs, that are not designated as IRR or irAE, study 
treatments will be withheld until resolution to ≤ Grade 1, or baseline. Patients with AEs 
leading to dose interruption that does not resolve to ≤ Grade 1 within 12 weeks, despite 
optimal medical management, should be discontinued from the study.  
Dose interruption is allowed for patients with intolerable or persistent Grade 2 drug-related 
AEs. Permanently discontinue study drug for persistent Grade 2 AE for which treatment with 
study drug has been held, and that does not recover to Grade 0 - 1 within 12 weeks of the last 
dose. 
Patients who experience Grade 4 drug-related events should be permanently discontinued 
from the study with the following exceptions: 
• Grade 4 lymphopenia 
• isolated laboratory abnormalities lasting less than 72 hours and not otherwise 
associated with clinical complications 
 
4.1.5 
Trastuzumab (HERCEPTIN®)  
Patients may continue trastuzumab (marketed as HERCEPTIN®) therapy during periods of 
reversible, chemotherapy-induced toxicity. Additional monitoring for resolution of 
chemotherapy-related toxicity may be warranted. 
The trastuzumab package insert should be consulted for any modifications or adjustments to 
the dosing schedule or rate of infusion. Trastuzumab dosing will be modified for infusion 
reactions and cardiomyopathy. 
• Infusion-related reactions: Follow the guidelines described in Section 7.1 
• Decreased cardiac function: Withhold trastuzumab for at least 4 weeks if either of 
the following criteria are met: 
• ≥ 16 % absolute decrease in LVEF from the pre-treatment value, or  
• LVEF below institutional normal limits (or 50% if no limits are available) and 
≥ 10% absolute decrease in LVEF from pretreatment values 
 
LVEF will be monitored at regular intervals during the study. If a decrease in cardiac function 
is suspected, LVEF should be determined using the same method as used prior to treatment. 
Trastuzumab may be resumed if, within 8 weeks, the LVEF returns to within normal limits 
and the percentage point decrease from baseline is ≤ 15%. Trastuzumab should be 
Confidential
Page
51
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
permanently discontinued if a decline in LVEF persists for > 8 weeks or if dosing is 
interrupted for more than 3 occasions due to cardiomyopathy. 
4.1.6 
Chemotherapy  
General guidance for dose modification for toxicity due to chemotherapy agents are provided 
in Table 8. However, this guidance is not intended to replace local requirements or standard 
practice of medicine. 
One or more chemotherapy agents can be interrupted for chemotherapy-related toxicity. A 
change to a different chemotherapy regimen is not allowed. Continued treatment with other 
assigned study drugs may continue. Chemotherapy treatment should be reinstituted once 
toxicity has improved or resolved. If continued treatment is not tolerable with interruption or 
dose modification, chemotherapy may be discontinued. The patient may continue the other 
components of the chemotherapy regimen. Patients who require cessation of chemotherapy 
because of chemotherapy-related toxicity should continue on the other study treatments. If all 
components of chemotherapy regimen were held for 2 or more consecutive cycles due to 
toxicity, prior to completing 8 cycles or XELOX or 12 cycles of mFOLFOX-6, restart of 
chemotherapy is not allowed.  
Confidential
Page
52
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
Table 8 
Dose Modification Recommendations for Chemotherapy  
Agent 
Toxicity 
Grade a 
Action  
Subsequent Dosing 
5-FU 
Palmar-plantar 
erythrodysesthesia 
2-3 
Interrupt 
Resume at a 25% dose 
reduction dose when 
resolved to ≤ Grade 1 
Mucositis 
3-4 
Myelosuppression 
4 
Other severe toxicity 
3-4 
Diarrhea 
2 
Resume at 100% dose 
2 (recurrent) 
Resume at a 25% dose 
reduction dose when 
resolved to ≤ Grade 1 
3-4 
Capecitabine b 
Second appearance any AE 
2 
Interrupt 
50-75% dose reduction 
when resolved to ≤ Grade 1 
Third appearance any AE 
50% dose reduction when 
resolved to ≤ Grade 1 
Fourth appearance any AE 
Discontinue 
Drug withdrawn 
First appearance any AE 
3 
Interrupt 
50-75% dose reduction 
when resolved to ≤ Grade 1 
Second appearance any AE 
50% dose reduction when 
resolved to ≤ Grade 1 
Third appearance any AE 
Discontinue 
Drug withdrawn 
First appearance any AE 
4 
Discontinue 
Drug withdrawn 
Oxaliplatin 
Neuropathy 
2 (persistent) 
Interrupt 
Reduce to  
65 mg/m2 
(mFOLFOX-6) or 100 
mg/m2 (XELOX) 
3 (persistent) 
Interrupt 
Consider discontinuation 
4 
Discontinue 
Drug withdrawn 
Neutropenia 
4 
Interrupt 
Delay the next dose until 
neutrophils ≥ 1.5 × 109/L   
Febrile neutropenia 
3-4 
Thrombocytopenia 
3-4 
Interrupt 
Delay the next dose until 
neutrophils ≥ 75 × 109/L   
Gastrointestinal AE 
3-4 
Interrupt 
Reduce dose to 65 mg/m2 
and dose reduce 5-FU to 
300 mg/m2 IV bolus and 
1800 mg/m2 as a 46-hour 
infusion (m-FOLFOX-6). 
or 100 mg/m2 
(XELOX) 
Hypersensitivity Reaction 
Any 
Discontinue 
Drug withdrawn 
Posterior reversible 
encephalopathy syndrome 
Confirmed interstitial lung 
disease or pulmonary fibrosis 
Rhabdomyolysis 
a. NCI CTCAE v5.0   
b. Recommendations for dose reductions reflect local availability of dosage forms of capecitabine. 
 
 
Confidential
Page
53
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
4.2 
Study Duration  
Study treatment will continue until completion of protocol-specified therapy, persistent CR, 
disease progression, unacceptable toxicity, withdrawal of consent, physician recommendation 
to discontinue therapy, or death. 
The maximum duration of protocol-specified study treatments are:  
Cohort A 
35 cycles of margetuximab and INCMGA00012 
Cohort B, 
Part 1 
Arm 
Chemotherapy 
Anti-HER2 Therapy 
Anti PD-1/PD-L1 Therapy 
Control 
8 cycles XELOX or 
12 cycles mFOLFOX-6 
35 cycles trastuzumab 
N/A 
1 
35 cycles margetuximab 
35 cycles INCMGA00012 
2 
35 cycles margetuximab 
35 cycles MGD013 
3 
Until disease progression 
N/A 
Discontinuation of study treatment may be considered for patients have attained persistent 
CR. The criteria for persistent CR include: 
• confirmed CR and at least 8 cycles of XELOX or 12 cycles of mFOLFOX-6 
(approximately 6 months) of study treatments, and 
• an additional 2 cycles of study treatment must be completed beyond the date of 
initial CR. 
Patients in Cohort A only who have radiographic progression but are clinically stable may 
remain on study treatments until the next scheduled radiographic evaluation, upon Sponsor 
Medical Monitor consultation.  
There is no crossover in this study to a different treatment arm or different cohort. Following 
discontinuation of study treatment, each patient will be followed for safety for up to 30 days, 
or until initiation of subsequent anticancer therapy, whichever is earlier. Patients currently in 
survival follow-up will be discontinued from the study, as having completed protocol-
specified follow-up. 
4.2.1 
Definition of End of Study  
The end of study occurs after the last patient completes the safety follow-up period. 
4.3 
Appropriateness of Measurements  
4.3.1 
MSI Status  
Microsatellites are short, tandem repeated DNA sequences 1–6 base pairs in length. 
Microsatellite markers can be used to detect a form of genomic instability called microsatellite 
instability (MSI). MSI is a change in length of a microsatellite allele due to insertion or 
Confidential
Page
54
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
deletion of repeat units during DNA replication and failure of the DNA mismatch repair 
system to correct these errors. 
Previous clinical trials have demonstrated the utility of MSI status as a predictive marker for 
response to PD-1 blockade in Stage 4 cancer including GC. Pembrolizumab monotherapy has 
been approved for MSI-H solid tumors. Pembrolizumab as a single agent has been studied as 
third-line treatment in patients with gastric cancer (KEYNOTE-059). Study results indicated a 
lower response rate for non-MSI-H patients of 9.0%, compared to a response rate of 57% in 
MSI-H patients (18, 36). The higher efficacy of anti-PD1 monotherapy in MSI-H patients 
could confound the assessment of contribution of treatment components in this combination 
study. Patients with unknown MSI status are not excluded from the study; however, if the 
patient has MSI-H status, they will be excluded from the analyses as described in Section 14 
of the protocol. For Cohort B, the correlation of MSI status with efficacy will be assessed in a 
sensitivity analysis. Previous studies have demonstrated that approximately 8% of patients 
with Stage 4 GC are MSI-H (34, 45). In the TCGA database, including 92.5% of patients with 
early stage disease (Stage 1-3), 21.7% of patients we found to be MSI-H (10). 
Based on previous reports (19, 58) there is only a small overlap of gastric patients with HER2 
amplification and MSI-H expression based on The Cancer Genome Atlas (10). Huang et al 
reported that of 59 HER2 positive tumors, 3 (5.1%) were MSI high in resectable (Stage II-III) 
GC (30). In the CP-MGAH22-05 study, MSI-H was detected in 1 of the 88 (1.1%) patients 
tested for MSI status. Therefore, based on these reports and the data from the 
CP-MGAH22-05 trial, it is anticipated that only a small number of patients 
(e.g., approximately 5% or less) with HER2+ and MSI-H GC would be enrolled into the trial. 
MSI status will be determined with comparison of allelic profiles of microsatellite markers 
between tumor DNA and normal DNA at the central laboratory. Genomic DNA is extracted 
from tumor specimen and whole blood (normal DNA) and flowed by polymerase chain 
reaction-based-assay using 5 mononucleotide repeat microsatellite markers (BAT-25, BAT-26, 
MONO-27, NR-21, and NR-24). Greater or equal to 2 abnormal allelic shifts of the 
mononucleotide repeat markers out of 5 markers will be considered as MSI-H. 
4.3.2 
HER2 IHC Testing  
As margetuximab is an anti-HER2 directed therapy, all patients must meet the inclusion 
criteria for HER2 positivity. HER2 testing for study for Cohort A will be conducted at a 
College of American Pathologists (CAP)/Clinical Laboratory Improvement Amendments 
(CLIA) certified central laboratory using an FDA-approved assay. In Cohort B, HER2 testing 
may be conducted at an appropriately qualified local laboratory using HercepTest™ and HER2 
FISH pharmaDx™ assays.  A confirmatory standardized HER2 test will be performed at a 
central laboratory contracted by the Sponsor, using an FDA-approved assay. 
4.3.3 
PD-L1 IHC Testing  
Anti–PD-1 agents have demonstrated improved efficacy in GC patients with tumors that 
express PD-L1 as determined by IHC (18, 50). The present study will define PD-L1 
expression based on IHC staining using the FDA approved 22C3 pharmDx assay. 
Confidential
Page
55
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
PD-L1 testing will be performed for all patients. For Cohort A, testing will be used to identify 
eligible patients with tumors that are positive for both HER2 (HER2+) and PD-L1 (PD-L1+) 
expression. For patients in Cohort B, PD-L1 expression will be determined retrospectively to 
enable pre-specified subset analyses of clinical efficacy. 
The prevalence of PD-L1 positivity in patients with metastatic GC, using the 22C3 Pharm Dx 
and CPS ≥ 1% cutoff has been reported as approximately 70% (50). 
4.3.4 
Fcγ Receptor  
Margetuximab is an Fc-engineered anti-HER2 mAb designed with increased affinity for 
activating Fc-receptors and reduced affinity for inhibitory Fc-receptors compared to 
trastuzumab. Distinct high- (V) and low- (F) affinity alleles have been described for the 
activating Fc-receptor, CD16A. Margetuximab binds with increased affinity to either the V or 
F allele of CD16A. Notably, in patients with HER2+ GC, trastuzumab efficacy appears to be 
reduced in patients harboring one or more F alleles (CD16A V/F and F/F) (59). The 
homozygous V/V genotype is present in approximately 15% each of Caucasian, African 
American, and Asian populations, and the lower affinity F/F and intermediate affinity F/V 
carriers comprise the remainder of the population. Since most patients carry the lower affinity 
allele of CD16A, the engineered Fc domain of margetuximab is expected to confer benefit to 
the whole patient population and not disproportionately to the higher affinity CD16A V/V 
homozygotes. 
4.3.5 
Clinical Laboratory Evaluations  
Routine laboratory evaluations including hematology, chemistry, special chemistry, 
coagulation, and urinalysis will be performed. 
Local safety laboratory assessments will be used to make treatment-related decisions. 
4.3.6 
Pharmacokinetic Assessments  
Serum concentrations of margetuximab, INCMGA00012, and MGD013 will be analyzed 
using validated assay methods that will be carried out in the Sponsor’s designated central 
laboratory to characterize the immunogenicity of margetuximab, INCMGA00012, and 
MGD013. Analysis of PK data will be carried out using industry standard software. 
Descriptive PK summaries will be provided. 
4.3.7 
Immunogenicity  
Blood samples will be collected and assayed to determine the presence of ADA to 
margetuximab, INCMGA00012, and MGD013 during the study. A central laboratory, chosen 
by the Sponsor, will perform the assay. 
 
 
Confidential
Page
56
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
5 
SELECTION AND WITHDRAWAL OF PATIENTS  
The patient population to be enrolled in this study will consist of adult patients with 
histologically or cytologically confirmed, previously untreated, locally advanced unresectable 
or metastatic HER2+ GC/GEJ cancer. 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. Patient must provide signed informed consent prior to initiation of any study-
related tests or procedures that are not part of standard of care. 
2. Age ≥ 18 years old. 
3. Histologically confirmed diagnosis of previously untreated locally advanced 
unresectable or metastatic HER2+ GC or GEJ adenocarcinoma (see the histology 
table in (Appendix 4). GEJ cancer is defined as any tumor that invades the GEJ.  
a. Prior systemic perioperative treatment is allowed. The patient must have a 
disease-free interval of at least 6 months from complete surgical resection 
or initiation of adjuvant chemotherapy, whichever is later.  
b. Patients receiving perioperative anti-HER2 therapy require repeat testing of 
HER2 status for eligibility.  
c. Cohort A: HER2+ (by IHC 3+) and PD-L1–positive (by IHC with 22C3 
CPS ≥ 1%), per central review. 
d. Cohort B: HER2+ (by IHC 3+ or IHC 2+ in combination with FISH+) by 
local review. HER2 local test must be conducted at a CAP or equivalent 
accreditation organization using HercepTest™ and HER2 FISH 
pharmaDx™ assays. PD-L1 status is not required for enrollment. 
 
