A Phase 1/2, First-in-Human, Open-Label, Dose-Escalation Study of MGC018 (Anti-B7-H3 Antibody Drug Conjugate) Alone and in Combination With MGA012 (Anti-PD-1 Antibody) in Patients With Advanced Solid Tumors
Phase: PHASE1
Conditions: Squamous Cell Carcinoma of Head and Neck, Triple Negative Breast Cancer, Melanoma, Advanced Solid Tumor, Adult, Metastatic Castrate Resistant Prostate Cancer, Non Small Cell Lung Cancer
Sponsor: MacroGenics

MGC018, MGA012
MacroGenics, Inc.
Clinical Trial Protocol: CP-MGC018-01
Amendment 6, 16 August 2021
CLINICAL STUDY PROTOCOL: CP-MGC018-01
PROTOCOL AMENDMENT 6
Study Title:
A Phase 1/2, First-in-Human, Open-Label, Dose-Escalation Study 
of MGC018 (Anti–B7-H3 Antibody Drug Conjugate) Alone and in 
Combination with MGA012 (Anti–PD-1 Antibody) in Patients 
with Advanced Solid Tumors 
Study Number:
CP-MGC018-01
Study Phase:
Phase 1/2
Product Number:
MGC018, MGA012 
IND Number:
EudraCT Number:
2018-003555-38 
Indication:
Advanced Solid Tumors
Coordinating 
Principal 
Investigator:
TBD
Sponsor:
MacroGenics, Inc.
9704 Medical Center Drive
Rockville, MD 20850
301-251-5172
Sponsor’s Medical 
Monitor:
Refer to study contact list
Confidentiality Statement
 This document 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
169
NCT03729596   

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
 
Confidential
Page
2
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
TABLE OF CONTENTS 
SPONSOR SIGNATURES ..................................................................................................... 10 
 
 
.
 
LIST OF ABBREVIATIONS ................................................................................................. 12 
1 
SYNOPSIS .................................................................................................................. 16 
2 
BACKGROUND INFORMATION ............................................................................ 21 
2.1 
Rationale for Study ............................................................................................ 21 
2.2 
Disease Background........................................................................................... 25 
2.2.1 
SCCHN .................................................................................................... 25 
2.2.2 
Prostate Cancer ........................................................................................ 26 
2.2.3 
Non-small Cell Lung Cancer ................................................................... 26 
2.2.4 
Triple Negative Breast Cancer ................................................................. 27 
2.2.5 
Melanoma ................................................................................................ 28 
2.3 
Background on B7-H3 and PD-L1 .................................................................... 28 
2.3.1 
B7-H3 ....................................................................................................... 28 
2.3.1.1 
MGC018 Nonclinical Experience .................................................. 29 
2.3.2 
PD-1 ......................................................................................................... 35 
2.3.2.1 
MGA012 Clinical Background ...................................................... 36 
2.4 
Dose Selection MGC018 ................................................................................... 37 
2.4.1 
Multiples of Monkey Exposure ............................................................... 37 
2.4.2 
Dose Selection: MGA012 ........................................................................ 39 
2.5 
MGC018 and MGA012 Combination Dose Selection ...................................... 41 
3 
STUDY PURPOSE AND OBJECTIVES ................................................................... 42 
3.1 
Primary Objective .............................................................................................. 42 
3.2 
Secondary Objectives......................................................................................... 42 
3.3 
Exploratory Objectives ...................................................................................... 42 
4 
STUDY DESIGN ........................................................................................................ 44 
4.1 
Overall Study Design and Plan .......................................................................... 44 
4.1.1 
Dose Escalation Phase ............................................................................. 47 
4.1.2 
Cohort Expansion Phase .......................................................................... 48 
4.2 
Dose Limiting Toxicity ...................................................................................... 49 
4.2.1 
Hematologic Dose Limiting Toxicity ...................................................... 49 
4.2.2 
Non-hematologic Dose Limiting Toxicity ............................................... 50 
4.2.3 
Hepatic Non-hematologic Dose Limiting Toxicity .................................. 51 
4.3 
Dose Escalation Rules........................................................................................ 51 
4.4 
Guidelines for Dose Modification ..................................................................... 53 
4.4.1 
Guidelines for Other Study Drug Related Toxicities ............................... 54 
4.4.2 
Dose Delays ............................................................................................. 55 
Confidential
Page
3
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
4.4.2.1 
COVID-19/SARS-CoV-2 Infection or Vaccination ....................... 56 
4.5 
Study Duration ................................................................................................... 56 
4.5.1 
Participant Accrual ................................................................................... 57 
4.5.2 
Definition of End of Study ....................................................................... 57 
4.6 
Appropriateness of Measurements ..................................................................... 57 
5 
SELECTION AND WITHDRAWAL OF PARTICIPANTS ....................................... 58 
5.1 
Inclusion Criteria ............................................................................................... 58 
5.2 
Exclusion Criteria .............................................................................................. 61 
5.3 
Withdrawal of Participant from the Study ......................................................... 64 
5.4 
Rules for Study Treatment Discontinuation ....................................................... 64 
5.5 
Guidelines for Discontinuation of Participant from Study ................................ 65 
6 
STUDY TREATMENTS ............................................................................................ 66 
6.1 
Description of Treatments .................................................................................. 66 
6.2 
Method of Assigning Participants to Treatment Groups .................................... 66 
6.3 
Blinding.............................................................................................................. 66 
6.4 
Emergency Unblinding ...................................................................................... 66 
6.5 
Study Drug and Supplies ................................................................................... 66 
6.5.1 
MGC018 .................................................................................................. 66 
6.5.2 
MGA012 .................................................................................................. 67 
6.6 
Study Infusion Preparation ................................................................................ 68 
6.6.1 
General Guidelines and Precautions ........................................................ 68 
6.6.1.1 
MGC018 (Module A and B) ........................................................... 68 
6.6.1.2 
MGA012 (Module B only) ............................................................. 69 
6.6.2 
Study Drug Preparation and Administration ............................................ 69 
6.6.2.1 
MGC018 ......................................................................................... 70 
6.6.2.2 
MGA012......................................................................................... 70 
6.6.3 
Combination Therapy .............................................................................. 70 
6.7 
Treatment Compliance ....................................................................................... 71 
6.8 
Packaging and Labeling ..................................................................................... 71 
6.9 
Storage and Accountability ................................................................................ 71 
6.9.1 
MGC018 .................................................................................................. 72 
6.9.2 
MGA012 .................................................................................................. 72 
6.10 
Investigational Product Disposition at End of Study ......................................... 72 
7 
POTENTIAL ADVERSE EVENTS AND SUPPORTIVE CARE MEASURES ....... 73 
7.1 
Infusion Related Reactions Including Cytokine Release Syndrome ................. 73 
7.1.1 
Grading and Management of Infusion Reactions .................................... 73 
7.1.2 
Premedication and Prophylaxis ................................................................ 74 
7.1.3 
Management of Observed Infusion Reactions ......................................... 74 
7.2 
Immune-Related Adverse Events ....................................................................... 77 
Confidential
Page
4
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
7.2.1 
Diarrhea or Colitis .................................................................................... 78 
7.2.2 
Hepatic Toxicity ....................................................................................... 79 
7.2.2.1 
Elevations in Transaminases .......................................................... 79 
7.2.2.2 
Elevations in Total Bilirubin .......................................................... 80 
7.2.3 
Pneumonitis .............................................................................................. 81 
7.2.4 
Dermatologic Toxicity ............................................................................. 82 
7.2.5 
Nephritis ................................................................................................... 83 
7.2.6 
Immune-Mediated Hypophysitis ............................................................. 83 
7.2.7 
Thyroid Toxicity ...................................................................................... 84 
7.3 
Ocular Toxicity .................................................................................................. 85 
7.3.1 
Uveitis ...................................................................................................... 85 
7.3.2 
Blepharitis ................................................................................................ 86 
7.4 
Hematologic Toxicity ......................................................................................... 86 
7.4.1 
Neutropenia .............................................................................................. 87 
7.4.2 
Thrombocytopenia ................................................................................... 87 
7.4.3 
Anemia ..................................................................................................... 88 
7.5 
Palmar-Plantar Erythrodysesthesia .................................................................... 88 
7.6 
Pleural and Pericardial Effusions ....................................................................... 88 
7.6.1 
Pleural Effusion........................................................................................ 89 
7.6.2 
Pericardial Effusion.................................................................................. 90 
7.7 
Nervous System Toxicity ................................................................................... 91 
7.8 
Cardiotoxicity .................................................................................................... 91 
7.9 
Musculoskeletal Toxicity ................................................................................... 92 
8 
CONCOMITANT THERAPY AND RESTRICTIONS ............................................. 93 
8.1 
Concomitant Therapy ......................................................................................... 93 
8.1.1 
Prohibited Therapy ................................................................................... 93 
8.1.2 
Permitted Therapies ................................................................................. 94 
8.1.3 
Contraception ........................................................................................... 94 
8.2 
Restrictions ........................................................................................................ 95 
8.2.1 
Fluid and Food Intake .............................................................................. 95 
8.2.2 
Participant Activity Restrictions .............................................................. 95 
9 
STUDY PROCEDURES ............................................................................................ 96 
9.1 
Informed Consent............................................................................................... 96 
9.2 
Screening Period ................................................................................................ 96 
9.3 
Registration ........................................................................................................ 96 
9.4 
Medical History ................................................................................................. 97 
9.5 
Prior and Concomitant Medications .................................................................. 97 
9.6 
Physical Examination......................................................................................... 97 
9.6.1 
Vital Signs ................................................................................................ 98 
Confidential
Page
5
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
9.7 
ECOG Performance Status ................................................................................ 98 
9.8 
Clinical Laboratory Tests ................................................................................... 98 
9.8.1 
Central Laboratory Assays ....................................................................... 98 
9.8.2 
Pharmacokinetics ..................................................................................... 98 
9.8.3 
Pharmacodynamics/Biomarkers .............................................................. 99 
9.8.4 
Sample Collection, Storage, and Shipping .............................................. 99 
9.9 
Radiographic, CT, PET, MRI or Bone Assessments .......................................... 99 
9.10 
Electrocardiography ........................................................................................... 99 
9.11 
Echocardiography/MUGA scan ......................................................................... 99 
9.12 
Ophthalmological Examination ......................................................................... 99 
9.13 
Archival Tissue ................................................................................................ 100 
9.14 
Tumor Biopsy Specimens ................................................................................ 100 
9.15 
Patient-reported Outcome ................................................................................ 100 
9.16 
End of Treatment Visit ..................................................................................... 101 
9.17 
Post-Treatment Follow-up Visit ....................................................................... 101 
10 
ASSESSMENT OF PHARMACOKINETICS AND PHARMACODYNAMICS ... 102 
10.1 
Pharmacokinetics Assessments ........................................................................ 102 
10.2 
Immunogenicity Assessments .......................................................................... 102 
10.3 
Pharmacodynamic/Biomarker Assessments .................................................... 102 
10.3.1 
Tests Performed for Both Dose Escalation and Cohort 
Expansion Participants ........................................................................... 102 
10.3.2 
Tests Performed for Cohort Expansion Phase Participants 
Only ........................................................................................................ 102 
11 
ASSESSMENT OF EFFICACY ............................................................................... 104 
11.1 
Efficacy Assessments ....................................................................................... 104 
11.1.1 
Disease Response Assessments .............................................................. 104 
11.1.2 
Survival Assessments ............................................................................. 104 
12 
ADVERSE EVENT REPORTING AND ASSESSMENT OF SAFETY ................. 105 
12.1 
Definitions........................................................................................................ 105 
12.1.1 
Adverse Event ........................................................................................ 105 
12.1.2 
Adverse Drug Reaction .......................................................................... 105 
12.1.3 
Adverse Event of Special Interest .......................................................... 106 
12.1.4 
Attribution/Assessment of Causality ..................................................... 106 
12.1.5 
Serious Adverse Event ........................................................................... 107 
12.1.6 
Severity Criteria ..................................................................................... 107 
12.2 
Adverse Event Collection and Documentation ................................................ 108 
12.2.1 
All Adverse Events ................................................................................ 108 
12.2.2 
Immediately Reportable Events ............................................................. 109 
12.2.3 
Serious Adverse Events ...........................................................................110 
Confidential
Page
6
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
12.2.4 
Protocol-Specific Adverse Events of Special Interest ............................112 
12.2.5 
Pregnancy ................................................................................................112 
12.2.6 
Reporting of Adverse Events to the Sponsor ..........................................113 
12.3 
Other Assessment of Safety ..............................................................................114 
12.3.1 
Symptomatic Skeletal Events .................................................................114 
13 
PRODUCT QUALITY COMPLAINT HANDLING ................................................115 
13.1 
Procedure ..........................................................................................................115 
13.2 
Contacting sponsor Regarding Product Quality ...............................................115 
14 
STATISTICAL ANALYSIS .......................................................................................116 
14.1 
Determination of Sample Size ..........................................................................116 
14.2 
Analysis Populations .........................................................................................117 
14.3 
Demographics and Baseline Characteristics .....................................................117 
14.4 
Study Drug Exposures and Concomitant Medications .....................................117 
14.5 
Pharmacokinetic/Pharmacodynamic Analysis ..................................................117 
14.5.1 
Pharmacokinetic Analysis .......................................................................117 
14.5.2 
Immunogenicity Analysis .......................................................................118 
14.5.3 
Pharmacodynamic Analysis ....................................................................118 
14.6 
Efficacy and Endpoint Analyses .......................................................................118 
14.6.1 
Response Endpoints and Analyses ..........................................................118 
14.6.2 
Analysis of Tumor Size Change Over Time ...........................................118 
14.6.3 
Time-to-Event Endpoints and Analyses ..................................................118 
14.6.4 
Endpoints and Analyses in mCRPC ....................................................... 120 
14.6.4.1 
Radiographic Progression-free Survival ...................................... 120 
14.6.4.2 
Prostate-specific Antigen.............................................................. 120 
14.6.4.3 
Symptomatic Skeletal Events ....................................................... 120 
14.6.5 
Patient-reported Outcome ...................................................................... 121 
14.7 
Safety Endpoints and Analyses ........................................................................ 121 
14.7.1 
Adverse Events ...................................................................................... 121 
14.7.2 
Laboratory Values .................................................................................. 121 
14.7.3 
Other Safety Endpoints .......................................................................... 122 
14.8 
Other Assessments or Analyses ....................................................................... 122 
15 
QUALITY CONTROL AND ASSURANCE ........................................................... 123 
15.1 
Monitoring, Auditing and Inspections ............................................................. 123 
15.2 
Data Collection and Management .................................................................... 124 
16 
ADMINISTRATIVE CONSIDERATIONS.............................................................. 125 
16.1 
Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) Approval................................................................................................. 125 
16.2 
Ethical Conduct of the Study ........................................................................... 126 
16.3 
Participant Information and Consent ............................................................... 126 
Confidential
Page
7
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
16.4 
Participant Confidentiality ............................................................................... 126 
16.5 
Case Report Forms and Study Records ........................................................... 127 
16.6 
Access to Source Documentation .................................................................... 127 
16.7 
Retention of Data ............................................................................................. 127 
16.8 
Sample Retention and Further Testing ............................................................. 127 
16.9 
Financial Disclosure......................................................................................... 128 
16.10 
Publication and Disclosure Policy ................................................................... 128 
16.11 
Discontinuation of the Study or Study Sites .................................................... 128 
16.11.1 
Discontinuation of Study Sites ............................................................... 128 
16.11.2 
Discontinuation of the Study ................................................................. 129 
16.12 
Identification of the Coordinating Principal Investigator ................................ 129 
17 
REFERENCE LIST .................................................................................................. 130 
 
LIST OF TABLES  
Table 1 
Predicted Exposure Parameters of ADC, SYD986, and TAB 
After the First Dose (at Steady-State) of MGC018 and Exposure 
Multiples in Humans .................................................................................... 38 
Table 2 
Predicted Exposure Parameters for the 375 mg Q3W Dose 
Compared to 10 mg/kg Q2W Dose and Multiples of Exposure ................... 41 
Table 3 
MGC018 Dose Levels: Module A Dose Escalation Phase ........................... 47 
Table 4 
MGC018 and MGA012 Dose Levels: Module B Dose 
Escalation Phase ........................................................................................... 48 
Table 5 
Expansion Cohorts ........................................................................................ 49 
Table 6 
Guidelines for Other Study Drug Related Toxicities .................................... 55 
Table 7 
MGC018 Drug Product Composition ........................................................... 67 
Table 8 
MGA012 Drug Product Composition .......................................................... 68 
Table 9 
Safety Reporting by Event Type ..................................................................113 
Table 10 
Response Rates and 95% Confidence Intervals ..........................................116 
Table 11 
Censoring Rules for Primary Analysis of PFS ............................................119 
Table 12 
Module A: Pharmacokinetic, Immunogenicity, and 
Pharmacodynamic Biomarkers Blood Sampling Schedule: 
MGC018 Monotherapy Q3W Dose Escalation Phase ................................ 150 
Table 13 
Module A: Pharmacokinetic, Immunogenicity, and 
Pharmacodynamic Biomarkers Blood Sampling Schedule: 
MGC018 Monotherapy Q3W Cohort Expansion Phase............................. 152 
Table 14 
Module B: Pharmacokinetic, Immunogenicity, and 
Pharmacodynamic Biomarkers Blood Sampling Schedule: 
MGC018 and MGA012 Combination Therapy Q3W ................................ 154 
 
Confidential
Page
8
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
LIST OF FIGURES  
Figure 1 
Schematic Representation of MGC018 and Mechanism of 
Release of Prodrug from MGC018 and Conversion to the Active 
Duocarmycin Drug DUBA ........................................................................... 23 
Figure 2 
MGC018 Mode of Action ............................................................................. 23 
Figure 3 
Antitumor Activity of MGC018 in CD1 Nude (Homozygous) 
Mice Bearing PA-1 Ovarian Cancer Xenografts: Single-Dose 
Administration .............................................................................................. 31 
Figure 4 
Antitumor Activity of MGC018 in CD1 Nude (Homozygous) 
Mice Bearing PA-1 Ovarian Cancer Xenografts: Single- vs. 
Repeat-Dose Administration ........................................................................ 32 
Figure 5 
MGC018 Overall Study Design ................................................................... 45 
Figure 6 
MGC018 Monotherapy Dosing Schedule (Q3W) (Module A) .................... 46 
Figure 7 
MGC018 and MGA012 Combination Dosing Schedule (Q3W) 
(Module B) ................................................................................................... 46 
 
LIST OF APPENDICES  
APPENDIX 1 
TIME AND EVENTS SCHEDULES 
APPENDIX 2 
CLINICAL LABORATORY TESTS 
APPENDIX 3 
PHARMACOKINETICS, IMMUNOGENICITY, AND 
PHARMACODYNAMIC BIOMARKERS BLOOD SAMPLING 
SCHEDULE FOR MODULE A AND B 
APPENDIX 4 
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS 
APPENDIX 5 
RECIST V1.1 GUIDELINES 
APPENDIX 6 
BRIEF PAIN INVENTORY-SHORT FORM (BPI-SF) 
APPENDIX 7 
PRINCIPAL INVESTIGATOR’S AGREEMENT 
 
 
Confidential
Page
9
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
SPONSOR SIGNATURES  
Study Title: 
A Phase 1/2, First-in-Human, Open-Label, Dose-Escalation Study 
of MGC018 (Anti–B7-H3 Antibody Drug Conjugate) Alone and in 
Combination with MGA012 (Anti–PD-1 Antibody) in Patients with 
Advanced Solid Tumors  
Study Number: 
CP-MGC018-01 
 
This clinical study protocol has been approved by the sponsor: 
Signed: 
See Appended Electronic Signature Page 
Date: 
 
 
 
 
Executive Clinical Research Director  
MacroGenics, Inc. 
 
 
 
 
Signed: 
See Appended Electronic Signature Page 
Date: 
 
 
  
Senior Principal Biostatistician, Biostatistics 
MacroGenics, Inc. 
 
 
 
 
Confidential
Page
10
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
RATIONALE FOR PROTOCOL AMENDMENT 6  
Confidential
Page
11
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
LIST OF ABBREVIATIONS  
ADA 
anti-drug antibody 
ADC(s) 
antibody-drug conjugate(s) 
AE 
adverse event 
AESI 
adverse event of special interest 
AI 
accumulation index 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUC(0-T) 
AUC from time 0 to time 
AUC(INF) 
AUC from time 0 to infinity 
AUC(TAU) 
AUC in a dosing interval 
BOR 
best overall response 
BPI-sf 
Brief Pain Inventory-Short Form 
BW 
body weight 
Cmax 
maximum concentration 
Ctrough 
lowest concentration 
CAP 
College of American Pathologists 
CBC 
complete blood count 
CI 
confidence interval 
CL 
clearance 
COVID-19 
coronavirus disease 2019 
CR 
complete response 
CRF 
case report form 
CRP 
C-reactive protein 
CRS 
cytokine release syndrome   
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTFG 
Clinical Trial Facilitation Group 
CTL 
cytotoxic T lymphocyte 
Confidential
Page
12
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
CTLA-4 
cytotoxic T-lymphocyte–associated protein 4 
DCs 
dendritic cells 
DLT 
dose-limiting toxicity 
DoR 
duration of response 
DNA 
deoxyribonucleic acid 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EOI 
end of infusion 
EOTV 
end of treatment visit 
FDA 
Food and Drug Administration 
FIH 
first-in-human 
G-CSF 
granulocyte colony stimulating factor 
GLP 
Good Laboratory Practice 
GM-CSF 
granulocyte-macrophage colony stimulating factor 
HER2 
human epidermal growth factor receptor 2 
HNSTD 
highest non-severely toxic dose 
HPV 
human papillomavirus 
hr 
hour(s) 
ICD 
immunologic cell death 
ICF 
informed consent form  
IEC 
Independent Ethics Committee 
IFNγ 
interferon gamma 
IL 
interleukin 
IHC 
immunohistochemistry 
irAEs 
immune-related adverse events 
IRB 
Institutional Review Board 
IRE 
immediately reportable event 
IP 
intraperitoneal 
IRR 
infusion-related reaction 
IV 
intravenous(ly) 
LAG-3 
lymphocyte-activation gene 3 
LTFU 
lost to follow-up 
LVEF 
left ventricular ejection fraction 
Confidential
Page
13
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
mAb 
monoclonal antibody 
MAD 
maximum administered dose 
mcg 
microgram 
mCRPC 
metastatic castration-resistant prostate carcinoma 
mL 
milliliter 
MRI 
magnetic resonance imaging 
MSI-H 
microsatellite instability – high 
MTD 
maximum tolerated dose 
MUGA 
multigated acquisition (scan) 
n 
number 
NA or N/A 
not applicable 
NE 
not evaluable 
nM 
nanomolar 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PBS 
phosphate buffered saline 
PGWG2 
Prostate Cancer Working Group 2 
PD 
progressive disease 
PD-1 
programmed death–1 
PD-L1 
programmed death–ligand 1 
PET 
positron emission tomography 
PFS 
progression-free survival 
pg 
picogram 
Ph. Eur. 
European Pharmacopoeia 
PK 
pharmacokinetic(s) 
PPE 
palmar-plantar erythrodysesthesia 
PQC 
product quality complaint 
PR 
partial response 
PRO 
patient-reported outcome 
PSA 
prostate-specific antigen 
PT 
preferred term; prothrombin time 
PTT 
partial thromboplastin time 
QW 
once weekly 
Confidential
Page
14
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Q2W 
once every 2 weeks 
Q3W 
once every 3 weeks 
Q4W 
once every 4 weeks 
Q6W 
once every 6 weeks 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended phase II dose 
rPFS 
radiographic progression-free survival 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SCCHN 
squamous cell cancer of the head and neck 
SEM 
standard error of the mean 
SD 
stable disease 
SJS 
Stevens Johnson syndrome 
SOC 
system organ class 
SPP 
statistical programming plan 
SSE 
symptomatic skeletal event 
TAB 
total antibody  
TBD 
to be determined 
TBSE 
total body skin examination 
TCR 
T-cell receptor  
TEAEs 
treatment emergent adverse events 
TEN 
toxic epidermal necrolysis 
TILs 
tumor-infiltrating lymphocytes 
TK 
toxicokinetic 
TNBC 
triple negative breast cancer 
TNFα 
tumor necrosis factor alpha 
ULN 
upper limit of normal 
US 
United States 
USP-NF 
United States Pharmacopeia-National Formulary 
v 
version 
 
 
Confidential
Page
15
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
1 
SYNOPSIS  
Sponsor: MacroGenics, Inc. 
 
Name of Product: MGC018 (Anti–B7-H3 Antibody Drug Conjugate) 
Study Title: A Phase 1/2, First-in-Human, Open-Label, Dose-Escalation Study of MGC018 (Anti–B7-H3 
Antibody Drug Conjugate) Alone and in Combination with MGA012 (Anti–PD-1 Antibody) in Patients with 
Advanced Solid Tumors 
Study Number: CP-MGC018-01 
Study Phase: Phase 1/2 
Investigator(s)/Centers: 
The study will be conducted at approximately 30 institutions globally. 
Primary Objective(s): To characterize the safety, tolerability, dose-limiting toxicities (DLTs), and maximum 
tolerated dose (MTD) or maximum administered dose (MAD) (if no MTD is defined) for MGC018 
administered as monotherapy or in combination with MGA012, each administered intravenously (IV), in 
participants who have relapsed/refractory, unresectable locally advanced or metastatic solid tumors. 
Secondary Objective(s): 
•
To characterize the pharmacokinetics (PK) and immunogenicity of MGC018 alone and in 
combination with MGA012. 
•
To describe antitumor activity of MGC018 administered as monotherapy or in combination with 
MGA012 in participants with advanced solid tumors using Response Evaluation Criteria in Solid 
Tumors version 1.1 (RECIST v1.1) (Appendix 5). 
•
To describe the radiographic progression free survival (rPFS) in metastatic castration-resistant 
prostate carcinoma (mCRPC). 
•
To describe the prostate-specific antigen (PSA) response rate and best PSA percent change in 
mCRPC. 
Study Drug: 
•
MGC018 is a humanized B7-H3 antibody drug conjugate (ADC). The duocarmycin-based 
linker/payload incorporated into MGC018 is licensed from Byondis (formerly known as Synthon 
Biopharmaceuticals).  
•
MGA012 (also known as INCMGA00012) is an anti–programmed death–1 (anti–PD-1) monoclonal 
antibody (mAb) protein produced in 
. 
 
Study Design: 
This study is a Phase 1/2, first-in-human, open-label, dose-escalation and cohort expansion study designed to 
characterize the safety, tolerability, PK, pharmacodynamics, immunogenicity, and preliminary antitumor 
activity of MGC018 administered by IV infusion, alone (Module A) and in combination with MGA012 
(Module B) (see figure below); Module B will commence upon sponsor notification after the MTD or MAD 
of MGC018 monotherapy (Module A) has been defined. Each module of the study consists of a Dose 
Escalation Phase to determine the MTD (or MAD, if no MTD is defined), followed by a Cohort Expansion 
Phase to further define the safety and initial antitumor activity of the respective monotherapy (Module A) and 
combination (Module B) regimens, using doses defined in the Dose Escalation Phase of each respective 
module. 
Module B will commence only upon sponsor notification to all the study investigators/institutions.  
I 
Confidential
Page
16
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Participants with relapsed or refractory, unresectable locally advanced or metastatic solid tumors of any 
histology will be enrolled in the Dose Escalation Phase of each module. The Module A Cohort Expansion 
Phase will be limited to mCRPC, NSCLC, TNBC, squamous cell cancer of the head and neck (SCCHN), and 
melanoma. The Module B Cohort Expansion Phase will be limited to specific cohorts of participants with 
SCCHN, mCRPC, and a cohort to be determined (TBD) at a later date, guided by evolving experience from 
the Dose Escalation Phase of the study.  
 
MGC018 Overall Study Design 
 
Note: 
MTD-2 = the dose level that is 2 dose levels below the MTD defined for MGC018 monotherapy. 
 
MTD-1 = the dose level that is 1 dose level below the MTD defined for MGC018 monotherapy. 
Abbreviations: mCRPC = metastatic castrate-resistant prostate carcinoma; MTD = maximum tolerated dose; 
NSCLC = non-small cell lung cancer; Q3W = every 3 weeks; RP2D = recommended phase II dose; 
SCCHN = squamous cell carcinoma of the head and neck; TBD = to be determined; TNBC = triple negative 
breast cancer.  
MGC018 will be administered alone or in combination with MGA012. For Module A, MGC018 alone will be 
administered IV over 60 minutes on Days 1 and 22 of Cycle 1 and every subsequent 42-day cycle thereafter. 
The first administration of MGC018 in participants in the first 2 dose levels in Module A will be staggered by 
at least 48 hours. For Module B, MGC018 alone will be administered IV over 60 minutes on Day 1 of Cycle 1 
and with MGA012 on Day 22 of Cycle 1. Both MGC018 and MGA012 will be administered on Days 1 and 
22 of every subsequent 42-day cycle thereafter, at the assigned dose for each cohort. MGA012 will be 
administered IV over 60 minutes. On days when the MGC018 and MGA012 are to be administered on the 
same day (Module B only), MGA012 should be given first, followed immediately thereafter by MGC018. 
For the Dose Escalation Phase tumor assessments will occur at Day 42 of each cycle, for the first 4 cycles, and 
every other cycle thereafter. For the Module A Cohort Expansion Phase the tumor assessments will be every 
9 weeks (63 days). For Module A, the DLT evaluation period will be 21 days in duration; for Module B, the 
DLT evaluation period will be 42 days in duration (see Section 4.1.1 for more details). Participants 
who complete a given cycle, remain clinically stable, do not experience a DLT or other unacceptable 
toxicity, and do not otherwise meet the criteria for permanent treatment discontinuation may be eligible for 
Module A: MGC018 M onotherapy Q3W 
SCCHN ] 
N= 16 
mCRPC ] 
N= 16 
TBD 
] 
N= 16 
Confidential
Page
17
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
additional treatment with MGC018 alone or in combination with MGA012 for up to a total of 18 cycles 
(approximately 2 years). 
Following the last dose of study drug, all participants in Module A or Module B Cohort Expansion Phases 
will be followed every 3 months (90 days) for survival during a 2-year Survival Follow-up Period. 
Participants in Module A Dose Escalation will be followed similarly for survival status until approval of 
Amendment 3, at which point they will be discontinued from follow up. 
Dose-Limiting Toxicities: 
For the purpose of guiding study decisions regarding dose escalation, DLTs will be defined based on drug-
related adverse events (AEs) (or laboratory abnormalities) that occur up to Study Day 21 of Cycle 1 in the 
Dose Escalation Phase only for Module A, and Study Day 42 of Cycle 1 in the Dose Escalation Phase only for 
Module B. The severity of AEs will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events version 4.03 (NCI CTCAE v4.03). DLTs will be defined separately 
for hematologic, non-hematologic, and hepatic non-hematologic events. 
Number of Participants Enrolled: 
The maximum to be enrolled in this study will be approximately up to 182 participants. This number does not 
take into account participants who may be replaced or the possibility of expanding the mCRPC cohort with an 
additional 24 participants at the discretion of the sponsor.  
The number of participants enrolled in the Dose Escalation Phase could range from 6 up to 54 participants 
depending on results during the course of the study and the number of dose levels explored. This participant 
number does not take into account participant replacement for non-evaluable participants or the possibility of 
expanding an individual dose escalation cohort up to 15 participants to allow for further evaluation of safety, 
PK, and antitumor activity of the study drugs at the dose level in that cohort. 
The Cohort Expansion Phase of the study will enroll up to 128 participants.  
•
Module A Cohort Expansion Phase will include 5 cohorts of up to 16 participants each with mCRPC, 
NSCLC, TNBC, SCCHN, and melanoma.  
•
Module B Cohort Expansion Phase will include 3 cohorts of up to 16 participants each with SCCHN, 
mCRPC and a tumor type TBD at a later date, based on the experience during dose escalation. 
During the Cohort Expansion Phase of the study, participants who withdraw before completing the first tumor 
assessment for a reason other than progression of disease may be considered unevaluable for response. In 
these cases, additional participants may be enrolled. In addition, up to 4 participants may be added per cohort.  
Participant Population/Key Entry Criteria: 
The participant population to be enrolled in the Dose Escalation Phase of this study will consist of adult 
participants with relapsed or refractory, unresectable locally advanced or metastatic solid tumors of any 
histology. The Cohort Expansion Phase will include participants with mCRPC, NSCLC, TNBC, SCCHN, and 
melanoma (Module A), and unresectable, locally advanced or metastatic SCCHN, mCRPC, and a cohort TBD 
at a later date (Module B). Tumor specimens for determination of B7-H3 and PD-L1 expression via IHC 
staining will be collected on all participants during both Dose Escalation and Cohort Expansion and will be 
assayed at a central laboratory designated by the sponsor. Determination of B7-H3 and PD-L1 IHC testing 
results will not be required prior to protocol enrollment. 
Duration of Treatment and Study Duration:  
Treatment for all participants may continue for up to 18 cycles, with each cycle consisting of 6 weeks 
(42 days). For participants with a dose delay > 21 days, the total number of cycles may be < 18 cycles and the 
time on MGC018 will be no more than 2 years. 
It is expected that enrollment of the Dose Escalation Phase of the study (including Module A and Module B) 
will occur over approximately 18 months, and that enrollment of the Cohort Expansion Phase of the study will 
Confidential
Page
18
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
take approximately 12 months from the time of initiation of the Cohort Expansion Phase for each Module A 
and Module B.  
The total time for conduct of the trial is expected to be approximately 78 months (which includes 2 years of 
survival follow-up). These estimates of the timing for study conduct may vary from that observed in the actual 
conduct of the trial. 
Criteria for Evaluation:  
Safety Assessments: 
The safety assessment will be based on the evaluation of adverse events (AEs) that occur from the time of 
initiation of administration of study drug through 30 days following the last dose of study drug or until the 
start of a subsequent systemic anticancer therapy (whichever occurs first) and will be determined based on 
signs, symptoms, physical examination findings, and/or laboratory test results from enrolled participants as 
appropriate. Progression of the underlying tumor resulting in hospitalization or death (e.g., participant 
hospitalized for or dies from progressive disease [PD]) will be documented as a tumor response and not as a 
serious adverse event (SAE). 
Response Assessments: 
Tumor assessments will be obtained using computed tomography (CT) or positron emission tomography/CT 
(PET/CT) and/or magnetic resonance imaging (MRI) scans. For mCRPC participants a bone scan will be 
obtained in addition to CT and/or MRI scans at baseline and on study. Target and non-target lesions will be 
designated at screening and then evaluated at every 6 weeks (42 days) for the first four cycles, and every other 
cycle thereafter while the participant in Module A Dose Escalation and Module B is on study treatment. 
Target and non-target lesions will be designated at screening and then evaluated every 9 weeks (63 days) 
while the participant is on study treatment in Cohort Expansion Phase for Module A. For mCRPC a lymph 
node is to be ≥ 20 mm to be a target lesion. In situations where the bone scan ﬁndings are suggestive of a ﬂare 
reaction or apparent new lesion(s) may represent trauma, additional imaging to conﬁrm these results with 
other imaging modalities such as MRI or ﬁne-cut CT should be obtained. At each tumor assessment time 
point, the overall response status will be determined based on assessment of target and non-target lesions as 
well as appearance of any new lesions. For RECIST v1.1 (Appendix 5), the overall responses will be 
categorized as complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), 
or not evaluable (NE).   
Survival Assessments: 
All participants in Module A or Module B Cohort Expansion Phases who have discontinued study treatment 
will be followed for survival status every 3 months (90 days) for a 2-year survival follow-up period following 
the last dose of MGC018 alone (Module A) or in combination with MGA012 (Module B), until criteria are 
met for study discontinuation. Participants in Module A Dose Escalation will be followed similarly for 
survival status until approval of Amendment 3, at which point they will be discontinued from follow up. 
Pharmacokinetic Assessments: 
Serum concentrations of conjugated antibody and total antibody following administration of MGC018 and 
serum concentrations of MGA012 will be monitored using quantitative bioanalytical methods. SYD986 levels 
will be measured from plasma using a liquid chromatography-tandem mass spectrometry assay. Single- and 
multiple-dose PK parameters will be derived from MGC018 and MGA012 serum concentrations and SYD986 
plasma concentration versus time data. 
Immunogenicity Assessments: 
The anti-drug antibody (ADA) against MGC018 and the ADA against MGA012 will each be detected using 
validated bridging assay methods.  
Pharmacodynamics/Biomarkers: 
Tests to be performed for PD/biomarker assessments are indicated in Section 10.3. 
Confidential
Page
19
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Analysis Populations: Two populations will be used for the purposes of this analysis - the Safety Population 
and the Response Evaluable Population as defined below. 
Safety Population: All participants who received at least one dose of study drug. This population will be used 
for analyses of safety, pharmacodynamics, and immunogenicity. It will also be used for summary of baseline 
data and analyses of progression-free survival (PFS), rPFS, and overall survival (OS). 
Response Evaluable Population: All participants who received at least one dose of study drug, had baseline 
measurable or non-measurable disease, and had at least one post-baseline radiographic tumor assessment or 
discontinued from treatment due to clinical progressive disease or death. This population will be used for 
summary of tumor assessment data and analyses of response rates. 
PSA Response Evaluable Population: mCRPC participants with a baseline PSA ≥ 2 ng/mL and at least 1 
post-baseline PSA measurement. This population will be used to calculate and summarize PSA response rates. 
STATISTICAL METHODS:  
A separate statistical analysis plan (SAP) and statistical programming plan (SPP) will further describe the 
details regarding statistical methods and will govern the analysis. 
Sample Size: The study plans to enroll approximately up to 182 participants (107 in Module A and 75 in 
Module B). In Module A, 27 participants were enrolled, of which 26 participants were treated with MGC018 
monotherapy in the Dose Escalation Phase. Up to 80 participants with mCRPC, NSCLC, TNBC, SCCHN, and 
melanoma (up to 16 in each) will be enrolled to the Cohort Expansion Phase of Module A. In Module B, up to 
27 participants will be enrolled in the Dose Escalation Phase based on a 3+3+3 design with planned 3 dose 
cohorts with MGC018 and MGA012 combination therapy. The Cohort Expansion Phase of Module B will 
enroll up to 16 participants in each of 3 tumor specific cohorts (SCCHN, mCRPC, and participants with a 
tumor type TBD at a later date) treated with MGC018 in combination with MGA012. 
Safety: Treatment-emergent AEs will be summarized by system organ class (SOC) and preferred term (PT), 
by relationship to study drugs, and by highest severity. For laboratory tests, number and percent of 
participants shifted from baseline to post-baseline maximum severity in Common Terminology Criteria for 
Adverse Events (CTCAE) grade will be summarized. 
Efficacy: Number and percent of participants with their best overall response (BOR) will be summarized. 
Objective response rate will be calculated as the proportion of participants in the response evaluable 
population achieving a best response of CR or PR. The response rates will be determined using RECIST v1.1. 
PSA response rate (a ≥ 50% decline from baseline in PSA with confirmation at least 3 weeks later) will be 
summarized. The best PSA percent change from baseline will be presented by waterfall plot. Two-sided 95% 
exact binomial confidence intervals (CIs) will be calculated around the response rates. Kaplan-Meier methods 
will be used to estimate the time-to-event endpoints. 
 