4. Patients enrolled on the study will be required to have an identified formalin-fixed, 
paraffin-embedded (FFPE) tumor specimen for HER2, PD-L1, LAG-3 and MSI 
testing. The specimen may be a formalin-fixed paraffin-embedded (FFPE) tumor 
specimen block, or a minimum of 10 unstained slides, with adequate tumor cells 
for analysis, or contemporaneous biopsy.  
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, 
verified within 3 days of Day 1. 
6. Life expectancy ≥ 6 months. 
7. Has adequate organ function as determined by the site Investigator. 
Confidential
Page
57
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
8. 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).  
9. Acceptable laboratory parameters as follows: 
a. Platelet count ≥ 100 × 103/µL without transfusion within 28 days prior to 
the initiation of study treatment. 
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 treatment. 
c. ALT/AST ≤ 3.0 × 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. 
 
10. 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. 
11. 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 7 months after discontinuation of study drug administration. Male 
patients must agree to abstain from sperm donation during the course of the study. 
12. 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 7 months after the last dose of study drug. 
 
5.2 
Exclusion Criteria  
1. Has a known additional malignancy that is progressing or has required treatment 
within the past 5 years. Patients who have been successfully treated for, and are 
disease free, non-melanomatous skin cancer, localized prostate cancer (Gleason 
Score < 6), or carcinoma in situ are eligible for participation in the study. 
2. Patients with known MSI-H status. 
3. Has poorly controlled diarrhea, despite optimal medical intervention. 
Confidential
Page
58
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
4. Clinically significant accumulation of pleural, ascitic, or pericardial fluid requiring 
drainage or diuretic drugs.  
5. 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. 
a. Known chronic hepatitis B virus (HBV) infection (as evidenced by 
detectable HBV surface antigen and HBV DNA ≥ 500 IU/ml).  
 The patient with resolved HBV infection (as evidenced by detectable 
HBV surface antibody, detectable HBV core antibody, undetectable 
HBV DNA, and undetectable HBV surface antigen) is eligible. 
b. Co-infection with hepatitis B (as evidenced by detectable HBV surface 
antigen and HBV DNA ≥ 500 IU/ml) and C (as evidenced by detectable 
hepatitis C virus [HCV] RNA); OR, hepatitis D infection in patients with 
hepatitis B. 
 The patient with a history resolved hepatitis B and detectable HCV 
antibody is eligible. 
c. Has a known history of human immunodeficiency virus 1 or 2 antibodies or 
has a diagnosis of immune-deficiency.  
d. Has had an allogeneic stem cell or tissue/solid organ transplant. 
e. Patients with central nervous system metastases.  
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 
parenteral 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 trastuzumab, margetuximab, INCMGA00012, or 
MGD013 drug formulation (Section 6.4) or contraindications to the 
specified chemotherapy regimens. 
Confidential
Page
59
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
j. Any serious underlying medical or psychiatric condition (e.g., known 
complete DPD deficiency) 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 registration. 
l. Active or history of alcohol or other substance abuse within 1 year prior to 
registration. 
 
6. Vaccination with any live virus vaccine within 4 weeks prior to the initiation of 
study treatment. Inactivated annual influenza vaccination is allowed. 
7. Has received an investigational agent within 4 weeks prior to the initiation of study 
treatment. Prior neoadjuvant or adjuvant treatment with immunotherapy is 
excluded.  
8. Major surgical procedure, including gastrectomy, or trauma within the 4 weeks 
prior to the initiation of study treatment. 
9. Treatment with systemic corticosteroids (≥ 10 mg per day prednisone or 
equivalent) or other immune suppressive drugs within the 14 days prior to the 
initiation of study treatment.  
10. 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 treatment.  
b. Stroke or transient ischemic attack within 6 months prior to the initiation of 
study treatment. 
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. 
i. LVEF < 50%, or below the institutional lower limit of normal.  
 
11. Clinically significant gastrointestinal disorders including: 
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. Clinically significant gastrointestinal bleeding in the opinion of the 
Investigator. 
Confidential
Page
60
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
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. 
 
12. A history of (non-infectious) pneumonitis that required steroids, or current 
pneumonitis. 
13. Severe dyspnea at rest due to complications of advanced malignancy or requiring 
supplemental oxygen therapy. 
14. Clinically significant pulmonary compromise, including a requirement for 
supplemental oxygen use to maintain adequate oxygenation. 
15. The female patient who is pregnant or breastfeeding, or expecting to conceive, 
AND the male patient who is expecting to father children within the projected 
duration of the trial, starting with the screening visit through 7 months after the last 
dose of trial treatment. 
16. Dementia or altered mental status that would preclude understanding and rendering 
of informed consent. 
17. Employees of MacroGenics, Inc. and Zai Lab or its corporate business partners, 
including Incyte Corporation, unless approved by institutional review board (IRB) 
and principal Investigator.  
18. Prisoners or other individuals who are involuntarily detained. 
19. Any investigative site personnel directly affiliated with this study. 
 
5.3 
Rules for Study Treatment Discontinuation  
Patients who tolerate study 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: 
• Persistent CR (see Section 4.2) 
• Completion of protocol defined therapy (Section 4.2) 
• PD according to RECIST v1.1. 
o Patients with clinical deterioration should be evaluated carefully either due 
to clinical progression or due to AEs. If study treatment discontinuation is 
due to clinical progression without radiographical or clinical evidence, 
clear documentation is required.  
Confidential
Page
61
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
o Patients in Cohort A only who have radiographic progression but are 
clinically stable may remain on study treatments until the next radiographic 
evaluation upon Sponsor Medical Monitor consultation. 
• Discontinuation of treatment due to an AE 
• Withdrawal of patient consent: Patients who withdraw consent are withdrawn from 
all further assessment and follow-up. Study documentation should reflect the 
patient’s decision to decline any further study contacts. 
• Patient decision: Patients may decide to discontinue study treatment without 
withdrawing consent for the study. Patients may remain in the study after treatment 
discontinuation for safety assessment.  
• Protocol violation or non-compliance: If the Investigator recognizes compliance 
issues of patients, such as repeated administration of prohibited concomitant 
medications, Sponsor’s Medical Monitor consultation is recommended prior to 
treatment discontinuation. 
• Pregnancy 
• Lost to follow-up (LTFU) 
o A patient may be determined to be LTFU after there have been at least 
3 documented contact attempts. If this fails, a letter should be sent via 
traceable mail to the patient. Only after these attempts have failed can a 
patient be determined to be LTFU. 
• The Sponsor, Investigator, or Regulatory Agency terminates the study 
 
5.4 
Guidelines for Discontinuation of Patient from Study  
Patients who are no longer on treatment but are still followed on the study for survival can be 
terminated from the study for the following reasons: 
• Completion of protocol-defined follow-up period (Section 4.2)  
• LTFU 
• Withdrawal of consent 
• The Sponsor, Investigator, or regulatory agency terminates the study 
• Death 
• End of study 
 
Confidential
Page
62
of
129

Margetuximab, INCMGA00012, MGD013
MacroGenics, Inc.
Clinical Trial Protocol: CP-MGAH22-06
Amendment 5, 06 June 2022
6 
STUDY TREATMENTS 
6.1 
Description of Treatments 
An overview of study treatments to be administered during this study is presented in Table 9. 
The order of administration of combination therapy is displayed in Figure 5.
Table 9
Overview of Study Treatments
Cohort
Study Arm/Study Agent
Dose
Schedule
Route
Cohort A 
Single Experimental Arm 
INCMGA00012 
375 mg 
Q3W 
IV 
margetuximab 
15 mg/kg 
Q3W 
IV 
Cohort B 
Control Arm 
trastuzumab 
8 mg/kg loading 
dose then 6 mg/kg 
Q3W 
IV 
chemotherapy a, b 
Experimental Arm 1 
INCMGA00012 
375 mg 
Q3W 
IV 
margetuximab 
15 mg/kg 
Q3W 
IV 
chemotherapy a, b 
Experimental Arm 2 
MGD013 
600 mg 
Q3W 
IV 
margetuximab 
15 mg/kg 
Q3W 
IV 
chemotherapy a, b
Experimental Arm 3 
margetuximab 
15 mg/kg 
Q3W 
IV 
chemotherapy a, b
Chemotherapy: mFOLFOX-6 option a, b 
leucovorin 
400 mg/m2 
Q2W 
IV 
oxaliplatin 
85 mg/m2 
Q2W 
IV 
5-FU bolus
400 mg/m2 
Q2W 
IV 
5-FU 46 hr. continuous infusion
2400 mg/m2 
Q2W 
IV 
Chemotherapy: XELOX option a, b 
capecitabine 
1000 mg/m2 
BID on Days 1-
14 of each cycle 
Oral 
oxaliplatin c
130 mg/m2 
Day 1 Q3W 
IV 
BID = twice daily; IV = intravenous infusion 
a.
The chemotherapy option selected must be approved for use per local regulations.
b.
Chemotherapy must be used at the protocol-indicated starting doses and route of administration. Dosing
modifications are permitted per local standard. Dose adjustments to improve tolerability and manage
toxicities are permitted per local standard.
c.
All chemotherapy will be capped at approximately 6 months of treatment (XELOX = 8 cycles,
mFOLFOX-6 =12 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 case report form (CRF).
I 
Confidential
Page
63
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
Figure 5 
Sequence of Study Drug Administration for Each Cohort/Arm 
 
 
6.1.1 
Method of Assigning Patients to Treatment Groups  
Cohort A is a nonrandomized, uncontrolled cohort evaluating margetuximab plus 
INCMGA00012. Patients will be assigned sequentially. 
Cohort B Part 1 will enroll 200 patients in a 1:1:1:1 randomization for trastuzumab plus 
chemotherapy (Control Arm), INCMGA00012 plus margetuximab plus chemotherapy 
(Experimental Arm 1), MGD013 plus margetuximab plus chemotherapy (Experimental 
Arm 2), or margetuximab plus chemotherapy (Experimental Arm 3). The stratification factors 
are chemotherapy regimen (XELOX vs mFOLFOX-6) and results of local HER2 testing 
(IHC2+/FISH+ vs IHC3+). 
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 IRT at least 
2 weeks in advance. 
Cohort A (single arm) 
/ 
INCMGA00012 /z ·I Margetuximab I 
Cohort B: Control Arm 
I 
Trastuzumab I~ Chemotherapy] 
Cohort B: Experimental Arm #1 
/ 
INCMGA00012 ;;z.1 Margetuximab rl 
Chemotherapy ] 
Cohort B: Experimental Arm #2 
/ 
MGD013 7 ___. .... I M-ar_g_e-tu-x-im_a_b_r[ Chemotherapy ] 
Cohort B: Experimental Arm #3 
I 
Margetuximab H __ C_h_e_m_o-th_e_r_a_p_y_) 
Confidential
Page
64
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
Normal saline in 100-mL or 250-mL IV bags will be obtained from the institution’s usual 
commercial supplier for the dilution of study drugs in solution for IV administration. 
6.4.1 
Margetuximab  
Margetuximab is a sterile, preservative-free, clear to slightly opalescent, colorless to pale 
yellow or pale brown solution, essentially free from visible foreign particles, but may contain 
proteinaceous particles. Margetuximab is supplied at a nominal protein concentration of 
25 mg/mL in a single-dose vial containing 250 mg/10 mL. The product is formulated in a 
sterile solution of 1.1 mg/mL sodium phosphate monobasic monohydrate, 0.58 mg/mL sodium 
phosphate dibasic heptahydrate, 2.9 mg/mL sodium chloride, 11 mg/mL L-arginine 
hydrochloride, 30 mg/mL sucrose, and 0.1 mg/mL polysorbate 80, pH 6.1. 
6.4.2 
INCMGA00012  
INCMGA00012 is a sterile, preservative-free, clear to slightly opalescent, colorless to pale 
yellow solution, 
 
 
 
 
6.4.3 
MGD013  
 
 
 
6.5 
Other Study Treatments  
6.5.1 
Trastuzumab  
 HERCEPTIN® will be provided by MacroGenics, or its corporate business partners in China, 
except Taiwan. 
The use of trastuzumab biosimilars in this study is strictly prohibited. 
6.5.2 
Chemotherapy  
All treatment arms in Cohort B will include XELOX or mFOLFOX-6 chemotherapy. The 
choice of chemotherapy (as it is widely approved and available therapy) will be made by the 
treating physician prior to randomization and is not considered as investigational medicinal 
product. The chemotherapy regimen selected must be allowed for use per local regulations 
Confidential
Page
65
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
and will be supplied locally unless an alternate source for the selected agent is needed. The 
choice of therapy should be made based on the patient’s co-morbidities and the physician’s 
best judgment about the most appropriate chemotherapy for a given patient. Chemotherapies 
must be used at the protocol-indicated starting doses, schedule, and route of administration 
(see Table 9); however, dose adjustments to improve tolerability and manage toxicities are 
permitted. Changes in chemotherapy will not be allowed following patient randomization (see 
Section 6.1.1). Substitution of generic equivalents for branded products is acceptable if such 
products have been approved by local regulatory authorities for use in the treatment of human 
diseases. 
6.6 
Study Treatment Preparation and Administration  
Information on the packaging, labeling, storage, preparation and administration of study 
treatments, and active comparator, may be found in the Pharmacy Manual.  
6.7 
Treatment Compliance  
All study treatments 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 
Storage and Accountability  
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. 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 at 
the site for inspection by the study monitors and auditors. 
6.9 
Investigational Product Disposition at End of Study  
Upon completion or termination of the study, sites whose drug destruction SOP or Clinical 
Trial Management Destruction Survey has been submitted and approved by MacroGenics may 
destroy all unused, used, and expired study drug on-site upon receipt of written authorization 
from MacroGenics. All sites who have not been approved for on-site destruction must return 
all unopened, expired, and used vials of study drug to the applicable clinical supply depot. All 
drug returns 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, and any 
Confidential
Page
66
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
corresponding documentation, are filed with the Pharmacy study records, and copies provided 
to the Sponsor for filing. 
 
Confidential
Page
67
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
7 
POTENTIAL ADVERSE EVENTS AND SUPPORTIVE CARE 
MEASURES  
7.1 
Infusion Related Reactions Including Cytokine Release Syndrome  
Infusion reactions (including CRS) associated with mAbs, or DARTs 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 IRRs 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.  
7.1.1 
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 local medical practice 
and availability. 
Cycle 1, guidelines – Recommendations prior to first infusion of study treatment: 
• Acetaminophen 650-1000 mg orally (PO) or ibuprofen 400 mg PO 
• Diphenhydramine 50 mg PO or IV  
• Ranitidine 300 mg PO or IV  
• Dexamethasone 10-20 mg IV  
 
No pre-infusion prophylactic steroid administration is required for subsequent infusions. 
Non-steroidal premedication may be administered prior to the subsequent infusion, 
if warranted. 
For patients who had infusion reactions following the first dose of margetuximab, 
INCMGA00012, or MGD013 that were not adequately or only moderately controlled with 
acetaminophen, diphenhydramine, or ranitidine, IV corticosteroids may be added to the 
premedication for subsequent administration of the given study drug. Dexamethasone (10 to 
20 mg IV) may be used as premedication in addition to acetaminophen, diphenhydramine, and 
ranitidine if the patient experiences a Grade ≥ 2 infusion reaction with the first infusion. 
Permanently discontinue study treatment if there are continued IRR after use of recommended 
prophylaxis. 
 
 
Confidential
Page
68
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
7.1.2 
Management of Observed Infusion Reactions  
The following are treatment guidelines (which may be modified as needed by the Investigator 
according to the best practices of medicine) for infusion reactions. Equivalent medications 
may be substituted based on local medical practice and availability. 
Grade 
Description 
Treatment 
Subsequent Infusions 
1 
Mild reaction: treatment 
intervention not indicated. 
Interrupt or slow the rate of 
infusion. 
Monitor vital signs closely until 
medically stable. 
Consider premedication with an 
antipyretic 
(eg, acetaminophen/paracetamol 
500-1000 mg PO) and a histamine 
blocker (eg, diphenhydramine 50 mg 
PO) for participants who have had 
previous systemic reactions to 
protein-product infusions or when 
recommended by institutional policy. 
2 
Requires infusion interruption 
but responds promptly to 
symptomatic treatment (eg, 
histamine blockers, NSAIDs, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤ 24 hours. 
First occurrence: Stop 
infusion and initiate appropriate 
treatment (eg, IV fluids, 
histamine blockers, NSAIDs, 
antipyretics, narcotics) per 
institutional preferences. 
Monitor vital signs closely until 
medically stable. 
If symptoms resolve within 
1 hour, infusion may be 
resumed at 50% of the original 
infusion rate. 
Subsequent occurrences (after 
recommended prophylaxis): 
Permanently discontinue study 
treatment. 
Premedicate at least 30 minutes 
before infusion with a histamine 
blocker (eg, diphenhydramine 50 mg 
PO) and an antipyretic (eg, 
acetaminophen/paracetamol 
500-1000 mg PO). 
Additional supportive measures may 
be acceptable (per institutional 
preference) but should be discussed 
with medical monitor. 
Next infusion should start at 50% of 
the original infusion rate. If no 
reaction, rate of infusion can be 
increased by 25% every 15 minutes 
until a rate of 100% has been 
reached. Subsequent infusions can 
begin at 100%. 
3 or 4 
Grade 3: Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption of 
infusion); recurrence of 
symptoms following initial 
improvement; hospitalization 
indicated for other clinical 
sequelae (eg, renal 
impairment, pulmonary 
infiltrates). 
Grade 4: Life-threatening; 
pressor or ventilatory support 
indicated. 
Stop infusion and initiate 
appropriate treatment (eg, IV 
fluids, histamine blockers, 
NSAIDs, antipyretics, 
narcotics, oxygen, pressors, 
epinephrine, corticosteroids) 
per institutional preferences. 
Monitor vital signs closely until 
medically stable. 
Hospitalization may be 
indicated. 
Permanently discontinue study 
treatment. 
Note for NCI CTCAE (v5.0) Grade 3 
infusion-related reaction: if rapidly 
responsive to symptomatic 
medication and/or to brief 
interruption of infusion, study drug 
does not need to be permanently 
discontinued. 
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. 
Confidential
Page
69
of
129

Margetuximab, INCMGA00012, MGD013
MacroGenics, Inc.
Clinical Trial Protocol: CP-MGAH22-06
Amendment 5, 06 June 2022
7.2 
Immune-Related Adverse Events 
Adverse events of a potential immunologic etiology, or irAEs, may be defined as AEs of 
unknown etiology, associated with drug exposure, and consistent with an immune 
phenomenon. Immune-related AEs may be predicted based on the nature of the compounds, 
their mechanism of action, and reported experience with immunotherapies that have a similar 
mechanism of action. Special attention should be paid to AEs that may be suggestive of 
potential irAEs. An irAE can occur shortly after the first dose or several months after the last 
dose of treatment.
If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, 
toxic, or other etiologic causes before labeling an AE as an irAE.
Recommendations for the management of specific irAEs known to be associated with 
INCMGA00012, MGD013 and other PD-1 inhibitors (eg, pembrolizumab, nivolumab) are 
detailed in Table 10. If treatment-related toxicity does not resolve to Grade 0-1 within 12 
weeks after the last dose of study drug, or if the corticosteroid dose cannot be reduced to ≤ 10 
mg prednisone or equivalent per day within 12 weeks, study drug should be permanently 
discontinued. Severe and life-threatening irAEs should be treated with IV corticosteroids 
followed by oral corticosteroids. Other immunosuppressive treatment should begin if irAEs 
are not controlled by corticosteroids.
For management of irAEs not specifically mentioned in Section 7.2, refer to current National 
Comprehensive Cancer Network Guidelines for the Management of Immune-related 
Toxicities (https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf).
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. All toxicities will be graded according to NCI CTCAE v5.0.
Confidential
Page
70
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
Table 10 
Toxicity Management Guidelines for Immune Related Adverse Events                                         
Immune-Related 
Adverse Event 
Toxicity Grade or Conditions (CTCAE 
v5.0) 
Action Taken with Study 
Treatment 
Adverse Event Management  
Pneumonitis 
Grade 1 
No action 
None 
Grade 2 
Withhold for at least 2 weeks 
and until ≤ Grade 1 
Evaluate participants with suspected pneumonitis with 
radiographic imaging and administer systemic 
corticosteroids per local practice followed by taper 
Add prophylactic antibiotics for opportunistic infections 
Grades 3 or 4 or recurrent Grade 2 
Permanently discontinue 
Diarrhea/colitis 
Grade 1 
No action 
None 
Grades 2 or 3 
Withhold until ≤ Grade 1 
Consider prompt initiation of standard antidiarrheal agents 
and other necessary supportive care as needed (eg, oral 
and/or IV fluids) 
Administer systemic corticosteroids per local practice 
followed by taper 
Consider prophylactic antibiotics per local practice 
Consider gastrointestinal consultation and performing 
endoscopy to rule out colitis 
Consider stool sample evaluation to rule out 
Clostridioides difficile and infectious etiologies 
Grade 4 or recurrent Grade 3 
Permanently discontinue 
AST/ALT elevation 
and/or increased total 
bilirubin/hepatitis 
Grade 1 
No action 
None 
Grade 2 ALT or AST increase or 
Total bilirubin increases to > 1.5 × and up 
to 3 × ULN 
Withhold until ≤ Grade 1 
Administer systemic corticosteroids per local practice 
followed by taper 
Consider monitoring liver enzymes weekly (or more 
frequently) until liver enzyme value returns to baseline or 
is stable 
Consider monitoring total bilirubin, direct bilirubin, and 
alkaline phosphatase weekly (or more frequently) 
Grades 3 or 4 ALT or AST increase or 
In participants with liver metastases with 
baseline Grade 2 elevation of AST or 
ALT, hepatitis with AST or ALT 
increases ≥ 50% and lasts ≥ 1 week or 
Total bilirubin increases to > 3 × ULN 
Permanently discontinue 
Confidential
Page
71
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
Table 10 
Toxicity Management Guidelines for Immune Related Adverse Events                                         
Immune-Related 
Adverse Event 
Toxicity Grade or Conditions (CTCAE 
v5.0) 
Action Taken with Study 
Treatment 
Adverse Event Management  
Endocrinopathies 
Hypothyroidism 
Hyperthyroidism 
Type 1 diabetes 
mellitus 
Hyperglycemia 
Grades 1 or 2 
No action 
None 
Grades 3 or 4 hypothyroidism 
Withhold until ≤ Grade 1 or is 
otherwise clinically stable 
Initiate thyroid replacement hormones (eg, levothyroxine, 
liothyronine) per SOC 
Grades 3 or 4 hyperthyroidism 
Withhold until ≤ Grade 1 or is 
otherwise clinically stable 
Initiate symptomatic management 
Grades 3 or 4 Type 1 diabetes mellitus (or 
hyperglycemia) 
Withhold until ≤ Grade 1 or is 
otherwise clinically stable 
Initiate treatment with antihyperglycemics or insulin as 
clinically indicated 
Endocrinopathies 
(continued) 
Adrenal insufficiency 
Grade 1  
No action 
None. 
Grade 2  
Withhold until ≤ Grade 1 or 
otherwise clinically stable 
Initiate treatment with hormone replacement therapy as 
clinically indicated 
Grades 3 or 4  
Withhold until ≤ Grade 1 after 
corticosteroid taper to ≤ 10 
mg/day prednisone or 
equivalent or is otherwise 
clinically stable 
Administer prednisone or equivalent at initial dose of 
1-2 mg/kg/day followed by a taper and initiate treatment 
with hormone replacement therapy as clinically indicated 
Endocrinopathies 
(continued) 
Hypophysitis 
Grade 1  
No action. 
None. 
Grade 2 (asymptomatic) 
Withhold until ≤ Grade 1 
May restart study drug after 
controlled by hormone 
replacement therapy 
Initiate treatment with hormone replacement therapy 
Grade 2 (symptomatic, eg, headaches, 
visual disturbances) 
Withhold until ≤ Grade 1 
May restart study drug after 
controlled by hormone 
replacement therapy, if 
indicated, and corticosteroid 
taper is complete 
Administer corticosteroids at initial dose of 1-2 mg/kg/day 
prednisone or equivalent followed by a taper and initiate 
treatment with hormone replacement therapy as clinically 
indicated 
Consult with endocrinologist as needed 
Confidential
Page
72
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
Table 10 
Toxicity Management Guidelines for Immune Related Adverse Events                                         
Immune-Related 
Adverse Event 
Toxicity Grade or Conditions (CTCAE 
v5.0) 
Action Taken with Study 
Treatment 
Adverse Event Management  
Grades 3 or 4 (symptomatic) 
Permanent discontinuation 
should occur if after 
withholding study drug, the 
toxicity does not resolve to 
≤ Grade 1 within 12 weeks after 
last dose of study drug, or if 
corticosteroid dose cannot be 
reduced to ≤ 10 mg/day 
prednisone or equivalent within 
12 weeks 
Permanent discontinuation of 
study drug should take place 
earlier, at the investigator's 
discretion, if corticosteroids 
and/or hormone replacement 
therapy cannot balance the 
participant's pituitary function 
Nephritis and renal 
dysfunction 
Grade 1 
No action 
None 
Grades 2 or 3 increased blood creatinine 
Withhold until ≤ Grade 1 
Administer corticosteroids per local practice followed by 
taper 
Grade 4 increased blood creatinine 
Permanently discontinue 
Skin 
(Eg, SJS, TEN) 
Grade 1 
No action 
None 
Grade 2 
No action 
Manage with topical corticosteroids with or without drug 
interruption. 
Confidential
Page
73
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
Table 10 
Toxicity Management Guidelines for Immune Related Adverse Events                                         
Immune-Related 
Adverse Event 
Toxicity Grade or Conditions (CTCAE 
v5.0) 
Action Taken with Study 
Treatment 
Adverse Event Management  
Grade 3a, persistent Grade 2 (≥ 2 weeks), 
or suspected SJSb                                         
Withhold until ≤ Grade 1 after 
corticosteroid taper to ≤ 10 
mg/day prednisone or 
equivalent 
Administer corticosteroids per local practice followed by 
taper. Additionally, oral histamine blockers such as 
diphenhydramine or famotidine (per institutional 
preference) may be utilized as needed 
Refer to dermatology consult if no resolution with these 
measures 
Refer to dermatology consult if SJS or TEN is suspected 
Participants with Grade 3 rash in the absence of desquamation, with no mucosal involvement, not requiring systemic corticosteroids, 
and resolving or improving to ≤ Grade 1 within 14 days do not have to interrupt study drug/treatment. Permanent discontinuation of 
study drug/treatment may be necessary if there is recurrence of Grade 3 rash after resuming study drug/treatment 
Grade 4 or confirmed Grade 4 SJS or 
TEN 
Permanently discontinue 
Administer prednisone or equivalent at initial dose of 
1-2 mg/kg/day followed by a taper 
Refer to dermatology consult 
Myocarditis 
Grade 2-4 
Permanently discontinue 
Treatment with systemic corticosteroids should be initiated 
(initial dose of 1-2 mg/kg/day of prednisone or 
equivalent). Taper as appropriate. 
Refer to cardiology consult 
Manage cardiac symptoms according to SOC and with 
guidance from cardiology. Consider cardiac MRI and 
myocardial biopsy for diagnosis. 
Important nervous 
system events 
(eg, Guillain-Barré 
syndrome, auto-
immune encephalitis, 
myasthenia gravis, 
autonomic 
neuropathy, 
transverse myelitis) 
Grade 2 
Withhold until ≤ Grade 1 
Refer to neurology consult 
Initiate treatment with systemic corticosteroids (initial 
dose of 1-2 mg/kg/day of prednisone or equivalent). Taper 
as appropriate. 
For Grade 2 transverse myelitis, consider permanent 
discontinuation 
Manage symptoms according to SOC and with guidance 
from neurology 
Grades 3 or 4 
Permanently discontinue 
Confidential
Page
74
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
Table 10 
Toxicity Management Guidelines for Immune Related Adverse Events                                         
Immune-Related 
Adverse Event 
Toxicity Grade or Conditions (CTCAE 
v5.0) 
Action Taken with Study 
Treatment 
Adverse Event Management  
All other irAEs 
Grades 2 or 3 based on severity and type 
of reaction 
Withhold until ≤ Grade 1 
Based on severity of AE, administer corticosteroids 
Ensure adequate evaluation to confirm etiology or exclude 
other causes. 
Recurrent Grade 3 or persistent Grades 2 
or Grade 3 
Permanently discontinue 
Grade 4 (excluding endocrinopathies)   
Permanently discontinue 
Confidential
Page
75
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
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 the End of 
Treatment Visit (EOTV) must be recorded in the source document. 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 other small molecules, biologics, or radiotherapy are not allowed.  
• Patients may not receive other investigational drugs during the period of study 
participation. 
• 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. 
• Because INCMGA00012 and MGD013 have a mechanism of action dependent 
upon the engagement of T lymphocytes, 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 INCMGA00012- or MGD013-associated irAEs in consultation with the 
Sponsor’s Medical Monitor. Steroids for topical, ophthalmic, inhaled, or nasal 
administration are allowed. 
• Trastuzumab biosimilar products are not allowed.  
• Capecitabine or 5-FU precautions 
o Per the EMA direct healthcare professional communication (DHPC), as 
treatment of patients with 5-FU or capecitabine-containing medicinal 
products is contraindicated in patients with known complete DPD 
deficiency, DPD testing is recommended during screening 
(https://www.ema.europa.eu/en/documents/dhpc/5-fluorouracil-
ivcapecitabine-tegafur-containing-products-pre-treatment-testing-identify-
dpd_en.pdf). These tests can be conducted locally where available. 
Confidential
Page
76
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
o Patients receiving concomitant capecitabine or 5-FU and oral coumarin-
derivative anticoagulants such as warfarin and phenprocoumon should have 
their anticoagulant response (INR or prothrombin time) monitored 
frequently in order to adjust the anticoagulant dose accordingly. Altered 
coagulation parameters have been reported during concomitant use. 
o Phenytoin: Monitor phenytoin levels in patients taking capecitabine 
concomitantly with phenytoin. The phenytoin dose may need to be reduced. 
o CYP2C9 substrates: Care should be exercised when capecitabine is co-
administered with CYP2C9 substrates. 
• Oxaliplatin 
o Since platinum-containing species are eliminated primarily through the 
kidney, clearance of these products may be decreased by co-administration 
of potentially nephrotoxic compounds. Exercise caution in 
coadministration with other nephrotoxic compounds. 
 