 
 
Confidential
Page
20
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
2 
BACKGROUND INFORMATION  
2.1 
Rationale for Study  
Antibody-drug conjugates (ADCs) have emerged as a powerful class of therapeutic agents for 
the targeted treatment of cancer. ADCs combine the tumor target specificity of a monoclonal 
antibody (mAb) with highly potent cytotoxic “payloads” for the selective delivery of 
cytotoxic agents to cancer cells. The targeted delivery of cytotoxic agents to cancer cells 
offers the potential for increased efficacy, while at the same time minimizing exposure to 
normal tissues, thereby expanding the therapeutic window. 
Immune-checkpoint blockade has emerged as a promising approach for the treatment of 
patients with various solid tumors or hematologic malignancies. Inhibitors of programmed 
death–1 (PD-1), programmed death–ligand 1 (PD-L1), and cytotoxic T-lymphocyte–
associated protein 4 (CTLA-4) are currently approved for use in patients with advanced stage 
melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), squamous cell 
carcinoma of head and neck (SCCHN), urothelial cancer, Hodgkin’s lymphoma, and 
microsatellite instability – high (MSI-H) or mismatch repair (MMR) deficient solid tumors. 
However, there is a significant proportion of patients that do not derive clinical benefit from 
these agents. Combination immunotherapies may enhance the ability to prevent immune 
escape by targeting multiple mechanisms of resistance of tumor cells to the immune system 
(45). Data from clinical studies suggest a relationship between patient response and 
intratumoral level of CD8+ T-cells prior to treatment (66, 69). Further, an increased number of 
CD3+ T-cells as well as an increased ratio of cytotoxic CD8+ T-cells (CTLs) over FOXP3+ 
regulatory T-cells (Tregs) within tumors following chemotherapy treatment was predictive of 
therapeutic responses in breast and colorectal cancer patients treated with anthracyclines and 
oxaliplatin, respectively (20, 29, 75). In addition to direct activation and maturation of 
dendritic cells (DCs) (47), cytotoxic agents may induce antitumor immunity by inducing 
immunologic cell death (ICD). ICD is characterized by endoplasmic reticulum stress leading 
to cell surface expression of calreticulin, followed by release of the soluble mediators high 
mobility group box 1 protein and adenosine triphosphate, and type I interferon (26). Both 
activation and maturation of DCs and induction of ICD trigger an immune response toward 
tumors via engagement of the adaptive immune response through cross-presentation of tumor 
derived antigens and priming of specific CD8+ effector T-cells. Importantly, several recent 
reports indicate that several classes of ADC payloads with varied mechanisms of action, 
including tubulin agents and DNA disrupting agents, can induce ICD and elicit antitumor 
immunity. Increases in tumor-infiltrating lymphocytes (TILs), particularly T cells, were 
observed within tumors in a preclinical orthotopic breast cancer model following treatment 
with ado-trastuzumab emtansine. Treatment with the combination of ado-trastuzumab 
emtansine and CTLA-4– and PD-1–blocking antibodies in this model resulted in strong 
antitumor efficacy and protection from tumor rechallenge, indicating a strong, T cell–directed, 
immunological memory response in the treated mice. Consistent with these observations, 
ado-trastuzumab emtansine treatment of patients with HER2-positive/estrogen receptor 
(ER)-positive breast cancer has been shown to elicit intratumoral recruitment of TILs (48). 
Similarly, ADCs carrying the tubulin disrupting agent tubulysin or the DNA disrupting agent 
pyrrolobenzodiazepine dimer (PBD) payload have been shown to induce ICD, immunologic 
Confidential
Page
21
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
modulation and memory, and synergistic antitumor efficacy when combined with several 
different checkpoint inhibitors in mouse models (57). Additionally, CD30-targeted lymphoma 
therapy with brentuximab vedotin has been shown to induce activation of patient DCs, T cells, 
and B cells, leading to sustained clinical responses and tumor-specific immunity in an 
allogenic setting (67). Taken together, these observations and the complementary mechanisms 
of action of these agents, provides strong rationale for combining ADCs with immune 
checkpoint blockade, and is currently being investigated clinically for a number of ADCs. It is 
hypothesized that in combination, MGC018 (anti–B7-H3 ADC) and MGA012 
(anti-PD-1 antibody [also known as INCMGA00012]), could mediate antitumor activity that 
is greater than that achieved with either single agent alone. 
MGC018, also known as AEX4089DC1, is an ADC targeted against B7-H3 (see Section 2.3). 
MGC018 is comprised of the cleavable linker-duocarmycin payload, valine-citrulline-seco-
Duocarmycin hydroxyBenzamide-Azaindole (vc-seco-DUBA; SYD980) (21, 23), conjugated 
through reduced interchain disulfides, to the anti–B7-H3 humanized immunoglobulin G 1 
(IgG1) kappa mAb MGA017. MGA017, which is based on the mouse mAb PRCA157, is 
cross-reactive with human and cynomolgus monkey B7-H3. 
MGC018 has an average drug-to-antibody ratio (DAR) of ~ 2.7, and an average molecular 
weight of ~ 150 kDa. MGC018 is designed to bind to cell-surface B7-H3, internalize into 
cells, and release the cytotoxic duocarmycin drug. Following binding to cell-surface B7-H3 
and internalization of MGC018 through endocytosis, the peptide linker is cleaved by 
lysosomal proteases, such as cathepsin B. Subsequently, 2 self-elimination reactions occur on 
the duocarmycin moiety to generate seco-DUBA (SYD978), which then spontaneously 
rearranges to form the activated duocarmycin drug (also known as DUBA or SYD986), which 
can then bind and alkylate DNA (Figure 1). The irreversible alkylation of DNA disrupts the 
nucleic acid architecture, ultimately leading to cell death. Due to the nature of the “cleavable” 
linker/payload, the protease-cleaved, activated DUBA is membrane permeable and, when 
released by dying cells, can cause bystander killing of neighboring tumor cells, irrespective of 
B7-H3 expression (70) (Figure 2). Importantly, the bystander killing property of the 
vc-seco-DUBA linker/payload may afford MGC018 therapeutic benefit toward heterogeneous 
B7-H3–expressing tumors. 
Confidential
Page
22
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Figure 1 
Schematic Representation of MGC018 and Mechanism of Release 
of Prodrug from MGC018 and Conversion to the Active 
Duocarmycin Drug DUBA  
 
Figure 2 
MGC018 Mode of Action  
 
 
MGC018 
MGA017 
SYD980 
SYD978 
Anbbocly"'illll 
Unhr 
s-
0 
malelmlde Inker 
M11-tlimln'110n 
0 
N 
vdne clltulllne 
PASC 
~o 
PtOI ,s.CSH~ 
OH 
SY0978 
I 
0 
I 
Sporaneouo "1n:s:eJn 
cyc/lzar...., 
$1Co-d\lOCarmycln p<odrug 
-
cJuvege and 
co,,com/'flll ~tin 
eycnar,on 
SYD98e 
octivo duocarmycln drug 
0 
lnaclivaled payload 
AcUvaled pa\llOad 
Linker 
-<:J Targel (antigen) 
<
Antibody 
) 
o/ 
Confidential
Page
23
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
MGC018 binds to its target antigen with a binding affinity of 22.7 nM. In support of the 
cynomolgus monkey as a relevant species for nonclinical toxicology evaluation, MGC018 
exhibited equivalent binding affinity (22.1 nM) toward B7-H3 of this species as that observed 
for human B7-H3. 
In vitro studies on cell lines and xenograft studies in CD-1 Nude (homozygous) mice have 
characterized the biological activity of MGC018. Consistent with its binding properties, 
MGC018 exhibited potent cytotoxic activity toward human tumor cell lines expressing a 
range of B7-H3 levels, and the cytotoxic activity of MGC018 was dependent on B7-H3 
expression. In vivo efficacy studies with MGC018 established dose response profiles 
following single- and repeat-dose administration and identified cancer types that exhibit 
sensitivity to MGC018, which may serve as therapeutic indications for clinical studies. In 
single-dose experiments, MGC018 exhibited antitumor activity toward human tumor 
xenografts representing breast, lung, and ovarian cancer, as well as melanoma. Antitumor 
activity (reduction in percentage of mean tumor size in the treatment group relative to mean 
tumor size of the vehicle control group [% T/C] and number of complete responses) was 
generally observed at the lowest dose levels tested (1 or 3 mg/kg), depending on the study. 
Repeat-dose administration of MGC018 led to greater antitumor activity in ovarian, breast, 
and lung cancer xenograft studies compared to a single dose administration. Dose-dependent 
antitumor activity was observed in all 3 models, with a minimal efficacious dose established 
at 1.0 mg/kg for Calu-6 lung cancer and 0.3 mg/kg for PA-1 ovarian cancer and MDA-MB-
468 breast cancer. 
A Good Laboratory Practice (GLP) tissue cross-reactivity study of human tissues with 
MGC018 revealed that plasma membrane and cytoplasmic reactivity was observed in 
mononuclear cells in lymphoid tissues, including reticulo-endothelium in the spleen, heart, 
and stomach, as well as the membrane and cytoplasm of the following epithelial cell 
types: liver hepatocytes, the epidermis and hair follicle epithelium in the skin, and extravillous 
trophoblasts and amniotic epithelium in the human placenta. The reactivity was generally 
weak, or weak to moderate in intensity, and rare to occasional in frequency. All other 
reactivity was cytoplasmic in nature. 
MGC018 administered as a 1-hour intravenous (IV) infusion once every 3 weeks (Q3W) (total 
of 3 doses) was tolerated in cynomolgus monkeys up to 10 mg/kg/dose, the highest dose 
tested in the GLP toxicology study. As there were no MGC018-related life-threatening 
toxicities, irreversible findings, or mortality, the highest non-severely toxic dose (HNSTD) for 
this study was determined to be 10 mg/kg/dose. 
MGC018 demonstrated favorable binding properties, potent cytotoxic activity toward multiple 
B7-H3–expressing human tumor cells in vitro, and antitumor activity in B7-H3 human tumor 
xenografts representing breast cancer, ovarian cancer, lung cancer and melanoma in vivo. 
Further, MGC018 exhibited a favorable tissue cross-reactivity profile across a panel of 
34 normal human tissues and an acceptable safety profile following repeat-dose 
administration in cynomolgus monkeys. The data from the nonclinical pharmacology studies 
provide strong scientific rationale for the evaluation of MGC018 as a therapeutic candidate for 
the treatment of B7-H3–expressing malignancies. 
Confidential
Page
24
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
2.2 
Disease Background  
2.2.1 
SCCHN  
Head and neck cancer accounts for about 3% of malignancies in the United States (US). 
Approximately 62,000 patients are diagnosed annually in the US and approximately 
13,000 deaths occur annually secondary to SCCHN (60). Globally, over 500,000 patients are 
diagnosed with this disease annually (34). Infection with human papillomavirus (HPV), 
specifically the cancer-causing type, HPV-16, is now considered a risk factor for certain head 
and neck cancers, particularly oropharyngeal cancers involving the tonsils or the base of the 
tongue (13, 27). In the US, the incidence of oropharyngeal cancers caused by HPV infection is 
increasing, whereas the incidence of oropharyngeal cancers related to other causes is falling 
(13). 
Treatment for patients with locally advanced SCCHN remains unsatisfactory. Less than 
40% of patients are cured with primary treatment with combination of radiation therapy and 
cisplatin-based chemotherapy. Survival is less than 20% at 2 years in patients with recurrent 
disease following treatment with radiochemotherapy. The combination of cetuximab, a 
blocking antibody for epidermal growth factor receptor (EGFR), with radiotherapy showed 
significant improvement in outcomes for patients with locally advanced disease when 
compared with radiotherapy alone. However, it failed to change the rate of distant metastasis. 
The combination of cetuximab with radiochemotherapy failed to improve progression-free 
survival (PFS) and overall survival (OS) in patients with advanced stage disease (5). In 
addition, there is evidence to suggest the role of immune checkpoints that limit T cell 
responses to tumors in SCCHN. Pembrolizumab has been recently approved for treatment of 
patients with recurrent or metastatic SCCHN with disease progression on or after 
platinum-containing chemotherapy, irrespective of the HPV status. The objective response 
rate (ORR) following pembrolizumab in this population is about 16%, with a CR rate of 5% 
(4, 16). There is no significant difference in response rate based on HPV status of the tumor. 
Although this is an improvement over prior standard therapy, there is a need to identify new 
therapeutic options for patients with SCCHN.  
B7-H3 is expressed on a high percentage of SCCHN tumors (36, 51). In addition, the level of 
B7-H3 expression as determined by immunohistochemistry (IHC) staining on the tumor was 
inversely correlated with the number of tumor infiltrating CD8 + T-cells and directly 
proportional to the development of distal metastases and decreased survival (36). 
Collectively, these observations provide a supportive rationale for targeting B7-H3 with 
MGC018 in patients with SCCHN and for the exploration of combined administration of 
MGC018 with anti–PD-1 antibody (MGA012) in this population. Participants with SCCHN 
who have relapsed or who have refractory disease following treatment with platinum-based 
therapy will be enrolled in this study to assess the preliminary clinical activity of MGC018 
alone or in combination with MGA012. 
Confidential
Page
25
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
2.2.2 
Prostate Cancer  
Prostate cancer is the most commonly diagnosed cancer in men and is the second-leading 
cause of cancer-related deaths. In the US, it is estimated that 160,360 men in 2017 will be 
diagnosed with prostate cancer, and 26,730 deaths will occur secondary to prostate cancer 
(61). Although hormone therapy is associated with significant responses in metastatic and 
advanced disease, virtually all patients develop hormone-refractory disease and may receive 
docetaxel for metastatic castration-resistant prostate carcinoma (mCRPC). Newer androgen 
receptor therapies such as abiraterone have shown improved PFS over docetaxel in mCRPC; 
however, the need for novel treatments in this setting remains. Cross-resistance between 
taxanes and new hormonal agents abiraterone and enzalutamide, may affect drug sequence 
choices in mCRPC (71). 
Based on a Phase 1 study (NCT01391143) of the Fc engineered anti–B7-H3 mAb 
enoblituzumab, 89% (88/99) of prostate cancer patients screened were B7-H3 positive. Thus, 
a very high proportion of patients with prostate cancer may be anticipated to have B7-H3-
positive tumors, supporting targeting this disease with MGC018. Initial indications of clinical 
activity were noted in the Phase 1 trial of enoblituzumab in participants with prostate cancer, 
including one participant with a 23% tumor reduction per Response Evaluation Criteria in 
Solid Tumors (RECIST) and a 46% prostate-specific antigen (PSA) decrease following 
progression on sipuleucel-T, abiraterone, enzalutamide, radium 223, and Taxotere® and one 
patient post-radiotherapy with a 58% tumor reduction per RECIST and a 51% decrease in 
PSA (MacroGenics unpublished data). 
PD-1 inhibitors have not shown significant activity as monotherapy in patients with metastatic 
prostate cancer. However, more recently, pembrolizumab given in combination with 
enzalutamide in a Phase 2 study showed evidence of clinical benefit in castration resistant 
prostate cancer (28). High expression of B7-H3 makes prostate cancer a good candidate for 
evaluation of MGC018. It is also hypothesized that cytoreduction mediated by administration 
of MGC018 could also serve to potentiate the immune stimulatory activity of MGA012. The 
combination of MGC018 and MGA012 could be synergistic and mediate greater antitumor 
activity than either single agent alone for patients with mCRPC. 
2.2.3 
Non-small Cell Lung Cancer  
Lung cancer is the most commonly diagnosed cancer worldwide (7). In 2018, an estimated 
2.1 million new cases of lung cancer were diagnosed globally, accounting for approximately 
11.6% of the global cancer burden. An estimated 1.76 million lung cancer deaths occurred in 
2018. In 2020, an estimated 228,820 adults (116,300 men and 112,520 women) in the US will 
be diagnosed with lung cancer (62). An IHC screen performed by MacroGenics, Inc. of 
NSCLC specimens revealed that 144 of 156 total specimens (100%) exhibited B7-H3 
expression at any level, while 124 of 86 (70%) had H-scores > 100 (i.e., moderate or strong 
expression). 
In the first-line treatment setting, due to the introduction of new drugs and patient selection 
based on histological subtypes and driver mutations that influence the biology of these 
Confidential
Page
26
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
malignancies, median overall survival (OS) for patients with advanced NSCLC receiving 
platinum-based chemotherapy in combination with agents targeting specific histologies and 
mutations has improved to 12 months or longer in controlled studies (56). However, despite 
availability of multiple treatment options in the second-line setting, clinical outcomes remain 
poor. Response rates are, on average, less than 10%, and median OS is 7–9 months from start 
of second-line therapy (80).  
In a meta-analysis, B7-H3 was significantly associated with lymph node metastasis, and 
advanced TNM stage in NSCLC (77). High levels of B7-H3 protein have a negative 
prognostic impact in lung carcinomas (2). These observations provide rationale for targeting 
B7-H3 with MGC018 in patients with NSCLC. 
2.2.4 
Triple Negative Breast Cancer  
About 12% of breast cancers known as TNBC are negative for estrogen receptor, progesterone 
receptor, and human epidermal growth factor receptor 2. TNBC is associated with a poorer 
prognosis than other types of breast cancer (63). An IHC screen of TNBC specimens 
performed at MacroGenics, Inc., revealed that 12 of 17 (71%) exhibited B7-H3 expression at 
any level, while 8/17 (47%) exhibited ≥ 2+ B7-H3 expression. 
Breast cancer demonstrates several characteristics that suggest that this tumor may elicit an 
immune response. These include the presence of infiltrating immune cells and lymphocytes 
within the tumor microenvironment; the prognostic value of an immunity-related gene 
signature; and genetic instability leading to increased number of mutations, translated into 
more neoantigens. The characteristics are more pronounced in TNBC and human epidermal 
growth factor receptor 2 HER2-positive tumors. These 2 are considered the most 
immunogenic subtypes of breast cancer (17). 
TNBC has been divided into 6 molecular subtypes, including an immunomodulatory subtype 
characterized by an immune gene expression pattern, high number of immune cells infiltrating 
the tumor stroma, higher PD-L1 expression, and high mutation rate. These features make 
TNBC patients good candidates for immunotherapy (24, 38). 
Studies on TILs derived from tumor tissue from patients with TNBC have shown expression 
of lymphocyte-activation gene3 (LAG-3) and PD-1. In a study of 259 TNBC tumor samples, 
PD-1 and LAG-3 were expressed in TILs of 30% and 18%, respectively. Co-expression of 
PD-1 and LAG-3 was seen in 15% of tumors (6). Increased stromal TILs have been associated 
with increased relapse free survival and increased OS in patients with TNBC. 
Some recent studies of immunotherapy agents have shown activity in TNBC. The ADC 
IMMU-132, which binds to the protein Trop2 and delivers SN-38, the active metabolite of 
irinotecan, to the tumor is in clinical trials for TNBC. A Phase 1/2 trial enrolled 
60 participants with TNBC, with a 33% ORR and PFS of 5.6 months (33). Vantictumab (anti-
Fzd7 mAb), in combination with paclitaxel, produced partial responses in 6 of 15 (40%) 
patients with TNBC (1). Antitumor activity has also been seen in early clinical trials with 
PD-1/PD-L1 inhibitors in TNBC (30), which further supports MGC018 and MGA012 
combination therapy. 
Confidential
Page
27
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
In the Cohort Expansion Phase of this study, the antitumor activity of MGC018 will be 
evaluated in a cohort of participants with TNBC, who have progressed after at least one 
systemic therapy for locally advanced unresectable or metastatic disease. 
2.2.5 
Melanoma  
In 2018, an estimated 287,723 new cases of melanoma of the skin were diagnosed globally, 
with 60,712 deaths due to the disease (7). In the US, estimates for 2020 were 100,350 new 
cases and 6,850 deaths attributable to melanoma of the skin (62). Melanoma is the most 
serious and deadly form of skin cancer, affecting adults of all ages. Even though melanoma 
accounts for approximately less than 2% of all skin cancers, it causes over 80% of skin 
cancer-related deaths. Despite new anticancer therapies, the vast majority of patients with 
advanced melanoma will have disease progression that requires further therapy. Even with the 
recent advancements in treatment, the median PFS for patients with advanced melanoma on 
pembrolizumab was approximately 5.5 months (median OS not reached at 12 months), and 
with ipilimumab treatment, the median OS and median PFS are approximately 10 months and 
2.9 months, respectively (31) (see Keytruda® US prescribing information). Thus, although 
current treatment options such as pembrolizumab or ipilimumab monotherapy provide a 
survival benefit in advanced disease, there remains a medical need for continued improved 
treatment in advanced cases. 
In addition to the above, a high percentage of melanoma tumors demonstrate membranous 
surface expression of B7-H3, whereas nevi have either no or low levels of membranous 
expression (68, 74). In addition, B7-H3 expression levels on melanoma are associated with 
stage and prognosis, with higher levels associated with higher tumor stage and shorter 
survival than in patients having tumors with lower intensity staining (68, 74). 
2.3 
Background on B7-H3 and PD-L1  
2.3.1 
B7-H3  
The B7 family of cell surface molecules consists of structurally related protein ligands that 
bind to receptors on lymphocytes and regulate immune responses. Activation of T and B 
lymphocytes is initiated by engagement of antigen-specific receptors, T cell antigen receptor 
(TCR), and membrane-bound immunoglobulin (mIg) respectively, but additional signals 
delivered simultaneously to members of the CD28 family of receptors by B7 ligands 
determine the ultimate immune response (18). 
B7-H3, also referred to as CD276, is a novel member of the B7 family. B7-H3 is a type-1 
transmembrane glycoprotein containing extracellular immunoglobulin-like domains. Although 
B7-H3 mRNA is widely distributed, B7-H3 protein expression in normal human tissues is 
limited, presumably due to the negative regulation of B7-H3 protein expression by the 
microRNA miR-29 (78). B7-H3 protein, however, is overexpressed in a variety of solid 
tumors, due in part to the downregulation of miR-29 in tumor tissues (78). B7-H3 has been 
implicated in the delivery of both co-stimulatory and co-inhibitory signals (32). The apparent 
contrasting activities of B7-H3 may be attributed to multiple factors. While the murine B7-H3 
Confidential
Page
28
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
molecule exists as a 2-Ig form, the human counterpart has undergone gene duplication and 
exists primarily as a 4-Ig molecule (64). Further, as with other members of the B7 family, 
B7-H3 may bind, on different cells, to multiple receptors that remain to be identified. 
B7-H3 is an attractive target for tumor immunotherapy, without regard to its immunological 
properties, because of its overexpression in many malignant tumors and limited expression in 
normal tissues. A large number of solid tumor types have been reported to overexpress B7-H3, 
including, but not limited to, prostate cancer (14, 40, 59, 79); melanoma (40, 54, 73); renal 
cell carcinoma (19, 40, 53), where B7-H3 is broadly expressed in tumor epithelium and 
tumor-associated vasculature; breast cancer (39, 40, 42); non-small cell lung cancer (NSCLC) 
(35, 40, 43, 65); and oral squamous carcinoma (15). In the majority of cancers, overexpression 
of B7-H3 has been correlated with multiple adverse clinical and pathological features of 
disease, increased risk of recurrence, and reduced survival. A more extensive survey of 
published literature reporting B7-H3 expression in cancer, and correlation with clinical 
features and outcome is presented in the MGC018 Investigator Brochure. 
2.3.1.1 
MGC018 Nonclinical Experience  
2.3.1.1.1 
MGC018 Pharmacology  
The nonclinical pharmacology program for MGC018 was designed to characterize the binding 
affinity and biological activity of MGC018 in vitro and in vivo and is briefly summarized 
below. Further information can be obtained from the MGC018 Investigator Brochure. 
The binding of MGC018 to its target antigen was characterized by surface plasmon resonance 
analysis using recombinant soluble B7-H3 (4Ig). MGC018 preserves the antigen-binding 
properties exhibited by the non-conjugated precursor molecule (MGA017) and exhibits a 
binding affinity of 22.7 nM toward human B7-H3. In support of the cynomolgus monkey as a 
relevant species for nonclinical toxicology evaluation, MGC018 exhibited equivalent binding 
affinity (22.1 nM) toward B7-H3 of this species as that observed for human B7-H3. MGC018 
binding on various human B7-H3 cancer cell lines was confirmed and measured by 
quantitative flow cytometry. 
Consistent with its binding properties and designed mechanism of action, MGC018 exhibited 
potent cytotoxicity toward human B7-H3–expressing cancer cell lines in vitro. MGC018 
exhibited potent cytotoxic activity toward human tumor cell lines expressing a range of 
B7-H3 levels, with half maximal inhibitory concentration values ranging from 181 to 
1447 pM. The cytotoxic activity of MGC018 was dependent on B7-H3 expression, as cells 
with undetectable cell surface B7-H3 expression (Raji B cell lymphoma) remained insensitive 
to MGC018; moreover, tumor cell lines knocked out for B7-H3 (Hs700T/B7-H3 KO) were 
also insensitive to MGC018. 
The antitumor activity of MGC018 was demonstrated in a series of in vivo pharmacology 
studies that evaluated the efficacy of MGC018 toward human tumor xenografts following 
single and repeat-dose administration. Human tumor cell line xenografts representing breast 
cancer (MDA-MB-468), lung cancer (Calu-6), ovarian cancer (PA-1), and melanoma 
(A375.S2) were tested in CD-1 Nude (homozygous) mice. MDA-MB-468 tumor cells were 
Confidential
Page
29
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
implanted orthotopically in the mammary fat pad, whereas Calu-6, PA-1 and A375.S2 tumor 
cells were implanted subcutaneously. It is important to note that MGC018 exhibits 
poor stability in mouse serum and rapid clearance in mice following IV and intraperitoneal 
(IP) dose administration, due to the sensitivity of the vc-seco-DUBA linker payload moiety to 
the rodent-specific carboxylesterase (CES1c) which is not expressed by primates (21, 23). The 
rapid clearance of MGC018 in mice may under-predict the anti-tumor activity of MGC018, 
making reliable extrapolations from exposure-response analyses difficult. Additionally, 
SYD988, a nontargeting anti-CD20 control ADC, which contains the same vc-seco-DUBA 
linker-payload as MGC018 and is similarly susceptible to CES1c cleavage and the release of 
free payload, may exhibit a background level of non-specific antitumor activity in some tumor 
xenograft models. 
In single-dose experiments, MGC018 exhibited antitumor activity toward human tumor 
xenografts representing breast, lung, and ovarian cancer, as well as melanoma. Antitumor 
activity (reduction in percent mean tumor size in treatment group relative to mean tumor size 
of vehicle control group [% T/C] and number of complete responses) was observed at all dose 
levels and generally observed at the lowest dose levels tested (1 or 3 mg/kg depending on the 
study). Figure 3 shows the results of a study with PA-1 ovarian cancer tumor xenografts 
treated with a single dose administration of MGC018. Antitumor activity was observed at all 
3 dose levels of MGC018. A reduction in tumor volume of 89%, 91%, and 43%, with 3/6, 2/6, 
and 1/6 complete responses, respectively, was observed following treatment with MGC018 at 
10, 6, and 3 mg/kg, respectively, on Day 59. The nontargeting SYD988 control ADC, which 
contains the same vc-seco-DUBA linker-payload as MGC018, exhibited minimal antitumor 
activity, with reductions in tumor volume of 16% and 11% following treatment at 10 and 
6 mg/kg, respectively; a slight increase in tumor volume (12% increase) at 3 mg/kg; and no 
complete responses. 
Confidential
Page
30
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Figure 3 
Antitumor Activity of MGC018 in CD1 Nude (Homozygous) Mice 
Bearing PA-1 Ovarian Cancer Xenografts: Single-Dose 
Administration  
 
Female CD1 Nude (homozygous) mice (n = 6/group) were implanted subcutaneously with PA-1 tumor cells 
(5 × 106 cells). When tumors reached ~ 150 mm3, mice were randomized and treated intraperitoneally with 
vehicle control (PBS), nontargeting control ADC (SYD988), and targeting ADC (MGC018) on Day 24 
(arrow) at the dose levels indicated for a total of one dose. Tumor volume is shown as group mean ± SEM. 
Abbreviations: PBS = phosphate buffered saline; SEM = standard error of the mean. 
The vast majority of ADCs are administered via a repeat-dose regimen in the clinical setting, 
with intervals ranging from once weekly (QW) to once every 6 weeks (Q6W). To evaluate the 
antitumor activity following repeat-dose administration, a study was performed in PA-1 
ovarian cancer tumor xenografts comparing single-dose (QWx1) to once weekly, 4 times 
(QWx4) and once every 2 weeks, 4 times (Q2Wx4) administration. As shown in Figure 4, 
repeat-dose administration of MGC018 led to a much greater antitumor response than 
administration of a single dose. A single dose of 3 mg/kg MGC018 achieved short-term tumor 
stasis of approximately 10 days, followed by tumor regrowth, with a reduction in tumor 
volume of 29% on Day 77. Repeat-dose administration of 3 mg/kg MGC018 led to a decrease 
in tumor volume, resulting in a 97% and 92% reduction in tumor volume with 4/6 and 2/6 
complete responses for QWx4 and Q2Wx4 treatment, respectively. SYD988 at 3 mg/kg 
exhibited minimal antitumor activity, with reductions in tumor volume of 13%, 8% and 7% 
for single, QWx4 and Q2Wx4 administration, respectively; only 1 animal treated with 
SYD988 (QWx4 group) showed a complete response. 
2500 
-
M 
2000 
.... Vehicle (PBS) 
-
---
MGC018 [1 0mg/kg] 
1500 
..... MGC018 [6mg/kg] 
::::, 
1000 
-+-
MGC018 [3mg/kg] 
... 
-a-
SYD988 [1 0mg/kg] 
0 
E 500 
-Ir SYD988 [Gmg/kg] 
::::, 
I-
....... SYD988 [3mg/kg] 
0 
0 
20 
40 
60 
80 
Study Day 
Confidential
Page
31
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Figure 4 
Antitumor Activity of MGC018 in CD1 Nude (Homozygous) Mice 
Bearing PA-1 Ovarian Cancer Xenografts: Single- vs. Repeat-Dose 
Administration  
 
Female CD1 Nude (homozygous) mice (n = 6/group) were implanted subcutaneously with PA-1 ovarian 
cancer tumor cells (5 × 106 cells). When tumors reached ~ 150 mm3, mice were randomized and treated 
intravenously with vehicle control (PBS), nontargeting control ADC (SYD988), and targeting ADC 
(MGC018) for a single-dose administration (QWx1) on Day 39 (black arrow); repeat-dose administration 
once weekly x 4 doses (QWx4) on Days 39, 46, 53, and 60 (dark gray arrows); or repeat-dose 
administration once every 2 weeks x 4 doses (Q2Wx4) on Days 39, 53, 67, and 81 (light gray arrows) at the 
dose level indicated for a total of 4 doses. Tumor volume is shown as group mean ± SEM. 
Abbreviation: SEM, standard error of the mean. 
Additional repeat-dose administration in vivo efficacy studies with MGC018 in mice bearing 
breast cancer, ovarian cancer, and NSCLC are presented in the MGC018 Investigator 
Brochure. 
2.3.1.1.2 
MGC018 Pharmacokinetics and Toxicology  
A summary of nonclinical pharmacokinetic (PK) and toxicology data with MGC018 are 
provided below; please reference the MGC018 Investigator Brochure for a more detailed 
description. 
The nonclinical toxicology program for MGC018 was performed exclusively in the 
cynomolgus monkey as MGC018 does not bind to B7-H3 in mouse or rat. The cynomolgus 
monkey was selected as the most appropriate animal model for nonclinical safety evaluation 
of MGC018 given the homology of cynomolgus monkey and human B7-H3, the ability of 
MGC018 to bind with nearly identical affinity to human and cynomolgus monkey B7-H3, and 
the concordance of staining pattern for MGC018 toward panels of normal human and 
cynomolgus monkey tissues. 
1500 
t t t t 
-
t t t t 
M 
E 
...... Vehicle (PBS) 
E 
t 
MGC018 [3mg/kg QWx1] 
-;1000 
---
E 
...... MGC018 [3mg/kg QWx4] 
:::, 
MGC018 [3mg/kg Q2Wx4] 
0 
-+-
> 
'-
500 
-e-
SYD988 [3mg/kg QWx1] 
0 
E 
.... SYD988 [3mg/kg QWx4] 
::I 
I-
-+-
SYD988 [3mg/kg Q2Wx4] 
0 
0 
20 
40 
60 
80 
Study Day 
Confidential
Page
32
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
A GLP tissue cross-reactivity study, performed on a panel of normal human tissues, 
demonstrated that MGC018 staining the membrane and cytoplasm of mononuclear cells found 
in human lymphoid tissues (spleen, thymus, and tonsil), as well as rare or very rare cases of 
stomach or heart, respectively. Membrane and cytoplasm staining was observed in a few 
epithelial cell types: hepatocyte epithelium in liver (2 of 3 samples with weak intensity and 
occasional staining at the higher of 2 validated MGC018-biotinylated (MGC018-Bio) 
antibody concentrations); the epidermis and hair follicle epithelium in skin (2 of 3 samples 
with weak to moderate intensity and rare to occasional staining at both the high and low 
MGC018-Bio antibody concentrations); and extravillous trophoblasts and amniotic epithelium 
in the placenta. All staining in this study represented expected reactivity, and no unanticipated 
cross-reactivity of MGC018 was observed (41, 52, 55, 59, 64, 81, 82). 
In the repeat-dose GLP toxicology study, MGC018 was administered at dose levels of 
0 (vehicle control), 1, 3, 6, and 10 mg/kg/dose to cynomolgus monkeys (n = 5/sex/group) and 
was tolerated as 1-hour IV infusions on a Q3W schedule for a total of 3 doses. Other MGC018 
studies included single-dose studies up to 27 mg/kg and an exploratory repeat-dose toxicology 
study with MGC018 dosed every 2 weeks (Q2W) at 6 or 20 mg/kg. There were no MGC018-
related observations in animals evaluated at these dose levels for the following parameters: 
food consumption, ophthalmology, electrocardiograms (ECGs), body temperature, blood 
pressure, heart rate, respiration rate, or functional observation battery (FOB) examinations and 
assessment for autonomic, sensorimotor, reflexive motor, or physiological functions. 
The 3 components of MGC018 (i.e., conjugated antibody, total antibody, or unconjugated 
SYD986) were examined in the toxicity GLP study. The maximum serum concentration 
(Cmax) for conjugated and total antibody increased proportionally with increasing MGC018 
dose level. Exposure of the conjugated and total antibody at MGC018 doses ranging from 1 to 
6 mg/kg increased more than proportionally with dose level and the clearance (CL) decreased 
with increasing dose levels of MGC018. However, at MGC018 doses > 6 mg/kg, exposure of 
conjugated or total antibody increased proportionally with dose level and the CL was 
essentially unchanged. 
Animals from the individual dose groups achieved comparable exposure of conjugated or total 
antibody during the first dose interval. However, exposure decreased in a few animals during 
the second dose interval and in most of the animals during the third dose interval due to ADA. 
There was no accumulation of ADC or total antibody after 3 MGC018 doses administered 
Q3W (observed accumulation ratio < 1). The Cmax of unconjugated SYD986 also increased 
proportionally with increasing dose level and was 2070- to 8862-fold lower than that of the 
SYD986 conjugated to MGC018 for the 1 to 10 mg/kg dose groups. Unconjugated SYD986 
had an accumulation ratio of 1.37 to 1.96 for the 3, 6, and 10 mg/kg dose groups, which could 
be expected when SYD986 is released from MGC018 in serum, plasma, or blood. 
MGC018-related clinical signs were predominantly dose dependent and included skin 
findings (hyperpigmentation, dry skin, erythema), occasional inappetence, soft/watery feces, 
thin body condition in single females at 6 and 10 mg/kg/dose, and sparse hair noted in a 
subset of animals particularly at ≥ 6 mg/kg/dose. Slight changes in body weight gain were 
noted but not considered adverse. 
Confidential
Page
33
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
MGC018-related changes in hematology parameters were noted in neutrophil and lymphocyte 
counts, red blood cell parameters, and reticulocyte counts, all of which were not considered 
adverse as changes were within the historical control range for these parameters in 
cynomolgus monkeys. A trend toward transient but repeated decreases in neutrophil counts, 
relative to predose levels, was observed in 2 males at 6 mg/kg/dose and the majority of the 
males at 10 mg/kg/dose on Days 36, 48, or 53.  Minimal to mild transient decreases in 
lymphocyte counts were observed in both sexes at 10 mg/kg/dose (up to -49%) relative to 
Day 1 predose mean values. These changes resolved prior to or during the recovery period and 
without microscopic correlates. 
Minimal to mild decreases in red cell mass (erythrocyte count, hemoglobin concentration, 
and/or hematocrit) relative to predose values started on Day 3 and corresponded to mild to 
moderate increase in reticulocytes, reflecting an appropriate regenerative erythroid response 
attributed to repeated blood collections. Starting on Day 23, the decrease in red cell mass was 
more pronounced and associated with a less pronounced increase in reticulocyte counts in 
males administered ≥ 6 mg/kg/dose and to a lesser extent in females that received 
10 mg/kg/dose. These are suggestive of diminished or suppressed erythropoiesis, although no 
microscopic correlates were observed at termination. Red cell mass and reticulocyte changes 
were fully resolved during the recovery period. 
MGC018-related changes in clinical chemistry parameters were noted in in C-reactive protein 
(CRP), aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT), and alkaline 
phosphatase (ALP) and were not considered adverse as changes remained in or very close to 
the historical control range for cynomolgus monkeys. Increases in CRP concentrations were 
noted across all groups, including controls following each dose and considered related to 
dosing procedures. However, males at ≥ 3 mg/kg/dose (all 3 doses) and females at 
≥ 1 mg/kg/dose had more pronounced CRP increases and was associated with concurrent 
fibrinogen increases at 10 mg/kg/dose following the last dose. This is suggestive of an 
inflammatory stimulus and may have been related to microscopic skin findings at termination. 
Transient, minimal to mild increases in AST and/or ALT levels were noted at all dose levels 
including control animals; however, greater increases in 1 or 2 individuals of each sex were 
observed at ≥ 1 mg/kg/dose. These changes were partially to fully resolved by the following 
sample collection and did not result in microscopic correlates at termination. Decreased ALP 
levels were observed at 6 mg/kg/dose, lacked correlative findings among other clinical 
pathology or microscopic endpoints, resolved during the recovery period, and were not likely 
biologically meaningful. 
A spectrum of microscopic findings was present in the skin overlying the last infusion site, 
skin from the routine section of skin (flank), and additional locations including the forelimbs, 
hindlimbs, and head. The findings ranged in severity and/or presence within individuals and 
across animals, but the features of the findings were generally similar within a dose group and 
displayed a clear dose response in severity and extent of the findings, which were generally 
more prominent at ≥ 6 mg/kg/dose and included increases in pigment, lymphocytic 
inflammation, epidermal hyperplasia, and single cell necrosis. Complete reversal of 
lymphocytic inflammation and single cell necrosis was observed at the end of the recovery 
phase, and pigment changes and hyperplasia showed ongoing resolution. 
Confidential
Page
34
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
In a non-GLP study, a higher repeat-dose level of 20 mg/kg/dose administered at a 2-week 
interval was associated with similar, but greater, clinical pathology MGC018-related changes 
that in some cases resulted in microscopic correlates. These included an inflammatory 
response (increased fibrinogen, CRP, and globulin concentrations and decreased albumin 
concentrations) that was likely associated with cutaneous skin lesions, suppressed 
hematopoiesis (decreased red cell mass and decreased reticulocyte, neutrophil, and platelet 
counts) that correlated with decreased hematopoietic cellularity of the sternal bone marrow, 
and decreased lymphocyte counts that correlated with lymphoid depletion of the thymus. 
Microscopic skin findings were more severe in animals administered the higher repeat-dose 
level of 20 mg/kg/dose. Skin erosion that consisted of separation of the epidermis from the 
underling basement membrane and dermis resulted in grossly visible ulcers and led to 
euthanasia in extremis in 1 out of 3 animals. 
Animals that received MGC018 as a single dose at ≥ 20 mg/kg and necropsied 48 hours 
post-dose had microscopic findings not observed at later necropsy days or in animals that 
received 10 mg/kg. 
 
 
 
 
 
 
 
 
 
 
Based on the GLP toxicology study, the HNSTD for MGC018 was 10 mg/kg/dose 
administered as a 1-hour IV infusion Q3W (total of 3 doses) as there were no 
MGC018-related life-threatening toxicities, irreversible findings, or mortality. This 
corresponds to a peak and systemic exposure of 260.27 mcg/mL (Cmax) and 11821 hr*mcg/mL 
[area under the concentration-time curve (AUC)0-504hr)] for the conjugated antibody, 
233.85 mcg/mL (Cmax) and 11475 hr*mcg/mL (AUC0-504hr) for the total antibody and 
309.5 pg/mL (Cmax) and 11188 hr*pg/mL (AUC0-504hr) for SYD986 (payload), respectively. 
2.3.2 
PD-1  
The PD-1 receptor is an inhibitory receptor expressed by T cells, which is engaged by ligands 
including PD-L1 and PD-L2, expressed by antigen-presenting cells. Interaction of PD-1 with 
its ligands leads to the delivery of a negative signal to the T-cell expressing PD-1 and inhibits 
T-cell function. This pathway helps the body maintain self-tolerance. Many tumor cells, 
however, have co-opted this pathway and express high levels of PD-L1 and thereby evade 
T cell attack. Within the tumor microenvironment, PD-1/PD-L1 interactions limit 
inflammation and inhibit cytotoxic T lymphocyte (CTL) activity. PD-1 activation inhibits 
CD8+ CTL proliferation, survival, and their effector function and can also induce apoptosis of 
TILs and promote differentiation of CD4+ T cells into Treg cells. 
Confidential
Page
35
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Immune checkpoint blockade utilizing anti–PD-1 or anti–PD-L1 antibodies has now proven to 
have clinical benefit among numerous clinical indications, including both hematologic 
malignancies and solid tumors. Furthermore, anti–PD-1/PD-L1 directed therapeutics are now 
being investigated in combination studies across various indications. Existing literature 
suggests that cytotoxic therapy may be combined with checkpoint inhibition to achieve 
antitumor activity that is superior to either modality alone and has led to numerous clinical 
studies of chemotherapy in combination with checkpoint inhibition, including studies that 
have supported the recent FDA approval of the combinations of pembrolizumab and 
chemotherapy in patients with NSCLC. It is hypothesized that targeted delivery of a cytotoxic 
payload (duocarmycin) using MGC018 in various cancers known to express B7-H3 could 
also achieve additive or synergistic clinical activity when administered in combination with 
anti–PD-1 (MGA012). 
2.3.2.1 
MGA012 Clinical Background  
Study CP-MGA012-01 is a Phase 1, open-label, multicenter dose-escalation study to define 
the toxicity profile, maximum tolerated dose (MTD), immunogenicity, PK, and potential 
antitumor activity of MGA012 in participants with relapsed, refractory advanced solid tumors 
for whom no standard therapy is available. The study consists of a Dose Escalation Phase and 
a Cohort Expansion Phase. During the Dose Escalation Phase, 2 schedules of administration 
were evaluated, Q2W and once every 4 weeks (Q4W), using a standard 3 + 3 design. Cohort 
expansion to assess further activity in specific solid tumors (endometrial carcinoma, cervical 
carcinoma, NSCLC, and sarcoma) is ongoing. 
Phase 1 dose-finding results in participants with advanced cancer (N = 37) have been 
presented (37). Based on a data cutoff of 23 September 2018, MGA012 demonstrated 
acceptable tolerability with no dose-limiting toxicity observed at doses ranging from 1 to 
10 mg/kg Q2W (Q4W administration was also studied). An MTD was not reached.  The T½ 
(β) was approximately 17 days, and steady state was achieved in approximately 85 days. Full 
and sustained receptor occupancy of MGA012 on both CD4+ and CD8+ T cells along with 
complete loss of competing fluorescently labeled anti–PD-1 staining (eJBio105 clone) were 
observed at all dose levels. A dose of 3 mg/kg Q2W was selected for further expansion in 
NSCLC, endometrial cancer, cervical cancer, and sarcoma cohorts, with subsequent 
evaluation of flat dosing in tumor-agnostic and MSI-H uterine cancer cohorts.  
Interim results for the expansion cohorts have recently been presented (44). A total of 
132 participants were enrolled into the disease-specific expansion cohorts and another 30 in 
the tumor agnostic flat dosing cohorts at 500 and 750 mg Q4W. Participants were 
predominantly Caucasian and female; the median age ranged from 44 for the sarcoma cohort 
to 64 for endometrial cancer. The most frequently reported treatment emergent adverse events 
(TEAEs) (> 10%) in participants receiving body-weight based dosing were fatigue, diarrhea, 
and dyspnea. The most frequently reported TEAEs (≥ 20%) in participants receiving the fixed 
dose of 500 mg Q4W were fatigue, blood alkaline phosphatase increased, and blood bilirubin 
increased. These AEs were generally low-grade. Overall, 23/199 (12%) participants exposed 
to MGA012 in the study have experienced immune-related adverse events (irAEs). Most 
irAEs were transient, with the exception of endocrine-related irAEs. Non-endocrine irAEs that 
Confidential
Page
36
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
did not resolve were lipase increased, stomatitis, proctitis, diarrhea, ALT increased, and blood 
bilirubin increased (all 1 participant each). There were no fatal irAEs.   
Confirmed RECIST responses were observed in all the expansion cohorts, none of which had 
been enriched by a predictive biomarker (eg, MSI or PD-L1 status). Specifically, 5/27 (19%) 
of the evaluable NSCLC participants had confirmed RECIST responses, as did 4/29 (14%) 
cervical cancer, 4/23 (17%) endometrial cancer, and 1 sarcoma. ORR and median DoRs have 
not yet been established.   
2.4 
Dose Selection MGC018  
Using the Guidance-based approach (10), the maximum recommended starting dose 
(MRSD) for the proposed Phase 1/2 trial was determined as follows: The HNSTD in the 
GLP toxicology study in cynomolgus monkeys was determined to be 10 mg/kg 
administered by 1-hour IV infusion Q3W. The starting dose was defined as 1/6 the HNSTD 
(10 * 1/6 = 1.67 mg/kg) (10). The human equivalent of the starting dose, based on a body 
surface area conversion factor, was calculated as 0.5 mg/kg (i.e., 1.67 mg/kg * 0.32) (11). 
MGC018 has nearly identical single arm binding affinity to human and cynomolgus monkey 
B7-H3 (KD of 22.7 vs. 22.1 nM, respectively); thus, no further adjustment for affinity 
differential was undertaken. Because of high systemic exposure multiples, the 0.5 mg/kg dose 
was considered as the MRSD. Subsequent to the first dose level of 0.5 mg/kg, successive dose 
levels of 1.0, 2.0, 3.0, 4.0, and 5.0 mg/kg will be explored, guided by dose escalation rules 
outlined in Section 4.3. 
2.4.1 
Multiples of Monkey Exposure  
Allometric scaling, modeling, and simulations were used to estimate exposure data (Cmax and 
AUC) in the human after the first dose of 0.5 to 5.0 mg/kg and compared to the mean 
cumulative exposure for the HNSTD in the cynomolgus monkey (10 mg/kg). The data are 
presented in Table 1. First-dose predicted exposure data suggested adequate multiples of 
monkey exposure for the proposed dose range (0.5 to 5.0 mg/kg) to be investigated in 
humans. Using exposure parameters for ADC, SYD986, and total antibody (TAB, which 
includes conjugated and unconjugated antibody), the safety margins at the starting dose of 
0.5 mg/kg in humans were 23.0-, 22.6- and 20.7-fold, respectively, based on Cmax and 17.6-, 
17.1-, and 7.6-fold, respectively, and based on cumulative AUC as calculated using human 
(predicted) and monkey (actual) exposure parameters. Multiples of monkey exposure at the 
proposed top dose of 5.0 mg/kg were in the range of 0.8- to 4.3-fold. 
 
 
Confidential
Page
37
of
169

MGC018, MGA012
MacroGenics, Inc.
Clinical Trial Protocol: CP-MGC018-01
Amendment 6, 16 August 2021
Table 1
Predicted Exposure Parameters of ADC, SYD986, and TAB After 
the First Dose (at Steady-State) of MGC018 and Exposure 
Multiples in Humans     
Species
Analyte
Dose
(mg/kg)
Exposure Parameters a 
Multiples of Monkey
Exposure Based on
Cmax
(mcg/mL or 
pg/mL)
AUC
(h•mcg/mL or 
h•pg/mL)
Cmax
AUC
Human 
ADC b
0.5 
11.3 (11.5) 
671 (688) 
23.0 (22.6) 
17.6 (17.2) 
1.0 
22.7 (23.2) 
1554 (1626) 
11.5 (11.2) 
7.6 (7.3) 
2.0 
45.5 (46.9) 
3705 (4033) 
5.7 (5.5) 
3.2 (2.9) 
3.0 
68.3 (71.1) 
6219 (7038) 
3.8 (3.7) 
1.9 (1.7) 
4.0 
91.1 (96.0) 
9026 (10602) 
2.9 (2.7) 
1.3 (1.1) 
5.0 
113.9 (121.8) 
12090 (12847) 
2.3 (2.1) 
1.0 (0.9) 
SYD986 c
0.5 
13.7 (13.9) 
1473 (1453) 
22.6 (22.3) 
7.6 (7.7) 
1.0 
21.0 (21.3) 
2827 (2746) 
14.7 (14.5) 
4.0 (4.1) 
2.0 
34.0 (34.9) 
5523 (5234) 
9.1 (8.9) 
2.0 (2.1) 
3.0 
46.7 (48.4) 
8261 (7710) 
6.6 (6.4) 
1.4 (1.5) 
4.0 
59.2 62.3) 
11034 (10266) 
5.2 (5.0) 
1.0 (1.1) 
5.0 
71.8 (76.5) 
13819 (12959) 
4.3 (4.0) 
0.8 (0.9) 
TAB b
0.5 
11.3 (11.5) 
671 (689) 
20.7 (20.3) 
17.1 (16.7) 
1.0 
22.7(23.2) 
1555 (1627) 
10.3 (10.1) 
7.4 (7.1) 
2.0 
45.5 (46.9) 
3706 (4033) 
5.1 (5.0) 
3.1 (2.8) 
3.0 
68.3 (71.1) 
6220 (7039) 
3.4 (3.3) 
1.8 (1.6) 
4.0 
91.1 (96.0) 
9027 (10603) 
2.6 (2.4) 
1.3 (1.1) 
5.0 
113.9 (121.8) 
12091 (14694) 
2.1 (1.9) 
0.9 (0.8) 
Monkey d 
ADC 
10 
260.27 
11821 
NA 
NA 
SYD986 
10 
309.50 
11188 
NA 
NA 
TAB 
10 
233.85 
11475 
NA 
NA 
NOTE: Cmax in monkeys represents the mean maximum observed concentration after the third dose. AUC in monkeys 
represents AUC0-50 4 hr after the third dose (Report 1020-013-SR-TK).  
a
Values in parentheses are steady-state values after Q3W dosing in humans. 
b
Units for ADC and TAB Cmax and AUC are mcg/ml and h•mcg/mL, respectively. 
c
Units for SYD986 Cmax and AUC are pg/mL and h•pg/mL, respectively. 
d
The 10 mg/kg dose in the monkeys is the HNSTD 
Abbreviations: ADC = antibody drug conjugate; AUC = area under the serum concentration-time curve 
extrapolated to infinite time (first dose) or over a dosing interval of 3 weeks (steady-state); Cmax = maximum 
serum concentration; HNSTD = high non-severely toxic dose; NA = not applicable; Q3W = once every 
3 weeks; SR = scientific report; SYD986 = drug (also known as payload); TAB = total antibody; TK = 
toxicokinetic.
Exposure safety margins in the human at steady-state were also estimated for the Q3W dosing 
regimen using Cmax and AUC. In this estimation, predicted exposure parameters in a dosing 
interval of 3 weeks in humans at steady-state were compared to the actual cumulative 
exposure parameters in monkeys following administration of the HNSTD dose (10 mg/kg). 
These data in humans are summarized in Table 1. Consistent with first-dose data, predicted 
Confidential
Page
38
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
steady-state exposure data provided similar fold multiples of monkey exposure for the 
proposed dose range of 0.5 to 5.0 mg/kg MGC018 Q3W to be investigated in the FIH study. 
2.4.2 
Dose Selection: MGA012  
With a few exceptions, in general, the doses of therapeutic mAbs have been traditionally 
administered on a body size basis (mg/kg or mg/m2), with the supposition that this approach 
may reduce the intersubject variability in drug exposure compared with the flat (or fixed) 
dosing approach (72). However, recent studies recommend the use of flat dosing over body 
size–based dosing in clinical trials, as both approaches performed similarly in reducing 
variability in drug exposure, with flat dosing being superior for some mAbs (3, 72). 
Furthermore, flat dosing offers the advantages of convenience, compliance, cost-effectiveness, 
and safety due to less risk of dosing errors (3). Consistent with this recommendation, a current 
strategy for dosing PD-1 inhibitors is to use flat dosing (mg) in addition to or instead of body 
weight–based dosing (mg/kg) (25, 49, 50). Since the degree of the impact of body weight 
(BW on the PK of MGA012 in humans has not been delineated and since it is unknown 
whether body size–based dosing would influence intersubject variability in drug exposure, the 
study design in the current study will utilize a flat dosing scheme. This approach will allow 
for the evaluation of the PK/pharmacodynamic parameters corresponding to participants 
treated with a flat dose of MGA012. 
Aligned with the above premise, MGA012 dosing regimen of 375 mg IV given on a Q3W 
schedule as a 60-minute infusion will be investigated in this study. This dose was selected 
based on the safety profile, PK, and pharmacodynamics from the ongoing Phase 1, FIH dose 
escalation and expansion Study CP-MGA012-01. In the latter study, dose escalation was 
carried out from 1 mg/kg Q2W to 10 mg/kg Q2W or Q4W with no reported dose-limiting 
toxicities (DLTs) and, thus, no MTD was exceeded or defined. The safety profile of MGA012 
based on a total of 169 participants exposed to MGA012 in Study CP-MGA012-01 
demonstrated that the majority of AEs were mild or moderate (CTCAE Grade 1 or 2), with 
toxicities manageable by standard medical therapy. See Section 2.3.2.1 for a more detailed 
description of the safety profile from Study CP-MGA012-01. 
Modeling and simulations of the PK data of MGA012 were performed on 10 subjects treated 
with a 3 or 10 mg/kg Q4W schedule who had PK profiles characterized up to 672 hours. The 
mean BW of these subjects was 87.7 kg with a range from 50.0 to 109.8 kg. Based on the 
mean BW, the top dose of 10 mg/kg Q2W corresponds to a flat dose of 877 mg Q2W, and in a 
6-week interval (because of difference in the dosing intervals, Q2W versus Q3W for the 
10 mg/kg versus 375 mg, respectively), the total dose administered is 2631 mg (877 mg × 3). 
Over the same 6-week interval, the total dose administered for the 375 mg Q3W dose is 
750 mg (375 mg × 2). Thus, the 375 mg Q3W dose is approximately 3.5-fold lower than the 
top dose investigated in Study CP-MGA012-01 (10 mg/kg Q2W), providing adequate safety 
margins. However, concerns may still remain that the dose exposure may be higher for 
subjects with low BW given a 375 mg Q3W dose. For example, the BW based dose for a 
subject weighing 50 kg, receiving 375 mg Q3W dose, will be 7.5 mg/kg Q3W. The latter dose 
is approximately 2-fold lower than the top dose investigated in Study CP-MGA012-01 
(10 mg/kg Q2W), further supporting the adequacy of the safety margins. 
Confidential
Page
39
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Safety margins were also investigated based on MGA012 exposure data [Cmax, AUC(TAU), and 
lowest concentration (Ctrough)]. Modeling and simulations were performed, and the predicted 
first dose and steady-state exposure parameters for the flat dosing schedule (375 mg Q3W) 
were compared to the exposure parameters for the 10 mg/kg Q2W dose in Study 
CP-MGA012-01 (Table 2). In this analysis, comparison of AUC was made over a 6-week 
interval because of the differences in the frequency of administration. The mean or median 
first dose or steady-state Cmax and Ctrough values for the 375 mg Q3W dose were lower than the 
mean values for the 10 mg/kg Q2W dose. More importantly, the mean or median AUC(TAU) for 
the 375 mg Q3W dose was also lower than the mean value for the 10 mg/kg Q2W dose. 
Furthermore, there was minimal overlap in the 5th to 95th percentile intervals for the exposure 
parameters between the 375 mg Q3W and 10 mg/kg Q2W doses. These data suggest that the 
predicted exposure parameters in subjects treated with the flat dose of 375 mg Q3W was 
below the corresponding exposures for the MGA012 10 mg/kg Q2W, the clinically 
established safe and tolerable dose. Predicted exposures for the 375 mg Q3W dose were 2.3- 
to 4.1-fold lower than the exposures for the 10 mg/kg Q2W dose, suggesting adequate safety 
margins. 
Based on receptor occupancy (RO) data, the 375 mg Q3W doses (~ 4 mg/kg Q3W dose [based 
on a mean BW of 87.7 kg]) should result in maximum RO on CD4+ and CD8+ T cells. 
In summary, the totality of the safety, PK, and pharmacodynamic data support the 
investigation of MGA012 at the dose of 375 mg Q3W. 
Confidential
Page
40
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Table 2 
Predicted Exposure Parameters for the 375 mg Q3W Dose 
Compared to 10 mg/kg Q2W Dose and Multiples of Exposure          
Interval 
Exposure 
Parameter 
10 mg/kg Q2W (N=10) 
375 mg Q3W (N=10) 
Multiples of 
10 mg/kg 
Q2W 
Exposure 
 
 
GeoMean 
(%CV) 
Median 
(P05, P95) 
GeoMean 
(%CV) 
Median 
(P05, P95) 
First Dose 
Cmax 
(mcg/mL) 
207.0 
(17) 
198.5 
(164.8, 282.6) 
90.4 
(27) 
83.1 
(67.6, 144.3) 
2.3 
 
AUC(TAU) 
(mcg•h/mL) 
90801 
(21) 
92385 
(69225, 
129567) 
32896 
(36) 
30182 
(21526, 
68120) 
2.8 
 
Ctrough 
(mcg/mL) 
50.9 
(29) 
56.8 
(32.0, 69.2) 
15.9 
(51) 
16.6 
(6.9, 38.5) 
3.2 
Steady 
State 
Cmax 
(mcg/mL) 
330.8 
(24) 
343.1 
(223.8, 435.0) 
121.2 
(32) 
108.5 
87.2, 229.9) 
2.7 
 
AUC(TAU) 
(mcg•h/mL) 
184905 
(33) 
196776 
(103326, 
266811) 
53806 
(45) 
49922 
(32196, 
133326) 
3.4 
 
Ctrough 
(mcg/mL) 
118.5 
(50) 
135.4 
(40.7, 194.3) 
28.6 
(71) 
37.3 
(7.6, 86.1) 
4.1 
Abbreviations: AUC(TAU) = area under the serum concentration-time curve in a dosing interval; Cmax = maximum observed 
serum concentration; Ctrough = trough serum concentration (concentration at the end of a dosing interval); CV = coefficient 
of variation; GeoMean = geometric mean; N = number of subjects; P05 = 5th percentile; P95 = 95th percentile; Q2W = 
once every 2 weeks: Q3W = once every 3 weeks. 
NOTE: For the 10 mg/kg Q2W and 375 mg Q3W doses, AUC(TAU) was multiplied by 3 and 2, respectively, to report it 
over a 6-week interval. 
 
2.5 
MGC018 and MGA012 Combination Dose Selection  
In the combination portion of the study (Module B, dose escalation), the initial dose for 
MGC018 will begin at 0.5 mg/kg or the MTD-2 (the dose level that is 2 dose levels below the 
MTD defined for MGC018 monotherapy), whichever is higher, and will also be administered 
as a 60-minute IV infusion every 3 weeks. Successive escalation to doses levels will range 
from 1.0 to 5.0 mg/kg may be performed as tolerated up to a maximum of 5 mg/kg and will be 
guided by decision rules outlined in Section 4.3. MGA012 will be administered at a flat dose 
of 375 mg as a 60-minute IV infusion Q3W. On days when the MGC018 and MGA012 are to 
be administered on the same day (Module B only), MGA012 should be given first, followed 
immediately thereafter by MGC018. 
Confidential
Page
41
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
3 
STUDY PURPOSE AND OBJECTIVES  
3.1 
Primary Objective  
The primary objective of this study is as follows: 
•
To characterize the safety, tolerability, DLTs, and MTD or maximum administered 
dose (MAD) (if no MTD is defined) for MGC018 administered as monotherapy or in 
combination with MGA012, each administered intravenously (IV), in participants who 
have relapsed/refractory, unresectable locally advanced or metastatic solid tumors. 
 
3.2 
Secondary Objectives  
The secondary objectives of this study are as follows: 
•
To characterize the PK and immunogenicity of MGC018 alone and in combination 
with MGA012. 
•
To describe antitumor activity of MGC018 administered as monotherapy or in 
combination with MGA012 in participants with advanced solid tumors using Response 
Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) (Appendix 5). 
•
To describe the radiographic progression free survival (rPFS) in mCRPC. 
•
To describe the prostate-specific antigen (PSA) response rate and best PSA percent 
change in mCRPC. 
 
3.3 
Exploratory Objectives  
Exploratory objectives are as follows: 
•
To explore patient-reported outcome (PRO) using the Brief Pain Inventory-Short Form 
(BPI-sf) in Cohort Expansion (Module A). 
•
To explore effect of MGC018 on symptomatic skeletal events (SSEs) in participants 
with mCRPC in Cohort Expansion (Module A). 
•
To explore the relationships between PK, pharmacodynamics of MGC018 alone and in 
combination with MGA012, and antitumor activity (Modules A and B). 
•
To explore the impact of MGC018 alone and in combination with MGA012 on 
progression-free survival (PFS) and overall survival (OS) in participants with 
advanced solid tumors (Modules A and B).  
•
To determine programmed death–ligand 1 (PD-L1) expression via 
immunohistochemistry (IHC) staining of formalin-fixed, paraffin-embedded tumor 
biopsy specimens on archival tissue (Module B) and on optional paired tumor biopsy 
specimens (pre/on-treatment post Cycle 1 biopsies) in Cohort Expansion (Modules A 
and B). 
Confidential
Page
42
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
•
To explore the relationship between B7-H3 expression (H-score) and clinical response 
using a qualified B7-H3 IHC assay (Modules A and B). 
•
To assess whether MGC018 in combination with MGA012 induces immunological 
cell death (ICD) within optional paired tumor biopsy specimens (pre/on-treatment post 
cycle 1 biopsies) from participants in Cohort Expansion (Module B) as assessed by 
IHC. 
•
To assess whether MGC018 in combination with MGA012 modulates immune cell 
subset phenotype (including PD-1 expression) (Module B). 
•
To explore whether MGC018 modulates T cell response within optional paired tumor 
biopsy specimens (pre/on-treatment post Cycle 1 biopsies) from participants in Cohort 
Expansion (Modules A and B) as assessed by immunohistochemistry and/or TCR 
spectratyping.  
•
To assess whether MGC018 alone or in combination with MGA012 induces an 
interferon gamma (IFNγ) gene expression signature in the optional paired tumor 
biopsy specimens (pre/on-treatment post Cycle 1 biopsies) from participants in Cohort 
Expansion (Modules A and B) via transcript profiling. 
•
To explore serum biomarkers including, but not limited to, IFNγ protein signature, in 
the peripheral circulation within the Cohort Expansion only (Modules A and B).  
•
To assess whether MGC018 modulates serum cytokine levels in Dose Escalation and 
Cohort Expansion Phases (Modules A and B). 
•
To determine MGA012 receptor occupancy on immune cells in participants treated 
with the combination of MGC018 and MGA012 (Module B only). 
The results of the exploratory objectives may not be included in the Clinical Study Report or 
database lock unless they represent meaningful findings.  
 