8.1.2 
Permitted Therapies  
Patients may receive the following concurrent therapies: 
• Antiemetics, antidiarrheals, 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 RANK-L inhibitors provided such agents are approved in the 
local jurisdiction and 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 allowed per local practice. 
 
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  
Confidential
Page
77
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
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. 
• 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. 
8.2.2 
Patient Activity Restrictions  
There are no restrictions on patient activities and no requirement for patient confinement 
during the study. 
 
 
Confidential
Page
78
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
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. 
9.1 
Informed Consent  
The Investigator is responsible for ensuring that the patient 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 IRB/Independent Ethics Committee (IEC) approved informed consent document 
(Consent for Study Participation). 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  
Patients may receive the first dose of study treatment up to 28 days after signing the informed 
consent. This period is defined as the 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. 
9.3 
Medical History  
A complete medical history should be obtained during the screening visit. 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 treatment should be 
recorded as medical history and not as an AE, unless it is due to a protocol-related-procedure. 
9.4 
Prior and Concomitant Medications  
Changes to concomitant medications, blood products, and procedures should be evaluated in 
light of potential AEs, and do not need to be recorded on the CRF. If a change to concomitant 
medications or procedures is related to an AE, record the AE on the eCRF.  
Prior courses of systemic cancer therapy (e.g., chemotherapy, immunotherapy, etc.) will be 
documented in the medical records and on the eCRF. 
9.5 
Physical Examination  
The Investigator will perform physical examination of all patients; the examination will be 
conducted as specified in Appendix 1. Full physical examination will be performed at 
screening, and it will include height (screening only), weight, and examination of skin, 
Confidential
Page
79
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
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 symptoms and tumor location, as clinically indicated. 
9.6 
Vital Signs  
Vital signs are obtained as clinically indicated according to the local standards and best 
practices and not recorded on the eCRF.  
9.7 
Pulse Oximetry  
Pulse oximetry is strongly recommended prior to each treatment cycle. Clinically significant 
out of range values should be reported as an AE. 
9.8 
Clinical Laboratory Tests  
Blood and urine samples will be collected at the times specified in Appendix 1. Hematology, 
serum chemistry, pregnancy, urinalysis, coagulation time, and endocrine evaluation tests will 
be collected and processed, according to instructions in the Laboratory Manual. Safety 
laboratory tests should be performed and reviewed before study treatment administration. 
Laboratory values are not entered on the eCRF. Clinically significant laboratory values should 
be reported as AEs, according to the criteria in Section 12.2.1, “Clinical Laboratory 
Changes.” 
9.8.1 
Local HER2 Testing  
In Cohort B, tissue must be tested for HER2 and documented from a reference laboratory that 
conforms to standards set for accreditation by (CAP/CLIA), or an equivalent accreditation 
organization. Per recognized guidelines such as CAP, American Society of Clinical 
Pathologists, and American Society of Clinical Oncology, HER2 status for GC or GEJ cancer 
should be based on the most recently available tumor biopsy collected from the gastric or GEJ 
cancer patient. 
The HER2 IHC and FISH test kit must be HercepTest™, and HER2 FISH pharmDx™ for use 
in GC. Use of test kits only approved for breast cancer is not permitted. Patients with IHC 2+ 
require confirmation with HER2 FISH pharmDx™. If the investigative site does not have 
access to specified test kits, samples may be sent to the central laboratory for testing. If patient 
samples are sent to the central lab for eligibility testing, the patient may not be enrolled in the 
study until the central laboratory results are communicated to the site. 
Refer to the Laboratory Manual for preparation, handling and shipping instructions. 
Patients who are enrolled based on the local HER2 test, and later do not meet protocol criteria 
based on central confirmation can continue in the study. 
Confidential
Page
80
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
9.9 
Central Laboratory Assays  
Clinical laboratory tests to be performed are presented in Appendix 2. Centralized testing of 
HER2, PD-L1, LAG-3, and MSI status, will be conducted at a central laboratory designated 
by the Sponsor. FDA-approved tests will be used for HER2 and PD-L1. See the Laboratory 
Manual for details regarding the collection, preparation and shipping of study samples. 
Collection of samples for PK, PD and ADA are no longer required.  
9.10 
Pharmacodynamics/Biomarkers  
Procedures for the acquisition, handling, and processing of pharmacodynamic biomarker 
specimens will be provided in the Laboratory Manual.  
Patients enrolled on the study will be required to have an identified FFPE tumor specimen 
block. A minimum of 10 unstained slides of 4- to 5-micron sections on positively charged 
slides from an FFPE tumor specimen or contemporaneous biopsy available for submission for 
HER2, PD-L1, MSI, and LAG-3. If possible, include one hematoxylin and eosin stained slide 
of the same tumor specimen to assist in location of tumor cells. 
Individual assay results of central MSI testing will not be provided to the Investigator and 
central radiology reviewers for tumor assessments. 
9.11 
Radiographic Assessments  
Baseline tumor imaging consists of a CT or 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 evaluated for 
disease progression only according to Appendix 1. No measurement of individual lesions is 
required. Only the RECIST 1.1 overall response will be recorded in the eCRF. 
A CT or MRI scan of the brain will be performed in cases where brain metastasis is suspected 
to rule out metastatic spread to the brain. 
9.12 
Electrocardiography  
Twelve-lead ECGs will be obtained at screening and as clinically indicated.  
Actual times and other parameters of the ECG assessments will be recorded on the eCRFs. 
9.13 
MUGA/Echocardiogram  
Multigated acquisition ventriculography scanning (MUGA) scans or echocardiograms will be 
obtained and analyzed locally in all patients according to the Time and Events Schedules 
(Appendix 1). The same modality should be used throughout the study for any given patient. 
All MUGA scans or echocardiography performed will be evaluated for the change in LVEF 
from baseline.  
Confidential
Page
81
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
9.14 
End of Treatment Visit  
A list of evaluations to be performed for the EOTV is provided in Appendix 1. The EOTV 
should be performed within 30 days after the patient has met study treatment discontinuation 
criteria specified in Section 5.3. 
9.15 
Post-Treatment Follow-up Visit  
The post-treatment follow-up period includes up to a 30-day follow-up after treatment 
discontinuation or initiation of subsequent anticancer therapy, whichever is earlier. Any 
patient currently in survival follow-up will be discontinued from study. 
 
Confidential
Page
82
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
10 
ASSESSMENT OF PHARMACOKINETICS AND 
PHARMACODYNAMICS  
10.1 
Pharmacokinetic Assessments  
Serum concentrations of study drugs will be measured using respective validated assay 
methods in the Sponsor’s designated laboratory. Descriptive PK summaries will be provided.  
10.2 
Pharmacodynamic/Biomarker Assessments  
Pharmacodynamics/Biomarker Assessments 
Biomarker assessments related to entry criteria will be performed prospectively prior to 
enrollment. Other biomarker assessments not related to entry criteria will be prospectively 
collected and retrospectively analyzed. 
Cohort A 
• MSI status performed by a central laboratory   
• PD-L1 and HER2 expression by IHC will be conducted with FDA-approved 
assays by a central laboratory for eligibility. 
 
Cohort B  
• Determination of MSI status performed by a central laboratory  
• LAG-3 expression based on FFPE tumor tissue  
• Determination of PD-L1 and HER2 expression will be conducted with 
FDA-approved assays for central confirmation.  
 
 
 
Confidential
Page
83
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
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 every 3 cycles (± 7 days) for approximately 9 months. Beginning with 
Cycle 13, assessments will occur every 4 cycles (± 7 days) while on treatment.  
Patients in Cohort A who have radiographic progression but are clinically stable may remain 
on study treatments until the next radiographic evaluation, upon Sponsor Medical Monitor 
consultation. 
11.1.2 
Survival Assessments  
Survival assessments will no longer continue.  Patients currently in survival follow up should 
be discontinued from the study. 
11.2 
Immunogenicity Assessments  
The generation of ADA for margetuximab, INCMGA00012, and MGD013 will be monitored 
using validated assay methods. 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 ADA assessment. 
 
 
Confidential
Page
84
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
12 
ADVERSE EVENT REPORTING AND ASSESSMENT OF 
SAFETY  
12.1 
Definitions  
12.1.1 
Adverse Event  
Adverse event (AE): any untoward medical occurrence in a patient or clinical trial patient 
associated with 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 
baseline, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities. 
 
12.1.2 
Adverse Drug Reaction  
Adverse drug reaction (ADR): 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 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 may 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  
An SAE is any AE that results in any of the following outcomes: 
• Death 
• Life-threatening (immediate risk of death) 
• 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 
Confidential
Page
85
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
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. 
Assessment of causality or relationship of AEs to study drug is provided by the Investigator 
and is determined by the Investigator. Criteria include 1) temporal relationship of the AE to 
study drug administration, 2) whether an alternative etiology has been identified, and 
3) biological plausibility. 
Causality assessment categories used for this study are described below. 
Causality assessments considered not related to study drug: 
• None: The event is related to an etiology other than study drug. Alternative 
etiology should be documented. 
• Unlikely: The event is unlikely related to study drug and likely 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 
a clinical opinion factor(s), agent(s), or process(es) likely to be causative of the event. 
Causality assessments 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. 
• 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 AE severity will be by NCI CTCAE v5.0. 
Confidential
Page
86
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
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 are 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 AEs 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. Events attributed to 
protocol-specified procedures will be collected on the Adverse Event eCRFs as appropriate. 
AEs, regardless of seriousness, severity, or relationship to study drug, are documented on the 
eCRF, including: 
• Duration, severity, and seriousness of each AE  
• Action taken with respect to study drug(s) 
• Investigator’s attribution/causality assessment 
• Event outcome 
 
When possible, diagnoses are given for signs and symptoms due to a common etiology 
(e.g., cough, runny nose, sneezing, sore throat, and head congestion reported as “upper 
Confidential
Page
87
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
respiratory infection”). All treatment for AE management will be recorded. Non-serious AEs 
should be entered into the eCRFs within 10 business days of study site awareness. 
Clinical Laboratory Changes: Safety laboratory assessments will be evaluated by the 
Investigator to ensure patient safety. Laboratory tests will be graded according to 
CTCAE v5.0. 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 associated with an intervention including, but 
not limited to, discontinuation of treatment, dose reduction/delay, or 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 RBC increased). 
The Sponsor assumes responsibility for appropriate reporting of AEs to the regulatory 
authorities. The Sponsor will also notify the Investigator of regulatory submissions, as 
appropriate. The Investigator is responsible for notifying the appropriate IEC or IRB that 
approved the protocol, unless otherwise required and documented by the IEC/IRB. 
12.2.2 
Serious Adverse Events  
All SAEs occurring during the study must be reported to the Sponsor. 
• Within 24 hours of becoming aware of an SAE, the Investigator should report the 
SAE to the Sponsor by completing the appropriate eCRF(s). Upon receipt of SAE 
follow-up information, the appropriate eCRFs should be completed within 24 
hours of becoming aware of the follow-up information. In the event of a system 
outage, SAE form can be utilized as the back-up reporting method. The completed 
SAE form should be emailed to saereports@macrogenics.com or faxed to 
(301)-354-3800. The SAE information should be entered into the eCRF(s) within 
24 hours of the system becoming available. 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. 
• 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). 
Confidential
Page
88
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
• 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 will follow all SAEs until resolution and record the date of 
resolution. Resolution is a return to pre-treatment status or stabilization of a 
chronic condition. 
• Unresolved SAEs at study end or upon patient withdrawal 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 an etiology other than study drug 
o It becomes unlikely additional information can be obtained due to patient 
or health care practitioner refusal, or LTFU after due diligence efforts. 
 