Confidential
Page
43
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
4 
STUDY DESIGN  
4.1 
Overall Study Design and Plan  
This study is a Phase 1/2, FIH, open-label, dose-escalation and cohort expansion study 
designed to characterize the safety, tolerability, PK, pharmacodynamics, immunogenicity, and 
preliminary antitumor activity of MGC018 administered by IV infusion, alone (Module A) 
and in combination with MGA012 (Module B) (see Figure 5); Module B will commence only 
after the MTD or MAD of MGC018 monotherapy (Module A) has been defined. Each module 
of the study consists of a Dose Escalation Phase to determine the MTD (or MAD, if no MTD 
is defined), followed by a Cohort Expansion Phase to further define the safety and initial 
antitumor activity of the respective monotherapy (Module A) and combination (Module B) 
regimens, using doses defined in the Dose Escalation Phase of each respective module. 
Module B will commence only upon sponsor notification to all the study investigators/ 
institutions.  
Participants with unresectable, relapsed or refractory, locally advanced or metastatic solid 
tumors of any histology will be enrolled in the Dose Escalation Phase of each module. The 
Module A Cohort Expansion Phase will be limited to mCRPC, NSCLC, TNBC, SCCHN, and 
melanoma. The Module B Cohort Expansion Phase will be limited to specific cohorts of 
participants with SCCHN, mCRPC, and a cohort to be determined (TBD) at a later date, 
guided by evolving experience from the Dose Escalation Phase of the study; see 
Section 4.1.2.  
Confidential
Page
44
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Figure 5 
MGC018 Overall Study Design  
 
Note: MTD-2 = the dose level that is 2 dose levels below the MTD defined for MGC018 monotherapy. 
   MTD-1 = the dose level that is 1 dose level below the MTD defined for MGC018 monotherapy. 
Abbreviations: mCRPC = metastatic castrate-resistant prostate carcinoma; MTD = maximum tolerated 
dose; NSCLC = non-small cell lung cancer; Q3W = every 3 weeks; RP2D = recommended phase II dose; 
SCCHN = squamous cell carcinoma of the head and neck; TBD = to be determined; TNBC = triple 
negative breast cancer. 
MGC018 will be administered alone or in combination with MGA012 (also known as 
INCMGA00012), as illustrated below in Figure 6 and Figure 7, respectively. For Module A, 
MGC018 alone will be administered IV over 60 minutes on Days 1 and 22 of Cycle 1 and 
every subsequent 42-day cycle thereafter. For Module B, MGC018 alone will be administered 
IV over 60 minutes on Day 1 of Cycle 1 and with MGA012 on Day 22 of Cycle 1. Both 
MGC018 and MGA012 will be administered on Days 1 and 22 of every subsequent 42-day 
cycle thereafter, at the assigned dose for each cohort. Similar to MGC018, MGA012 will be 
administered IV over 60 minutes. On days when the MGC018 and MGA012 are to be 
administered on the same day (Module B only), MGA012 should be given first, followed 
immediately thereafter by MGC018. 
odule A: MGCO 18Monoth erapy 
0 G;J[ m~: .. ] 
- [ ~:•:~ ) 
... [F===i===~ 
NSCLC 
N= 16 
TNBC 
N= 16 
SCCHN 
] 
N= 16 
Confidential
Page
45
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Figure 6 
MGC018 Monotherapy Dosing Schedule (Q3W) (Module A)  
 
Note:  Imaging for tumor assessments will be every 9 weeks (63 days) during the Cohort Expansion Phase 
for Module A.  
Figure 7 
MGC018 and MGA012 Combination Dosing Schedule (Q3W) 
(Module B)  
 
For both the Dose Escalation Phase of Module A and Module B and the Cohort Expansion 
Phase of Module B, tumor assessments will occur at Day 42 of each cycle, for the first 
4 cycles, and every other cycle thereafter. For the Cohort Expansion Phase of Module A, the 
tumor assessments will occur every 9 weeks (63 days). For Module A, the DLT evaluation 
period will be 21 days in duration; for Module B, the DLT evaluation period will be 42 days in 
duration (see Section 4.1.1 below for more details). Participants who complete a given cycle, 
remain clinically stable, do not experience a DLT or other unacceptable toxicity, and do not 
otherwise meet the criteria for permanent treatment discontinuation may be eligible for 
additional treatment with MGC018 alone or in combination with MGA012 for up to a total of 
18 cycles (approximately 2 years). For participants with a dose delay > 21 days, the total 
number of cycles may be < 18 cycles and the time on MGC018 will be no more than 2 years. 
Following the last dose of study drug, all participants in Module A and Module B Cohort 
Expansion Phases will be followed every 3 months (90 days) for survival during a 2-year 
Survival Follow-up Period, until criteria are met for study discontinuation. Participants in 
Module A Dose Escalation Phase will be followed similarly for survival status until approval 
of Amendment 3, at which point they will be discontinued from follow up. 
MODULE A 
JUli.toR 
ASSESS: 
MGC01'8 . 
OOSE: 
TUMOR 
ASSESS; 
M:GA01I2 
DOSEg 
DA'I' 
1 
MGCIUS ,.
, 
OOSEl 
DAY 
1 
• 
CYCLE 1 
DAY 
22 
CYCLE 1 
DAY 
22 
[lAY DAY 
4.2+/·3 1 
DAY DAY 
42+/-3 1 
CYCLf2 AND BEYOND 
DAY 
2.2 
CYCLi:2 AND BEYOND 
DAY 
22 
DAY 
42.+l-3 
DAY 
42+/-3 
It 
Confidential
Page
46
of
169

MGC018, MGA012
MacroGenics, Inc.
Clinical Trial Protocol: CP-MGC018-01
Amendment 6, 16 August 2021
4.1.1 
Dose Escalation Phase 
The goal of the Dose Escalation Phase of this study is to initially characterize the safety and 
tolerability of MGC018 administered alone or in combination with MGA012 and, more 
specifically, to define the MTD of these respective monotherapy and combination regimens. If 
no MTD is defined during the dose escalation of MGC018 monotherapy (Module A) after 
escalation to the maximum protocol-specified dose, then that dose level will be designated as 
the MAD for MGC018 monotherapy. Similarly, if no MTD is defined during dose escalation 
of the combination of MGC018 and MGA012 (Module B), after escalation to the maximum 
protocol-specified dose, then that dose level will be designated as the MAD for MGC018 and 
MGA012 combination therapy.
For the purposes of guiding decisions regarding dose escalation, the DLT Evaluation Period 
for Module A (monotherapy) will be 21 days following administration of the first dose of 
MGC018. For Module B (combination therapy), the DLT evaluation period will be 42 days in 
duration.
Dose escalation will follow a conventional 3+3+3 design: successive cohorts of 3 to 
9 participants each will be evaluated in sequential escalating doses of MGC018 administered 
alone (Module A) or in combination with MGA012 (Module B) as shown below (Table 3 and 
Table 4).
Sentinel dosing will be used for the first 2 dose levels.  The first administration of MGC018 in 
participants in the first 2 dose levels in Module A will be staggered by at least 48 hours.
In Module B, MGA012 will be administered at a dose of 375 mg (flat dose) Q3W, beginning 
on Day 22 of Cycle 1, and continuing on Days 1 and 22 of every cycle thereafter.
Participants who require dose delays greater than 21 days secondary to AEs considered 
unrelated to study treatment or any other cause unrelated to study treatment are considered 
unevaluable for safety and toxicity during the DLT evaluation period and will be replaced.
Intermediate dose levels may be explored based on review of the cumulative safety data and 
upon agreement between the investigators and the sponsor.
Table 3
MGC018 Dose Levels: Module A Dose Escalation Phase 
Cohort
MGC018 Dose (Q3W)
Cohort -1 
0.3 mg/kg 
Cohort 1 
0.5 mg/kg 
Cohort 2 
1.0 mg/kg 
Cohort 3 
2.0 mg/kg 
Cohort 4 
3.0 mg/kg 
Cohort 5 
4.0 mg/kg 
Cohort 6 
5.0 mg/kg 
Confidential
Page
47
of
169

MGC018, MGA012
MacroGenics, Inc.
Clinical Trial Protocol: CP-MGC018-01
Amendment 6, 16 August 2021
For Module A Dose Escalation, if the dose level in Cohort 1 exceeds the MTD, a de-escalation 
to Cohort -1 dose levels will be employed as summarized in Table 3.
Table 4
MGC018 and MGA012 Dose Levels: Module B Dose Escalation 
Phase     
Cohort
MGC018 Dose (Q3W)
MGA012 (Q3W)
Cohort -1 
MTD-3 (TBD) 
250 mg (TBD) 
Cohort 1 
MTD -2 
375 mg 
Cohort 2 
MTD -1 
375 mg 
Cohort 3 
MTD 
375 mg 
Note: MTD -2= the dose level that is 2 dose levels below the MTD defined for MGC018 monotherapy. 
   MTD -1= the dose level that is 1 dose level below the MTD defined for MGC018 monotherapy. 
Abbreviations: MTD = maximum tolerated dose; Q3W = every 3 weeks; TBD = to be determined. 
For Module B Dose Escalation Phase, if the dose level in Cohort 1 exceeds the MTD, a 
de-escalation to Cohort -1 dose levels will be employed as indicated in Table 4. Depending 
on the nature and timing of the observed toxicity, the MGC018 dose may be de-escalated to 
MTD-3, MGA012 may be decreased to 250 mg, or doses of both drugs may be adjusted to 
other levels at or below the Cohort 1 dose levels, as deemed most appropriate based on review 
of the cumulative data by the sponsor in consultation with the study investigators.
4.1.2 
Cohort Expansion Phase 
During the Cohort Expansion Phase, Module A, participants with relapsed/refractory, 
unresectable locally advanced or metastatic mCRPC, NSCLC, TNBC, SCCHN, and 
melanoma will receive MGC018 alone at the recommended phase II dose (RP2D) based on 
safety, PK, and antitumor activity from the Dose Escalation Phase of the study. The RP2D for 
the Cohort Expansion Phase of Module A was determined based on the review of the safety, 
tolerability, and PK data. Participants in Module A Cohort Expansion Phase will receive 
3 mg/kg every 3 weeks. The MGC018 dose will be capped for participants with a body weight 
≥ 100 kg.
During the Cohort Expansion Phase, Module B, cohorts of participants with unresectable, 
locally advanced or metastatic SCCHN or mCRPC, and a cohort of participants with tumor 
type TBD, based on the prior experience with Module A and Module B (including any 
evidence of emerging antitumor activity in a given tumor type) will be treated with MGC018 
in combination with MGA012 at the MTD/MAD dose based on the safety, PK and antitumor 
activity from the Dose Escalation Phase of the study for Module B. See Table 5 for an 
overview of the Expansion Cohort.
Confidential
Page
48
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Table 5 
Expansion Cohorts                    
Expansion Cohort per Module 
Tumor Type 
Planned Enrollment 
Module A 
mCRPC 
Up to 16 
Module A 
NSCLC 
Up to 16 
Module A 
TNBC 
Up to 16 
Module A 
SCCHN 
Up to 16 
Module A 
Melanoma 
Up to 16 
Module B 
SCCHN 
Up to 16 
Module B 
mCRPC 
Up to 16 
Module B 
Tumor Type TBD 
Up to 16 
Abbreviations: mCRPC = metastatic castrate-resistant prostate carcinoma; NSCLC = non-small cell lung cancer; SCCHN = 
squamous cell cancer of the head and neck; TBD = to be determined; TNBC = triple negative breast cancer. 
 
4.2 
Dose Limiting Toxicity  
For the purposes of guiding study decisions regarding dose escalation, DLTs will be based on 
study drug-related AEs or laboratory abnormalities that occur up to Study Day 21 of Cycle 1 
in the Dose Escalation Phase only for Module A and Study Day 42 of Cycle 1 in the Dose 
Escalation Phase only for Module B. The severity of AEs will be graded according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 
(NCI CTCAE v4.03). Dose-limiting toxicities will be defined separately for hematologic, 
non-hematologic, and hepatic non-hematologic events. 
In general, for participants who experience toxicity that may meet the criteria for a DLT, 
subsequent administration of the study drugs should be held pending management and/or 
resolution of the event and assessment of attribution to the study drug. Criteria for 
discontinuation of therapy are outlined in Section 5.4. 
4.2.1 
Hematologic Dose Limiting Toxicity  
Hematologic DLT is defined as follows: 
•
Grade 4 neutropenia lasting > 7 days 
•
≥ Grade 3 febrile neutropenia lasting > 48 hours or any ≥ Grade 3 febrile neutropenia 
associated with hemodynamic compromise or objective evidence of infection 
•
Grade 4 thrombocytopenia, irrespective of duration 
•
Grade 3 thrombocytopenia associated with clinically significant bleeding 
•
≥ Grade 3 hemolysis 
 
Confidential
Page
49
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
The following events will be specifically excluded from the definition of hematologic DLT: 
•
≥ Grade 3 lymphopenia 
•
Grade 3 anemia that is not associated with other clinically significant complications 
 
4.2.2 
Non-hematologic Dose Limiting Toxicity  
Non-hematologic DLT is defined as any ≥ Grade 3 non-hematologic event  
•
Skin toxicity that meets the definition of Stevens Johnson syndrome (SJS) or toxic 
epidermal necrolysis (TEN) regardless of duration will be considered a dose limiting 
toxicity. SJS and TEN are to be reported immediately to the sponsor as an Immediately 
Reportable Events (IRE) and Adverse Events of Special Interest (AESI) per 
Section 12.2.2. 
The following events will be specifically excluded from the definition of non-hematologic 
DLT: 
•
Grade 3 electrolyte abnormality that lasts < 72 hours, is not otherwise associated with 
clinical complications, and responds to medical intervention 
•
Grade 3 fever that lasts < 72 hours and is not associated with hemodynamic 
compromise 
•
Grade 3 nausea or vomiting that lasts < 72 hours and responds to medical intervention 
•
Grade 3 or greater amylase and/or lipase elevation that is not associated with clinical 
or radiographic evidence of pancreatitis requiring hospitalization 
•
Grade 3 gastrointestinal AEs of diarrhea, constipation, abdominal pain, cramping, 
dyspepsia, or dysphagia that resolves to ≤ Grade 1 or baseline within 72 hours with 
maximal supportive care 
•
Grade 3 fatigue that lasts < 72 hours 
•
Grade 3 infusion-related reaction (IRR) or cytokine release syndrome (CRS) that lasts 
< 12 hours and responds to medical intervention 
•
Grade 3 endocrinopathy that is adequately controlled with hormone supplementation 
•
Grade 3 skin toxicity that resolves to ≤ Grade 1 or baseline within 72 hours with 
maximal supportive care 
•
Grade 3 dry eye or Grade 3 photophobia that lasts ≤ to 72 hours 
•
Grade 3 inflammatory reaction (e.g., with associated pain, swelling) attributed to a 
local antitumor response (e.g., inflammatory reaction at sites of metastatic disease, 
lymph nodes, etc.) that resolves to ≤ Grade 1 or baseline within 5 days 
 
Confidential
Page
50
of
169

MGC018, MGA012
MacroGenics, Inc.
Clinical Trial Protocol: CP-MGC018-01
Amendment 6, 16 August 2021
Note: The following Grade 2 non-hematologic AEs may also be considered as DLTs:
•
Grade 2 AEs that are prolonged inordinately, based upon the medical judgment of the 
investigator, and/or lead to permanent discontinuation of study drugs due to participant 
intolerance
•
Any hepatic laboratory abnormalities meeting all 3 Hy’s law criteria (described within 
Section 4.2.3)
•
Eye pain or reduction in visual acuity that does not respond to topical ophthalmic 
therapy and does not improve to Grade 1 within 14 days of the initiation of topical 
ophthalmic therapy, or that requires systemic treatment
4.2.3 
Hepatic Non-hematologic Dose Limiting Toxicity 
Hepatic Non-Hematologic DLT will be defined as follows:
•
Any elevation of one or more transaminases > 8 × the institutional reference
laboratory upper limit of normal (ULN) irrespective of duration
•
Any Grade 3 elevation of one or more transaminases > 5.0 – 8.0 × ULN that does not
resolve to Grade 2 (i.e., > 3.0 – 5.0 × ULN) within 7 days and Grade 1
(i.e., > ULN - 3.0 × ULN) within 14 days. In addition, steroids must be tapered to
≤ 10 mg of prednisone or equivalent per day, by Day 14. Please see Section 7.2.2.1 for
further management guidelines.
•
A Grade 3 elevation of total bilirubin that is > 5 × the ULN irrespective of duration.
•
Any Grade 3 elevation of total bilirubin > 3.0 – 5.0 × ULN that does not resolve to
Grade 2 (i.e., > 1.5 – 3.0 × ULN) within 7 days and Grade 1 (i.e., > ULN –
1.5 × ULN) within 14 days. In addition, steroids must be tapered to ≤ 10 mg of
prednisone or equivalent per day, by Day 14. Please see Section 7.2.2.2 for further
management guidelines.
•
Any event meeting the criteria for Hy’s law as follows (all 3 features):
o
Aspartate aminotransferase (AST) and/or alanine aminotransferase
(ALT) > 3 × ULN
o
Concurrent elevation of total bilirubin > 2 × ULN without initial
evidence of cholestasis
o
No alternative etiology can be identified
4.3 
Dose Escalation Rules 
The Dose Escalation Phase of this trial will proceed using a conventional 3 + 3 + 3 approach. 
Confidential
Page
51
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
If 0 of the first 3 participants treated at a given dose level experience a drug-related DLT 
during the DLT evaluation period, the dose will be escalated, and 3 participants will be 
enrolled and treated at the next higher dose level (up to the planned highest dose level). 
If 1 of the first 3 participants treated at a given dose level experiences a drug-related DLT, 
then 3 additional participants will be enrolled at that dose level (thus making a total of 
6 participants in this cohort) to further assess the safety of MGC018 alone (Module A) or in 
combination with MGA012 (Module B). 
•
If ≥ 2 of these 3 additional participants (i.e., ≥ 3 of the 6 participants enrolled in the 
cohort) experience a DLT, it will be concluded that the MTD has been exceeded, and 
3 participants will be enrolled and treated at the next lower dose level. 
•
If 1 of these 3 additional participants experiences a drug-related DLT, then another 
3 additional participants (for a total of 9 participants in the cohort, 3 + 3 + 3) will be 
enrolled and treated at that dose level to further characterize the safety of MGC018 
alone (Module A) or in combination with MGA012 (Module B). 
•
If 0 of the 3 additional participants experiences a DLT, then the dose will be escalated, 
and 3 participants will be enrolled at the next higher dose level. 
 
If ≥ 2 participants out of the first 3 participants treated at a given dose level, or ≥ 3 of 
6 participants treated at a given dose level, or ≥ 3 out of 9 participants treated at a given dose 
level experience a drug-related DLT, then it will be concluded that the MTD for MGC018 
alone (Module A) or in combination with MGA012 (Module B) has been exceeded at that 
dose level, and all subsequent participants will be treated at the next lower dose level. 
If ≥ 2 participants out of the first 6 participants treated at a given dose level experience the 
same drug-related DLT, then the enrollment in that cohort will stop, and it will be concluded 
that the MTD for MGC018 alone (Module A) or in combination with MGA012 (Module B) 
has been exceeded and all subsequent participants will be treated at the next lower dose level. 
In categorizing DLTs, all related MedDRA Preferred Terms will be used to determine whether 
the same DLT has occurred in a given cohort.   
If ≥ 2 participants out of the first 6 participants treated at a given dose level experience a 
Grade 4 DLT, then the enrollment in that cohort will stop, and it will be concluded that the 
MTD for MGC018 alone (Module A) or in combination with MGA012 (Module B) has been 
exceeded and all subsequent participants will be treated at the next lower dose level. 
For participants being treated at a dose level subsequently determined to exceed the MTD for 
a given cohort of the study, the dose of MGC018 alone (Module A) or in combination with 
MGA012 (Module B) will be reduced to the next lower dose level as summarized in Table 3 
and Table 4. Following these rules for dose escalation, the MTD/MAD will be the highest 
dose administered during the Dose Escalation Phase of the study at which the incidence of 
DLT is < 33%. 
Confidential
Page
52
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Dose escalation to the next dose level is permitted only after the participants enrolled in the 
current dose cohort have completed the DLT evaluation period and the safety data have been 
reviewed by the sponsor medical monitor, Independent Safety Monitor, and the investigators 
participating in the study. Evaluation of safety data from each cohort will include an 
assessment of the proportion of participants who receive planned doses, and the percentage of 
participants that require dose reductions or dose discontinuations for toxicity. The sponsor 
medical monitor, Independent Safety Monitor and investigators will consider all available data 
from participants both during and beyond the DLT evaluation period when making dose 
escalation decisions and in the determination of the recommended phase 2 dose to be 
evaluated in expansion cohorts. In particular, if a Grade 4 febrile neutropenia has been 
observed, the sponsor will review and evaluate the safety database for other events of any 
grade febrile neutropenia prior to making a decision to dose escalate. 
At the discretion of the sponsor, dose escalation may be stopped before an MTD is reached. In 
this case, the MAD may be chosen based on an assessment of PK, pharmacodynamics, 
biomarker, safety, and response data. An MTD does not have to be reached to expand a dose 
cohort if the available data demonstrate that a lower dose level may provide antitumor activity 
while minimizing potential risk. In addition, if an MTD is established, the sponsor may decide 
to open the Cohort Expansion Phase at a dose lower than the MTD, based on the totality of the 
PK, pharmacodynamic, biomarker, safety, and response data. 
At the discretion of the sponsor, any escalation cohort at a dose level not exceeding the MTD 
may be expanded to a maximum of 15 participants for further evaluation of safety, PK, and 
antitumor activity. 
When an MTD or MAD is established, any participant remaining on treatment at a lower dose 
level will be given the option to escalate to the MTD/MAD dose. 
4.4 
Guidelines for Dose Modification  
Dose modifications are allowed for toxicity related to study drug according to the guidelines 
in Section 7. 
Modification of dose or schedule may be necessitated by the observation of suspected study 
drug-related AEs. The investigator should use their best medical judgment to safeguard the 
participant’s welfare.  
In general, observation of any study drug-related  Grade 3 AE by CTCAE v4.03 should 
result in suspension of all study drug administration pending evaluation. Reinstitution of 
assigned study drug administration should be delayed until the study drug-related AE has 
resolved to  Grade 1 or baseline for that participant (whichever is greater).  
If the study drug-related  Grade 3 AE fails to resolve to  Grade 1 or baseline (whichever is 
greater), causing the participant to miss > 2 scheduled doses of study drug, the investigator 
should consider whether the participant should be withdrawn from further study drug 
administration unless there are extenuating circumstances and the investigator reviews the 
Confidential
Page
53
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
situation with and receives permission to continue study drug from the medical monitor (refer 
to Section 5.4). 
If the participant experiences a second (either similar or different) study drug-related 
 Grade 3 AE after reinstituting assigned study drugs for a first occurrence of a study 
drug-related  Grade 3 AE, study drug administration should be delayed. Reinstitution of 
study drug administration should be delayed until the AE has resolved to  Grade 1 or 
baseline (from Cycle 1 Day 1, pre-dose) for that participant (whichever is greater), with 
exceptions noted under Section 7. If resolution occurs and the participant misses ≤ 2 
scheduled dose(s), the investigator upon consultation with the medical monitor may reinstitute 
study drug.  
If the second  Grade 3 study drug-related AE fails to resolve to  Grade 1 or baseline 
causing the participant to miss ≥ 2 scheduled doses of study drug, the investigator should 
consider whether the participant should be withdrawn from further study drug administration 
(refer to Section 5.4). 
If a third possibly, probably, or definitely related  Grade 3 AE occurs, the investigator in 
consultation with the sponsor’s medical monitor should consider whether the participant 
should be withdrawn from further study drug administration. 
4.4.1 
Guidelines for Other Study Drug Related Toxicities  
For all other study drug-related toxicity not listed in Section 7 dose modifications of study 
drug may be allowed for participants (see Table 6 for general guidelines). The investigator 
should contact the sponsor to discuss the appropriate dose of study drug based on the safety 
profile and evidence of antitumor activity. Sponsor approval must be obtained in advance of 
the dose modification of study drug. 
For study drug-related ≥ Grade 3 toxicities except fatigue, local reaction, fluid retention, 
anemia, laboratory abnormalities without clinical significance, and toxicities without serious 
morbidity to participants, study drug should be held up to 21 days from the planned date of 
reinfusion until resolution to ≤ Grade 1 or baseline (from Cycle 1 Day 1, pre-dose) for that 
participant (whichever is greater), then reinstituted, if medically appropriate. Any measures 
such as frozen gloves or socks or scalp cooling cap to prevent cutaneous toxicity or alopecia 
are left to the investigator’s judgment. 
Confidential
Page
54
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Table 6 
Guidelines for Other Study Drug Related Toxicities  
Adverse Event 
Severity Grade 
MGC018 Management Guidelines 
Medical Care Guidelines 
1 
No dose modification necessary. Consider 
delaying dose of MGC018 until < Grade 1 
or baseline (from Cycle 1 Day 1, pre-dose) 
for that participant (whichever is greater). 
Consider dose reduction of one dose level. 
Consider clinical evaluation of the 
participant once weekly or every other 
week to monitor. Obtain clinical laboratory 
evaluations as indicated e.g., weekly CBC, 
chemistry. 
2 
Consider delaying dose of MGC018 until 
≤ Grade 1 or baseline (from Cycle 1 Day 1, 
pre-dose) for that participant (whichever is 
greater). Consider dose reduction of one 
dose level. 
Consider clinical evaluation of the 
participant once weekly or every other 
week to monitor. Obtain clinical laboratory 
evaluations as indicated e.g., weekly CBC, 
chemistry. 
3 
Delay dose of MGC018 until ≤ Grade 1 or 
baseline (from Cycle 1 Day 1, pre-dose) for 
that participant (whichever is greater). 
Consider dose reduction of one or two dose 
levels. If the same event ≥ Grade 3 recurs 
consider study drug discontinuation. 
Consider hospitalization. Consider clinical 
evaluation of the participant ≥1 time per 
week or every week to monitor. Perform 
imaging and/or other evaluations to 
determine the etiology of the event. Obtain 
clinical laboratory evaluations as indicated 
e.g., weekly CBC, chemistry. 
4 
Delay dose of MGC018 until ≤ Grade 1 or 
baseline (from Cycle 1 Day 1, pre-dose) for 
that participant (whichever is greater). 
Consider dose reduction of one or two dose 
levels. Consider study drug 
discontinuation. If the same event 
≥ Grade 3 recurs consider study drug 
discontinuation. 
General guidance includes hospitalization 
and emergent medical care. Perform 
imaging and/or other evaluations to 
determine the etiology of the event. 
Consider clinical evaluation of the 
participant ≥ 1 time per week or every 
week to monitor. Obtain clinical laboratory 
evaluations as indicated e.g., weekly CBC, 
chemistry. 
Abbreviations: CBC: complete blood count. 
 
4.4.2 
Dose Delays  
Participants who experience toxicity should have study drug held pending assessment, 
management, and resolution of the toxicity. Participants in whom the toxicity is assessed to be 
unrelated to study drug or for whom the toxicity does not meet the criteria for discontinuation, 
may reinstitute study drug as per guidelines outlined in Section 4.4.1 and Section 7. 
Reinstitution of study drug shall be conducted as follows: 
•
For participants in whom the toxicity is assessed to be related to study drug, dose 
delays of up to 21 days are allowed.  
•
For participants in whom the toxicity is unrelated to study drug, dose delays of up to 
21 days are allowed. Dose delays up to 4 weeks are allowed for participants who 
require palliative radiotherapy only in consultation with the medical monitor (see 
Section 8.1.1).  
Confidential
Page
55
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
•
The medical monitor must be consulted prior to the restart of study drug after a dose 
delay. 
 
A participant with a dose delay > 21 days due to an AE, but who has otherwise experienced 
clinical benefit, in the judgement of the investigator in consultation with medical monitor, 
may continue to receive study drug. 
4.4.2.1 
COVID-19/SARS-CoV-2 Infection or Vaccination  
The following guidelines apply to participants with confirmed (positive by regulatory 
authority approved/authorized test) or presumed (test pending/clinical suspicion) coronavirus 
disease 2019 (COVID-19)/severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
infection: 
•
For participants 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, participants 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 cases of COVID-19/ 
SARS-CoV-2 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. Participants may have study drug held to allow for COVID-19 vaccination; 
delays of up to 5 days are allowed. 
4.5 
Study Duration  
It is expected that enrollment of the Dose Escalation Phase of the study (including Module A 
and Module B) will occur over approximately 18 months and that enrollment of the cohort 
expansion portions of the study will take approximately 12 months from the time of initiation 
of the Cohort Expansion Phase for each Module A and Module B. 
The total time for conduct of the trial is expected to be approximately 78 months (which 
includes 2 years of survival follow-up). These estimates of the timing for study conduct may 
vary from that observed in the actual conduct of the trial. 
Confidential
Page
56
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
4.5.1 
Participant Accrual  
The maximum number of participants to be enrolled in this study will be approximately 
182 participants. This number of participants does not take into account participants who may 
be replaced or the possibility of expanding the mCRPC cohort with an additional 
24 participants at the discretion of the sponsor. 
The number of participants enrolled in the Dose Escalation Phase cannot be precisely 
determined in advance and could range from 6 up to 54 participants depending on results in 
the course of the trial and the number of dose levels explored. This participant number does 
not take into account replacement of non-evaluable participants or the possibility of 
expanding an individual escalation cohort up to 15 participants to allow for further evaluation 
of safety, PK, and antitumor activity of the study drugs at the dose level in that cohort. 
The Cohort Expansion Phase of the study will enroll up to 128 participants. Module A Cohort 
Expansion Phase will enroll up to 16 participants into each of 5 cohorts (mCRPC, NSCLC, 
TNBC, SCCHN, and melanoma) treated with MGC018 monotherapy. Module B will enroll up 
to 16 participants into each of 3 cohorts treated with the combination of MGC018 and 
MGA012: participants with unresectable, locally advanced or metastatic SCCHN, mCRPC, 
and participants with a tumor type TBD at a later date. During the Cohort Expansion Phase of 
the study, participants who withdraw before completing the first tumor assessment for a 
reason other than progression of disease may be considered unevaluable for response. In these 
cases, additional participants may be enrolled. In addition, up to 4 participants may be added 
per cohort. 
4.5.2 
Definition of End of Study  
The end of study will occur after the last participant has met off-study criteria and the data 
collection process is completed (time of study database lock). 
End of study for each participant is defined as follows: participant is lost to follow-up (LTFU) 
(Section 5.3) or discontinues from the study due to any reason listed in Section 5.5. Each 
participant’s end of study status will be recorded in the End of Study CRF page. 
4.6 
Appropriateness of Measurements  
Routine laboratory evaluations including hematology, chemistry, coagulation, endocrine 
tumor markers, and urinalysis will be carried out in local institutional laboratories. Additional 
local safety laboratory assessments may be used to supplement the protocol-prescribed 
assessments and may be used to evaluate AEs. 
Confidential
Page
57
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
5 
SELECTION AND WITHDRAWAL OF PARTICIPANTS  
To be eligible for study participation, participants must meet all the inclusion criteria. 
Participants will be excluded from the study if they meet any exclusion criteria. No exceptions 
to these criteria will be granted by the sponsor. 
The participant population to be enrolled in this study will consist of adult participants with 
histologically proven, relapsed or refractory, unresectable locally advanced or metastatic solid 
tumors. 
5.1 
Inclusion Criteria  
1. Ability to provide informed consent and documentation of informed consent prior to 
initiation of any study-related tests or procedures that are not part of standard-of-care 
for the participant’s disease. Participants must also be willing and able to comply with 
study procedures, including the acquisition of specified research specimens. 
2. Age ≥ 18 years old. 
3. Archival or formalin-fixed paraffin-embedded (FFPE) tissue must be available for 
determination of B7-H3 (Module A) and B7-H3 and PD-L1 expression (Module B). 
Participants may undergo a fresh tumor biopsy to obtain a specimen for testing if a 
tumor sample is not available; mCRPC with bone only disease not amenable to fresh 
biopsy may be eligible in consultation with the sponsor. 
4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. 
5. Life expectancy ≥ 12 weeks for Dose Escalation Phase and ≥ 24 weeks for Cohort 
Expansion Phase. 
6. Measurable disease as per RECIST v1.1 criteria (Appendix 5). Participants with 
mCRPC without measurable disease may be enrolled. Cutaneous or subcutaneous 
lesions must be measurable by calipers. Note: Lesions to be used as measurable 
disease for the purpose of response assessment must not reside in a field that has been 
subjected to prior radiotherapy. 
7. Tumor Histology Types 
Dose Escalation Phase of the Study: 
a. Participants with histologically proven, relapsed or refractory, unresectable locally 
advanced or metastatic solid tumors of any histology for whom no therapy with 
demonstrated clinical benefit is available.  
Cohort Expansion Module A: 
a. mCRPC that has progressed during or following one prior line of chemotherapy 
for metastatic disease, and if approved and available, no more than two prior lines 
of an anti-hormonal agent (e.g., abiraterone, enzalutamide) with a PSA value of at 
least 2 ng/mL and meeting at least one of the following:  
•
Progression in measurable disease (RECIST v1.1). 
Confidential
Page
58
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
•
Appearance of 2 or more new bone lesions according to Prostate Cancer 
Working Group 2 (PCWG2). 
•
Rising PSA defined as at least two sequential rises in PSA (PSA obtained 
≥ 1 week apart) over a reference value (the last PSA [PSA ≥ 2 ng/mL] 
measured before the first rise in PSA) (as defined by the PCWG2). 
 
b. NSCLC 
•
Metastatic NSCLC who have failed standard cytotoxic, targeted, and 
biologic or checkpoint inhibitor therapy.  No more than two prior lines of 
cytotoxic chemotherapy. 
 
c. TNBC 
•
Locally advanced or metastatic TNBC that has progressed during or 
following at least one systemic therapy. American Society of Clinical 
Oncology (ASCO) College of American Pathologists (CAP) guidelines 
should be followed for establishing the diagnosis of TNBC (76).  
 
d. SCCHN that has progressed during or following at least one systemic therapy for 
metastatic or recurrent unresectable disease. No more than 2 prior lines of 
cytotoxic chemotherapy are allowed. 
e. Melanoma that has progressed during or following at least one systemic treatment 
for unresectable locally advanced or metastatic disease. Patients who are intolerant 
of or refused standard therapy are eligible. 
 
Cohort Expansion Module B: 
Participants with histologically proven, unresectable, locally advanced or metastatic 
solid tumors for whom no therapy with demonstrated clinical benefit is available as 
described below.  
a. SCCHN that has progressed following treatment with platinum-based 
chemotherapy for metastatic or recurrent disease, or progression of disease within 
6 months of completing prior platinum therapy used as part of neoadjuvant, 
concurrent chemoradiation, or adjuvant therapy.  
•
Participants with upper esophageal or salivary gland tumors will not be 
considered as SCCHN. 
•
Participants who refuse radical resection for recurrent disease are eligible. 
b. mCRPC that has progressed during or following one prior line of chemotherapy 
for metastatic disease, and if approved and available, no more than two prior lines 
of anti-hormonal agent (e.g., abiraterone, enzalutamide) with a PSA value of at 
least 2 ng/mL and meeting at least one of the following: 
Confidential
Page
59
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
•
Progression in measurable disease (RECIST v1.1). 
•
Appearance of 2 or more new bone lesions according to Prostate Cancer 
Working Group 2 (PCWG2). 
•
Rising PSA defined as at least two sequential rises in PSA (PSA obtained 
≥ 1 week apart) over a reference value (the last PSA [PSA ≥ 2 ng/mL] 
measured before the first rise in PSA) (as defined by the PCWG2). 
c. Tumor type TBD at a later date; cancer will be required to have progressed or 
recurred despite prior standard therapy for that specific tumor.  
8. Acceptable laboratory parameters as follows: 
a. Platelet count  100 × 103/µL without transfusion within 28 days prior to the 
initiation of study drug, 
b. Absolute neutrophil count  1.5 × 103/µL in the absence of any growth factor 
support within 21 days prior to the initiation of study drug, 
c. ALT/AST  3.0 × ULN; for participants with hepatic metastases, ALT and AST 
≤ 5 × ULN, 
d. Total bilirubin  1.5 × ULN, except participants with Gilbert’s syndrome, who 
may enroll if the conjugated bilirubin is within normal limits, 
e. Creatinine < 2 mg/dL, or a calculated creatinine clearance (based on the 
Cockcroft-Gault formula) or measured creatinine clearance > 50 mL/min, 
f. Negative urine or serum pregnancy test for women of childbearing potential. 
g. Albumin ≥ 3.0 g/dL 
h. Hemoglobin ≥ 8.0 g/dL without transfusion within 28 days prior to initiation of 
study drug. 
9. Female participants of childbearing potential, 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 
participants should abstain from egg donation during the study. 
10.Female participants of childbearing potential and male participants with partners who 
are females of childbearing potential must agree to use highly-effective methods of 
contraception according to Section 8.1.3 from the time of consent through 27 weeks 
after discontinuation of study drug administration. Male participants should abstain 
from sperm donation during the study. 
11.The female of childbearing potential is not pregnant or breastfeeding or male 
participant is not expecting to father children within the projected duration of the 
study, starting with screening visit through 27 weeks after the last dose of study drug. 
Confidential
Page
60
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
12.Module B only: Previous Checkpoint Inhibitor Therapy: Participants who have 
previously received an immune checkpoint inhibitor (e.g., anti–PD-L1, anti–PD-1, 
anti–CTLA-4) prior to enrollment must have toxicities related to the checkpoint 
inhibitor resolved to ≤ Grade 1 or baseline (prior to the checkpoint inhibitor) to be 
eligible for enrollment. Note that participants who experienced previous 
hypothyroidism toxicity on a checkpoint inhibitor are eligible to enter study regardless 
of Common Terminology Criteria for Adverse Events (CTCAE) grade resolution as 
long as the participant is well controlled on thyroid replacement hormones. 
 
5.2 
Exclusion Criteria  
Participants who meet any of the following criteria will be excluded from the study. 
1. Participants with history of prior central nervous system (CNS) metastasis must 
have been treated, must be asymptomatic, and must not have any of the following at 
the time of enrollment: 
a. Concurrent treatment for the CNS disease (e.g., surgery, radiation, 
corticosteroids > 10 mg prednisone/day or equivalent), 
b. Progression after primary treatment of CNS metastases on imaging with 
MRI, CT or positron emission tomography (PET)/CT within 6 months prior 
to screening,  
c. History of leptomeningeal disease or spinal cord compression. 
2. Module B only: Participants 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 
participants with a history of Grave’s disease that are now euthyroid clinically and 
by laboratory testing. 
3. Treatment with any investigational therapy within the 4 weeks prior to the initiation 
of study drug administration. 
4. Module B only: Previous Checkpoint Inhibitor Therapy: Participants who 
experienced the following immune checkpoint inhibitor-related AEs make the 
participant ineligible, despite the AE resolving to ≤ Grade 1 or baseline: 
a. ≥ Grade 3 ocular AE, 
b. Changes in liver function tests that met the criteria for Hy's Law 
(> 3 × ULN of either ALT/AST with concurrent > 2 × ULN of total 
bilirubin and without alternate etiology), 
c. ≥ Grade 3 neurologic toxicity, 
d. ≥ Grade 3 colitis,  
e. ≥ Grade 3 pneumonitis, 
f. ≥ Grade 3 renal toxicity, 
Confidential
Page
61
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
g. ≥ Grade 3 skin toxicity. 
5. Prior treatment with MGD009, enoblituzumab, or other B7-H3 targeted agents for 
cancer. 
6. Treatment with any systemic anti-cancer therapy within the interval provided prior 
to study drug administration 
a. 4 weeks for cytotoxic chemotherapy for all tumor types or anti-hormonal 
therapy (e.g., enzalutamide, abiraterone) for mCRPC, 
b. 14 days or 5 half-lives, whichever is longer, for small molecule targeted or 
kinase inhibitors, 
c. 4 weeks prior for biologic agents, 
d. Prior radioligand (e.g., radium-223) within 6 months for mCRPC in the 
Cohort Expansion Phase. 
7. Treatment with mediastinal or pelvic radiation therapy within 4 weeks prior to the 
initiation of study drug administration. Palliative, limited field radiation for 
symptom control to soft tissues, or bone lesions within 2 weeks prior to the 
initiation of study drug administration.  
8. Module B only: 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 drug administration.  
9. Clinically significant cardiovascular disease including but not limited to: 
a. Myocardial infarction or unstable angina within the 6 months prior to the 
initiation of study drug, 
b. Stroke or transient ischemic attack within 6 months prior to the initiation of 
study drug, 
c. Clinically significant cardiac arrhythmias, e.g., atrial fibrillation that are not 
well controlled with optimal medical intervention, 
d. Uncontrolled hypertension: systolic blood pressure > 180 mmHg, diastolic 
blood pressure > 100 mmHg, 
e. Congestive heart failure (New York Heart Association class I-IV), 
f. Pericarditis or pericardial effusion, 
g. Myocarditis, 
h. Participants with a baseline left ventricular ejection fraction (LVEF) of 
< 50%, 
i. Prolongation of QTcF > 480 milliseconds. 
10.Clinically significant pulmonary compromise, including pneumonia, pneumonitis, 
or a requirement for supplemental oxygen use to maintain adequate oxygenation or 
history of ≥ Grade 3 drug-induced or radiation pneumonitis.   
Confidential
Page
62
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
11.Evidence of active viral, bacterial, or systemic fungal infection requiring parenteral 
antibiotic, antiviral, or antifungal treatment within 7 days prior to the initiation of 
study drug. Participants requiring any systemic antiviral, antifungal, or antibacterial 
therapy for active infection must have completed treatment no less than one week 
prior to the initiation of study drug. 
12.Known history of positive testing for human immunodeficiency virus or history of 
acquired immune deficiency syndrome. 
13.Known history of hepatitis B or hepatitis C infection or known positive test for 
hepatitis B surface antigen, hepatitis B core antigen, or hepatitis C polymerase 
chain reaction. 
14.History of prior allogeneic bone marrow, stem-cell, or solid organ transplantation. 
15.Second primary invasive malignancy that has not been in remission for greater than 
2 years except non-melanoma skin cancer; cervical carcinoma in situ on biopsy; or 
squamous intraepithelial lesion on Pap smear; localized prostate cancer (Gleason 
score < 6); or resected melanoma in situ. 
16.Major trauma or major surgery within 4 weeks prior to the initiation of study drug 
administration. 
17.Any serious underlying medical or psychiatric condition that would impair the 
ability of the participants to receive or tolerate the planned treatment at the study 
site. 
18.Known hypersensitivity to recombinant proteins, 
 or any excipient 
contained in the drug formulation or custom vehicle (Section 6.5). 
19.Vaccination with any live virus vaccine within 4 weeks prior to the initiation of 
study drug administration. Inactivated annual influenza vaccination is allowed. 
20.Dementia or altered mental status that would preclude understanding and rendering 
of informed consent. 
21.Prisoners or other individuals who are involuntarily detained. 
22.Any investigative site personnel directly affiliated with this study. 
23.Any issue that, in the opinion of the investigator in consultation with the sponsor, 
would contraindicate the participant’s participation in the study or confound the 
results of the study. 
24.Clinically significant venous insufficiency. 
25.> Grade 1 peripheral neuropathy. 
26.Evidence of pleural effusion. 
27.Evidence of ascites. 
28.Serum testosterone >50 ng/dl or >1.7 nmol/L in mCRPC in Module A Cohort 
Expansion Phase and Module B Cohort Expansion Phase.  
Confidential
Page
63
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
29.Confirmed or presumed COVID-19/SARS-CoV-2 infection. While SARS-CoV-2 
testing is not mandatory for study entry, testing should follow local clinical practice 
guidelines/standards. Participants with a positive test result for SARS-CoV-2 
infection, known asymptomatic infection, or presumed infection are excluded. 
 
5.3 
Withdrawal of Participant from the Study  
Participants who withdraw before Study Day 21 (Module A) or Study Day 42 (Module B) 
during the Dose Escalation Phase for a reason unrelated to drug toxicity may be considered to 
have inadequate data to support dose escalation. In this case, replacement participants may be 
enrolled in the same dose level. These participants will be followed for safety assessments 
(see Section 12.2). 
A participant may be determined to be LTFU after there have been at least 3 documented 
phone or electronic contact attempts. If this fails, a certified letter should be sent to the 
participant. Only after these attempts have failed can a participant be determined to be LTFU. 
5.4 
Rules for Study Treatment Discontinuation  
Participants who tolerate treatment may continue to receive treatment with the study drug(s) 
as specified in the protocol until any one of the following conditions are met: 
•
Participant meets RECIST v1.1 criteria for disease progression  
•
Participant meets PCWG-2 criteria for radiographic progression 
•
Withdrawal of participant due to an AE or SAE 
•
Withdrawal of participant consent 
•
Completion of protocol-defined therapy 
•
Investigator discretion 
•
Pregnancy 
•
Occurrence of drug-related DLT or AEs that lead to discontinuation of study drug 
•
Dose delay > 21 days due to AEs unless approved by the sponsor.  
•
The sponsor, investigator, or regulatory agency terminates the study 
•
Death 
 
For individual participants who meet these criteria, but who are otherwise considered to be 
experiencing clinical benefit in the judgment of the investigator, consideration may be given 
to continue therapy of MGC018 alone (Module A) or in combination with MGA012 
(Module B), for up to maximum of total of 18 cycles (i.e. approximately 2 years), on a 
case-by-case basis in consultation with the sponsor. If the investigator decides that the 
participant should be withdrawn from the study or from dosing for any reason other than 
Confidential
Page
64
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
disease progression, the sponsor or its designee must be alerted within 24 hours by completing 
the appropriate electronic case report forms (eCRFs) (Section 12.2.2). 
5.5 
Guidelines for Discontinuation of Participant from Study  
Participants who are no longer on treatment but are still followed on the study can be 
terminated from the study for the following reasons: 
•
Completion of protocol-defined follow-up period 
•
Uncontrolled intercurrent illness unrelated to cancer that prevents continuing study 
follow-up 
•
Noncompliance with protocol-required evaluations 
•
The participant requests to be discontinued from the study, i.e., withdrawal of consent 
•
The sponsor, investigator, or regulatory agency terminates the study 
•
Death 
 
Confidential
Page
65
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
6 
STUDY TREATMENTS  
6.1 
Description of Treatments  
For Module A, MGC018 will be administered on Days 1 and 22 of each 42-day cycle. For 
Module B, MGC018 will be administered on Days 1 and 22 of each 42-day cycle. In addition, 
for Module B, MGA012 will be administered on Day 22 of Cycle 1 and on Days 1 and 22 of 
every 42-day cycle thereafter. Each cycle is 42 days.  
MGC018 will be administered as an IV infusion over 60 minutes. MGA012 will be 
administered by IV infusion over 60 minutes. On days when the MGC018 and MGA012 are 
to be administered on the same day (Module B only), MGA012 should be given first, 
followed immediately thereafter by MGC018. MGC018 and MGA012 will be administered as 
separate IV infusions.  
6.2 
Method of Assigning Participants to Treatment Groups  
Participants will be assigned sequentially to the dose escalation cohorts and cohort expansion 
cohorts as specified in Section 4.1.1 and Section 4.1.2, respectively. Participants in the Cohort 
Expansion Phase will receive doses of MGC018, alone (Module A) or in combination with 
MGA012 (Module B), at the MTD (or MAD if no MTD is defined) based on results from the 
Dose Escalation Phase of the respective modules. A predetermined number of participants will 
then be enrolled in each cohort. 
6.3 
Blinding  
This is an open-label study. 
6.4 
Emergency Unblinding  
Not applicable. This is an open-label study. 
6.5 
Study Drug and Supplies  
6.5.1 
MGC018  
 
 
 
 
 
Confidential
Page
66
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
MGC018 must be diluted with sterile 0.9% Sodium Chloride Injection, USP (normal saline), 
prior to administration. MGC018 will be administered by IV infusion over 60 minutes. 
MGC018 must not be administered as an IV push or bolus. 
6.5.2 
MGA012  
 
 
 
 
 
 
 
MGA012 must be diluted with sterile 0.9% Sodium Chloride Injection, USP (normal saline), 
prior to administration. MGA012 will be administered by IV infusion over 60 minutes. 
MGA012 must not be administered as an IV push or bolus. 
Confidential
Page
67
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Table 8 
MGA012 Drug Product Composition                    
6.6 
Study Infusion Preparation  
6.6.1 
General Guidelines and Precautions  
Under no circumstances is the investigator allowed to release these clinical supplies for use by 
another physician not named on Form FDA 1572 or equivalent form or to administer study 
drug to a participant who is not enrolled in this study. Study drug must be dispensed at an 
institution specified on Form FDA 1572 or equivalent form. 
6.6.1.1 
MGC018 (Module A and B)  
The calculated dose of MGC018 will be administered based on the participant’s actual weight 
at Cycle 1, Day 1 (or up to 24 hours prior to Cycle 1, Day 1). In the cohort expansion phase, 
the MGC018 dose will be capped for participants with a body weight ≥ 100 kg. Body weight 
will be measured at Screening and Days 1 and 22 of each cycle. Significant (≥ 10%) change in 
BW from baseline should prompt recalculation of dose using the most recent body weight. 
Refer to the pharmacy manual for further instructions on allowable parameters for dose 
rounding. 
MGC018 should not be administered as an IV push or bolus. All doses of MGC018 will be 
diluted in normal saline and administered as an IV infusion over 60 minutes with a 
commercially available infusion pump or syringe pump. All infusion pumps must be 
calibrated in accordance with the institutional standards, policies, and procedures to ensure 
consistent, accurate delivery of MGC018. 
Infusion or allergic reactions may occur with the infusion of monoclonal antibodies and other 
protein-based therapeutics. Precautions for anaphylaxis should be observed during 
administration. Supportive measures may include, but are not limited to, epinephrine, 
antihistamines, corticosteroids, IV fluids, vasopressors, oxygen, bronchodilators, 
diphenhydramine, and acetaminophen. Please refer to Section 7.1 for specific guidelines 
Confidential
Page
68
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
regarding the management of infusion reactions. Supportive care measures consistent with 
optimal participant care will be provided throughout the study according to institutional 
standards. 
On days when the MGC018 and MGA012 are to be administered on the same day (Module B 
only), MGA012 should be given first, followed immediately thereafter by MGC018. 
Note: Participants should remain in the infusion center for 4 hours after the completion of 
administration of the first dose of MGC018 alone (Module A, Day 1 of Cycle 1). For 
Module B, participants should remain in the infusion center for 4 hours after the completion 
of administration of the first dose of MGC018 alone (Day 1 Cycle 1) and 4 hours after the 
completion of the first dose of combined administration of MGC018 and MGA012 (Day 22, 
Cycle 1). 
6.6.1.2 
MGA012 (Module B only)  
MGA012 should not be administered as an IV push or bolus. All doses of MGA012 will be 
diluted in normal saline and administered as an IV infusion over 60 minutes with a 
commercially available infusion pump or syringe pump. All infusion pumps must be 
calibrated in accordance with the institutional standards, policies, and procedures to ensure 
consistent, accurate delivery of MGA012. Refer to the pharmacy manual for instructions on 
infusion preparation. 
MGA012 dose will be administered as per Table 4. 
Infusion or allergic reactions may occur with the infusion of monoclonal antibodies and other 
protein-based therapeutics. Precautions for anaphylaxis should be observed during MGA012 
administration. Supportive measures may include, but are not limited to, epinephrine, 
antihistamines, corticosteroids, IV fluids, vasopressors, oxygen, bronchodilators, 
diphenhydramine, and acetaminophen. Please refer to Section 7.1 for specific guidelines 
regarding the management of infusion reactions. Supportive care measures consistent with 
optimal participant care will be provided throughout the study according to institutional 
standards. 
6.6.2 
Study Drug Preparation and Administration  
Visually inspect parenteral drug products for particulate matter and discoloration prior to 
administration. Return the vial if the solution is cloudy, there is pronounced discoloration 
(solution may have pale-yellow color), or there is foreign particulate matter. 
Instructions on the thawing and preparation of the study drugs (MGC018 and MGA012) for 
IV infusion are detailed in the pharmacy manual. 
Do not mix the study drugs with, or administer as an infusion with, other medicinal products. 
Confidential
Page
69
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
6.6.2.1 
MGC018  
All doses of MGC018 must be diluted in sterile 0.9% Sodium Chloride Injection, USP 
(normal saline) prior to dose administration. MGC018 diluted in normal saline must be within 
the concentration range of 0.1 mg/mL to 6.0 mg/mL for syringe pump administration and 
0.5 mg/mL to 2.9 mg/mL for infusion pump administration. Administer the diluted dosing 
solution over 60 minutes through an IV line with a commercially available infusion pump or 
syringe pump. Up to 10 additional minutes of infusion time (i.e. up to a total infusion time of 
70 minutes) is permitted to allow for flushing the line. A sterile, non-pyrogenic, low protein 
binding PES 0.2 µm in-line filter administration set should be used for IV administration of 
MGC018. Do not administer as an IV push or bolus. 
Because there is no preservative and drug loss may occur over time. The administration of 
study drug should begin immediately after preparation, but no later than 4 hours at room 
temperature after preparation. Alternatively, the dose-prepared IV bag or syringe may be 
stored for up to 24 hours at 2° to 8°C. If the dose solution is stored at 2° to 8°C, it should be 
removed from the refrigerator at least 30 to 60 minutes prior to administration, to allow 
solution to reach room temperature. If there is a delay in administration of study drug such 
that the drug will not be administered according to the above parameters, the medical monitor 
must be notified immediately, and instructions on how to proceed will be provided. 
6.6.2.2 
MGA012  
All doses of MGA012 must be diluted to a concentration range of 0.3 mg/mL to 12.0 mg/mL 
in sterile 0.9% Sodium Chloride Injection, USP (normal saline).  Administer the diluted 
dosing solution over 60 minutes through an IV line with a commercially available infusion 
pump. A sterile, non-pyrogenic, low protein binding PES 0.2 µm in-line filter administration 
set must be used for IV administration of MGA012. MGA012 should not be administered as 
an IV push or bolus. 
The administration of study drug should begin immediately after preparation. The 
administration should be no later than 4 hours and study drug kept at room temperature after 
preparation. Alternatively, the dose-prepared IV bag may be stored for up to 24 hours at 2° to 
8°C. If the dose solution is stored at 2° to 8°C, it should be removed from the refrigerator at 
least 30 to 60 minutes prior to administration, to allow solution to reach room temperature. If 
there is a delay in administration of study drug such that the drug will not be administered 
according to the above parameters, the medical monitor must be notified immediately, and 
instructions on how to proceed will be provided. 
6.6.3 
Combination Therapy  
When MGC018 and MGA012 are to be administered on the same day (Module B only), 
MGA012 should be given first, followed immediately thereafter by MGC018.  
Confidential
Page
70
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
After MGA012 infusion, the IV line should be cleared with normal saline infusion given at 
the same rate as the MGA012 infusion. 
Do not manually push normal saline after MGA012 or MGC018 infusion. 
6.7 
Treatment Compliance  
The study drug will be administered by healthcare professionals under the supervision of the 
investigator or designee. Records of dose calculation, administration, and dosing regimen will 
be accurately maintained by site staff. The monitor will review dose calculation, 
administration, and regimen as well as medication accountability during study site visits and 
at the completion of the study. 
6.8 
Packaging and Labeling  
MGC018 drug product is supplied as a single-use, 
 packaged in a 
United States Pharmacopeia-National Formulary (USP-NF) and European Pharmacopoeia 
(Ph. Eur.) conforming Type 1 borosilicate, 20 cc clear glass vial with a 20 mm FluroTec® and 
B2-40® -coated 4023/50 gray butyl rubber serum stopper. The vial is sealed with a 20 mm 
aluminum closure with a plastic overseal. MGC018 is supplied in 93 mg/9.3 mL (10 mg/mL) 
single-use vials. MGC018 is labeled according to local regulatory health authority 
requirements. Please see the pharmacy manual for detailed information about the packaging of 
the study drug. 
MGA012 drug product is supplied 
 packaged in a USP 
and Ph. Eur. conforming Type I borosilicate, 10 mL glass vial with a 4432/50 gray butyl 
rubber stopper with B2-40® coating and FluroTec® coating on plug. The vial is sealed with a 
20 mm aluminum closure with a plastic overseal. MGA012 is supplied as 10 mL 
(250 mg/vial) single-use vials. MGA012 is labeled according to local regulatory health 
authority requirements. Please see the pharmacy manual for detailed information about the 
packaging of the study drug. 
Please see the MGC018 and MGA012 pharmacy manuals for detailed information about the 
packaging of the study drugs. All study drug will be labelled with a minimum of the protocol 
number, directions for use, and storage conditions; the statements “For clinical trial use only,” 
and/or “CAUTION: New Drug – Limited by Federal (United States) Law for Investigational 
Use”; and the sponsor’s name and address. 
6.9 
Storage and Accountability  
The investigator or his/her designee is required to maintain accurate drug accountability 
records. A binder containing instructions and the required accountability documentation will 
be provided to the investigator or his/her designee. When the study is completed, copies of 
study drug accountability records must be sent to the sponsor. The original drug accountability 
records must be maintained with the rest of the documentation in accordance with 
Section 15.1 of the protocol. 
Confidential
Page
71
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Accurate accounting of all study medication 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. Additional details 
regarding storage, handling, and accountability can be found in the pharmacy manual. 
6.9.1 
MGC018  
Vials containing study drug should be stored 
 in an 
appropriate, locked room accessible only to pharmacy personnel, the investigator, or duly 
designated personnel. 
 used for drug storage must be maintained at a temperature 
 To ensure compliance with storage conditions, temperature logs should be 
maintained. Vials should be protected from light during storage and should not be shaken. 
Standard laboratory practices should be used for avoidance of contact with MGC018. 
6.9.2 
MGA012  
Vials containing MGA012 must be stored upright 
 
 in an appropriate, locked room accessible only to pharmacy personnel, the investigator, 
or duly designated personnel. To ensure compliance with storage conditions, temperature logs 
will be maintained. Vials should be protected from light during storage and should not be 
shaken or frozen. Standard laboratory practices should be used for avoidance of contact with 
MGA012. 
6.10 
Investigational Product Disposition at End of Study  
Upon completion or termination of the study, all unopened vials of study drug must be 
returned to MacroGenics or its representative, unless the site has received written 
authorization from MacroGenics to destroy study drug at the site. All drug returns to 
MacroGenics or its representative must be accompanied by the appropriate documentation and 
be clearly identified by protocol number and study site number on the outermost shipping 
container. If MacroGenics approves the destruction of drug at the site, the investigator must 
ensure arrangements are made for proper disposal and that appropriate records of disposal are 
documented and maintained, and copies provided to the sponsor. 
Confidential
Page
72
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
7 
POTENTIAL ADVERSE EVENTS AND SUPPORTIVE CARE 
MEASURES  
7.1 
Infusion Related Reactions Including Cytokine Release Syndrome  
Infusion reactions (including CRS) associated with the administration of mAb-based 
therapeutics 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). 
Participants should be monitored closely for the development of infusion related reactions 
(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 and may include, but are not limited to, subcutaneous 
epinephrine (0.3 to 0.5 mL of a 1:1000 solution), antihistamines (e.g., diphenhydramine 25 to 
50 mg IV), corticosteroids (e.g., hydrocortisone 20 to 40 mg IV push or equivalent), IV fluids, 
vasopressors, oxygen, bronchodilators, and antipyretics. Resuscitation equipment and other 
supplies for the emergency management of an allergic/toxic reaction must be available. The 
participant should be treated according to the best available local practices and procedures. All 
supportive measures consistent with optimal participant care will be provided throughout the 
study according to institutional standards. 
Should symptoms of fever or chills develop, it may be difficult to distinguish among potential 
causes of the symptoms including emerging infection, or infusion reaction. Participants should 
be evaluated carefully for the presence of infection (including COVID-19), with the 
acquisition of cultures and/or implementation of empiric antibiotic therapy as appropriate 
based on the assessment of the investigator. Please refer to Section 7.1.3 for guidance 
regarding the management of infusion reactions. 
7.1.1 
Grading and Management of Infusion Reactions  
Infusion reactions will be categorized as follows: 
•
Grade 1: mild reaction; infusion interruption not indicated, intervention not indicated; 
Note: although interruption in infusion is not indicated, temporary rate reduction 
indicated before resuming original rate, as participant tolerates (see Section 7.1.3); 
•
Grade 2: therapy or infusion interruption indicated but responds promptly to 
symptomatic treatment (e.g., antihistamines, non-steroidal anti-inflammatory 
drugs [NSAIDS], narcotics, IV fluids);  
•
Grade 3: prolonged (e.g., not rapidly responsive to medication and/or brief interruption 
of infusion); recurrence of symptoms following initial improvement; hospitalization 
indicated for clinical sequelae (e.g., renal impairment, pulmonary infiltrates); 
•
Grade 4: life-threatening consequences; pressor or ventilatory support indicated; 
Confidential
Page
73
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
•
Grade 5: death. 
 
The above grading scale is the CTCAE v4.0.3 grading scale for CRS, which is nearly identical 
to the CTCAE v4.0.3 grading scale for infusion reaction and allergic reaction and is therefore 
considered appropriate for grading all infusion reactions in this study, irrespective of the 
underlying mechanism of the reaction. The sponsor’s medical monitor or designee should be 
contacted immediately if questions arise concerning the grade of the reaction. 
7.1.2 
Premedication and Prophylaxis  
The following are guidelines for the investigator regarding prophylactic pre-infusion measures 
to be followed to mitigate the occurrence or severity of potential infusion reactions. 
At least 30 minutes prior to each infusion of MGC018 alone or the combination of MGC018 
and MGA012: 
•
Acetaminophen 650 to 1000 mg orally (PO), or ibuprofen 400 mg PO 
•
Diphenhydramine 50 mg PO or IV or equivalent H1 antagonist 
•
Famotidine 40 mg PO or 20 mg IV, or equivalent H2 antagonist 
•
Corticosteroid eg. Dexamethasone 4 mg IV or equivalent 
 
For subsequent administration of MGC018 alone or in combination with MGA012, 
participants who had infusion reactions that were not adequately or only moderately 
controlled, other medications may also be considered as a part of the pre-medication regimen 
for subsequent doses. Non-steroidal pre-medications may be administered prior to the 
subsequent infusion, if warranted. 
For participants treated on Module B (combination of MGC018 and MGA012), if the 
administration of the MGC018 is delayed by more than 4 hours after completion of MGA012 
administration, repeat dosing of pre-medications may be considered prior to administration of 
MGC018.  
7.1.3 
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 IRR: 
Grade 1: 
•
Slow the infusion rate by 50%. 
•
Monitor the participant for worsening of condition. 
Confidential
Page
74
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
•
Continue rate at 50% reduction and increase dose rate to the original rate by 
doubling the infusion rate after 30 minutes, as tolerated to the initial rate. 
Consideration can be given to beginning subsequent infusions at 50% rate and 
increasing as tolerated. 
•
If a participant has an infusion reaction, prophylactic pre-infusion medications 
should be given prior to all subsequent infusions. The following prophylactic pre-
infusion medications are recommended prior to future infusions of MGC018 alone 
or in combination with MGA012 for participants who experience Grade 1 infusion 
reactions: diphenhydramine 25 to 50 mg (or equivalent) PO/IV and acetaminophen 
650 mg PO and/or ibuprofen 400 mg PO, with or without famotidine 40 mg PO or 
20 mg IV (or equivalent H2-antagonist) at least 30 minutes before additional study 
drug administrations. 
 
Grade 2: 
•
Stop the infusion. 
•
Administer diphenhydramine hydrochloride 25 to 50 mg IV. 
•
Acetaminophen 650 mg PO or ibuprofen 400 mg PO for fever. 
•
Oxygen and bronchodilators for mild bronchospasm. 
•
Resume the infusion at 50% of the prior rate once the infusion reaction has 
resolved or decreased to Grade 1. The rate may then be escalated to the original 
rate after 30 minutes, as tolerated. Consideration can be given to beginning all 
subsequent infusions at 50% rate and increasing as tolerated.   
•
Monitor for worsening condition. If symptoms recur, discontinue the infusion; no 
further study drug will be administered at that visit. 
•
Prophylactic pre-infusion medications should be given prior to subsequent 
infusions of MGC018 alone or in combination with MGA012. Participants who 
experience a Grade 2 infusion reaction, for subsequent doses of MGC018 alone or 
in combination with MGA012, pre-medicate with diphenhydramine hydrochloride 
25 to 50 mg IV/PO, acetaminophen 650 mg PO and/or ibuprofen 400 mg PO, with 
or without famotidine 40 mg PO or 20 mg IV (or equivalent H2-antagonist) at least 
30 minutes before additional study drug administrations. For these participants, 
corticosteroids (dexamethasone 10 mg IV or hydrocortisone 25 to 100 mg IV or 
higher) also may be added to the premedication regimen for subsequent dosing of 
MGC018 alone or in combination with MGA012. 
 
Grade 3: 
•
STOP THE INFUSION AND DISCONNECT THE INFUSION TUBING FROM 
THE PARTICIPANT. 
Confidential
Page
75
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
•
TO AVOID EXACERBATION OF INFUSION REACTION OR CRS: DO NOT 
FLUSH THE TUBING – ASPIRATE RESIDUAL DRUG FROM THE 
VASCULAR ACCESS DEVICE. 
•
Administer diphenhydramine hydrochloride 25 to 50 mg IV, dexamethasone 20 mg 
IV (or equivalent), and other medications/treatment as medically indicated. Higher 
doses of corticosteroids (e.g., methylprednisolone 2 to 4 mg/kg IV or the 
equivalent) may also be considered for acute management. 
•
IV fluids, supplemental oxygen, and bronchodilators should be considered, as 
appropriate. 
•
If the Grade 3 infusion reaction occurs with administration of MGC018 alone or in 
combination with MGA012, it will be discontinued for that day. If symptoms have 
resolved to baseline within 12 hours, MGC018 alone or combination with 
MGA012 may be infused the next day. In addition, participants should be 
pre-medicated for this re-challenge and for any subsequent doses of MGC018 
alone or in combination with MGA012 with the following: diphenhydramine 
hydrochloride 25 to 50 mg IV, acetaminophen 650 mg PO and/or ibuprofen 
400 mg PO, with or without famotidine 40 mg PO or 20 mg IV (or equivalent 
H2-antagonist). Corticosteroids (dexamethasone 10 to 20 mg IV or hydrocortisone 
50 to 100 mg IV or higher) should be considered as well. 
•
Participants who have a Grade 3 infusion reaction that does not resolve within 
12 hours despite medical management should not receive further treatment with 
MGC018 alone or in combination with MGA012. Participants who experience a 
second Grade 3 infusion reaction at the time of re-challenge of MGC018 alone or 
in combination with MGA012 will permanently discontinue treatment with study 
drugs. 
•
Report as an IRE within 24 hours. 
•
Report the event as a SAE, if appropriate. 
 
Grade 4: 
•
STOP THE INFUSION AND DISCONNECT THE INFUSION TUBING FROM 
THE PARTICIPANT. 
•
TO AVOID EXACERBATION OF INFUSION REACTION OR CRS: DO NOT 
FLUSH THE TUBING – ASPIRATE RESIDUAL DRUG FROM THE 
VASCULAR ACCESS DEVICE. 
•
Administer diphenhydramine hydrochloride 50 mg IV, dexamethasone 20 mg IV 
(or more as considered appropriate), and other medications/treatment as medically 
indicated (e.g., an IL-6 receptor inhibitor or IL-6 inhibitor, an IL-2 receptor 
inhibitor, and/or an anti-TNF antibody). 
•
Give epinephrine or bronchodilators as indicated. 
•
Support ventilation and blood pressure as indicated. 
Confidential
Page
76
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
•
Report as an IRE within 24 hours. 
•
Report the event as an SAE. 
•
Participants who have a Grade 4 infusion reaction will not receive further 
treatment with MGC018 alone or in combination with MGA012. 
 
Grade 5: 
•
Report as an IRE within 24 hours.  
•
Report the event as an SAE. 
 
All changes in the infusion of MGC018 and MGA012, including interruption of the infusion 
and its duration as well as reductions in infusion rate and duration, must be recorded. 
7.2 
Immune-Related Adverse Events  
Blockade of immune checkpoints has been associated with several immune-mediated AEs that 
develop as a result of disruption of immune tolerance in normal tissues (31, 58, 65). These 
include, but are not limited to: pneumonitis, colitis, autoimmune hepatitis, arthritis, 
glomerulonephritis, myocarditis and cardiomyopathy, hypophysitis, thyroiditis, myositis, 
uveitis, neurotoxicity, pericarditis, autoimmune endocrinopathies (e.g., pancreatitis and 
diabetes), and dermatologic toxicity (including Stevens Johnson syndrome and toxic 
epidermal necrolysis). The occurrence of any of these may dictate delay and potentially 
discontinuation of study drug administration pending further evaluation and reporting them to 
the sponsor as adverse events of special interest (AESI). Most low-grade irAEs can be 
managed symptomatically. Persistent low grade or moderate toxicities may require treatment 
with corticosteroids or in refractory cases other immune suppressing agents such as 
mycophenolate or infliximab. High-grade immune-related toxicities will, in almost all cases, 
require treatment with high-dose corticosteroids. 
General guidelines for specific toxicity regarding dosing and treatment are provided below. 
All toxicities will be graded according to NCI CTCAE v4.03. Refer to the National 
Comprehensive Cancer Network Guidelines for the Management of Immune-related 
Toxicities (https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf) for 
toxicities not specifically mentioned in this section. Unless otherwise specified, Grade 1 irAEs 
may be monitored without administering specific interventions. Guideline principles may be 
adapted to local standard of care at the investigator’s discretion. 
For participants who receive corticosteroid therapy for ≥ 4 weeks at a dose equivalent to 
≥ 20 mg of prednisone per day, consideration should be given to implementation of antibiotic 
prophylaxis for opportunistic infections. 
Confidential
Page
77
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
7.2.1 
Diarrhea or Colitis  
Diarrhea that develops in participants while receiving the study drugs may reflect immune 
reactivity against normal colonic epithelium, and careful monitoring for potential 
immune-related colitis should be instituted. Participants should be monitored closely for 
evidence of diarrhea or other change in bowel habits, as well as other signs and symptoms 
suggestive of colitis. Participants who develop signs or symptoms including abdominal pain, 
bloating, nausea, vomiting, diarrhea, or blood in the stools should be evaluated carefully for 
potential colitis. 
•
Grade 1 diarrhea - Closely monitor the diarrhea until resolution. 
•
Grade 2 diarrhea - Increase frequency of monitoring until resolution. For 
management of symptoms: 
o Loperamide/diphenoxylate 
o Low-dose steroids if clinically indicated 
o Consider management of prolonged Grade 2 event lasting more than 5 to 
7 days or relapsed diarrhea as Grade 3 diarrhea (see below) 
•
Grade 3 diarrhea - Hold study drugs. Hospitalize participant promptly for further 
evaluation and management, including the following: 
o Bowel rest 
o Supplemental IV fluids with close monitoring of fluid and electrolyte status 
o Monitor frequency of bowel movements 
o Consider imaging to rule out bowel obstruction or perforation 
o Consideration of colonoscopy as appropriate 
o Implementation of initial empiric immune suppression consisting of IV 
corticosteroids using methylprednisolone at a dosage of 2 mg/kg/day (or 
equivalent) divided twice daily. As tolerated, participants may be converted 
to oral corticosteroids (i.e., prednisone 2 mg/kg/day divided twice daily) 
and tapered as appropriate guided by the participants’ clinical status. 
o Taper corticosteroids as clinically indicated 
o For participants with severe colitis, or those who do not respond to 
corticosteroids, additional immune suppression with anti–TNF α antibodies 
(i.e., infliximab) should be considered early in the course 
o It is determined there is no colitis and an alternative cause of diarrhea is 
found, consider restarting study drug(s) if:  
 Diarrhea resolves to ≤ Grade 1 within 21 days 
•
Grade 4 diarrhea - discontinue study drugs and treat as for Grade 3. 
 
Confidential
Page
78
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
7.2.2 
Hepatic Toxicity  
7.2.2.1 
Elevations in Transaminases  
Management guidelines for participants experiencing hepatic toxicity are as follows: 
•
Grade 1 elevations - No specific therapy required. 
•
Grade 2 elevations - For elevations in transaminases 3 to 5 × ULN, rule out viral and 
other etiologies. Consider imaging studies such as ultrasound or CT scan and liver 
biopsy to ascertain etiology of liver dysfunction. Consider starting oral prednisone 
60 mg/day divided twice daily and hold study drugs. 
o If improvement to ≤ Grade 1 does not occur within 48 hours with oral 
steroids, consider IV steroids such as methylprednisolone at 2 mg/kg/day 
divided twice daily or oral steroids such as prednisone 60 to 120 mg per 
day, divided twice daily 
o Resume study drugs at the next scheduled dose if no more than one dose of 
MGC018 alone or in combination with MGA012 was missed. 
o If improvement to ≤ Grade 1 does not occur within 21 days, discontinue 
study drugs. 
•
Grade 3 elevations - Hold study drugs. 
o For elevations in transaminases > 8 × ULN, permanently discontinue study 
drugs. 
 Begin immediate IV steroids and, 
 If no response to corticosteroid therapy within 3 to 5 days is 
observed, consider adding immune suppression therapy with 
mycophenolate. 
 Monitor liver function tests at least twice weekly (or more 
frequently as clinically appropriate in the judgment of the 
investigator) until transaminases have returned to Grade 1 or 
baseline. 
o For elevations in transaminases > 5 but ≤ 8 × ULN: 
 Begin immediate IV steroids; suggest methylprednisolone at a 
dosage of 2 mg/kg/day divided twice daily. 
 Consider additional immune suppression as above for participants 
who do not respond to corticosteroid therapy within 3 to 5 days. 
 Monitor liver function tests at least twice weekly (or more 
frequently as clinically appropriate in the judgment of the 
investigator) until transaminases have returned to Grade 1 or 
baseline. 
Confidential
Page
79
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
 If the elevation does not improve to Grade 2 within 7 days and to 
Grade 1 within 21 days, discontinue study drugs. 
o Resume study drugs administration if following conditions are met: 
 Laboratory elevations improved to ≤ Grade 2 within 7 days and 
improve to ≤ Grade 1 or baseline within 21 days. 
 Steroids have been tapered to ≤ 10 mg per day of prednisone or 
equivalent. 
 On resuming study drugs, AST, ALT, and total and direct bilirubin 
laboratory test values will be evaluated at least once per week for 
3 consecutive weeks. 
o Permanently discontinue study drug treatment in the case of a second 
increase of AST or ALT to ≥ Grade 3. 
•
Grade 4 elevation - Discontinue study drugs and treat as for Grade 3 elevation. 
 