• Any event requiring hospitalization or its prolongation during study drug will be 
reported as a SAE, except hospitalization: 
o A standard hospitalization for administration of study drug  
o For a protocol/disease-related procedure e.g., surgery, scans, endoscopy, 
and sampling of marrow, blood, or other tissue.  
o Hospitalizations not intended to treat an acute illness or AE, including 
social reasons such as pending placement in long-term care or hospice 
facility. 
o Documented surgery or procedure planned before study entry. 
 
• 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. 
Confidential
Page
89
of
129

Margetuximab, INCMGA00012, MGD013
MacroGenics, Inc.
Clinical Trial Protocol: CP-MGAH22-06
Amendment 5, 06 June 2022
12.2.3 
Protocol-Specific Adverse Events of Special Interest 
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). A list of protocol-specific AESIs are displayed in Table 11.
Table 11
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 
≤ Grade 2 IRRs or CRS events 
Within 10 days of the study site’s 
awareness of the event. 
≥ Grade 3 IRRs or CRS events 
Within 24 hours of the study site’s 
awareness of the event 
≥ Grade 3 immune-related AEs 
Within 24 hours of the study site’s 
awareness of the event 
Decreased LVEF defined as:  
≥ 16% absolute decrease from the pre-treatment value, or 
< institutional normal limits (or 50% if no limits are available) and ≥ 
10% absolute decrease from pre-treatment values 
Within 24 hours of the study site’s 
awareness of the event 
12.2.4 
Pregnancy 
Pregnancy in a female patient or partner of a male patient must be reported on the Pregnancy 
Exposure Form (from the Study Procedures manual) within 24 hours of study site awareness. 
The reporting period is from consent through 7 months after the last dose of study treatment, 
or initiation of subsequent 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.
Confidential
Page
90
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
12.2.5 
Special Reporting Situations  
12.2.5.1 
Overdose  
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. 
12.2.5.1.1 
INCMGA00012  
Retifanlimab has been safely administered at doses up to 750 mg Q4W. In case of overdose, 
participants should be closely monitored for signs or symptoms of adverse reactions, and 
treatment should consist of general supportive measures. 
12.2.5.1.2 
MGD013 and Margetuximab  
Overdose is any accidental administration of study drug ≥ 20% of the assigned dose. In the 
event of an overdose, the patient should be closely monitored for potential AEs. 
12.2.5.2 
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. 
12.2.5.3 
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. 
 
Confidential
Page
91
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
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 
patient’s, 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). A sample of the 
suspected product should be maintained for further investigation if requested by the Sponsor. 
13.2 
Contacting Sponsor Regarding Product Quality  
Product quality issues should be reported via e-mail to: 
Quality.complaints@macrogenics.com. 
 
 
Confidential
Page
92
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
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 will further describe the details regarding statistical methods and will govern the 
analysis. 
14.1 
Determination of Sample Size  
The planned sample sizes are described below. The study enrollment was closed. At the time 
of this protocol amendment, there are 48 patients treated in Cohort A. There were 34 patients 
randomized, of which 33 patients were treated in Cohort B Part 1. Cohort B Part 2 has never 
started.   
Cohort A  
The sample size of approximately 100 non-MSI-H patients is based on a Simon two-stage 
design to provide approximately 83% power to test ORR of 
 at a 2-sided alpha 
level of 0.05. The first stage (Part 1) will enroll and treat 40 response evaluable non-MSI-H 
patients. If at least 21 (53%) responders (CR or partial response [PR]) are observed, the study 
will move to the second stage (Part 2) with enrollment of approximately 60 additional 
response evaluable non-MSI-H patients. Other efficacy data such as DoR and PFS will be 
considered as well in enrollment decision-making. If the study continues to enroll an 
additional 60 patients, the null hypothesis H0: ORR = 
would be rejected at 1-sided alpha 
level of 0.025 (or equivalently, 2-sided 0.05) if the observed ORR from all 100 response 
evaluable non-MSI-H patients is ≥ 
. However, the totality of the data will be assessed to 
determine not only statistical significance but a clinically meaningful effect. The total number 
of patients to be enrolled in Cohort A is expected to be approximately 110 in order to obtain 
approximately 100 non-MSI-H patients. 
Cohort B 
The sample size for Cohort B is determined based on a Phase 2/3 design. The sample size will 
consist of patients that are HER2+ by central confirmation. Entry criteria for HER2 may be 
based on a local test, however, enrollment will continue until the sample size is accrued based 
on central confirmation. The total planned sample size for Cohort B is approximately 750, 
consisting of two parts: 
• In the Cohort B Part 1, a total of approximately 250 patients with centrally 
confirmed HER2+ will be enrolled as follows. First, approximately 200 patients 
will be randomized in a 1:1:1:1 ratio to 1 of 4 arms (one control arm and three 
margetuximab-containing arms). The randomization will be stratified by two 
stratification factors: chemotherapy regimen (XELOX or mFOLFOX-6) and 
results of local HER2 testing (IHC 2+/FISH+ vs IHC 3+). Selection of which of 
2 margetuximab and CPI-containing arms to move to the Phase 3 part of the study 
(Cohort B Part 2) for further testing will be primarily based on ORR but will also 
take into consideration PFS and safety. After this randomization portion of 
Confidential
Page
93
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
enrollment is complete, enrollment of up to approximately 50 additional non-
randomized patients will continue into the margetuximab + chemotherapy arm 
only. 
• In Cohort B Part 2, approximately 500 patients with centrally-confirmed HER2+ 
will be randomized in a 1:1 ratio between the control arm and the selected 
margetuximab arm. The randomization will be stratified by two stratification 
factors: chemotherapy regimen (XELOX vs. mFOLFOX-6) and results of local 
HER2 testing (IHC 2+/FISH+ vs IHC 3+).  
 
By applying the closed testing procedure (27) and the inverse normal p-value combining 
method (5) to test primary endpoint OS at the end of Cohort B Part 2, the sample size of 
approximately 650 patients planned enrollment [Cohort B Part 1: control arm (50 patients), 2 
margetuximab and CPI-containing arms (100 patients) and 500 patients from Cohort B Part 2] 
will provide approximately 80% power to detect OS HR = 
 (median OS increase from 
 months for control arm to 
months for either margetuximab and CPI-containing arm) at 
1-sided 0.025 (or equivalently, 2-sided 0.05) alpha level. The total sample size for Cohorts A 
and B is approximately 860. 
14.2 
Independent Data Monitoring Committee  
An IDMC will oversee the ongoing monitoring and interpretation of the safety and efficacy 
data from this study. An IDMC charter will be created, reviewed, and approved by the 
committee prior to study initiation.  
The IDMC will evaluate aggregate safety data for the relevant treatment arms, and also 
evaluate efficacy for the specified analyses. Frequency of IDMC meetings may be adjusted in 
accordance with the consensus of the IDMC and reflected in the IDMC Charter.   
• For Cohort A, the first IDMC meeting will take place after the first 12 patients 
have completed at least 1 cycle of study treatment, or at 6 months from first 
enrollment, whichever comes first. Reviews will continue in 6-month intervals 
(± 1 month). 
• In Cohort B, the first evaluation will take place after 20 patients in each arm have 
been enrolled and completed at least 1 cycle of treatment, or approximately 6 
months from first enrollment, whichever comes first. The IDMC may meet at any 
time if evolving safety data warrant a safety review. Reviews will continue in 6-
month intervals (± 1 month). 
• Once the first assessment in Cohort B is completed, to the extent possible, safety 
and efficacy data from Cohort A and Cohort B will be reviewed at the same 
meeting.  
 
Confidential
Page
94
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
The IDMC will also review safety and efficacy data for each of the cohorts. When 
approximately 40 patients (Cohort A) or 200 patients (Cohort B Part 1) have at least one CT 
scan to evaluate response or discontinued study treatment prior to first tumor assessment, the 
IDMC will be asked to make a recommendation regarding continuation of full enrollment for 
the cohort or suspending enrollment pending Sponsor final decision.  
The committee will be provided with safety and efficacy tables and data listings for these 
reviews. Additional details on the IDMC monitoring, and administration may be found in the 
IDMC Charter. 
14.3 
Analysis Populations  
The study analyses will be performed on the following populations: 
• Safety Population: All patients who receive at least one dose of study drug. The 
safety population will be used to summarize safety data for Cohort A and Cohort B 
of the study, respectively. Patients enrolled in Cohort B will be analyzed according 
to the actual treatment received rather than the treatment group they were assigned. 
This population will also be used to summarize baseline data for Cohort A. 
• PK Evaluable Population: All patients who received at least one dose of study 
drug, date and time of dose administration and relative PK sample collection are 
known and have sufficient concentration data to derive at least one PK parameter.  
• ADA Evaluable Population: All patients who received at least one dose of study 
treatment, date and time of dose administration and relative PK sample collection 
are known and have sufficient concentration data to derive at least one PK 
parameter.  
• ITT Population: All patients who are assigned to treatment in Cohort A and all 
patients who are randomized into Cohort B of the study. Patients will be analyzed 
according to the treatment assigned. This population will be used to summarize 
baseline data and evaluate PFS. 
• Response Evaluable Population (REP): All patients who received at least one dose 
of study treatment and had baseline radiographic tumor assessment. This 
population will be used for objective response related efficacy analyses for 
Cohort A and Cohort B, respectively, and will be analyzed according to the actual 
treatment received. 
 
14.4 
Demographics and Baseline Characteristics  
Patient disposition, demographics, baseline characteristics, disease history, medical history, 
and prior cancer treatment will be summarized using descriptive statistics. 
Confidential
Page
95
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
14.5 
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 administrated as 
well as the total dose intended, and the dose intensity which is calculated as percentage of 
total dose administered divided by total dose intended during whole treatment period. 
14.6 
PK/PD and Immunogenicity Analysis  
14.6.1 
Pharmacokinetics Analysis  
Serum samples from patients with positive ADA results will be analyzed for concentrations of 
relevant study treatments. Concentration data will be summarized accordingly to evaluate the 
relationship between study drug exposure and ADA positivity.  
14.6.2 
Immunogenicity Analysis  
The proportion of patients who are negative for study drug-specific ADA (i.e., margetuximab, 
INCMGA00012, or MGD013) at baseline and have a study drug-specific ADA-positive after 
administration of study treatment(s), the proportion of patients who are negative at baseline 
and remain negative, and the proportion of patients who have a positive ADA at baseline that 
increases or decreases in titer over the course of treatment will be summarized. 
14.6.3 
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 as will possible associations between changes in 
pharmacodynamic measures of interest and study drug and exposure may be explored. 
14.7 
Efficacy and Endpoint Analyses  
14.7.1 
Primary Efficacy Endpoints and Analyses for Cohort A  
The primary efficacy endpoint for Cohort A is ORR per RECIST v1.1, defined as the 
proportion of non-MSI-H patients in the response evaluable population who achieve the BOR 
of CR or PR (called responders) per RECIST v1.1. The 2-sided 95% exact binomial CI of 
ORR will be calculated.  
For RECIST v1.1, the BOR will be categorized as CR, PR, stable disease (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. 
The analysis of ORR will be based on investigator review determined response data. 
Confidential
Page
96
of
129

Margetuximab, INCMGA00012, MGD013
MacroGenics, Inc.
Clinical Trial Protocol: CP-MGAH22-06
Amendment 5, 06 June 2022
14.7.2 
Secondary Efficacy Endpoints and Analyses for Cohort A 
The secondary efficacy endpoints for non-MSI-H patients in Cohort A are:
•
PFS, defined as the time from start of study treatment to the first documented
disease progression per RECIST v1.1 or death due to any cause, whichever occurs
first. For patients who are not known to be dead or progressed at time of data cut-
off for PFS analysis, the PFS will be censored at the last tumor assessment.
Specifically, the following censoring rules will be applied as the analysis of PFS
(Table 12).
Table 12
Censoring Rules for PFS Analysis
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 anticancer 
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 two or 
more consecutive scheduled tumor 
assessments 
Date of last tumor assessment prior 
to missed assessments 
Censored 
•
DoR, 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 12 will be applied. The DoR analyses will be performed only if 
there are enough responders to render the analyses meaningful.
•
DCR, 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. The Kaplan-Meier method 
will be applied to estimate PFS, DoR, curves; their median times; PFS rates at 6, 9, and 12 
Confidential
Page
97
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
months. The method of Brookmeyer and Crowley (9) will be used to construct 95% CIs for 
median time of each time-to-event endpoint. The 95% CIs for PFS rates at each time point of 
interest will be calculated by normal approximation after log(-log) transformation. The 
analyses of PFS and DoR will be performed using investigator assessed response data.  
Note that all primary and secondary efficacy endpoints will be analyzed only for non-MSI-H 
patients.  
14.7.3 
Efficacy Endpoints and Analyses for Cohort B Part 1  
The efficacy endpoints include ORR and DCR, defined in the same way as for Cohort A, 
based on investigator assessments. The BOR, ORR, and DCR will be summarized in the REP. 
14.7.4 
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 may be presented by spider plot. The best 
tumor size change from baseline will be presented by waterfall plot. 
14.8 
Safety Endpoints and Analyses  
14.8.1 
Adverse Events  
Only TEAEs will be summarized. The following TEAEs will be provided in summary tables 
as well as displayed in listings:  
• All TEAEs  
• TEAEs by CTCAE ≥ Grade 3 
• TRAEs 
• TRAEs by CTCAE ≥ Grade 3 
• TEAEs related to each individual study drug 
• Any SAEs  
• Treatment-related SAEs 
• SAEs related to each individual study drug 
• TEAEs that result in study treatment discontinuation 
• TRAEs that result in study treatment discontinuation 
• TEAEs which lead to interruption of each individual study drug 
Confidential
Page
98
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
• TEAEs that lead to withdrawal of each individual study drug 
• Fatal AEs 
• AESIs 
 
All of these tables will display the number and percent of patients that experience the given 
event and will display events by Medical Dictionary for Regulatory Activities (MedDRA) 
System Organ Class (SOC) and Preferred Term (PT). Events will be displayed alphabetically 
for SOC and PT. An overall summary of AEs will display the number and percent of 
patient/patients who experience at least one event of each of the above types. 
14.8.2 
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.  
14.8.3 
Other Safety Endpoints  
ECGs and LVEF will be collected and analyzed for evidence of cardiac toxicity. Vital signs 
will be summarized with descriptive statistics at each visit and time point where they are 
collected. Shift tables may be performed. 
14.9 
Interim Analysis  
Cohort A 
There is a planned interim analysis after 40 patients in the REP have been enrolled and their 
responses have been assessed by independent review. As described in Section 14.1, if at least 
21 (53%) responders (CR or PR) per independent review are observed, then enrollment will 
continue. The Investigator assessed response, PFS based on both independent review and 
Investigator assessment, and safety data will also be summarized to assist in decision making. 
14.10 
Final Analysis  
The final analysis will occur after all patients have completed treatment and the 30-day 
follow-up. 
14.11 
Other Assessments or Analyses  
No other analyses are planned. 
 