7.2.2.2 
Elevations in Total Bilirubin  
Management guidelines for participants experiencing elevations in total bilirubin are as 
follows: 
•
Grade 1 elevations - No specific therapy required. 
•
Grade 2 elevations - Hold study drugs until improvement to ≤ Grade 1. 
o Rule out viral and other etiologies. Consider imaging studies such as 
ultrasound or CT scan and liver biopsy to ascertain etiology of liver 
dysfunction. Consider oral steroids. 
o If improvement to ≤ Grade 1 does not occur within 21 days, discontinue 
study drugs and begin oral steroids. 
•
Grade 3 elevations - Hold study drugs. 
o For elevations in total bilirubin > 5 × ULN, permanently discontinue study 
drugs and initiate IV steroids, suggest methylprednisolone at a dosage of 
2 mg/kg/day divided twice daily, and, 
 If no response to corticosteroid therapy within 3 to 5 days is 
observed, consider adding immune suppression therapy with 
mycophenolate. 
 Monitor liver function testing at least twice weekly (or more 
frequently as clinically appropriate in the judgment of the 
investigator) until total bilirubin has returned to Grade 1 or baseline. 
o For elevations in total bilirubin > 3.0 but ≤ 5 × ULN: 
 Begin immediate IV steroids, suggest methylprednisolone at a 
dosage of 2 mg/kg/day divided twice daily. Consider additional 
Confidential
Page
80
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
immune suppression as above for participants who do not respond 
to corticosteroid therapy within 3 to 5 days. 
 Monitor liver function including total bilirubin testing at least twice 
weekly (or more frequently as clinically appropriate in the judgment 
of the investigator) until total bilirubin has returned to Grade 1 or 
baseline. 
 If the elevation does not improve to Grade 2 within 7 days and to 
Grade 1 within 21 days, discontinue study drugs. 
 Resume study drugs administration if: 
• Laboratory elevations downgrade to ≤ Grade 2 within 7 days 
and improve to ≤ Grade 1 or baseline within 21 days. 
• Steroids have been tapered to ≤ 10 mg per day of prednisone 
or equivalent 
• On resuming study drugs, AST, ALT, and total bilirubin 
laboratory test values will be evaluated at least once per 
week for 3 consecutive weeks. 
 Permanently discontinue study drugs in the case of a second 
increase of total bilirubin to ≥ Grade 3. 
•
Grade 4 elevations - Discontinue study drugs and treat as for Grade 3 elevation. 
 
7.2.3 
Pneumonitis  
Management guidelines for participants experiencing pneumonitis are as follows: 
•
Grade 1 pneumonitis - No specific therapy required; close monitoring of lung function 
and imaging. 
•
Grade 2 pneumonitis - Hold study drugs. 
o Consider corticosteroids: 1 to 2 mg/kg of oral prednisone or equivalent per 
day divided twice daily. 
o Taper corticosteroids over 4 weeks or as clinically indicated.  
o Resume study drug administration at next scheduled dose if pneumonitis 
resolves to ≤ Grade 1 within 5 days with or without treatment. 
•
Grade 3 and 4 pneumonitis - Permanently discontinue study drugs. 
o Hospitalize. 
o Recommend a pulmonary consult/diagnostic evaluation including chest 
X-ray and CT scan. 
Confidential
Page
81
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
o Initiate maximal supportive care including IV corticosteroids, suggest 
methylprednisolone at 2 to 4 mg/kg/day divided twice daily. Higher doses 
may be used in consultation with the sponsor’s medical monitor. 
o If no response to corticosteroid therapy is observed within 3 to 5 days, 
consider adding immune suppression therapy (i.e., infliximab, etc.). 
An evaluation for infection including COVID-19 should be performed. 
7.2.4 
Dermatologic Toxicity  
Management guidelines for participants experiencing dermatologic toxicity are as noted 
below. Participants should limit sun exposure and apply broad-spectrum sunscreen to exposed 
skin when outdoors. 
•
Grade 1 or 2 skin reactions: 
o For dry skin, consider application of moisturizers as needed to affected 
area. 
o Symptomatic treatment with low-dose topical corticosteroids 
(betamethasone 0.1% or hydrocortisone 1%) or antihistamines 
(diphenhydramine). 
o Persistent Grade 1 or 2 rash should be managed with higher dose topical 
corticosteroids and/or oral prednisone (1 to 2 mg/kg/day) if there is not 
improvement with topical therapies or the rash is associated with other 
dermal toxicities such as pruritus. 
o Evaluate participant use of concomitant medications and herbal 
supplements that may exacerbate skin toxicity.  
•
Grade 3 skin reactions – Hold study drugs. 
o Initiate oral corticosteroids (oral prednisone 1 to 2 mg/kg/day). 
o Evaluate participant use of concomitant medications and herbal 
supplements that may exacerbate skin toxicity.  
o Consider obtaining skin biopsy if SJS or TEN is suspected. If possible, 
refer to specialized care center for clinical management. Cyclosporine 
and/or IV immunoglobulin may be considered for management of SJS or 
TEN. 
o Resume study drug administration at next scheduled dose if: 
 Skin toxicity resolves to ≤ Grade 1 or baseline within 21 days with 
maximal supportive care. 
o Discontinue study drugs if skin toxicity does not resolve to ≤ Grade 1 or 
baseline within 21 days, or for any grade SJS or TEN of any duration. 
•
Grade 4 skin reactions – Permanently discontinue study drugs. 
o Initiate oral corticosteroids (oral prednisone 1 to 2 mg/kg/day). 
Confidential
Page
82
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
o Evaluate participant use of concomitant medications and herbal 
supplements that may exacerbate skin toxicity.  
o Consider obtaining a skin biopsy if a possible diagnosis of SJS or TEN. If 
possible, refer to specialized care center for clinical management. 
Cyclosporine and/or IV immunoglobulin may be considered for 
management of SJS or TEN.  
o Consideration should be given to start IV corticosteroids 
(methylprednisolone 1 to 2 mg/kg/day) for Grade 4 dermatologic toxicities 
with tapering on resolution to < Grade 2 over 30 days. 
 
7.2.5 
Nephritis  
Management guidelines for participants experiencing nephritis are as follows: 
•
Grade 1 nephritis - No specific therapy required; close monitoring of renal 
function. 
•
Grade 2 nephritis - Hold study drugs. 
o Consider nephrology consultation and renal biopsy to confirm interstitial 
nephritis. 
o Begin corticosteroids: 1 to 2 mg/kg of oral prednisone or equivalent per 
day divided twice daily. Taper corticosteroids over 4 weeks or as clinically 
indicated. 
o Resume study drug administration at next scheduled dose if: 
 Nephritis resolves to ≤ Grade 1 within 21 days with or without 
treatment 
•
Grade 3 and 4 nephritis - Permanently discontinue study drugs. 
o Consider hospitalization, nephrology consultation, and renal biopsy to 
confirm interstitial nephritis 
o Begin corticosteroids: 2 to 4 mg/kg of oral or IV methylprednisolone or 
equivalent per day divided twice daily. Taper corticosteroids over 4 weeks 
or as clinically indicated. 
 
7.2.6 
Immune-Mediated Hypophysitis  
Management guidelines for participants experiencing hypophysitis are as follows: 
•
Grade 1 hypophysitis - No specific therapy required. 
•
Grade ≥ 2 hypophysitis - Hold study drugs. 
o Consult endocrinologist. 
Confidential
Page
83
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
o Consider hospitalization.  
o Consider short course of high dose IV 
corticosteroids: e.g., methylprednisolone 2 to 4 mg/kg IV (or 
equivalent) divided twice daily. 
o Initiate hormonal replacement as indicated. 
o Study drug administration may be resumed as allowed by protocol when: 
 Endocrinopathy is controlled with appropriate replacement therapy. 
 Corticosteroid dose reduced to ≤ 10 mg prednisone or equivalent 
per day. 
o  Brain MRI recommended. 
 
7.2.7 
Thyroid Toxicity  
Thyroid disorders may occur at any time during treatment with study drugs. Monitor 
participants for changes in thyroid function per protocol and as indicated based on clinical 
evaluation and for clinical signs and symptoms of thyroid disorders. Isolated hypothyroidism 
may generally be managed with replacement therapy without treatment delay and without 
corticosteroids, and a suggested treatment guideline for hyperthyroidism is described below: 
•
Grade 1 hyperthyroidism - No specific therapy required. 
•
Grade 2 hyperthyroidism - Hold study drugs. 
o Consider starting oral corticosteroid therapy. 
o Short course of corticosteroid such as methylprednisolone 1 to 2 mg/kg IV 
(or equivalent) divided twice daily. 
•
Resume study drugs if corticosteroid dose is reduced to ≤ 10 mg prednisone or 
equivalent per day and stable on hormone replacement therapy (if necessary). 
•
Grade 3 or 4 hyperthyroidism - Hold study drugs. 
o Consider hospitalization and consulting endocrinologist. 
o Begin IV corticosteroids such as methylprednisolone 2 to 4 mg/kg IV (or 
equivalent) divided twice daily. 
o Initiate hormonal replacement as necessary. 
o Consider restarting study drugs with complete resolution or stable on 
hormone replacement therapy within 21 days and if corticosteroid dose is 
reduced to ≤ 10 mg prednisone or equivalent per day. 
 
Confidential
Page
84
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
7.3 
Ocular Toxicity  
Ocular toxicity, including, but not limited to, dry eye, photophobia or blurry vision have been 
observed in participants treated with antibody drug conjugates, and could occur at any time 
during treatment with MGC018 administered alone or in combination with MGA012. Uveitis 
has been observed in participants treated with checkpoint inhibitors, including anti-PD-1 
antibodies, and could be seen in participants treated with MGA012. Prophylactic eye drops 
(e.g., corticosteroid, antihistamine, artificial tears) are recommended for participants 3 times 
per day, or as needed. Participants are advised not to wear contact lenses or rub their eyes 
during treatment. Participants with dry eye, photophobia or blurry vision that persists for more 
than 72 hours or worsens, or signs/symptoms suggestive of keratitis, conjunctivitis, or uveitis 
irrespective of duration, should obtain a prompt ophthalmology evaluation for further 
assessment and management, including local topical care and/or immune suppression as 
appropriate. 
7.3.1 
Uveitis  
•
Grade 1 - Refer to Ophthalmology within 7 days. Apply lubricating eye drops. 
•
Grade 2 - Hold study drugs. Refer to Ophthalmology within 2 days.  
o Coordinate management with Ophthalmology. Evaluations, under the 
guidance of ophthalmology, including but not limited to, red reflex, pupil 
size, shape, and reactivity, fundoscopic examination, and inspection of 
anterior part of eye with penlight. Consider cycloplegic eye drops, 
topical/ocular and/or systemic corticosteroids. 
o Short course of corticosteroid such as methylprednisolone 1 to 2 mg/kg IV 
(or equivalent) divided twice daily. 
o Resume study drugs if resolved to ≤ Grade 1 within 7 days. Continued 
topical/ocular and/or systemic corticosteroids are permitted when resuming 
therapy to manage and minimize local toxicity. 
•
Grade 3 - Hold study drugs. 
o Consult Ophthalmology within 24 hours. 
o Coordinate management with Ophthalmology. Evaluations, under the 
guidance of ophthalmology, including but not limited to, red reflex, pupil 
size, shape, and reactivity, fundoscopic examination, and inspection of 
anterior part of eye with penlight. Consider cycloplegic eye drops, 
topical/ocular, intravitreal, periocular, and/or systemic corticosteroids. 
o Consider restarting study drugs with resolution to ≤ Grade 1 within 7 days 
and if corticosteroid dose is reduced to ≤ 10 mg prednisone or equivalent 
per day. Continued topical/ocular and/or systemic corticosteroids are 
permitted when resuming therapy to manage and minimize local toxicity. 
•
Grade 4 - Permanently discontinue study drugs.  
o Consult Ophthalmology within 24 hours. 
Confidential
Page
85
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
o Coordinate management with Ophthalmology. Evaluations, under the 
guidance of ophthalmology, including but not limited to, red reflex, pupil 
size, shape, and reactivity, fundoscopic examination, and inspection of 
anterior part of eye with penlight. Consider cycloplegic eye drops, 
topical/ocular, intravitreal, periocular, and/or systemic corticosteroids. 
 
7.3.2 
Blepharitis  
•
Grade 1 - No specific therapy required. Daily cleansing with warm, clean cloth. 
Apply lubricating eye drops. 
•
Grade 2 - Hold study drugs 
o Consider topical/ocular corticosteroids, antihistamine, artificial tears. 
o Resume study drugs if resolved to ≤ Grade 1 within 7 days. 
•
Grade 3 - Hold study drugs. 
o Consider Ophthalmology consultation.  
o Consider topical/ocular and/or systemic corticosteroids. 
o Resume study drugs if resolved to ≤ Grade 1 within 7 days. 
•
Grade 4 - Permanently discontinue study drugs.  
o Consult Ophthalmology within 24 hours. 
o Treat as for Grade 3 and as appropriate for life-threatening symptoms. 
 
7.4 
Hematologic Toxicity  
Blood counts should be monitored to determine if dose modification is needed. Consider 
monitoring CBC bi-weekly or weekly based on the participant’s medical history and 
incidence of myelosuppressive AEs during study drug administration.  
In Cohort Expansion Phase for Module A and Module B, use of granulocyte colony 
stimulating factor (G-CSF) is permitted after Cycle 1 Day 1. Blood counts will be performed 
in case of fever (a measured temperature of 100.4°F [38°C] or greater) or evidence of 
infection. Neutropenic complications should be managed promptly with antibiotic support and 
use of G-CSF according to current ASCO guidelines for use of white blood cell growth 
factors.  
Consider transfusion of platelets for thrombocytopenia. Use of anticoagulants and platelet 
inhibitors (e.g., aspirin or nonsteroidal anti-inflammatory drugs, e.g., ibuprofen) should be 
held until thrombocytopenia resolves. 
Anemia should be evaluated and treated for other underlying etiology e.g., iron or vitamin B12 
deficiency, bleeding, and renal insufficiency. Consider transfusion of red blood cells or whole 
Confidential
Page
86
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
blood for anemia. Caution is recommended in participants with ≥ Grade 2 anemia, with 
appropriate measures taken as clinically indicated. Participants will be supported 
appropriately by the treating physician. The investigator should refer to current ASCO 
guidelines for management of cancer-associated anemia with erythropoiesis-stimulating 
agents. 
No specific treatment or study drug holds are required for lymphopenia, regardless of CTCAE 
grade, unless associated with opportunistic infection. If the participant develops an 
opportunistic infection with concurrent lymphopenia, study drug should be delayed until 
resolution of lymphopenia and the opportunistic infection (see Table 6). 
7.4.1 
Neutropenia  
•
Grade 1 or Grade 2 - No specific therapy required. Study drug should not be given 
to participants with neutrophil counts ≤ 1,500 cells/mm3. Consider dose reduction 
of study drug. 
•
Grade 3  
o Hold study drug until recovery to ≤ Grade 1 
o Monitor neutrophil counts weekly until recovery to ≤ Grade 1 
o Discontinue study drug if not recovered to ≤ Grade 1, within 21 days. 
o Restart study drug at one lower dose level if recovered to ≤ Grade 1 within 
21 days. 
•
Grade 4 
o Hold study drug until recovery to ≤ Grade 1 
o Monitor neutrophil counts weekly until recovery to ≤ Grade 1 
o Discontinue study drug if not recovered to ≤ Grade 1 within 21 days. 
o Restart study drug with one or two level dose reduction if recovered to 
≤ Grade 1. 
 
7.4.2 
Thrombocytopenia  
•
Grade 1 - No specific therapy required. Consider dose reduction of study drug. 
•
Grade 2 or Grade 3  
o Hold study drug until recovery to ≤ Grade 1 
o Monitor platelet counts weekly until recovery to ≤ Grade 1 
o Restart study drug with one level dose reduction if recovered to ≤ Grade 1 
o Discontinue study drug if not recovered to ≤ Grade 1 within 21 days. 
Confidential
Page
87
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
•
Grade 4 
o Hold study drug until recovery to ≤ Grade 1 
o Monitor platelet counts weekly until recovery to ≤ Grade 1 
o Restart study drug with one or two level dose reduction if recovered to 
≤ Grade 1 
o Discontinue study drug if not recovered to ≤ Grade 1 within 21 days. 
 
7.4.3 
Anemia  
•
Grade 1 - No specific therapy required.  
•
Grade 2  
o Consider iron replacement therapy, erythropoiesis stimulating agent 
•
Grade 3 
o Consider iron replacement therapy, erythropoiesis stimulating agent 
o Consider transfusion if symptomatic 
o Consider hold study drug until recovery to ≤ Grade 2 
o Dose reduction of one dose level for ≥ 2 events of Grade 3 anemia 
•
Grade 4 
o Transfuse with whole blood or packed red blood cells 
o Permanently discontinue study drug for Grade 4 anemia that persists 
despite intervention. 
 
7.5 
Palmar-Plantar Erythrodysesthesia   
Management guidelines for participants experiencing skin disorders due to study drug-related 
toxicity are documented in Section 7.2.4.  
For palmar-plantar erythrodysesthesia (PPE), hold study drug until toxicity resolves to 
≤ Grade 1. Study drug may be resumed with a study drug decrease of one dose level. 
Discontinue study drug if the participant does not recover to ≤ Grade 1 within 28 days. 
7.6 
Pleural and Pericardial Effusions  
Supportive care per institutional practice should be used to manage pleural and pericardial 
effusions. For pleural and pericardial effusions consider a dose delay and/or dose reduction. 
The investigator should contact the sponsor to discuss the appropriate dose of study drug 
based on the safety profile and evidence of antitumor activity with study drug. 
Confidential
Page
88
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
7.6.1 
Pleural Effusion  
•
Grade 1 - No specific therapy required; close monitoring of cardiac and lung 
function and imaging. 
o Consider diuretics.  
•
Grade 2 - Hold study drugs. 
o Consider diuretics or limited therapeutic thoracentesis. 
o Consider corticosteroids: 1 to 2 mg/kg of oral prednisone or equivalent per 
day divided twice daily. Taper corticosteroids (e.g., 5 to 10 mg every 1 to 2 
weeks from an initial dose above 40 mg prednisone per day) over 4 weeks 
or as clinically indicated.  
o Resume study drug administration with a one level dose reduction at next 
scheduled dose if pleural effusion resolves to ≤ Grade 1 within 21 days. If 
pleural effusion Grade 2 recurs further reduce dose by one dose level.  
•
Grade 3 - Hold study drugs. 
o Therapeutic thoracentesis 
o Consider corticosteroids: 1 to 2 mg/kg of oral prednisone or equivalent per 
day divided twice daily. Taper corticosteroids (e.g., 5 to 10 mg every 1 to 2 
weeks from an initial dose above 40 mg prednisone per day) over 4 weeks 
or as clinically indicated.  
o Resume study drug administration with a one level dose reduction at next 
scheduled dose if pleural effusion resolves to ≤ Grade 1 within 21 days. If 
pleural effusion Grade 3 recurs further reduce dose by one dose level.  
•
Grade 4 - Permanently discontinue study drugs. 
o Hospitalize. 
o Recommend a pulmonary consult/diagnostic evaluation including chest 
X-ray and CT scan. 
o Initiate maximal supportive care including IV corticosteroids, suggest 
methylprednisolone at 2 to 4 mg/kg/day divided twice daily. Continue IV 
methylprednisolone 2 mg/kg/day for a total of 5 days then switch to oral 
prednisolone 1 mg/kg/day × 3 days, then reduce to 60 mg/day 
prednisolone. Reduce prednisolone dose by 10 mg every 7 days (as toxicity 
allows) until dose is 10 mg/day. Once steroid dose is 10 mg/day, reduce by 
5 mg every 7 days then stop. Higher doses may be used in consultation 
with the sponsor’s medical monitor. 
 
Confidential
Page
89
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
7.6.2 
Pericardial Effusion  
•
Grade 2 - Hold study drugs. 
o Consider diuretics.  
o Consider corticosteroids: 1 to 2 mg/kg of oral prednisone or equivalent per 
day divided twice daily. Taper corticosteroids (e.g., 5 to 10 mg every 1 to 2 
weeks from an initial dose above 40 mg prednisone per day) over 4 weeks 
or as clinically indicated.  
o Resume study drug administration at next scheduled dose with a one level 
dose reduction if pericardial effusion resolves to ≤ Grade 1 within 21 days. 
If pericardial effusion Grade 2 recurs further reduce dose by one dose level. 
•
Grade 3 - Hold study drugs. 
o Consider pericardiocentesis. 
o Consider corticosteroids: 1 to 2 mg/kg of oral prednisone or equivalent per 
day divided twice daily. Taper corticosteroids (e.g., 5 to 10 mg every 1 to 2 
weeks from an initial dose above 40 mg prednisone per day) over 4 weeks 
or as clinically indicated.  
o Resume study drug administration at next scheduled dose with a one level 
dose reduction if pericardial effusion resolves to ≤ Grade 1 within 21 days. 
If pericardial effusion Grade 3 recurs further reduce dose by one dose level. 
•
Grade 4 - Permanently discontinue study drugs. 
o Hospitalize. Consider pericardiocentesis 
o Recommend a cardiology consult/diagnostic evaluation including 
echocardiogram. 
o Initiate maximal supportive care including IV corticosteroids, suggest 
methylprednisolone at 2 to 4 mg/kg/day divided twice daily. Continue IV 
methylprednisolone 2 mg/kg/day for a total of 5 days then switch to oral 
prednisolone 1 mg/kg/day × 3 days, then reduce to 60 mg/day 
prednisolone. Reduce prednisolone dose by 10 mg every 7 days (as toxicity 
allows) until dose is 10 mg/day. Once steroid dose is 10 mg/day, reduce by 
5 mg every 7 days then stop. Higher doses may be used in consultation 
with the sponsor’s medical monitor. 
 
Confidential
Page
90
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
7.7 
Nervous System Toxicity  
Consider discontinuation of MGA012 for patients who experience Grade 2 myasthenia gravis, 
Grade 2 Guillain-Barre syndrome, and permanently discontinue study drugs for any grade 
transverse myelitis. Management guidelines for participants experiencing nervous system 
toxicity are as follows: 
•
Grade 1 - No specific therapy required; close monitoring of neuropathy. 
•
Grade 2 - Hold study drugs. 
o Consider neurology consultation. 
o Consider corticosteroids: 1 to 2 mg/kg of oral prednisone or equivalent per 
day divided twice daily. Taper corticosteroids over 4 weeks or as clinically 
indicated. 
o Resume study drug administration at next scheduled dose if: 
 Resolves to ≤ Grade 1 within 21 days with or without treatment 
•
Grade 3 and 4 - Permanently discontinue study drugs. 
o Consider hospitalization and neurology consultation 
o Begin corticosteroids: 2 to 4 mg/kg of oral or IV methylprednisolone or 
equivalent per day divided twice daily. Continue IV methylprednisolone 
2 mg/kg/day for a total of 5 days then switch to oral prednisolone 
1 mg/kg/day × 3 days, then reduce to 60 mg/day prednisolone. Reduce 
prednisolone dose by 10 mg every 7 days (as toxicity allows) until dose is 
10 mg/day. Once steroid dose is 10 mg/day, reduce by 5 mg every 7 days 
then stop. 
 
7.8 
Cardiotoxicity  
Management guidelines for participants experiencing cardiovascular toxicity are as follows: 
•
Grade 1 - No specific therapy required; close monitoring. 
•
Grade 2 - Permanently discontinue study drugs for patients who experience Grade 
2 myocarditis. 
o Consider cardiology consultation. Evaluate cardiac biomarkers e.g., 
creatine kinase, troponin, and beta-natriuretic peptide. Echocardiogram and 
CT imaging if clinically indicated. 
o Consider corticosteroids: 1 to 2 mg/kg of oral prednisone or equivalent per 
day divided twice daily. Taper corticosteroids over 4 weeks or as clinically 
indicated. 
•
Grade 3 and 4 - Permanently discontinue study drugs. 
o Consider hospitalization and cardiology consultation 
Confidential
Page
91
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
o Evaluate cardiac biomarkers e.g., creatine kinase, troponin, and beta-
natriuretic peptide. Echocardiogram and CT imaging if clinically indicated. 
o Begin corticosteroids: 2 to 4 mg/kg of oral or IV methylprednisolone or 
equivalent per day divided twice daily. Continue IV methylprednisolone 
2 mg/kg/day for a total of 5 days then switch to oral prednisolone 
1 mg/kg/day × 3 days, then reduce to 60 mg/day prednisolone. Reduce 
prednisolone dose by 10 mg every 7 days (as toxicity allows) until dose is 
10 mg/day. Once steroid dose is 10 mg/day, reduce by 5 mg every 7 days 
then stop.  
o Consider infliximab. 
 
7.9 
Musculoskeletal Toxicity  
Management guidelines for participants experiencing musculoskeletal toxicity are as follows: 
•
Grade 1 - No specific therapy required; close monitoring. Consider nonsteroidal 
anti-inflammatory medication e.g., ibuprofen. 
•
Grade 2 - Hold study drugs. 
o Consider rheumatology consultation.  
o Consider corticosteroids: 1 to 2 mg/kg of oral prednisone or equivalent per 
day divided twice daily. Taper corticosteroids over 4 weeks or as clinically 
indicated. 
o Resume study drug administration at next scheduled dose if: 
 Resolves to ≤ Grade 1 within 21 days with or without treatment. 
•
Grade 3 and 4 - Hold or permanently discontinue study drugs. 
o Consider hospitalization and rheumatology consultation 
o Begin corticosteroids: 2 to 4 mg/kg of oral or IV methylprednisolone or 
equivalent per day divided twice daily. Continue IV methylprednisolone 
2 mg/kg/day for a total of 5 days then switch to oral prednisolone 
1 mg/kg/day × 3 days, then reduce to 60 mg/day prednisolone. Reduce 
prednisolone dose by 10 mg every 7 days (as toxicity allows) until dose is 
10 mg/day. Once steroid dose is 10 mg/day, reduce by 5 mg every 7 days 
then stop. 
o Consider infliximab. 
o If not responding within 14 days consider use of disease modifying 
antirheumatic drugs, e.g., sulfasalazine, methotrexate. 
 
Confidential
Page
92
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
8 
CONCOMITANT THERAPY AND RESTRICTIONS  
8.1 
Concomitant Therapy  
All concomitant medications, including prophylactic pre-infusion medications and IV fluids, 
and blood products administered during the participant’s participation in the study until the 
End of Treatment Visit must be recorded in the source document and on the eCRF. All 
changes in infusions, including interruptions and their duration as well as reductions in rate 
and duration, must be recorded. 
8.1.1 
Prohibited Therapy  
The following rules concerning concurrent treatment(s) will apply in this study: 
•
Any other anti-neoplastic therapies are prohibited, including but not limited to, 
chemotherapy or other small molecules, vaccines, biologics, radiotherapy (including 
radioligands e.g., radium-223) for all tumor types or androgen receptor antagonists or 
androgen synthesis inhibitors (e.g., enzalutamide or abiraterone, respectively) for 
mCRPC. 
o For participants who require palliative radiotherapy (i.e., cumulative dose 
less than 3000 rads, limited field of distribution) for reasons other than 
disease progression, therapy may be interrupted for up to 4 weeks. 
Palliative radiotherapy may not be given concurrently with the study drug. 
Treatment with palliative therapy should be initiated at least 24 hours after 
receiving study drug, and re-initiation of MGC018 alone (Module A) or in 
combination with MGA012 (Module B) can begin 2 weeks after the 
completion of palliative radiotherapy as appropriate, if there were no 
complications associated with the radiotherapy. If palliative radiotherapy 
fields overlap tumor lesions that are designated target lesions, the 
participant may continue on study, but will no longer be evaluable for 
objective response from the time palliative radiotherapy is initiated.  
•
Participants may not receive other investigational drugs during the period of study 
participation. 
•
Module B only: Because MGA012 has 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 in excess of 10 mg daily of 
prednisone or equivalent are prohibited other than for the management of drug-related 
adverse experiences. Steroids may be employed in the treatment of suspected 
MGA012 associated immune-inflammatory or autoimmune AEs in consultation with 
the sponsor. 
•
The use of other immuno-suppressive agents is prohibited, unless they are being used 
to treat an AE (including topical, otic, and ophthalmic corticosteroids). 
Confidential
Page
93
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
•
Prophylactic use of G-CSF, granulocyte-macrophage colony stimulating factor (GM-
CSF), or other growth factors is prohibited during Dose Escalation Phase with the first 
cycle of treatment with MGC018 administered alone or in combination with MGA012.  
•
Participants should not receive vaccination with any live virus vaccine during the 
study and for 120 days following a participant's last dose of study drug. Inactivated 
annual influenza and non-live SARS-CoV-2 vaccinations are allowed. 
 
8.1.2 
Permitted Therapies  
Participants may receive the following concurrent therapy: 
•
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. 
•
Use of bisphosphonates or receptor activator of nuclear factor kappa-B ligand 
(RANK-L) inhibitors is allowed. 
•
For participants with prostate cancer, testosterone suppression with human 
gonadotropin releasing hormone antagonists or agonists is allowed. 
•
The use of growth factors in Cohort Expansion Phase as prophylaxis in any cycle or 
with successive cycles of study drug is permitted. In Dose Escalation Phase growth 
factors may be considered on a case-by-case basis in consultation with the sponsor. 
 
8.1.3 
Contraception  
Male and female participants are required to use highly-effective contraceptive measures as 
specified below. Male participants are required to use a condom regardless of his female of 
childbearing potential partner’s method of contraception.  
•
Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation:  
o Oral  
o Intravaginal  
o Transdermal  
•
Progestogen-only hormonal contraception associated with inhibition of ovulation:  
o Oral  
o Injectable 
o Implantable   
Confidential
Page
94
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
•
Intrauterine device (IUD) 
•
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 female of child bearing potential 
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 participant. 
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 
participants during the study, although it is recommended that, to the extent possible, 
participants have an adequate fluid intake on days associated with PK sampling. 
8.2.2 
Participant Activity Restrictions  
There are no restrictions on participant activities and no requirement for participant 
confinement during the study. However, participants are advised to limit direct sun exposure 
and to use a broad-spectrum sunscreen when outdoors. Participants are advised not to wear 
contact lenses or rub their eyes during treatment. Participants should be advised to avoid 
activities that promote skin chafing, prolonged or untoward skin pressure, occlusive skin 
dressings, or hot tub baths. 
Confidential
Page
95
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
9 
STUDY PROCEDURES  
This section provides a general description of the procedures and assessments associated with 
this study. The timing of the study procedures and the windows permitted for the assessments 
is presented in Appendix 1. 
During the COVID-19 pandemic, alternative methods for conducting study assessments 
should be considered when compliance, feasibility, and safety can be assured. These methods 
may include: 
•
Telemedicine visits, e.g., via telephone/video (using compliant video-conference 
tools as permitted by health authority regulations) 
•
Use of primary care centers and local laboratories for blood draws and 
imaging/radiographs 
 
If alternative methods are used, local laboratory reference ranges will be documented and 
submitted to the sponsor. Local laboratory test results, laboratory accreditation (if possible), 
and reports of tumor assessments should be retrieved and documented in the participant’s 
study records. 
9.1 
Informed Consent  
The investigator is responsible for ensuring that the participant provides informed consent 
prior to performing any study-related assessments, evaluations, or procedures that are not part 
of standard-of-care for the participant’s disease. Informed consent for this study must be 
provided by signing an Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) approved informed consent document (Consent for Study Participation). A copy of the 
relevant signed informed consent document must be provided to the participant and the 
original maintained according to institutional procedures. The participant’s medical records 
will include documentation of the informed consent process. 
9.2 
Screening Period  
Participants may receive the first dose up to 28 days from signing the informed consent. This 
period is defined as the screening period. At the screening visit, participants 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 
participant. 
9.3 
Registration  
Only those participants who meet all inclusion/exclusion criteria specified in Section 5 will be 
entered into this study. 
Confidential
Page
96
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Once the participant has been determined to be eligible for enrollment into the study, the 
participant must be registered with MacroGenics. The following information should be 
provided during registration: 
•
Age 
•
Tumor type 
•
Date of signed informed consent 
•
Planned date of first administration 
 
Instructions for the registration process are provided in the Slot Assignment Plan. 
9.4 
Medical History  
A complete medical history will be obtained during the screening visit. All concurrent medical 
conditions and any past medical conditions in the medical record (e.g., hospitalizations, 
surgeries, chronic conditions, prior cancer history, etc.) will be collected. All PSA values in 
the medical record up to 12 months (mCRPC only), BRAF mutation status (melanoma only, if 
available), HPV status (SCCHN only, if available), and BRCA-1 and BRCA-2 results prior to 
enrollment will be collected (if available). Any untoward event that occurs prior to the first 
dose of study drug will be recorded as medical history and not as an AE, unless it is due to a 
protocol-related procedure. 
9.5 
Prior and Concomitant Medications  
All concomitant medications and blood products administered to participants during screening 
and participation in the study until the End of Treatment Visit (EOTV) must be recorded in the 
source document and 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. 
9.6 
Physical Examination  
The investigator will perform physical examination of all participants; the examinations will 
be conducted as specified in Appendix 1. A full physical examination will include height 
(screening only), weight, and examination of head, eyes, ears, nose, throat, lymph nodes, 
heart, chest, lungs, abdomen, extremities, neurologic system and total body skin examination 
(TBSE). If any visual signs or symptoms are noted at screening, an ophthalmologic 
examination will be performed. 
A directed physical examination will be conducted as specified in Appendix 1. The 
examination will be based on review of participant symptoms, history, and as clinically 
indicated. Each examination should include a TBSE to detect muco-cutaneous AEs. 
Confidential
Page
97
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
9.6.1 
Vital Signs  
Vital signs include temperature, pulse, blood pressure, and respiratory rate and are obtained as 
specified in Appendix 1. It is recommended vital signs are obtained in a seated, 
semi-recumbent, or supine position after an appropriate rest.  
9.7 
ECOG Performance Status  
ECOG performance status should be measured as specified in Appendix 1. 
9.8 
Clinical Laboratory Tests  
Blood and urine samples will be collected at the times specified in Appendix 1. Hematology, 
chemistry, pregnancy, urinalysis, coagulation time, and endocrine evaluation tests (as 
applicable) will be performed locally. Test results for pregnancy, chemistry, and hematology 
must be reviewed prior to all infusions of MGC018. On the dosing days, clinical laboratory 
tests should be collected prior to administration of prophylactic pre-medications. Local 
laboratory tests to be performed are presented in Appendix 2. 
•
A blood sample for local testing of the tumor marker PSA will be collected from 
participants with mCRPC. PSA measurements are performed at the times specified in 
Appendix 1 and approximately every 12 weeks during the post-treatment follow-up 
period until disease progression, start of another cancer therapy, or the study cutoff 
date, whichever comes first. 
•
A blood sample for testosterone will be collected from participants with mCRPC in 
Cohort Expansion. Testosterone measurements are performed at the times specified in 
Appendix 1 and approximately every 12 weeks during the post-treatment follow-up 
period until disease progression, start of another cancer therapy, or the study cutoff 
date, whichever comes first. 
 