 
Confidential
Page
99
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
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, 
Confidential
Page
100
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
study data etc.). The Investigator will ensure the capability for inspections of applicable 
study-related facilities (e.g., pharmacy, diagnostic laboratory, etc.). 
15.2 
Data Collection and Management  
The Investigator is responsible for maintaining accurate, complete, and up-to-date records for 
each patient. The Investigator is also responsible for maintaining any source documentation 
related to the study, including any films, tracings, or other media containing data pertaining to 
this protocol. 
The anonymity of participating patients must be maintained. For data collection, and 
management purposes, patients are to be identified by a patient number only. Documents that 
identify the patient beyond patient number (e.g., patient initials) will not be submitted to the 
Sponsor (e.g., the signed informed consent document) and must be maintained in strict 
confidence by the Investigator, except to the extent to allow auditing by the regulatory 
authorities, study monitor, or Sponsor representatives. 
Site personnel record all data for each patient through 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. As the person ultimately responsible for the accuracy 
of all eCRF data, 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, where they are tracked. Study sites 
resolve the queries and correct the entered data accordingly. Every change to data is captured 
in the EDC system audit trail. AEs are coded using MedDRA, whereas 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. Upon completion of the study, 
each study site will be provided with the eCRFs for each of their patients. 
Confidential
Page
101
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2020 
 
 
16 
ADMINISTRATIVE CONSIDERATIONS  
16.1 
Institutional Review Board or Independent Ethics Committee 
Approval  
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. Any 
documents that the IRB/IEC may need to fulfill its responsibilities, such as the protocol and 
any amendments, Investigator’s Brochures, and information concerning patient recruitment, 
payment or compensation procedures, or information from the Sponsor, will be submitted to 
the IRB/IEC. The IRB/IEC’s written approval of the study protocol and the ICFs will be in the 
possession of the Investigator and the Sponsor before the study drug is initiated at the 
Investigator’s site. The Investigator will transmit the IRB/IEC’s approval statement to the 
Sponsor. This approval must include the date of review and refer to the study by protocol title 
and/or study number and version number and refer to the ICFs by version number or date. 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. If approval 
of the ICFs is stamped on the forms (instead of documented in the IRB/IEC approval 
statement) the date of approval and/or expiration must be included. 
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, where required by local regulations, submit to the IRB/IEC the 
following: 
• The protocol and the Investigator’s Brochures and any amendments or updates. 
• The ICF(s) and any amendments or changes. 
• Any documents given to patients or potential patients (e.g., recruitment materials, 
diary cards) and the plan for distribution/use. 
• Revisions of other documents originally submitted for review or for notification. 
• Serious and/or unexpected AEs occurring during the study. 
• New information that may adversely affect the safety of patients or conduct of the 
study. 
• At minimum, an annual update and/or request for re-approval of study, unless 
otherwise specified by IRB/IEC. 
• Protocol deviations. 
Confidential
Page
102
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2020 
 
 
• Notification when the study has been completed. 
• Proof of indemnity/liability insurance. 
• Other documents required by the IRB/IEC. 
 
16.2 
Ethical Conduct of the Study  
The investigational study will be conducted according to the Protection of Human Patients 
(21 CFR [Code of Federal Regulations] 50), Institutional Review Boards (21 CFR 56), 
Obligations of Clinical Investigators (21 CFR 312.60 − 312.69), and/or the current ICH 
Guideline for Good Clinical Practice (ICH E6) and all other applicable regulations. 
16.3 
Patient Information and Consent  
It is the responsibility of the Investigator to obtain and document written informed consent 
from the patient. Informed consent in compliance with the principles of informed consent in 
ICH E6 and all applicable local regulations should be obtained before any protocol-specified 
procedures or interventions are conducted. 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 consent form generated by the Investigator must be approved by the IRB/IEC. The 
Investigator will provide the Sponsor with a copy of the IRB/IEC-approved consent forms and 
a copy of the IRB/IEC’s written approval before the start of the study. 
Consent forms must be written (and appropriately translated in the patient’s native language 
or language in which the patient has fluency) so as to be understood by the prospective 
patient. Informed consent will be documented by the use of a written consent form approved 
by the IRB/IEC. The form must be signed and dated by the patient, and by the person who 
conducted the discussion of the informed consent. 
All versions of each patient’s signed ICF must be kept on file by the Investigator for possible 
inspection by regulatory authorities and/or authorized MacroGenics monitoring and regulatory 
compliance persons. The patient should receive a copy of the signed and dated written ICF 
and any other written information provided to the patients. 
16.4 
Patient Confidentiality  
To maintain confidentiality of patients, 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 an individual with legal decision-making 
Confidential
Page
103
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2020 
 
 
authority for the patient or the patient’s interests, except as necessary for monitoring by the 
relevant regulatory authorities, the Sponsor of the clinical study, or the Sponsor’s 
representative. The Investigator must also comply with all local applicable privacy regulations 
[e.g., US Health Insurance Portability and Accountability Act of 1996 (HIPAA) or the General 
Data Protection Regulation (GDPR)], on protection of individuals with regard to personal 
data. 
16.5 
Case Report Forms and Study Records  
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 designed to capture data pertinent to the 
clinical investigation. Data should be recorded on paper source documents or electronic in an 
electronic medical records system. Electronic CRFs should be completely in their entirety by 
the Investigator or his/her designee. Prior to eCRF database lock, the Investigator will verify 
the completeness and accuracy of the data and indicate that he/she has done so by providing 
an electronic signature on the appropriate eCRF. The Investigator will retain a copy of all 
source documents. 
16.6 
Access to Source Documentation  
The Investigator and study center will permit the Sponsor, its representatives, IRB/IEC, and 
all relevant regulatory agencies access to all original source data and documents regardless of 
media, for study monitoring audits and inspections. 
16.7 
Retention of Data  
Per ICH guidelines, all essential documents, including eCRFs, source documents (regardless 
of media), signed ICFs, and laboratory test results, should be retained by the Investigator for 
at least 2 years after last approval of a marketing application in an ICH region and 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. 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. 
16.8 
Sample Retention  
Samples acquired for protocol-specified assays are retained according to local and regional 
regulatory requirements. If the patient consents, to the use of their study samples for 
secondary research purposes, samples may be used for exploratory testing and retained up to 
Confidential
Page
104
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2020 
 
 
15 years from the end of study. Please refer to the Laboratory Manual for the address and 
contact information for sample retention laboratories, including long-term storage.  
16.9 
Financial Disclosure  
The Investigator and Sub-Investigators will be required to disclose any applicable financial 
arrangement as defined in US regulation (i.e., 21 CFR 54).  
The following information will be collected about the Investigators, their spouse and each 
dependent child: any significant payments of other sorts from MacroGenics, Inc., or any 
alliance partner, such as a grant to fund ongoing research, compensation in the form of 
equipment, retainer for ongoing consultation or honoraria; any proprietary interest in the study 
drug; and any significant equity interest in MacroGenics, Inc., as defined in 21 CFR 54. 
Investigators are obliged to update the Sponsor with any changes in reported information up 
to 1 year following the end of the study. 
In addition, Investigators and Sub-Investigators will be required to disclose if they are an 
employee of MacroGenics, or an immediate family member of a MacroGenics employee, 
officer, or director. This is to assist MacroGenics with its compliance with Securities and 
Exchange Commission rules requiring disclosure of certain transactions with related persons 
as defined in 17 CFR 229.404. “Immediate family member of a MacroGenics employee” 
means a child, stepchild, parent, stepparent, spouse, sibling, mother-in-law, father-in-law, son-
in-law, brother-in-law, or sister-in-law of any MacroGenics employee, officer, or director or 
any person sharing the household of such MacroGenics employee, officer, or director. 
In consideration of participation in the study, MacroGenics, will pay the Investigator or 
nominated payee the sums set out in the payment schedule attached to the Investigator 
agreement. 
Financial disclosure information will be documented in writing and signed and dated by the 
Investigator. This information will be collected prior to that Investigator taking part in the 
research. 
16.10 
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. 
16.11 
Discontinuation of the Study or Study Sites  
16.11.1 
Discontinuation of the Study  
The study may be discontinued by a regulatory authority or at the discretion of the Sponsor. 
Confidential
Page
105
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2020 
 
 
The Investigator maintains the right to discontinue his/her participation in the study should 
his/her clinical judgment so dictate. The Investigator will notify the IRB/IEC of any study 
discontinuation. Study records must be retained as noted above. 
16.11.2 
Discontinuation of Study Sites  
Site participation may be discontinued if MacroGenics, the Investigator, a regulatory 
authority, or the IRB/IEC of the study sites deems it necessary for any reason. 
 
Confidential
Page
106
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
17 
REFERENCE LIST  
Note: Newly added literature references are in colored text. Previously cited submitted 
literature references are in black text. 
1. 
Andrews, LP, Marciscano, AE, Drake, CG, and Vignali, DA, LAG3 (CD223) as a 
cancer immunotherapy target. Immunol Rev, 2017. 276(1): p. 80-96. 
2. 
Ascierto, PA, Melero, I, Bhatia, S, Bono, P, Sanborn, R, Lipson, E, et al., Initial 
Efficacy of Anti-Lymphocyte Activation Gene-3 (anti-LAG-3; BMS-986016) in 
Combination with Nivolumab in Patients with Melanoma Previously Treated with 
Anti-PD-1/PD-L1 Therapy. ASCO 2017(15). 
3. 
Baksh, K and Weber, J, Immune checkpoint protein inhibition for cancer: preclinical 
justification for CTLA-4 and PD-1 blockade and new combinations. Semin Oncol, 
2015. 42(3): p. 363-77. 
4. 
Bang, YJ, Van, CE, Feyereislova, A, Chung, HC, Shen, L, Sawaki, A, et al., 
Trastuzumab in combination with chemotherapy versus chemotherapy alone for 
treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer 
(ToGA): a phase 3, open-label, randomised controlled trial. Lancet, 2010. 376(9742): 
p. 687-697. 
5. 
Bauer, P and Kohne, K, Evaluation of experiments with adaptive interim analyses. 
Biometrics, 1994. 50(4): p. 1029-41. 
6. 
Berton-Rigaud D, VI, Pautier P, A phase 1 study of retifanlimab (INCMGA00012), 
a PD-1 inhibitor, in patients with advanced solid tumors: preliminary results in 
recurrent MSI-high or dMMR endometrial cancer (POD1UM-101). Journal for 
Immunotherapy of Cancer, 2020. 8: p. p.A16-A165. 
7. 
Berton D, Pautier P, Lorusso D, Gennigens C, Gladieff L, Kryzhanivska A, 
Ranganathan S, Tian C, Bourayou N, Vergote I, 956 Retifanlimab 
(INCMGA00012) in patients with recurrent MSI-H or dMMR endometrial cancer: 
results from the POD1UM-101 study. Journal for Immunotherapy of Cancer, 2021. 
9((Sppl 2)): p. p.A1006-A1006. 
8. 
Boger, C, Behrens, HM, Mathiak, M, Kruger, S, Kalthoff, H, and Rocken, C, PD-
L1 is an independent prognostic predictor in gastric cancer of Western patients. 
Oncotarget, 2016. 7(17): p. 24269-83. 
9. 
Brookmeyer, R and Crowley, J, A Confidence Interval for the Median Survival 
Time. Biometrics, 1982. 38: p. 29-41. 
10. 
Cancer Genome Atlas Research, N, Comprehensive molecular characterization of 
gastric adenocarcinoma. Nature, 2014. 513(7517): p. 202-9. 
Confidential
Page
107
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
11. 
Carter, P, Presta, L, Gorman, CM, Ridgway, JB, Henner, D, Wong, WL, et al., 
Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl 
Acad Sci U S A, 1992. 89(10): p. 4285-9. 
12. 
Chaganty, BKR, Qiu, S, Gest, A, Lu, Y, Ivan, C, Calin, GA, et al., Trastuzumab 
upregulates PD-L1 as a potential mechanism of trastuzumab resistance through 
engagement of immune effector cells and stimulation of IFNgamma secretion. Cancer 
Lett, 2018. 430: p. 47-56. 
13. 
Dai, C, Wang, M, Lu, J, Dai, Z, Lin, S, Yang, P, et al., Prognostic and predictive 
values of PD-L1 expression in patients with digestive system cancer: a meta-analysis. 
Onco Targets Ther, 2017. 10: p. 3625-3634. 
14. 
Eisenhauer, EA, Therasse, P, Bogaerts, J, Schwartz, LH, Sargent, D, Ford, R, et 
al., New response evaluation criteria in solid tumours: revised RECIST guideline 
(version 1.1), in Eur J Cancer. 2009. p. 228-247. 
15. 
EMA, Summary of Positive Opinion for Herceptin. Evaluation of Medicines for 
Human Use, 2009. 
16. 
Foy, SP, Sennino, B, dela Cruz, T, Cote, JJ, Gordon, EJ, Kemp, F, et al., 
Poxvirus-Based Active Immunotherapy with PD-1 and LAG-3 Dual Immune 
Checkpoint Inhibition Overcomes Compensatory Immune Regulation, Yielding 
Complete Tumor Regression in Mice. PLoS One, 2016. 11(2): p. e0150084. 
17. 
Freshwater, T, Kondic, A, Ahamadi, M, Li, CH, de Greef, R, de Alwis, D, et al., 
Evaluation of dosing strategy for pembrolizumab for oncology indications. J 
Immunother Cancer, 2017. 5: p. 43. 
18. 
Fuchs, CS, Doi, T, Jang, RW, Muro, K, Satoh, T, Machado, M, et al., Safety and 
Efficacy of Pembrolizumab Monotherapy in Patients With Previously Treated 
Advanced Gastric and Gastroesophageal Junction Cancer: Phase 2 Clinical 
KEYNOTE-059 Trial. JAMA Oncol, 2018. 
19. 
Garattini, SK, Basile, D, Cattaneo, M, Fanotto, V, Ongaro, E, Bonotto, M, et al., 
Molecular classifications of gastric cancers: Novel insights and possible future 
applications. World J Gastrointest Oncol, 2017. 9(5): p. 194-208. 
20. 
Gavin, PG, Song, N, Kim, R, Lipchik, C, Johnson, NL, Bandos, H, et al., 
Association of Polymorphisms in FCGR2A and FCGR3A With Degree of 
Trastuzumab Benefit in the Adjuvant Treatment of ERBB2/HER2–Positive Breast 
Cancer Analysis of the NSABP B-31 Trial. JAMA Oncology, 2016: p. 5. 
21. 
Genentech, Herceptin Prescribing Information. 2010. 
22. 
Genentech, Herceptin Prescribing Information. Genentech, 2014. 
Confidential
Page
108
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
23. 
Gong, J, Liu, T, Fan, Q, Bai, L, Bi, F, Qin, S, et al., Optimal regimen of 
trastuzumab in combination with oxaliplatin/ capecitabine in first-line treatment of 
HER2-positive advanced gastric cancer (CGOG1001): a multicenter, phase II trial. 
BMC Cancer, 2016. 16: p. 68. 
24. 
Grignani G, BM, Depenni R, Guida M, Spagnolo F, Spada F, De Braud F, Pulini 
J, Shankar S, Tian C, Lebbé C, 1089P POD1UM-201: A phase II study of 
retifanlimab (INCMGA00012) in advanced or metastatic Merkel cell carcinoma 
(MCC). Annals of Oncology, 2020. 31: p. S739. 
25. 
Grignani G, RP, Lebbe C, Prinzi N, Grob J, Tanda ET, Guida M, Burgess M, 
Pulini J, Shankar S, Tian C, Bhatia S, 545 A phase 2 study of retifanlimab in 
patients with advanced or metastatic merkel cell carcinoma (MCC) (POD1UM-201). 
Journal for Immunotherapy of Cancer, 2021. 9((Suppl 2)): p. p.A574-A575. 
26. 
Grosso, JF, Kelleher, CC, Harris, TJ, Maris, CH, Hipkiss, EL, De Marzo, A, et 
al., LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- 
and tumor-tolerance systems. J Clin Invest, 2007. 117(11): p. 3383-92. 
27. 
Henning, KS and Westfall, PH, Closed Testing in Pharmaceutical Research: 
Historical and Recent Developments. Stat Biopharm Res, 2015. 7(2): p. 126-147. 
28. 
Hofmann, M, Stoss, O, Shi, D, Buttner, R, van, d, V, Kim, W, et al., Assessment of 
a HER2 scoring system for gastric cancer: results from a validation study. 
Histopathology, 2008. 52(7): p. 797-805. 
29. 
Huang, RY, Eppolito, C, Lele, S, Shrikant, P, Matsuzaki, J, and Odunsi, K, 
LAG3 and PD1 co-inhibitory molecules collaborate to limit CD8+ T cell signaling 
and dampen antitumor immunity in a murine ovarian cancer model. Oncotarget, 2015. 
6(29): p. 27359-77. 
30. 
Huang, SC, Ng, KF, Yeh, TS, Cheng, CT, Lin, JS, Liu, YJ, et al., Subtraction of 
Epstein-Barr virus and microsatellite instability genotypes from the Lauren 
histotypes: Combined molecular and histologic subtyping with clinicopathological 
and prognostic significance validated in a cohort of 1,248 cases. Int J Cancer, 2019. 
145(12): p. 3218-3230. 
31. 
Janjigian, YY, Maron, SB, Chatila, WK, Millang, B, Chavan, SS, Alterman, C, et 
al., First-line pembrolizumab and trastuzumab in HER2-positive oesophageal, gastric, 
or gastro-oesophageal junction cancer: an open-label, single-arm, phase 2 trial. 
Lancet Oncol, 2020. 
32. 
Janjingian, Y, Yuriy;, Y, Chou, J, Simmons, M, Momtaz, P, Sanchez-Vega, F, et 
al., First-line pembrolizumab (P), trastuzumab (T), capecitabine (C) and oxaliplatin 
(O) in HER2-positive metastatic esophagogastric adenocarcinoma (mEGA). ASCO 
GI, 2019. 
Confidential
Page
109
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
33. 
Kang, YK, Boku, N, Satoh, T, Ryu, MH, Chao, Y, Kato, K, et al., Nivolumab in 
patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or 
intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, 
ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. 
Lancet, 2017. 390(10111): p. 2461-2471. 
34. 
Kim, HS, Shin, SJ, Beom, SH, Jung, M, Choi, YY, Son, T, et al., Comprehensive 
expression profiles of gastric cancer molecular subtypes by immunohistochemistry: 
implications for individualized therapy. Oncotarget, 2016. 7(28): p. 44608-44620. 
35. 
Kim, JW, Nam, KH, Ahn, SH, Park, DJ, Kim, HH, Kim, SH, et al., Prognostic 
implications of immunosuppressive protein expression in tumors as well as immune 
cell infiltration within the tumor microenvironment in gastric cancer. Gastric Cancer, 
2016. 19(1): p. 42-52. 
36. 
Le, DT, Uram, JN, Wang, H, Bartlett, BR, Kemberling, H, Eyring, AD, et al., 
PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med, 2015. 
372(26): p. 2509-20. 
37. 
Liu, L, Yang, Y, Burns, R, Li, J, Li, H, Gorlatov, S, et al., 1538 / 7 - Margetuximab 
mediates greater Fcdependent anti-tumor activities than trastuzumab or pertuzumab in 
vitro. AACR Meeting Abstracts, 2019. 
38. 
Long, L, Zhang, X, Chen, F, Pan, Q, Phiphatwatchara, P, Zeng, Y, et al., The 
promising immune checkpoint LAG-3: from tumor microenvironment to cancer 
immunotherapy. Genes Cancer, 2018. 9(5-6): p. 176-189. 
39. 
Lopez, A, Harada, K, Mizrak Kaya, D, and Ajani, JA, Current therapeutic 
landscape for advanced gastroesophageal cancers. Ann Transl Med, 2018. 6(4): p. 78. 
40. 
Mehnert, JM, Joshua, AM, Lakhani, N, Banerji, U, Rasco, D, Lugowska, I, et al., 
First-in-Human Phase 1 Study of INCMGA00012 in Patients With Advanced Solid 
Tumors: Interim Results of the Cohort Expansion Phase. SITC Poster, 2018. 
41. 
Muro, K, Van Cutsem, E, Narita, Y, Pentheroudakis, G, Baba, E, Li, J, et al., 
Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of 
patients with metastatic gastric cancer: a JSMO-ESMO initiative endorsed by CSCO, 
KSMO, MOS, SSO and TOS. Ann Oncol, 2019. 30(1): p. 19-33. 
42. 
Musolino, A, Naldi, N, Bortesi, B, Pezzuolo, D, Capelletti, M, Missale, G, et al., 
Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of 
trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast 
cancer. J Clin Oncol, 2008. 26(11): p. 1789-1796. 
43. 
NCCN, Gastric Cancer. NCCN Guidelines, 2018. Version 2.2018. 
Confidential
Page
110
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
44. 
Pietrantonio, F, Caporale, M, Morano, F, Scartozzi, M, Gloghini, A, De Vita, F, et 
al., HER2 loss in HER2-positive gastric or gastroesophageal cancer after trastuzumab 
therapy: Implication for further clinical research. Int J Cancer, 2016. 139(12): p. 
2859-2864. 
45. 
Polom, K, Boger, C, Smyth, E, Marrelli, D, Behrens, HM, Marano, L, et al., 
Synchronous metastatic gastric cancer-molecular background and clinical 
implications with special attention to mismatch repair deficiency. Eur J Surg Oncol, 
2018. 44(5): p. 626-631. 
46. 
Qing, Y, Li, Q, Ren, T, Xia, W, Peng, Y, Liu, GL, et al., Upregulation of PD-L1 and 
APE1 is associated with tumorigenesis and poor prognosis of gastric cancer. Drug 
Des Devel Ther, 2015. 9: p. 901-9. 
47. 
Rao, VA, Kim, JJ, Patel, DS, Rains, K, and Estoll, CR, A Comprehensive 
Scientific Survey of Excipients Used in Currently Marketed, Therapeutic Biological 
Drug Products. Pharm Res, 2020. 37(10): p. 200. 
48. 
Ryu, MH, Yoo, C, Kim, JG, Ryoo, BY, Park, YS, Park, SR, et al., Multicenter 
phase II study of trastuzumab in combination with capecitabine and oxaliplatin for 
advanced gastric cancer. Eur J Cancer, 2015. 51(4): p. 482-8. 
49. 
Seo, S, Ryu, MH, Park, YS, Ahn, JY, Park, Y, Park, SR, et al., Loss of HER2 
positivity after anti-HER2 chemotherapy in HER2-positive gastric cancer patients: 
results of the GASTric cancer HER2 reassessment study 3 (GASTHER3). Gastric 
Cancer, 2019. 22(3): p. 527-535. 
50. 
Shitara, K, Ozguroglu, M, Bang, YJ, Bartolomeo, MD, Mandala, M, Ryu, MH, 
et al., Pembrolizumab versus paclitaxel for previously treated, advanced gastric or 
gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, 
controlled, phase 3 trial. Lancet, 2018. 
51. 
Siegel, RL, Miller, KD, and Jemal, A, Cancer statistics, 2018. CA Cancer J Clin, 
2018. 68(1): p. 7-30. 
52. 
Sierro, S, Romero, P, and Speiser, DE, The CD4-like molecule LAG-3, biology and 
therapeutic applications. Expert Opin Ther Targets, 2011. 15(1): p. 91-101. 
53. 
Smyth, EC, Verheij, M, Allum, W, Cunningham, D, Cervantes, A, Arnold, D, et 
al., Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and 
follow-up. Ann Oncol, 2016. 27(suppl 5): p. v38-v49. 
54. 
Soularue, E, Cohen, R, Tournigand, C, Zaanan, A, Louvet, C, Bachet, JB, et al., 
Efficacy and safety of trastuzumab in combination with oxaliplatin and fluorouracil-
based chemotherapy for patients with HER2-positive metastatic gastric and gastro-
oesophageal junction adenocarcinoma patients: a retrospective study. Bull Cancer, 
2015. 102(4): p. 324-31. 
Confidential
Page
111
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
55. 
Stagg, J, Loi, S, Divisekera, U, Ngiow, SF, Duret, H, Yagita, H, et al., Anti-ErbB-2 
mAb therapy requires type I and II interferons and synergizes with anti-PD-1 or anti-
CD137 mAb therapy. Proc. Natl. Acad. Sci. U. S. A, 2011. 108(17): p. 7142-7147. 
56. 
Takaya, S, Saito, H, and Ikeguchi, M, Upregulation of Immune Checkpoint 
Molecules, PD-1 and LAG-3, on CD4+ and CD8+ T Cells after Gastric Cancer 
Surgery. Yonago Acta Med, 2015. 58(1): p. 39-44. 
57. 
Torre, LA, Bray, F, Siegel, RL, Ferlay, J, Lortet-Tieulent, J, and Jemal, A, Global 
cancer statistics, 2012. CA Cancer J Clin, 2015. 65(2): p. 87-108. 
58. 
Velho, S, Fernandes, MS, Leite, M, Figueiredo, C, and Seruca, R, Causes and 
consequences of microsatellite instability in gastric carcinogenesis. World J 
Gastroenterol, 2014. 20(44): p. 16433-42. 
59. 
Wang, DS, Wei, XL, Wang, ZQ, Lu, YX, Shi, SM, Wang, N, et al., FcgammaRIIA 
and IIIA polymorphisms predict clinical outcome of trastuzumab-treated metastatic 
gastric cancer. Onco Targets Ther, 2017. 10: p. 5065-5076. 
60. 
Wein, L, Luen, SJ, Savas, P, Salgado, R, and Loi, S, Checkpoint blockade in the 
treatment of breast cancer: current status and future directions. Br J Cancer, 2018. 
119(1): p. 4-11. 
61. 
Wong, H and Yau, T, Targeted therapy in the management of advanced gastric 
cancer: are we making progress in the era of personalized medicine? Oncologist, 
2012. 17(3): p. 346-58. 
62. 
Woo, SR, Turnis, ME, Goldberg, MV, Bankoti, J, Selby, M, Nirschl, CJ, et al., 
Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell 
function to promote tumoral immune escape. Cancer Res, 2012. 72(4): p. 917-27. 
63. 
Wu, P, Wu, D, Li, L, Chai, Y, and Huang, J, PD-L1 and Survival in Solid Tumors: 
A Meta-Analysis. PLoS One, 2015. 10(6): p. e0131403. 
64. 
Yang, Y, Lin, B, Li, H, Liang, Y, Ye, Z, Ma, Y, et al., Efficacy of The 
Immunotargeting Therapeutic Antibody Trastuzumab in HER2-Positive Advanced 
Gastric Cancer: A Meta-Analysis. International Journal of Inflammation Research 
2018, 1(1), 2018. 
 