9.8.1 
Central Laboratory Assays  
Other laboratory tests (e.g., PK, anti-drug antibody [ADA] assays [Appendix 1 and 
Appendix 3]) will be performed at sponsor-specified central laboratories. Additional details 
on collection, processing, storage, and shipping of central laboratory samples will be provided 
in the laboratory manual. 
9.8.2 
Pharmacokinetics  
Blood samples for conjugated antibody, total antibody, and SYD986 and MGA012 PK will be 
collected at the time points shown in Appendix 3. Blood samples will be collected from the 
arm contralateral to the site of IV infusion. If an indwelling catheter is used, the fluid in the 
catheter will be removed and discarded prior to the collection of blood sample for PK 
assessment. 
Confidential
Page
98
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
9.8.3 
Pharmacodynamics/Biomarkers  
Procedures for the acquisition, handling, and processing of pharmacodynamic biomarker 
specimens will be provided in the laboratory manual. These tests will be collected according 
to Appendix 3. 
9.8.4 
Sample Collection, Storage, and Shipping  
Details on laboratory specimen processing, storage, and shipping will be provided in the 
laboratory manual. 
9.9 
Radiographic, CT, PET, MRI or Bone Assessments  
Baseline tumor imaging consists of a CT (or PET/CT) and/or MRI scans of the chest, 
abdomen, and pelvis with contrast per RECIST v1.1 (unless medically contraindicated) for all 
participants to document tumor burden. The subsequent tumor assessments on treatment 
should use the same imaging modality as that for the baseline assessment. In addition, a bone 
scan will be used in the Cohort Expansion Phase for participants with mCRPC. For 
participants with equivocal new bone lesion(s) on bone scan consider obtaining additional 
imaging to evaluate new lesion(s) for tumor involvement e.g., x-ray, CT or MRI.  
A CT or MRI scan of the brain will be performed in cases in which it is clinically indicated 
(e.g., history of or suspicion of brain metastases) and repeat brain scans will be performed 
only if the screening brain scan was positive, or as clinically indicated.  
9.10 
Electrocardiography  
Twelve-lead electrocardiogram (ECGs) will be obtained according to the Time and Events 
Schedules (Appendix 1) in order to evaluate the potential cardiac effect, including QTc 
interval prolongation.  
To account for intrinsic variability, all ECGs should be obtained in triplicate (3 ECGs per time 
point at approximately 1-minute intervals). Central interpretation of ECGs will be used for 
data analysis purposes. The actual time of the first of three ECGs per timepoint will be 
recorded as the actual time of the ECG. 
9.11 
Echocardiography/MUGA scan  
An echocardiogram (or MUGA scan) to evaluate LVEF will be performed according to the 
schedule in Appendix 1. Echocardiogram/MUGA scan may be performed at the investigator’s 
discretion as clinically indicated.   
9.12 
Ophthalmological Examination  
Ophthalmic examination should be performed by an ophthalmologist, according to the 
schedule for Dose Escalation Phase Module A and Module B and Cohort Expansion Phase 
Confidential
Page
99
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Module B in Appendix 1. The examination will include visual acuity testing (with 
correction), fundoscopic examination, and tonometry. Other directed studies (e.g., optical 
coherence tomography) will be performed as clinically indicated. If clinically indicated, 
participants should obtain an ophthalmology evaluation for further assessment and 
management. 
9.13 
Archival Tissue  
Participants to be enrolled on this study must have an identified archival tumor specimen 
block (FFPE) or at least 10 unstained slides from archival tumor specimen or 
contemporaneous biopsy for the determination of B7-H3 (Module A) and B7-H3 and PD-L1 
(Module B) expression. Tumor specimens for determination of B7-H3 and PD-L1 expression 
via IHC staining will be collected during screening on all participants during both Dose 
Escalation Phase and Cohort Expansion Phase and will be assayed at a central laboratory 
designated by the sponsor. Determination of B7-H3 and PD-L1 IHC testing results will not be 
required prior to protocol enrollment. Prior B7-H3 testing results may be accepted at the 
discretion of the sponsor to satisfy this requirement. Participants may undergo a fresh tumor 
biopsy to obtain a specimen for testing if a suitable sample cannot be identified. The 
specimens will be analyzed retrospectively and will not be used to determine participant 
eligibility. 
9.14 
Tumor Biopsy Specimens  
Tumor biopsies of accessible lesions, pre- and post-first cycle of treatment, are strongly 
encouraged for participants in the Cohort Expansion Phase of the study (Module A and B). 
Biopsy should be considered for any participant in the Cohort Expansion Phase with an 
accessible lesion and should be performed pre (baseline) and post the first Cohort Expansion 
Phase cycle (Day 42) of treatment. Tumor lesions used for biopsy should be lesions that are 
felt to be accessible with acceptable clinical risk in the judgment of the investigator and 
should not be lesions used as RECIST v1.1 target lesions. Lesions to be biopsied should be of 
sufficient size to enable acquisition of at least 2 tumor biopsy cores using a 16-gauge biopsy 
needle. Exceptions to the gauge of the needle may be considered after consultation with the 
sponsor’s medical monitor. Up to 3 additional biopsy cores may be obtained if this can be 
performed with acceptable clinical risk in the judgment of the investigator. Excisional biopsies 
are allowed if these can be performed with acceptable clinical risk in the judgment of the 
investigator. Immediate confirmation of the adequacy of the biopsy specimen and the presence 
of malignant cells in the tumor biopsy is strongly encouraged at the time of acquisition. 
Additional instructions for the processing and storage of tumor biopsy specimens will be 
provided in the laboratory manual.  
9.15 
Patient-reported Outcome  
Patient reported outcome (PRO) will be assessed using the BPI-sf (Appendix 6). The BPI-sf 
is an exploratory 9 item self-administered written questionnaire used to evaluate the severity 
of a participant's pain and the impact of the pain on daily functioning. The participant will be 
asked to rate their “worst,” “least,” “average,” and “right now” (current) pain intensity on a 
Confidential
Page
100
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
10-point scale ranging from zero (no pain) to 10 (pain as bad as you can imagine). Participants 
will also be asked to list their current treatments for pain and their perceived effectiveness (on 
a scale of 0% to 100%), and to rate the degree that pain interferes with 7 daily activities 
(general activity, mood, walking ability, normal work, relations with other persons, sleep, and 
enjoyment of life) on a 10 point scale ranging from zero (does not interfere) to 10 (completely 
interferes).  
9.16 
End of Treatment Visit  
A list of evaluations to be performed for the EOTV is provided in Appendix 1. The EOTV 
should be performed after the participant has met study treatment discontinuation criteria 
specified in Section 5.4; the visit should be performed within 30 days following the last dose 
of study drug. It is recognized that certain participants (such as those experiencing progression 
of disease) may be cared for in facilities other than the participating study site, may proceed to 
receive other cancer therapy, and/or may elect not to return to the study site. Therefore, this 
visit is considered optional, but should be carried out whenever possible. All required 
procedures and tests should be performed if the visit is performed. Note: the tumor assessment 
will not be performed at the EOTV for participants who had a previous scan performed 
< 28 days of the EOTV.  
9.17 
Post-Treatment Follow-up Visit  
The Post-Treatment Follow-up period includes the following: 
•
Survival follow-up for participants in the Cohort Expansion Phase of Module A or 
Module B: approximately a 2-year period for each participant following the last dose 
of MGC018; this period runs until the last participant in the study completes his/her 
survival follow-up period. Participants in Module A Dose Escalation will be followed 
for survival status until approval of Amendment 3, at which point they will be 
discontinued from follow up. 
•
During this time, participants will be followed via clinic visit, telephone, paper mail, 
or other electronic contact at 3-month (90 days) intervals for follow-up of OS.  
•
For mCRPC participants, serum testosterone and PSA will be collected approximately 
every 12 weeks during the follow-up period until disease progression, start of another 
cancer therapy, or the study cutoff date, whichever comes first.  
•
Response status: information regarding response status and/or the occurrence of 
disease progression may be collected every 3 months (90 days) on all participants who 
discontinued from study treatment due to reasons other than PD, if they have not 
initiated any other cancer-directed therapy. Tumor response results (e.g., CT imaging 
results) may be entered in the electronic data capture (EDC) system if available per 
standard of care procedures to document the date of progression. 
 
Post-Treatment Follow-up is performed until the end of study for each participant. Survival 
follow-up will be discontinued for participants enrolled in Module A Dose Escalation Phase 
after the approval of Amendment 3. 
Confidential
Page
101
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
10 
ASSESSMENT OF PHARMACOKINETICS AND 
PHARMACODYNAMICS  
10.1 
Pharmacokinetics Assessments  
Serum concentrations of conjugated antibody and total antibody following administration of 
MGC018 and serum concentrations of MGA012 will be monitored using quantitative 
bioanalytical methods. Plasma concentrations of SYD986 following administration of 
MGC018 will be monitored using a 
 
 Where applicable, single- and multiple-dose PK parameters, Cmax, Tmax, 
AUC(0-T), AUC(TAU), AUC from time 0 to infinity [AUC(INF)], Ctrough, CL, volume of 
distribution at steady state (Vss), t1/2, and accumulation index (AI), will be derived from serum 
or plasma concentration versus time data.  
10.2 
Immunogenicity Assessments  
Blood samples for the immunogenicity assessments will be collected at the time points shown 
in Appendix 3. The anti-drug antibodies (ADA) against MGC018 and MGA012 will be 
detected using validated bridging assay methods. 
10.3 
Pharmacodynamic/Biomarker Assessments  
10.3.1 
Tests Performed for Both Dose Escalation and Cohort 
Expansion Participants  
Tests to be performed for pharmacodynamic/biomarker assessments include, but are not 
limited to, the following: 
•
Expression of B7-H3 (Module A) and B7-H3 and PD-L1 (Module B) by IHC on 
archival and on fresh pre-treatment harvested tumor specimens will be performed 
retrospectively 
•
Characterization of immune cell subset phenotype on peripheral blood mononuclear 
cells (PBMCs) 
•
Characterization of serum cytokine levels 
•
PD-1 receptor occupancy on PBMC in participants who receive MGA012 (Module B 
only). 
 
10.3.2 
Tests Performed for Cohort Expansion Phase Participants Only  
Tests to be performed for pharmacodynamic/biomarker assessments may include, but are not 
limited to, the following: 
Confidential
Page
102
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
•
Characterization of ICD markers, immune infiltrate, PD-L1, and other markers, 
depending on tissue availability, within paired tumor biopsy specimens optional for 
participants that consent to biopsy (pre/on-treatment post Cycle 1 biopsies). 
•
Characterization of TCR repertoire using T-cell spectratyping on peripheral PBMCs 
and on immune-cellular infiltrate in the tumors done on paired tumor biopsy 
specimens (pre/on-treatment post Cycle 1 biopsies). Pre/on-treatment tumor biopsies 
are optional and will be carried out only during the Cohort Expansion Phase for 
participants that consent to biopsy.  
•
Characterization of IFNγ signature on paired tumor biopsy specimens 
(pre/on-treatment post Cycle 1 biopsies) via transcript profiling; and in circulation, 
pre/on-treatment tumor biopsies are optional and will be carried out only during the 
Cohort Expansion Phase for participants that consent to biopsy. 
•
Characterization of serum biomarkers, including, but not limited to, IFNγ signature, 
may be carried out depending on observed antitumor activity. 
 
Confidential
Page
103
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
11 
ASSESSMENT OF EFFICACY  
11.1 
Efficacy Assessments  
11.1.1 
Disease Response Assessments  
Tumor assessments will be obtained using CT (or PET/CT) and/or MRI scans. For mCRPC 
participants a bone scan will be obtained in addition to CT and/or MRI scans at baseline and 
on study. Target and non-target lesions will be designated at screening and then evaluated at 
every 6 weeks (42 days) for the first four cycles, and every other cycle thereafter while the 
participant in Module A Dose Escalation and Module B is on study treatment; every 9 weeks 
(63 days) for Cohort Expansion Module A participants. For mCRPC a lymph node is to be 
≥ 20 mm to be a target lesion. In situations where the bone scan ﬁndings are suggestive of a 
ﬂare reaction or apparent new lesion(s) may represent trauma, additional imaging to conﬁrm 
these results with other imaging modalities such as MRI or ﬁne-cut CT should be obtained. At 
each tumor assessment time point, the overall response status will be determined based on 
assessment of target and non-target lesions as well as appearance of any new lesions. 
Radiographic disease progression in mCRPC is defined in Section 14.6.4.1. Participants who 
discontinued from study treatment due to reasons other than documented, confirmed 
progressive disease, will be contacted every 3 months (90 days) during the Post-Treatment 
Follow-up period about the response status and survival of these participants, as applicable. 
For RECIST v1.1 (Appendix 5), the overall responses will be categorized as Complete 
Response (CR), Partial Response (PR), Stable Disease (SD), Progressive Disease (PD), or Not 
Evaluable (NE). For participants who experience an objective response of CR or PR, 
responses will be considered unconfirmed until the response has been documented by a 
subsequent confirmatory scan obtained no less than 4 weeks after the initial scan 
demonstrating an objective response. 
11.1.2 
Survival Assessments  
Participants who are discontinued from study treatment in the Cohort Expansion Phase of 
Module A or Module B will be followed for survival status every 3 months (90 days) for a 
2-year survival follow-up period following the last dose of MGC018 alone (Module A) or in 
combination with MGA012 (Module B), or until the event of death, they withdraw consent, or 
are lost to follow-up (see Section 9.17). Survival follow-up will be discontinued for 
participants enrolled in Module A Dose Escalation after the approval of Amendment 3. 
Confidential
Page
104
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
12 
ADVERSE EVENT REPORTING AND ASSESSMENT OF 
SAFETY  
The safety assessment will be based on the evaluation of AEs that occur from the time of 
initiation of administration of study drug through 30 days following the last dose of study 
drug or until the start of a subsequent systemic anticancer therapy (whichever occurs first) and 
will be determined based on signs, symptoms, physical examination findings, procedure 
findings, and/or laboratory test results from enrolled participants, as appropriate. 
Protocol-related AEs and SAEs will be collected from the time the participant has consented 
to study participation. AEs and SAEs reported between the time the participant signs the 
informed consent form (ICF) and the administration of the first dose of study drug will be 
captured as medical history unless the events are attributed to protocol-specified procedures 
that are not part of standard of care that occur during this time period, in which case the events 
will be collected on the Adverse Event CRFs.  
SAEs considered related to study drug may be reported at any time, even after the 
participant’s final visit. 
Progression of the underlying tumor resulting in hospitalization or death (e.g., participant 
hospitalized for or dies from progressive disease [PD] only, without any other SAE) will be 
documented as a tumor response outcome and not as an SAE. If an SAE occurs in a 
participant and it is unclear whether the event is related to PD, the SAE should be reported. 
12.1 
Definitions  
12.1.1 
Adverse Event  
Adverse event means any untoward medical occurrence in a participant or clinical trial 
participant associated with the use of a drug in humans, whether or not considered drug 
related. An AE can therefore 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. 
This includes any occurrence that is new in onset or aggravated in severity or frequency from 
the baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.  
12.1.2 
Adverse Drug Reaction  
Adverse drug reaction (ADR) is a noxious and unintended response to the medicinal product 
related to any dose. As used herein, the phrase “response to a medicinal product” means that a 
causal relationship between a medicinal product and an AE is at least a reasonable possibility. 
Confidential
Page
105
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
12.1.3 
Adverse Event of Special Interest  
An adverse event of special interest (AESI) is an event of scientific and medical interest or 
concern to the sponsor’s product or program, for which ongoing monitoring and rapid 
communication to the sponsor could be appropriate. It may be a serious or non-serious AE, 
which may require further investigation in order to characterize and understand it; refer to 
Section 12.2.4 for full details. 
12.1.4 
Attribution/Assessment of Causality  
Attribution/Assessment of Causality is a determination that describes the relationship or 
association of the study product with an adverse event.  
This assessment of causality or relationship of AEs to the study drug is provided by the 
investigator and is determined by 1) temporal relationship of the event to the administration of 
study drug; 2) whether an alternative etiology has been identified, and 3) biological 
plausibility. Causality must be assessed separately for each study drug. 
The causality assessment categories that will be used for this study are described below. 
Causality assessments that are considered not related to study drug: 
None: The event is related to an etiology other than the study drug (the alternative etiology 
should be documented in the participant’s medical record). 
Unlikely: The event is unlikely to be related to the study drug and likely to be related to 
factors other than study drug. An alternative explanation is more likely (e.g., concomitant 
drugs, concomitant disease), or the relationship in time suggests that a causal relationship is 
unlikely. 
If an SAE is considered “unlikely” or “unrelated” to study drug, the investigator should offer 
his/her clinical opinion as to what factor(s), agent(s), or process(es) were the likely causative 
mechanism for the event. 
Causality assessments that are considered related to study drug: 
Possible: There is an association between the event and the administration of the study drug 
and there is a plausible mechanism for the event to be related to study drug; but there may 
also be alternative etiology, such as characteristics of the participant’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 participant’s clinical status or an 
alternative etiology is not apparent. 
Confidential
Page
106
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
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 is ruled out, and/or the event re-appeared on re-exposure to the study drug. 
12.1.5 
Serious Adverse Event  
A SAE is any adverse event 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 
 
12.1.6 
Severity Criteria  
An assessment of severity grade will be made using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03 (v4.03). The CTCAE 
are published standardized definitions for AEs to describe the severity of laboratory and organ 
toxicity for participants receiving cancer therapy. The investigator should use clinical 
judgment in assessing the severity of events not directly experienced by the participant 
(e.g., laboratory abnormalities). 
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. 
 
Confidential
Page
107
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
12.2 
Adverse Event Collection and Documentation  
12.2.1 
All Adverse Events  
All participants who receive at least one dose of study drug will be considered evaluable for 
safety. AEs will be determined based on signs, symptoms, physical examination findings, 
and/or laboratory test results from enrolled participants as appropriate. 
All adverse events whether serious or non-serious, will be reported from the time a signed and 
dated ICF is obtained through 30 days following the last dose of study drug or until the start 
of a subsequent systemic anticancer therapy (whichever occurs first).  
Both protocol-related AEs and SAEs will be collected from the time the participant has 
consented to study participation. AEs and SAEs reported between the time the participant 
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 and SAE Report form as appropriate.  
All adverse events, regardless of seriousness, severity, or presumed relationship to study drug, 
must be recorded using medical terminology in the source document and the eCRF. All 
records will need to capture: 
•
the details of the duration, severity, and seriousness of each adverse event  
•
the action taken with respect to the study drug(s) 
•
the investigator’s attribution/causality assessment concerning the relationship of the 
adverse event to study therapy 
•
the outcome of the event 
 
Whenever possible, diagnoses should be given when signs and symptoms are due to a 
common etiology (e.g. cough, runny nose, sneezing, sore throat, and head congestion should 
be reported as “upper respiratory infection”). All treatment measures that are required for AE 
management must be recorded in the source document. The intensity (severity) of AEs will be 
assessed using NCI CTCAE v4.03 and serious events will be determined by the definition 
provided in Section 12.1.5 above. Generally, all non-serious AEs should be entered into the 
eCRFs within 10 calendar days of the site’s awareness. 
Confidential
Page
108
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Clinical Laboratory Changes: Safety laboratory assessments will be evaluated by the 
investigator to ensure participant safety. Laboratory tests will be graded according to 
NCI CTCAE v4.03. 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 should be reported as an AE if it is associated with an 
intervention. An intervention includes, but is not limited to, discontinuation of 
treatment, dose reduction/delay, or concomitant therapy. In addition, any medical 
important laboratory abnormality may be reported as an AE at the discretion of the 
investigator. This includes laboratory abnormalities for which there are no 
interventions, but the abnormal value(s) suggests a disease or organ toxicity. If clinical 
sequelae are associated with a laboratory abnormality, the diagnosis or medical 
condition should be reported (e.g., renal failure, hematuria) not the laboratory 
abnormality (e.g., elevated creatinine, urine RBC increased). 
 
Section 12.2.6 summarizes AE (e.g., SAEs, pregnancy, IREs, etc.) reporting to the sponsor 
timeframes. 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 Independent 
Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol, unless 
otherwise required and documented by the IEC/IRB. 
For this study, the participants must be provided with a “wallet (study) card” and instructed to 
carry this card with them for the duration of the study indicating the following: 
•
Study number 
•
Statement, in the local language(s), that the participant is participating in a clinical 
study 
•
Investigator's name and 24-hour contact telephone number 
•
Site number 
•
Participant number 
 
12.2.2 
Immediately Reportable Events  
IREs are events that must be reported immediately to MacroGenics within 24 hours of the 
study site’s awareness of the event. 
•
All SAEs including any suspected transmission of an infectious agent via a medicinal 
product  
Confidential
Page
109
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
•
Pregnancy in a study participant or partner of a study participant  
•
≥ Grade 3 infusion-related reactions or CRS 
•
Abnormal liver enzymes that meet the criteria for potential Hy’s Law, which is defined 
as AST and/or ALT that is greater than 3 × ULN and total bilirubin that is greater than 
2 × ULN and without any alternate etiology 
•
Immune-related AE of Grade 2 or greater; irAEs are defined in Section 7.2.  
•
SJS or TEN 
•
Ocular toxicity 
o ≥ Grade 3 keratoconjunctivitis sicca (dry eye) 
o ≥ Grade 3 conjunctivitis 
o ≥ Grade 3 keratitis 
•
Administration of a dose significantly greater (specifically, + 20% or higher) than the 
planned dose, and results in an event of clinical consequence 
•
AEs leading to permanent discontinuation of study drug in an individual participant 
•
Discontinuation of the participant from study drug administration for any reason other 
than disease progression 
•
Product quality issues with an associated clinical consequence  
•
Pleural effusion 
•
Pericardial effusion 
•
Confirmed or presumed COVID-19/SARS-CoV-2 infection 
 
In those cases, in which the IRE is considered related to study drug, the study drug may be 
discontinued, and the participant will continue participation in the study for observational 
safety and efficacy analysis (except for cases where the participant is withdrawn from the 
study by the investigator or withdrew the consent). 
12.2.3 
Serious Adverse Events  
All SAEs occurring during the study must be reported to the sponsor. 
After 30 days following the last dose of study drug administration, if an investigator becomes 
aware of an SAE that s/he suspects is related to study drug, the investigator should report the 
event to the sponsor.  
Within 24 hours of becoming aware of an SAE, the investigator should provide a completed 
SAE Report form, via email or fax, to the sponsor. Upon receipt of follow-up information 
pertaining to an SAE, a follow-up SAE Report form should be submitted to the sponsor within 
24 hours of becoming aware of the follow-up information. All SAEs should be entered into 
the eCRFs within 5 calendar days of the site’s awareness. 
Confidential
Page
110
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
All Grade 3 or Grade 4 SAEs considered related to study drug must be followed until 
recovery to baseline or Grade 1. 
The investigator must follow all SAEs until resolution and record the date of resolution. 
Resolution of an event is defined as the return to pre-treatment status or stabilization of the 
condition with the expectation that it will remain chronic. 
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the participant’s participation in the study, must be followed until any of 
the following occurs: 
•
The event resolves 
•
The event stabilizes 
•
The event returns to baseline, if a baseline value/status is available 
•
The event can be attributed to etiology other than the study drug or to factors unrelated 
to study conduct 
•
It becomes unlikely that any additional information can be obtained (participant or 
health care practitioner refusal to provide additional information, lost to follow-up 
after demonstration of due diligence with follow-up efforts) 
 
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the 
course of a participant’s participation in a study must be reported as a SAE, except 
hospitalizations for the following: 
•
A standard hospitalization for administration of study drug therapy will not be reported 
as an SAE 
•
A procedure for protocol/disease-related investigations (e.g., surgery, scans, 
endoscopy, sampling for laboratory tests, bone marrow sampling, pharmacokinetic or 
biomarker blood sampling)  
•
Hospitalizations not intended to treat an acute illness or adverse event (e.g., social 
reasons such as pending placement in long-term care or hospice facility) 
•
Surgery or procedure planned before entry into the study (must be documented in the 
eCRF) 
 
Adverse events related to disease progression should not be recorded as an AE or SAE term, 
as they will be collected as efficacy endpoints. However, if an AE or SAE occurs in a 
participant and it is unclear if the event is due to progressive disease, the AE or SAE should be 
reported.  
Confidential
Page
111
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
12.2.4 
Protocol-Specific Adverse Events of Special Interest  
Specific adverse events 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 in a timely 
manner, regardless of seriousness (i.e., serious and non-serious adverse events). 
•
All IRR or CRS events as defined in Section 7.1.1. Grade 3 IRR or CRS events are 
also considered an IRE, requiring notification to the sponsor within 24 hours. 
•
Abnormal liver enzymes that meet the criteria for potential Hy’s law, which is defined 
as AST and/or ALT that is greater than 3 × ULN and total bilirubin that is greater than 
2 × ULN and without any alternate etiology. This is also considered an IRE, requiring 
notification to the sponsor within 24 hours. 
•
Immune-related AE of Grade 2 or greater; irAEs are defined in Section 7.2. This is 
also considered an IRE, requiring notification to the sponsor within 24 hours. 
•
Skin toxicity that meets the definition of SJS or TEN.  
•
Pleural effusion 
•
Pericardial effusion 
•
PPE 
•
Ocular toxicity. This is also considered an IRE, requiring notification of the following 
to the sponsor within 24 hours: 
o ≥ Grade 3 keratoconjunctivitis sicca (dry eye) 
o ≥ Grade 3 conjunctivitis 
o ≥ Grade 3 keratitis 
  
12.2.5 
Pregnancy  
All reports of pregnancy in female participants or partners of male participants must be 
reported to the sponsor by study-site personnel within 24 hours of their knowledge of the 
event using the Pregnancy Exposure Form. Abnormal pregnancy outcomes (e.g., spontaneous 
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs 
and must be reported using the SAE Report form. Any participant who becomes pregnant 
during the study must discontinue further study drug administration. 
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male 
participants included in the study will be reported by the study-site personnel within 24 hours of 
their knowledge of the event. If the female partner of a male participant becomes pregnant, the 
partner must be requested to complete a Pregnant Partner Consent Form so that pregnant 
partner, fetal, and/or newborn information can be collected. 
Upon confirmation of serum or urine pregnancy testing, the participant will be followed for 
the outcome of pregnancy. Follow-up information will be collected for all live newborns at 
Confidential
Page
112
of
169

MGC018, MGA012
MacroGenics, Inc.
Clinical Trial Protocol: CP-MGC018-01
Amendment 6, 16 August 2021
birth and 6 months after the birth. All necessary information will be collected to assess the 
effects of study drug on the newborn. If necessary, the follow-up period will be extended for 
the newborn.
12.2.6 
Reporting of Adverse Events to the Sponsor 
Throughout the study, the investigator must document all AEs, SAEs, and other IREs, as 
defined in Section 12.2.2 in the eCRFs in a timely manner. See Table 9, Safety Reporting by 
Event Type, for details.
The investigator must immediately complete and transmit the SAE Report Form, within 
24 hours of identifying the event, to MacroGenics Product Safety or designee. The SAE 
Report form and Completion Guidelines, and Contact Information for Reporting SAEs, are 
provided by the sponsor. 
For reports of pregnancy, the MacroGenics Pregnancy Exposure Form must be completed and 
transmitted. 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 Pregnancy 
Exposure Form is provided by the sponsor.
Please refer to the Table 9 for reporting timeframes to MacroGenics by event type.
Table 9
Safety Reporting by Event Type 
Type of Event:
Hard Copy Form/Timeline for 
reporting/Where to Report
eCRF
Timeline for Data 
Entry
Serious Adverse Event (SAE) 
Serious Adverse Event Form within 24 hours 
of awareness 
Report Email to 
 
Or fax to 
 
Within 5 calendar 
days of awareness 
Pregnancy 
Pregnancy Exposure Form/ 
Within 24 hours of awareness/ 
Email to 
 
Or fax to 
 
Within 5 calendar 
days of awareness 
Other IREs, as defined in 
Section 12.2.2 
Not Applicable 
Within 24 hours of 
awareness 
Non-Serious Adverse Events 
(except for Pregnancy): 
Not Applicable 
Within 10 calendar 
days of awareness 
Abbreviations: eCRF = electronic case report form; IRE = immediately reportable event; SAE = serious adverse event. 
Confidential
Page
113
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
12.3 
Other Assessment of Safety  
12.3.1 
Symptomatic Skeletal Events  
Symptomatic skeletal events (SSEs) are a clinical trial endpoint to describe skeletal morbidity 
defined as symptomatic fracture, surgery or radiation to bone, or spinal cord compression. 
Any of the following events must be recorded in the source document and on the SSE eCRF 
regardless of relationship to disease progression: symptomatic bone fracture, bone pain 
requiring surgery, bone pain requiring radiation, and/or spinal cord compression. 
Confidential
Page
114
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
13 
PRODUCT QUALITY COMPLAINT HANDLING  
A product quality complaint (PQC) related to study drug 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 participants, 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 
Procedure  
All initial PQCs must be reported to the sponsor by the study-site personnel, after being made 
aware of the event, and those that are associated with clinical consequences must be reported 
within 24 hours. 
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 12.2.3, Serious Adverse 
Events). A sample of the suspected product should be maintained for further investigation if 
requested by the sponsor. 
13.2 
Contacting sponsor Regarding Product Quality  
Product quality issues should be reported via e-mail to:   
 
Confidential
Page
115
of
169

MGC018, MGA012
MacroGenics, Inc.
Clinical Trial Protocol: CP-MGC018-01
Amendment 6, 16 August 2021
14 
STATISTICAL ANALYSIS 
This section outlines the statistical methodology and principles which will be used for data 
analysis in this study. A separate statistical analysis plan (SAP) and statistical programming 
plan (SPP) will further describe the details regarding statistical methods and will govern the 
analysis. Analyses will be performed for MGC018 alone and in combination with MGA012 
respectively.
14.1 
Determination of Sample Size 
The study plans to enroll approximately up to 182 participants (107 in Module A and 75 in 
Module B). This number of participants does not take into account participants who may be 
replaced for non-evaluable participants or the possibility of expanding the mCRPC cohort 
with an additional 24 participants at the discretion of the sponsor.
In Module A, 27 participants were enrolled, of which 26 participants were treated with 
MGC018 monotherapy in the Dose Escalation Phase. Up to 80 participants with mCRPC, 
NSCLC, TNBC, SCCHN, and melanoma (up to 16 in each) will be enrolled to the Cohort 
Expansion Phase of Module A. Up to an additional 4 participants may be added per cohort. In 
Module B, up to 27 participants will be enrolled in the Dose Escalation Phase based on a 
3+3+3 design with planned 3 dose cohorts in MGC018 and MGA012 combination therapy. 
The Cohort Expansion Phase of Module B will enroll up to 16 participants into each of 
3 tumor specific cohorts (SCCHN, mCRPC, and participants with a tumor type TBD at a later 
date) treated with MGC018 in combination with MGA012. The sample size for each tumor 
specific cohort is primarily based on providing preliminary estimation of responses. Table 10 
provides the 2-sided 95% confidence interval (CI) for a number of potential responses. 
The sample size for the mCRPC cohort expansion is primarily based on providing preliminary 
estimation of a 6 month rPFS rate.
During the Cohort Expansion Phase, participants who withdraw before completing the first 
tumor assessment for a reason other than clinical disease progression or death are considered 
unevaluable for response. In these cases, additional participants may be enrolled. 
Table 10
Response Rates and 95% Confidence Intervals 
Sample Size
Number of Responses
Response Rate (%)
95% Confidence Interval (%)
16 
1 
6.3 
0.2, 30.2 
16 
2 
12.5 
1.6, 38.3 
16 
3 
18.8 
4.0, 45.6 
16 
4 
25.0 
7.3, 52.4 
16 
5 
31.3 
11.0, 58.7 
16 
6 
37.5 
15.2, 64.6 
Confidential
Page
116
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
14.2 
Analysis Populations  
The study analyses will be performed on the following populations: 
•
Safety Population: All participants who received at least one dose of study drug. This 
population will be used for analyses of safety, pharmacodynamics, and 
immunogenicity. It will also be used for summary of baseline data and analyses of 
PFS, rPFS, and OS. 
•
Response Evaluable Population: All participants who received at least one dose of 
study drug, had baseline measurable or non-measurable disease, and had at least one 
post-baseline radiographic tumor assessment or discontinued treatment due to clinical 
progressive disease or death. This population will be used for summary of tumor 
assessment data and analyses of response rates. 
•
PSA Response Evaluable Population: mCRPC participants with a baseline PSA 
≥ 2 ng/mL and at least 1 post baseline PSA measurement. This population will be used 
to calculate and summarize PSA response rates. 
 
14.3 
Demographics and Baseline Characteristics  
Participant disposition, demographics, baseline characteristics, disease history, medical 
history, and prior cancer treatment will be summarized using descriptive statistics. 
14.4 
Study Drug Exposures and Concomitant Medications  
Study drug exposures and concomitant medications will be summarized by descriptive 
statistics. The summary of study drug exposure will include descriptive statistics as well as 
frequency counts for the number of doses or cycles received, the total dose administered as 
well as the total dose intended, and the dose intensity, which is calculated as percentage of 
total dose actually administrated divided by total dose intended during whole treatment 
period. 
14.5 
Pharmacokinetic/Pharmacodynamic Analysis  
14.5.1 
Pharmacokinetic Analysis  
Summary statistics will be tabulated separately for serum PK parameters by MGC018 and 
MGA012 dose. Where applicable, geometric means and percent coefficients of variation will 
be reported for Cmax, AUC(0-T), AUC(TAU), AUC(INF), Ctrough and AI; arithmetic means and 
standard deviations will be reported for t1/2, CL, and Vss; and medians, minimum, and 
maximum will be reported for Tmax. Separate scatter plots of Cmax and AUC will be provided 
versus dose to assess dose dependency. Dose proportionality may be assessed using a power 
model. 
Confidential
Page
117
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
14.5.2 
Immunogenicity Analysis  
The proportion of participants who are negative for ADAs at baseline and become positive in 
this assay, the proportion of participants who are negative at baseline and remain negative, 
and those who have positive ADA at baseline that increases or decreases in titer over the 
course of treatment will be summarized. Analysis will be conducted separately for MGC018 
and MGA012. 
14.5.3 
Pharmacodynamic Analysis  
Summary statistics for pharmacodynamic parameters, such as, but not limited to, those listed 
under in Section 10.3 and corresponding changes from baseline will be summarized and/or 
may also be presented graphically. In addition, possible associations between changes in 
pharmacodynamic measures of interest and MGC018 monotherapy and in combination with 
MGA012 dose and exposure may be explored. 
14.6 
Efficacy and Endpoint Analyses  
14.6.1 
Response Endpoints and Analyses  
For RECIST v1.1, the best overall response (BOR) will be categorized as CR, PR, SD, PD, or 
NE. To be qualified as BOR, CR and PR requires confirmation at least 4 weeks after initial 
observation of such response, and SD requires to be observed at least once after 6 weeks from 
the start of MGC018 treatment for Module A or MGC018 and MGA012 combination 
treatment for Module B. 
The number and percent of participants with their BOR will be summarized. The ORR per 
RECIST v1.1 is estimated as the proportion of participants in the response evaluable 
population who achieve BOR of CR or PR. The 2-sided 95% exact binomial CIs of the 
response rates will be calculated.  
14.6.2 
Analysis of Tumor Size Change Over Time  
The tumor size is defined as the sum of diameters of the target lesions. The tumor size percent 
change from baseline over time will be summarized and will be presented by spider plot. The 
best tumor size percent change from baseline will be presented by waterfall plot. 
14.6.3 
Time-to-Event Endpoints and Analyses  
Progression-free survival will be defined as the time from the first dose date of MGC018 
treatment (Module A) or MGC018 and MGA012 combination treatment (Module B) to the 
date of first documented progression or death from any cause, whichever occurs first. The 
documented progression is determined by objective assessment of disease per RECIST v1.1. 
For participants who are not known to be dead or progressed at the time of data cut-off for 
PFS analysis, the PFS will be censored at the date of the last tumor assessment. Specifically, 
the following censoring rules will be applied to analysis of PFS. 
Confidential
Page
118
of
169

MGC018, MGA012
MacroGenics, Inc.
Clinical Trial Protocol: CP-MGC018-01
Amendment 6, 16 August 2021
Table 11
Censoring Rules for Primary Analysis of PFS 
Situation
Date
Outcome
No baseline tumor assessments 
First dose date 
Censored 
Death prior to first scheduled 
tumor assessment 
Date of death 
Progressed 
No post-baseline tumor 
assessments in absence of death 
prior to first scheduled tumor 
assessment 
First dose date 
Censored 
Documented progression 
Date of progression 
Progressed 
Initiation of alternative 
anti-cancer treatments in absence 
of documented progression 
Date of last tumor assessment on or 
prior to initiation of such treatment 
Censored 
Death or documented progression 
immediately after missing 2 or 
more consecutive scheduled 
tumor assessments 
Date of last tumor assessment prior 
to missed assessments 
Censored 
Abbreviation: PFS = progression-free survival 
Duration of Response (DoR) is defined as the time from the date of initial response (CR or 
PR) to the date of first documented progression or death from any cause, whichever occurs 
first. The DoR is calculated only for the responders. For responders who are not known to be 
dead or progressed at the time of data cut-off for DoR analysis, the DoR will be censored at 
the date of the last tumor assessment. Specifically, the last 3 situations described in Table 11 
will be applied. The DoR analyses will be performed only if there are enough responders to 
render the analyses meaningful.
Overall survival (OS) is defined as the time from the first dose date of MGC018 treatment for 
Module A or MGC018 and MGA012 combination treatment for Module B to the date of death 
from any cause. For participants who are not known to be dead at the time of data cut-off for 
OS analysis, the OS will be censored at the time they are last known to be alive.
The Kaplan-Meier method will be applied to estimate PFS, DoR and OS curves; their median 
times; PFS rates at 3 and 6 months; and OS rates at 6 and 12 months, respectively. The 
method of Brookmeyer and Crowley (8) will be used to construct 95% CI for median time of 
each time-to-event endpoint. The 95% CIs for PFS and OS rates at each time point of interest 
will be calculated by normal approximation after log(-log) transformation.  
The above PFS and DoR analyses will be performed with the documented progression 
determined by RECIST v1.1.
Confidential
Page
119
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
14.6.4 
Endpoints and Analyses in mCRPC  
The analyses of ORR, DoR, and OS indicated above will be performed for participants with 
mCRPC. In addition, the following analyses will be performed in mCRPC. 
14.6.4.1 
Radiographic Progression-free Survival  
The rPFS will be defined as the time from the first dose of study drug to the first occurrence 
of the following events: 
•
Radiographic progression of soft tissue lesions using RECIST v1.1 
•
Radiographic progression of bone lesions: appearance of 2 or more new bone lesions 
•
Death from any cause 
 
The censoring rules in Table 11 will apply to rPFS with the radiographic progression defined 
for rPFS. The analysis of rPFS will be the same as that described for PFS. 
14.6.4.2 
Prostate-specific Antigen  
PSA response will be defined as a ≥ 50% decline from baseline in PSA with confirmation at 
least 3 weeks later. PSA response rate will be calculated for participants with a baseline 
PSA ≥ 2 ng/mL and at least 1 post-baseline value. The 2-sided 95% exact binomial CI of the 
response rate will be calculated.  
The percent change in PSA from baseline overall time will be summarized by visit and 
presented individually by spider plot. The best PSA percent change from baseline will be 
presented by waterfall plot. 
PSA progression is defined as, if decline from baseline, a PSA increase that is ≥ 25% and 
≥ 2 ng/mL above the nadir, and which is confirmed by a second value at least 3 weeks later; if 
no decline from baseline, a PSA increase that is ≥ 25% and ≥ 2 ng/mL above the baseline 
value after 12 weeks. Time to PSA progression will be defined as the time from the first dose 
of study drug to the first documented PSA progression. Participants without PSA progression 
at the time of analysis will be censored to the date of their last PSA assessment. The Kaplan-
Meier method will be applied to estimate time to PSA progression. 
14.6.4.3 
Symptomatic Skeletal Events  
SSEs include new symptomatic pathological fracture, use of external beam radiation to relieve 
bone pain, spinal cord compression, or tumor-related orthopedic surgical intervention. SSE 
rate will be summarized. Time to SSE is defined as the time from the first dose of study drug 
to the first occurrence of SSE. Participants without SSE at the time of analysis will be 
censored at the last assessment. The Kaplan-Meier method will be applied to estimate time to 
SSE. 
Confidential
Page
120
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
14.6.5 
Patient-reported Outcome  
The BPI-sf will be used to assess pain. A mean pain severity score will be calculated from the 
average of 4 pain intensity item scores: items 3 (worst), 4 (least), 5 (average), and 6 (right 
now). Changes from baseline in pain intensity item scores, mean pain severity score, and pain 
interference scores will be summarized. 
 