 
 
Confidential
Page
112
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
Appendix 1 
Time and Events Schedules  
Time and Events Schedule, Cohort A 
EVALUATION/ 
PROCEDURE 
Screening 
D (-28 to -1) 
Cycle 1 
Subsequent 
Cycles 
EOTV 
Follow-Up 
D1 
D1 (± 3d) a 
INCMGA00012  
 
X 
X 
 
 
Margetuximab 
 
X 
X 
 
 
Informed Consent 
X 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical/Cancer History 
X 
 
 
 
 
Blood sample for MSI status 
X 
 
 
 
 
FFPE Tissue b 
X 
 
 
 
 
Eligibility Review 
X 
 
 
 
 
Registration 
X 
 
 
 
 
Physical Exam  
X 
X 
X 
X 
 
ECG (12-lead)  
X 
 
 
 
 
MUGA/ Echocardiogram c 
X 
 
X 
X 
 
Vital Signs d 
X 
X 
 
 
 
Clinical Laboratory Tests e 
X 
X 
X 
X 
 
TSH and free T4 e 
X 
X 
X 
 
 
PT or INR f 
X 
X 
 
 
 
Urinalysis f 
X 
X 
 
 
 
Pregnancy Test g 
X 
X 
X 
X 
 
Tumor Assessment h 
X 
 
X 
 
 
Adverse Events 
Continuous 
a. A cycle is 21 days ± 3 days is from the previous dosing day. There should be at least 18 days between 
administrations. 
b. FFPE tissue from the original diagnosis is required. If the patient has received perioperative anti-HER2 
therapy, FFPE from a subsequent biopsy is required to confirm HER2 status.  
c.  Echocardiogram or MUGA scan is obtained every 12 weeks (± 7 days) from Cycle 1 Day 1, and as 
clinically indicated. 
d. Vital signs are according to the local standard of care.  
e. See Appendix 2 for a list of required laboratory assessments.  Laboratory assessments may be drawn up 
to 3 days in advance of Day 1 of subsequent cycles.   
f. TSH and free T4 are required at Screening, C1D1, every odd cycle, and as clinically indicated.  Tests 
performed at screening and Cycle 1 Day 1, then as clinically indicated. 
g. Serum or urine pregnancy test for WOCBP. Serum pregnancy test is required at screening. 
h. Tumor assessments are performed every 3 cycles (± 7 days) for the first 9 months, beginning at Cycle 13 
every 4 cycles (± 7 days) for disease progression are performed until treatment discontinuation. Only 
RECIST 1.1 overall response will be recorded in the eCRF. 
 
Confidential
Page
113
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
Time and Events Schedule, Cohort B, Control Arm 
EVALUATION/ 
PROCEDURE 
Screening 
D (-28 to -1) 
Cycle 1 
Subsequent 
cycles  
 
EOTV 
Follow-
Up 
D1 
D1 (± 3d) a 
Investigator’s choice chemotherapy b 
 
X 
X 
 
 
Trastuzumab 
 
X 
X 
 
 
Informed Consent 
X 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical/Cancer History 
X 
 
 
 
 
Blood sample for MSI status 
X 
 
 
 
 
FFPE Tissue c 
X 
 
 
 
 
Registration 
X 
 
 
 
 
Physical Exam  
X 
X 
X 
X 
 
ECG (12-lead)  
X 
 
 
 
 
MUGA/ Echocardiogram d 
X 
 
X 
X 
 
Vital Signs e 
X 
X 
 
 
 
Clinical Laboratory Tests f 
X 
X 
X 
X 
 
TSH and free T4 f 
X 
 
 
 
 
Urinalysis g 
X 
X 
 
 
 
Pregnancy Test h 
X 
X 
X 
X 
 
Tumor Assessment i 
X 
 
X 
 
 
Adverse Events 
Continuous 
a. A cycle is 21 days ± 3 days from the previous dosing day and based on margetuximab dosing. There 
should be at least 18 days between administrations. 
b. Investigator’s choice of chemotherapy: XELOX or mFOLFOX-6. See Table 9 for study treatments, and 
Section 4.2 for duration of individual treatments. 
c. FFPE tissue from the original diagnosis is required. If the patient has received prior perioperative anti-
HER2 therapy, FFPE from a subsequent biopsy is required to confirm HER2 status.  
d.  Echocardiogram or MUGA scan is obtained every 12 weeks (± 7 days) from Cycle 1 Day 1, or as 
clinically indicated. 
e. Vital signs are obtained according to the local standard of care.  
f. See Appendix 2 for a list of required laboratory assessments. Laboratory assessments may be drawn up 
to 3 days in advance of Day 1 of subsequent cycles.  PT or INR collection is required while receiving 
capecitabine or 5-FU.  Post-screening TSH and free T4 are not required for patients in the Control Arm.    
g. Tests performed at screening and Cycle 1 Day 1, then as clinically indicated. 
h. Serum or urine pregnancy test for WOCBP.  Serum pregnancy test is required at screening.   
i. 
Tumor assessments are performed every 3 cycles (± 7 days) for the first 9 months, beginning at Cycle 13 
every 4 cycles (± 7 days) for disease progression are performed until treatment discontinuation. Only 
RECIST 1.1 overall response will be recorded in the eCRF. 
 
 
Confidential
Page
114
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
Time and Events Schedule, Cohort B, Experimental Arms 1 and 2 
EVALUATION/ 
PROCEDURE 
Screening 
D (-28 to -1) 
Cycle 1 
Subsequent 
Cycles 
EOTV 
Follow Up 
D1 
D1 (± 3d) a 
INCMGA00012 or MGD013 
 
X 
X 
 
 
Margetuximab 
 
X 
X 
 
 
Investigator’s choice chemotherapy b 
 
X 
X 
 
 
Informed Consent 
X 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical/Cancer History 
X 
 
 
 
 
Blood sample for MSI status 
X 
 
 
 
 
FFPE Tissue c 
X 
 
 
 
 
Registration 
X 
 
 
 
 
Physical Exam  
X 
X 
X 
X 
 
ECG (12-lead)  
X 
 
 
 
 
MUGA/ Echocardiogram d 
X 
 
X 
X 
 
Vital Signs e 
X 
X 
 
 
 
Clinical Laboratory Tests f 
X 
X 
X 
X 
 
TSH and free T4 f 
X 
X 
X 
 
 
Urinalysis g 
X 
X 
 
 
 
Pregnancy Test h 
X 
X 
X 
X 
 
Tumor Assessment i 
X 
 
X 
 
 
Adverse Events 
Continuous 
a. A Cycle is 21 days ± 3 days from the previous dosing day, and based on margetuximab dosing. There 
should be at least 18 days between administrations.  
b. Investigator’s choice of chemotherapy: XELOX or mFOLFOX-6. See Table 9 for study treatments, and 
Section 4.2 for duration of individual treatments 
c. FFPE tissue from the original diagnosis is required. If the patient has received prior perioperative anti-
HER2 therapy, FFPE from a subsequent biopsy is required to confirm HER2 status.  
d.  Echocardiogram or MUGA scan is obtained every 12 weeks (± 7 days) from Cycle 1 Day1, or as 
clinically indicated. 
e. Vital signs are obtained according to the local standard of care.  
f. See Appendix 2 for a list of required laboratory assessments. Laboratory assessments may be drawn up 
to 3 days in advance of Day 1 of subsequent cycles.  PT or INR collection is required while receiving 
capecitabine or 5-FU.   TSH and free T4 are required at Screening, C1D1, every odd cycle, and as 
clinically indicated.   
g. Tests performed at screening and Cycle 1 Day 1, then as clinically indicated. 
h. Serum or urine pregnancy test for WOCBP.  Serum pregnancy test is required at screening.   
i. 
Tumor assessments are performed every 3 cycles (± 7 days) for the first 9 months, beginning at Cycle 13 
every 4 cycles (± 7 days) for disease progression are performed until treatment discontinuation. Only 
RECIST 1.1 overall response will be recorded in the eCRF. 
 
 
Confidential
Page
115
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
Time and Events Schedule, Cohort B, Part 1 Experimental Arm 3 
EVALUATION/ 
PROCEDURE 
Screening 
D (-28 to -
1) 
Cycle 1 
Subsequent 
Cycles 
EOTV 
Follow Up 
D1 
D1 (± 3d) a 
Investigator’s Choice Chemotherapy b 
 
X 
X 
 
 
Margetuximab 
 
X 
X 
 
 
Informed Consent 
X 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical/Cancer History 
X 
 
 
 
 
Blood sample for MSI status 
X 
 
 
 
 
FFPE Tissue c 
X 
 
 
 
 
Registration 
X 
 
 
 
 
Physical Exam  
X 
X 
X 
X 
 
ECG (12-lead)  
X 
 
 
 
 
MUGA/ Echocardiogram d 
X 
 
X 
X 
 
Vital Signs e 
X 
X 
 
 
 
Clinical Laboratory Tests f 
X 
X 
X 
X 
 
TSH and free T4 f 
X 
 
 
 
 
Urinalysis g 
X 
X 
 
 
 
Pregnancy Test h 
X 
X 
X 
X 
 
Tumor Assessment i 
X 
 
X 
 
 
Adverse Events 
Continuous 
a. A cycle is 21 days ± 3 days is from the previous dosing day and based on margetuximab dosing. There 
should be at least 18 days between administrations. 
b. Investigator’s choice of chemotherapy: XELOX or mFOLFOX-6. See Table 9 for study treatments, and 
Section 4.2 for duration of individual treatments. 
c. FFPE tissue from the original diagnosis is required. If the patient has received prior perioperative anti-
HER2 therapy, FFPE from a subsequent biopsy is required to confirm HER2 status.  
d. Echocardiogram or MUGA scan is obtained every 12 weeks (± 7 days) from Cycle 1 Day 1, or as 
clinically indicated. 
e. Vital signs are obtained according to the local standard of care. 
f. See Appendix 2 for a list of required laboratory assessments. Laboratory assessments may be drawn up 
to 3 days in advance of Day 1 of subsequent cycles.  PT or INR collection is required while receiving 
capecitabine or 5-FU. Post-screening TSH and free T4 are not required for patients receiving Arm 3.  
g. Tests performed at screening and Cycle 1 Day 1, then as clinically indicated. 
h. Serum or urine pregnancy test for WOCBP.  Serum pregnancy test is required at screening.   
i. 
Tumor assessments are performed every 3 cycles (± 7 days) for the first 9 months, beginning at Cycle 13 
every 4 cycles (± 7 days) for disease progression are performed until treatment discontinuation. Only 
RECIST 1.1 overall response will be recorded in the eCRF. 
 
Confidential
Page
116
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
Appendix 2 
Clinical Laboratory Tests  
Pregnancy test: 
Blood or Urine Human chorionic gonadotropin 
(hCG). A repeat central pregnancy test is required for 
any positive local urine pregnancy test. 
 
Hematology: 
Hemoglobin  
Hematocrit  
Platelet count 
White blood cell count with absolute differential 
neutrophils, lymphocytes, and eosinophils* 
 
Serum chemistry: 
Albumin  
Alkaline phosphatase 
Alanine aminotransferase  
Aspartate aminotransferase 
Total Bilirubin  
Reflex to Direct Bilirubin, if elevated 
Blood urea nitrogen 
Chloride  
Creatinine 
Glucose  
Potassium 
Sodium 
 
Coagulation*: 
Prothrombin time (PT), or INR 
Urinalysis: 
Glucose 
Ketones 
Protein 
Occult blood 
 
Endocrine (after screening, for MGD013 or 
INCMGA00012 arms only) 
TSH 
Free T4 
 
*according to local lab. PT or INR collection is required while receiving capecitabine or 5-FU in Cohort B. 
Confidential
Page
117
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
 
 
 
Appendix 3 
RECIST 1.1 Guidelines  
Adapted from Eisenhauer 2009 (14). 
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: 
Confidential
Page
118
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
 
 
 
Bone lesions: 
• 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 
Confidential
Page
119
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
 
 
 
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. 
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 
Confidential
Page
120
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
 
 
 
which circumstance the next largest lesions which can be measured reproducibly should be 
selected. 
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 
Confidential
Page
121
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
 
 
 
absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters 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 CRF. 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. 
Confidential
Page
122
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
 
 
 
Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be non-
pathological in size (< 10 mm short axis). 
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. 
Confidential
Page
123
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
 
 
 
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 
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 BOR 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 BOR 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 BOR is determined once all the data for the patient is known. 
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 
Confidential
Page
124
of
129

Margetuximab, INCMGA00012, MGD013
MacroGenics, Inc.
Clinical Trial Protocol: CP-MGAH22-06
Amendment 5, 06 June 2022
Target lesions
Non-target lesions
New lesions
Overall response
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 PR 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 BOR can be interpreted as in Table A-2.
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 
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).
Confidential
Page
125
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
 
 
 
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 
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 (SD) 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). 
 
 
Confidential
Page
126
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
Appendix 4 
Gastric Adenocarcinoma Sub-types  
Patients with the following gastric cancer sub-types are eligible for enrollment into the study. 
World Health Organization (2010) 
Lauren Classification (1965) 
Papillary adenocarcinoma 
Intestinal type 
Tubular adenocarcinoma 
Mucinous adenocarcinoma 
Signet-ring cell carcinoma, 
and other poorly cohesive carcinoma 
Diffuse type 
Mixed carcinoma 
Indeterminate type 
 
 
 
Confidential
Page
127
of
129

Margetuximab, INCMGA00012, MGD013 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-06 
Amendment 5, 06 June 2022 
 
 
 
Appendix 5 
Principal Investigator’s Agreement  
Study Title: 
A Phase 2/3 Trial to Evaluate Margetuximab in Combination with 
INCMGA00012 and Chemotherapy or MGD013 and Chemotherapy 
in Patients with Metastatic or Locally Advanced, Treatment-naïve, 
HER2-Positive Gastric or Gastroesophageal Junction Cancer 
Study Number: 
CP-MGAH22-06 
 
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: 
 
 
 
Confidential
Page
128
of
129

CP-MGAH22-06 Protocol Amendment 5 (06-June-2022)
This is the electronic signature page for the above referenced document.
User Task: eSignatories Approval
Data Management/Statistics Approval
(Intended or Designee)
14-Jun-2022 15:16:50 GMT+0000
User Task: eSignatories Approval
 
pm nt Approval (Intended or Designee)
14-Jun-2022 18:54:58 GMT+0000
Confidential
Page
129
of
129