14.7 
Safety Endpoints and Analyses  
14.7.1 
Adverse Events  
Only treatment-emergent AEs will be summarized in tables. The following AEs will be 
provided in summary tables as well as displayed in listings:  
•
All AEs  
•
AEs with CTCAE severity Grade ≥ 3 
•
Study drug–related AEs 
•
Study drug–related AEs with CTCAE severity Grade ≥ 3 
•
SAEs  
•
Study drug–related SAEs 
•
AEs that result in discontinuation of study treatment 
•
AEs that led to dose interruption, dose delay, or discontinuation of individual study 
drug 
•
Fatal AEs 
•
Immediately reportable AEs (if applicable) 
•
AEs of special interest 
 
All of these tables will display the number and percent of participants that experience the 
given event and will display events by MedDRA System Organ Class (SOC) and Preferred 
Term (PT). Events will be displayed alphabetically for SOC and in descending order of 
overall PT incidence within each SOC. An overall summary of AEs will display the number 
and percent of participants who experience at least one event of each of the above types. 
14.7.2 
Laboratory Values  
Summaries of laboratory values will display descriptive statistics for numerically quantified 
laboratory test results. Summaries will be grouped by laboratory panel (eg, hematology, blood 
chemistry, and urinalysis) and will be displayed by visit for each laboratory parameter. 
Number and percent of participants shifted from baseline to post-baseline maximum severity 
in CTCAE grade will be summarized. 
Confidential
Page
121
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
14.7.3 
Other Safety Endpoints  
Twelve-lead ECGs will be collected and analyzed for evidence of cardiac toxicity, especially 
prolongation of QT interval. Vital signs will be summarized with descriptive statistics at each 
visit and time point at which they are collected. Shift tables may be performed. 
14.8 
Other Assessments or Analyses  
Additional analyses, if any, will be described in the SAP. 
Confidential
Page
122
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
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, completion of the eCRFs, and study procedures. 
•
Monitor protocol and GCP compliance on a regular basis (on-site visits and/or remote 
monitoring). 
•
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 participants 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 participant medical records in the participant 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 participant data recorded on eCRFs against source documents at the study site and/or 
remote monitoring. 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 activities. Queries may be raised if any datum is unclear or contradictory. The 
investigator and study site personnel must address all queries in a timely manner. 
Participation as an investigator in this study implies acceptance of the potential for inspection 
by the study sponsor/representatives, US or non-US government regulatory authorities, 
IRB/IEC, and applicable compliance and quality assurance offices. The investigator will 
permit study-related audits and inspections and will provide access to all study-related 
documents (e.g., source documents, regulatory documents, data collection instruments, 
study data etc.). The investigator will ensure the capability for inspections of applicable 
study-related facilities (e.g., pharmacy, diagnostic laboratory, etc.). 
Confidential
Page
123
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
15.2 
Data Collection and Management  
The investigator is responsible for maintaining accurate, complete, and up-to-date records for 
each participant. 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 participants must be maintained. For data collection, and 
management purposes, participants are to be identified by subject number only. Documents 
that identify the participant beyond participant number (e.g., participant 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 participant through eCRFs using the Medidata 
RAVE™, an EDC system provided and approved by the sponsor. Refer to the CRF 
Completion Guidelines for additional information regarding eCRFs, if any that will be used as 
source documentation. Study sites must complete eCRFs for each participant in a timely 
manner shortly after each participant visit. As the person ultimately responsible for the 
accuracy of all eCRF data, the investigator must sign the investigator’s Statement in each 
participant’s 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. Adverse events 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 participants. 
Confidential
Page
124
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
16 
ADMINISTRATIVE CONSIDERATIONS  
16.1 
Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) 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, IB, and information concerning participant 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 participants. 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 the following to the 
IRB/IEC: 
•
The protocol and the investigator’s brochure (IB) and any amendments or updates. 
•
The informed consent form(s) and any amendments or changes. 
•
Any documents given to participants or potential participants (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 participants 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. 
•
Notification when the study has been completed. 
•
Proof of indemnity/liability insurance. 
•
Other documents required by the IRB/IEC. 
Confidential
Page
125
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
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), the current ICH Guideline for 
Good Clinical Practice (ICH E6), and all other applicable regulations. 
16.3 
Participant Information and Consent  
It is the responsibility of the investigator to obtain and document written informed consent 
from the participant. 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 participant in both oral and written form, and participants 
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 participant’s native 
language or language in which the participant has fluency) so as to be understood by the 
prospective participant. 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 participant and by 
the person who conducted the discussion of the informed consent. 
All versions of each participant’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 participant should receive a copy of the signed and dated 
written ICF and any other written information provided to the participants. 
16.4 
Participant Confidentiality  
To maintain confidentiality of participants, 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 participant or an individual with legal decision 
making authority for the participant or the participant’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]), 
on protection of individuals with regard to personal data. 
Confidential
Page
126
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
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 participant’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 and Further Testing  
Samples acquired for protocol-specified assays will be retained for at least 1 year following 
the end of the study and may be retained up to 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. If participants consent, 
or an individual with legal decision-making authority for the participant or the participant’s 
interests consent, to the use of their study samples for non-study research purposes, these 
samples may also be used for exploratory testing (including assay development/ optimization) 
and may be retained up to 15 years from the end of the study. 
Confidential
Page
127
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
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 
employees of MacroGenics, or immediate family members of a MacroGenics employee, 
officer, or director. This is in order 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 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
128
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
16.11.2 
Discontinuation of the Study  
The study may be discontinued by a regulatory authority or at the discretion of the sponsor. 
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. 
16.12 
Identification of the Coordinating Principal Investigator  
A Coordinating Principal investigator will be appointed by the sponsor medical monitor prior 
to the end of the study. 
As part of his or her responsibilities, the coordinating principal investigator will review the 
final clinical study report (CSR). Agreement with the final CSR will be documented by the 
dated signature of the coordinating principal investigator. 
 
Confidential
Page
129
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
17 
REFERENCE LIST  
Note: Newly added literature references are in colored text. Previously cited submitted 
literature references are in black text. 
1. 
Adams S, Diamond J, Hamilton E, Pholman P, Tolaney S, Molinero L, et al. Phase 
1b trail of atezolizumab in combination with nab-paclitaxel in patients with metastic 
triple-negative breast cancer (mTNBC). Journal of Clinical Oncology. 2016. 
2. 
Altan M, Pelekanou V, Schalper KA, Toki MI, Gaule P, Syrigos KN, et al. B7-H3 
expression in NSCLC and its association with B7-H4, PD-L1 and Tumor Infiltrating 
Lymphocytes. Clin Cancer Res. 2017. 
3. 
Bai S, Jorga K, Xin Y, Jin D, Zheng Y, Damico-Beyer LA, et al. A guide to rational 
dosing of monoclonal antibodies. Clin. Pharmacokinet. 2012;51(2):119-35. 
4. 
Beckett D, Kovaleva E, Schatz PJ. A minimal peptide substrate in biotin holoenzyme 
synthetase-catalyzed biotinylation. Protein Sci. 1999;8(4):921-9. 
5. 
Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, et al. 
Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N 
Engl J Med. 2006;354(6):567-78. 
6. 
Bottai G, Raschioni C, Losurdo A, Di Tommaso L, Tinterri C, Torrisi R, et al. An 
immune stratification reveals a subset of PD-1/LAG-3 double-positive triple-negative 
breast cancers. Breast Cancer Res. 2016;18(1):121. 
7. 
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer 
statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 
cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424. 
8. 
Brookmeyer R, Crowley J. A Confidence Interval for the Median Survival Time. 
Biometrics. 1982;38:29-41. 
9. 
Butt MT, Whitney KM, Davis W, Akella S, Parker S, Foley GL. Microscopic 
background changes in brains of cynomolgus monkeys. Toxicol Pathol. 
2015;43(4):513-8. 
10. 
CBER. Guidance for Industry: S9 Nonclinical Evaluation for Anticancer 
Pharmaceuticals. 2010. 
11. 
CDER. Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial 
Clinical Trials for Therapeutics in Adult Healthy Volunteers. 2014, U.S.Department of 
Health and Human Services Food and Drug Administration Center for Drug 
Evaluation and Research (CDER), July 2005, Pharmacology and Toxicology. 
Confidential
Page
130
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
12. 
Chamanza R, Marxfeld HA, Blanco AI, Naylor SW, Bradley AE. Incidences and 
range of spontaneous findings in control cynomolgus monkeys (Macaca fascicularis) 
used in toxicity studies. Toxicol. Pathol. 2010;38(4):642-57. 
13. 
Chaturvedi AK, Engels EA, Pfeiffer RM, Hernandez BY, Xiao W, Kim E, et al. 
Human papillomavirus and rising oropharyngeal cancer incidence in the United States. 
J. Clin. Oncol. 2011;29(32):4294-301. 
14. 
Chavin G, Sheinin Y, Crispen PL, Boorjian SA, Roth TJ, Rangel L, et al. 
Expression of immunosuppresive B7-H3 ligand by hormone-treated prostate cancer 
tumors and metastases. Clin. Cancer Res. 2009;15(6):2174-80. 
15. 
Chen JT, Chen CH, Ku KL, Hsiao M, Chiang CP, Hsu TL, et al. Glycoprotein B7-
H3 overexpression and aberrant glycosylation in oral cancer and immune response. 
Proc Natl Acad Sci U S A. 2015;112(42):13057-62. 
16. 
Chow LQ, Haddad R, Gupta S, Mahipal A, Mehra R, Tahara M, et al. Antitumor 
Activity of Pembrolizumab in Biomarker-Unselected Patients With Recurrent and/or 
Metastatic Head and Neck Squamous Cell Carcinoma: Results From the Phase Ib 
KEYNOTE-012 Expansion Cohort. J Clin Oncol. 2016. 
17. 
Cimino-Mathews A, Foote JB, Emens LA. Immune targeting in breast cancer. 
Oncology (Williston Park). 2015;29(5):375-85. 
18. 
Collins M, Ling V, Carreno BM. The B7 family of immune-regulatory ligands. 
Genome Biol. 2005;6(6):223. 
19. 
Crispen PL, Sheinin Y, Roth TJ, Lohse CM, Kuntz SM, Frigola X, et al. Tumor 
cell and tumor vasculature expression of B7-H3 predict survival in clear cell renal cell 
carcinoma. Clin Cancer Res. 2008;14(16):5150-7. 
20. 
DeNardo DG, Brennan DJ, Rexhepaj E, Ruffell B, Shiao SL, Madden SF, et al. 
Leukocyte complexity predicts breast cancer survival and functionally regulates 
response to chemotherapy. Cancer Discov. 2011;1(1):54-67. 
21. 
Dokter W, Ubink R, van der Lee M, van der Vleuten M, van Achterberg T, Jacobs 
D, et al. Preclinical profile of the HER2-targeting ADC SYD983/SYD985: 
introduction of a new duocarmycin-based linker-drug platform. Mol Cancer Ther. 
2014;13(11):2618-29. 
22. 
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. 2009:228-47. 
23. 
Elgersma RC, Coumans RG, Huijbregts T, Menge WM, Joosten JA, Spijker HJ, 
et al. Design, Synthesis, and Evaluation of Linker-Duocarmycin Payloads: Toward 
Confidential
Page
131
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Selection of HER2-Targeting Antibody-Drug Conjugate SYD985. Mol Pharm. 
2015;12(6):1813-35. 
24. 
Emens LA. Breast cancer immunobiology driving immunotherapy: vaccines and 
immune checkpoint blockade. Expert Rev Anticancer Ther. 2012;12(12):1597-611. 
25. 
FDA. Modification of the Dosage Regimen for Nivolumab. US Food and Drug 
Administration. 2016. 
26. 
Gerber HP, Sapra P, Loganzo F, May C. Combining antibody-drug conjugates and 
immune-mediated cancer therapy: What to expect? Biochem Pharmacol. 2016;102:1-
6. 
27. 
Gillison ML, D'Souza G, Westra W, Sugar E, Xiao W, Begum S, et al. Distinct risk 
factor profiles for human papillomavirus type 16-positive and human papillomavirus 
type 16-negative head and neck cancers. J. Natl. Cancer Inst. 2008;100(6):407-20. 
28. 
Graff JN, Alumkal JJ, Drake CG, Thomas GV, Redmond WL, Farhad M, et al. 
Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. 
Oncotarget. 2016;7(33):52810-7. 
29. 
Halama N, Michel S, Kloor M, Zoernig I, Benner A, Spille A, et al. Localization 
and density of immune cells in the invasive margin of human colorectal cancer liver 
metastases are prognostic for response to chemotherapy. Cancer Res. 
2011;71(17):5670-7. 
30. 
Hartkopf AD, Taran FA, Wallwiener M, Walter CB, Kramer B, Grischke EM, et 
al. PD-1 and PD-L1 Immune Checkpoint Blockade to Treat Breast Cancer. Breast 
Care (Basel). 2016;11(6):385-90. 
31. 
Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. 
Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. 
Med. 2010;363(8):711-23. 
32. 
Hofmeyer KA, Ray A, Zang X. The contrasting role of B7-H3. Proc. Natl. Acad. Sci. 
U. S. A. 2008;105(30):10277-8. 
33. 
Immunomedics. Immunomedics. Sacituzumab Govitecan: Immunomedics Company 
Presentation. 2017 January; . Presentation. 2017. 
34. 
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer 
statistics. CA Cancer J Clin. 2011;61(2):69-90. 
35. 
Jin Y, Zhang P, Li J, Zhao J, Liu C, Yang F, et al. B7-H3 in combination with 
regulatory T cell is associated with tumor progression in primary human non-small cell 
lung cancer. Int J Clin Exp Pathol. 2015;8(11):13987-95. 
Confidential
Page
132
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
36. 
Katayama A, Takahara M, Kishibe K, Nagato T, Kunibe I, Katada A, et al. 
Expression of B7-H3 in hypopharyngeal squamous cell carcinoma as a predictive 
indicator for tumor metastasis and prognosis. Int. J. Oncol. 2011;38(5):1219-26. 
37. 
Lakhani N, Mehnert JM, Rasco D, Gordon M, Lohr J, Sharma S, et al. A Phase 1 
Study of the Safety, Tolerability, and Pharmacokinetics (PK) of MGA012 (anti-PD-1 
antibody) in Patients with Advanced Solid Tumors. 2017. 
38. 
Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. 
Identification of human triple-negative breast cancer subtypes and preclinical models 
for selection of targeted therapies. J Clin Invest. 2011;121(7):2750-67. 
39. 
Liu C, Liu J, Wang J, Liu Y, Zhang F, Lin W, et al. B7-H3 expression in ductal and 
lobular breast cancer and its association with IL-10. Mol. Med. Rep. 2013;7(1):134-8. 
40. 
Loo D, Alderson RF, Chen FZ, Huang L, Zhang W, Gorlatov S, et al. Development 
of an Fc-enhanced Anti-B7-H3 Monoclonal Antibody with Potent Antitumor Activity. 
Clin. Cancer Res. 2012;18(14):3834-45. 
41. 
Luan Y, Ju J, Luo L, Zhang Z, Wang J, Zhu DM, et al. Potential role of soluble B7-
H3 in liver immunopathogenesis during chronic HBV infection. J Viral Hepat. 
2012;19(1):23-31. 
42. 
Maeda N, Yoshimura K, Yamamoto S, Kuramasu A, Inoue M, Suzuki N, et al. 
Expression of B7-H3, a potential factor of tumor immune evasion in combination with 
the number of regulatory T cells, affects against recurrence-free survival in breast 
cancer patients. Ann. Surg. Oncol. 2014;21 Suppl 4:S546-S54. 
43. 
Mao Y, Li W, Chen K, Xie Y, Liu Q, Yao M, et al. B7-H1 and B7-H3 are 
independent predictors of poor prognosis in patients with non-small cell lung cancer. 
Oncotarget. 2015;6(5):3452-61. 
44. 
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. 
45. 
Morrissey KM, Yuraszeck TM, Li CC, Zhang Y, Kasichayanula S. Immunotherapy 
and Novel Combinations in Oncology: Current Landscape, Challenges, and 
Opportunities. Clin Transl Sci. 2016;9(2):89-104. 
46. 
MPI. Historical Control Non-Neoplastic Data Male Cynomolgus Monkey. 2014. 
47. 
Muller P, Martin K, Theurich S, Schreiner J, Savic S, Terszowski G, et al. 
Microtubule-depolymerizing agents used in antibody-drug conjugates induce 
antitumor immunity by stimulation of dendritic cells. Cancer Immunol Res. 
2014;2(8):741-55. 
Confidential
Page
133
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
48. 
Muller P, Kreuzaler M, Khan T, Thommen DS, Martin K, Glatz K, et al. 
Trastuzumab emtansine (T-DM1) renders HER2+ breast cancer highly susceptible to 
CTLA-4/PD-1 blockade. Sci. Transl. Med. 2015;7(315):315ra188. 
49. 
Ogungbenro K, Patel A, Duncombe R, Clark J, Lorigan P. A rational approach to 
dose optimisation of pembrolizumab using cost analysis and pharmacokinetic 
modelling and simulation. . Presented at the Society of Clinical Oncology Annual 
Meeting, Chicago, IL. 2016(9547). 
50. 
Oitate M, Masubuchi N, Ito T, Yabe Y, Karibe T, Aoki T, et al. Prediction of human 
pharmacokinetics of therapeutic monoclonal antibodies from simple allometry of 
monkey data. Drug Metab Pharmacokinet. 2011;26(4):423-30. 
51. 
Olsen KD, Kwon ED, Sheinin Y, Lohse CM, Kasperbauer JL, Moore EJ. B7-H1, 
B7-H3, and CA1X Expression in squamous Cell Carcinoma of Head and Neck 
Tumors. 2008. 7th International Conference on Head and Neck Cancer. 
52. 
Petroff MG, Kharatyan E, Torry DS, Holets L. The immunomodulatory proteins 
B7-DC, B7-H2, and B7-H3 are differentially expressed across gestation in the human 
placenta. Am. J. Pathol. 2005;167(2):465-73. 
53. 
Qin X, Zhang H, Ye D, Dai B, Zhu Y, Shi G. B7-H3 is a new cancer-specific 
endothelial marker in clear cell renal cell carcinoma. Onco. Targets. Ther. 
2013;6:1667-73. 
54. 
Quandt D, Fiedler E, Boettcher D, Marsch WC, Seliger B. B7-h4 expression in 
human melanoma: its association with patients' survival and antitumor immune 
response. Clin. Cancer Res. 2011;17(10):3100-11. 
55. 
Quandt D, Fiedler E, Muller A, Marsch WC, Seliger B. High constitutive B7-H3 
expression on human keratinocytes supports T cell immunity. J Dermatol Sci. 2017. 
56. 
Reck M, Heigener DF, Mok T, Soria JC, Rabe KF. Management of non-small-cell 
lung cancer: recent developments. Lancet. 2013;382(9893):709-19. 
57. 
Rios-Doria J, Harper J, Rothstein R, Wetzel L, Chesebrough J, Marrero A, et al. 
Antibody-Drug Conjugates Bearing Pyrrolobenzodiazepine or Tubulysin Payloads Are 
Immunomodulatory and Synergize with Multiple Immunotherapies. Cancer Res. 
2017;77(10):2686-98. 
58. 
Robert C, Thomas L, Bondarenko I, O'Day S, JW MD, Garbe C, et al. 
Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. 
J. Med. 2011;364(26):2517-26. 
59. 
Roth TJ, Sheinin Y, Lohse CM, Kuntz SM, Frigola X, Inman BA, et al. B7-H3 
ligand expression by prostate cancer: a novel marker of prognosis and potential target 
for therapy. Cancer Res. 2007;67(16):7893-900. 
Confidential
Page
134
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
60. 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 
2016;66(1):7-30. 
61. 
Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 
2017;67(1):7-30. 
62. 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 
2020;70(1):7-30. 
63. 
Society AC. Cancer Facts & Figures. Atlanta: American Cancer Society. 2015. 
64. 
Steinberger P, Majdic O, Derdak SV, Pfistershammer K, Kirchberger S, Klauser 
C, et al. Molecular characterization of human 4Ig-B7-H3, a member of the B7 family 
with four Ig-like domains, in J Immunol. 2004:2352-9. 
65. 
Sun Y, Wang Y, Zhao J, Gu M, Giscombe R, Lefvert AK, et al. B7-H3 and B7-H4 
expression in non-small-cell lung cancer. Lung Cancer. 2006;53(2):143-51. 
66. 
Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, et al. Association of PD-
1, PD-1 ligands, and other features of the tumor immune microenvironment with 
response to anti-PD-1 therapy. Clin Cancer Res. 2014;20(19):5064-74. 
67. 
Theurich S, Malcher J, Wennhold K, Shimabukuro-Vornhagen A, Chemnitz J, 
Holtick U, et al. Brentuximab vedotin combined with donor lymphocyte infusions for 
early relapse of Hodgkin lymphoma after allogeneic stem-cell transplantation induces 
tumor-specific immunity and sustained clinical remission. J Clin Oncol. 
2013;31(5):e59-63. 
68. 
Thompson RH, Kwon ED, Allison JP. Inhibitors of B7-CD28 costimulation in 
urologic malignancies. Immunotherapy. 2009;1(1):129-39. 
69. 
Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, et al. PD-
1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 
2014;515(7528):568-71. 
70. 
van der Lee MM, Groothuis PG, Ubink R, van der Vleuten MA, van Achterberg 
TA, Loosveld EM, et al. The Preclinical Profile of the Duocarmycin-Based HER2-
Targeting ADC SYD985 Predicts for Clinical Benefit in Low HER2-Expressing Breast 
Cancers. Mol Cancer Ther. 2015;14(3):692-703. 
71. 
van Soest RJ, van Royen ME, de Morree ES, Moll JM, Teubel W, Wiemer EA, et 
al. Cross-resistance between taxanes and new hormonal agents abiraterone and 
enzalutamide may affect drug sequence choices in metastatic castration-resistant 
prostate cancer. Eur J Cancer. 2013;49(18):3821-30. 
72. 
Wang DD, Zhang S, Zhao H, Men AY, Parivar K. Fixed dosing versus body size-
based dosing of monoclonal antibodies in adult clinical trials. J Clin Pharmacol. 
2009;49(9):1012-24. 
Confidential
Page
135
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
73. 
Wang J, Chong KK, Nakamura Y, Nguyen L, Huang SK, Kuo C, et al. B7-H3 
associated with tumor progression and epigenetic regulatory activity in cutaneous 
melanoma. J. Invest Dermatol. 2013;133(8):2050-8. 
74. 
Wang L, Kang FB, Shan BE. B7-H3 mediated tumor immunology: Friend or foe? 
Int. J. Cancer. 2013. 
75. 
West NR, Milne K, Truong PT, Macpherson N, Nelson BH, Watson PH. Tumor-
infiltrating lymphocytes predict response to anthracycline-based chemotherapy in 
estrogen receptor-negative breast cancer. Breast Cancer Res. 2011;13(6):R126. 
76. 
Wolff AC, Hammond MEH, Allison KH, Harvey BE, Mangu PB, Bartlett JMS, et 
al. Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American 
Society of Clinical Oncology/College of American Pathologists Clinical Practice 
Guideline Focused Update. J Clin Oncol. 2018;36(20):2105-22. 
77. 
Wu S, Zhao X, Wu S, Du R, Zhu Q, Fang H, et al. Overexpression of B7-H3 
correlates with aggressive clinicopathological characteristics in non-small cell lung 
cancer. Oncotarget. 2016;7(49):81750-6. 
78. 
Xu H, Cheung IY, Guo HF, Cheung NK. MicroRNA miR-29 modulates expression 
of immunoinhibitory molecule B7-H3: potential implications for immune based 
therapy of human solid tumors. Cancer Res. 2009;69(15):6275-81. 
79. 
Zang X, Thompson RH, Al-Ahmadie HA, Serio AM, Reuter VE, Eastham JA, et 
al. B7-H3 and B7x are highly expressed in human prostate cancer and associated with 
disease spread and poor outcome. Proc. Natl. Acad. Sci. U. S. A. 2007;104(49):19458-
63. 
80. 
Zer A, Leighl NB. Second-line therapy in non-small-cell lung cancer: the DELTA 
between different genotypes widens. J Clin Oncol. 2014;32(18):1874-81. 
81. 
Zhang G, Hou J, Shi J, Yu G, Lu B, Zhang X. Soluble CD276 (B7-H3) is released 
from monocytes, dendritic cells and activated T cells and is detectable in normal 
human serum. Immunology. 2008;123(4):538-46. 
82. 
Zhang GB, Zhou H, Chen YJ, Ge Y, Xie F, Shi Q, et al. Characterization and 
application of two novel monoclonal antibodies against 2IgB7-H3: expression analysis 
of 2IgB7-H3 on dendritic cells and tumor cells. Tissue Antigens. 2005;66(2):83-92. 
 
 
Confidential
Page
136
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Appendix 1 
Time and Events Schedules  
Module A Dose Escalation Phase 
EVALUATION/ 
PROCEDURE 
Screening (1) 
(Within 28 days) 
Cycle 1  
Cycle 2 and subsequent Cycles(3) 
EOTV 
(4) 
Post 
TRT 
FUP 
(5) 
Day 
1 
Days 2 
and 4 
Day 8 
(±1d) 
Day  
15 
(±1d) 
Day 
22 
(±1d) 
Day 42 (2) 
(± 3d) 
Day 1 
(±1d) 
Day 22 
(±1d)  
Days 23, 
25, 29, 
36 (±1d) 
Day 42 
(± 3d) 
STUDY DRUG ADMINISTRATION 
Administer MGC018 
 
X 
 
 
 
X 
 
X 
X 
 
 
 
 
ELIGIBILITY 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline Tumor Imaging 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Designate Target/ 
Non-Target Lesions  
X 
 
 
 
 
 
 
 
 
 
 
 
 
See Appendix 5 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Archival Tumor Specimen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
All participants to be enrolled in the study must have an identified formalin-fixed, paraffin embedded tumor specimen and or tumor specimens sufficient for 
10 slides; see Section 9.13. The specimens will be analyzed retrospectively and will not be used to determine participant eligibility.  
Physical Exam  
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weight 
X 
X 
 
 
 
X 
 
X 
X 
 
 
X 
 
Directed History/Physical 
 
 
 
X 
 
X 
 
 
X 
 
 
 
 
Concurrent Medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG PS 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
12-lead ECG  
X 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
To be performed in triplicate (approximately 1 minute apart). 
During non-treatment visits (Screening and EOTV), 12-lead ECG will be taken at 1 time point. 
Cycle 1 Day 1: Pre-infusion (within -30 minutes), EOI (within 30 minutes after EOI), and Hour 4 after EOI (± 10 minutes).  
Cycle 1 Day 22: Pre-infusion (within -30 minutes) and EOI (within 30 minutes of EOI).   
Cycle 2 and subsequent cycles: Day 1: 12-lead ECG is recorded pre-infusion (within -30 minutes) and EOI (within 30 minutes of EOI).   
Echocardiogram/MUGA 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
Echocardiogram or MUGA scan performed at screening, approximately every 12 weeks [at the end of C2, C4, C6…(± 7 days)], at the end of treatment visit 
and at other time points if clinically indicated. See Sections 9.11 
Confidential
Page
137
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Module A Dose Escalation Phase 
EVALUATION/ 
PROCEDURE 
Screening (1) 
(Within 28 days) 
Cycle 1  
Cycle 2 and subsequent Cycles(3) 
EOTV 
(4) 
Post 
TRT 
FUP 
(5) 
Day 
1 
Days 2 
and 4 
Day 8 
(±1d) 
Day  
15 
(±1d) 
Day 
22 
(±1d) 
Day 42 (2) 
(± 3d) 
Day 1 
(±1d) 
Day 22 
(±1d)  
Days 23, 
25, 29, 
36 (±1d) 
Day 42 
(± 3d) 
Ophthalmic Exam 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
Ophthalmic examinations including visual acuity testing (with correction), fundoscopic examination, and tonometry are performed at screening, at Cycle 2 
Day 42 (± 7 days), End of Treatment, and at other time points if clinically indicated. Other directed studies (e.g., optical coherence tomography) will be 
performed as clinically indicated. See Section 9.12. 
Pregnancy Test (serum or 
urine) 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
Serum pregnancy test is required for eligibility. Subsequent pregnancy tests may use serum or urine. Test results must be reviewed before the study drug 
infusion on Day 1 of Cycle 1 and all subsequent cycles. If screening test is performed within 72 hours of 1st infusion, repeat of the test on Day 1 may be 
deferred. 
Eligibility Checklist and 
Register Participant 
X 
 
 
 
 
 
 
 
 
 
 
 
 
SAFETY/PK/MECHANISTIC STUDIES 
Protocol Procedure Related 
AEs/SAEs 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Assess for Adverse Events 
 
Continuous 
 
Vital Signs 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
 
During non-treatment visits (Screening, Day 8, and EOTV), vital signs will be taken once. 
Cycle 1: Day 1 and Day 22: Pre-infusion (within -30 minutes); at 15 and 30 minutes after the start of the infusion (± 5 minutes), at EOI (± 10 minutes); and 
at 1- and 4-hours after EOI (± 10 minutes). Note: Cycle 1 Day 22, the 4-hour vital signs may be deferred based on the judgement of the investigator.  
Cycle 2 and Beyond: Pre-infusion (within -30 min), at EOI (± 10 minutes), and at 1-hour after EOI (± 10 minutes).  
CBC, PLTs, diff; Chemistry 
Panel 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
 
To be collected pre-infusion and prior to prophylactic pre-medications on dosing days. Day 1 laboratory blood samples can be collected up to 3 days before 
infusion. See Appendix 2 for list of assessments.  
PT or INR  
X 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
 
PT is preferred. INR is acceptable based on local availability. To be collected pre-infusion and prior to prophylactic pre-medications on dosing days. Day 1 
laboratory blood samples can be collected up to 3 days before infusion. See Appendix 2 for list of assessments. 
Free T4 and TSH 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Urinalysis   
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
To be collected pre-infusion and prior to prophylactic pre-medications on dosing days. Day 1 urine samples can be collected up to 3 days before infusion. 
See Appendix 2 for list of assessments. Collect urinalysis as scheduled and as clinically indicated. Reflex test for microscopic evaluation if abnormal. 
Confidential
Page
138
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Module A Dose Escalation Phase 
EVALUATION/ 
PROCEDURE 
Screening (1) 
(Within 28 days) 
Cycle 1  
Cycle 2 and subsequent Cycles(3) 
EOTV 
(4) 
Post 
TRT 
FUP 
(5) 
Day 
1 
Days 2 
and 4 
Day 8 
(±1d) 
Day  
15 
(±1d) 
Day 
22 
(±1d) 
Day 42 (2) 
(± 3d) 
Day 1 
(±1d) 
Day 22 
(±1d)  
Days 23, 
25, 29, 
36 (±1d) 
Day 42 
(± 3d) 
PSA (mCRPC only) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
PSA measurements to be performed at baseline and then repeated predose of each treatment visit, approximately 30 days after the last study treatment 
administration (EOTV), and every 12 weeks (± 7 days) during the follow-up period until disease progression, start of another cancer therapy, or the study 
cutoff date, whichever comes first. 
Pharmacokinetics  
See Appendix 3 
 
Serum Cytokines  
See Appendix 3 
 
Flow Cytometry (Subset) 
See Appendix 3 
 
Anti-Drug Antibody (ADA) 
See Appendix 3 
 
Tumor Assessment 
(CT/PET/MRI) 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
Radiographic disease assessments will occur on Day 42 ± 3 days for the first four cycles, and every other cycle thereafter. Assessment will also be done at 
EOTV as per Section 9.16. 
Survival Follow-up  
 
 
X  
Participants in Module A Dose Escalation will be followed for survival status until approval of Amendment 3, at which point they will be discontinued from 
follow up: survival follow-up collected every 3 months (90 days ± 7 days) by clinic visit, telephone, paper mail, or other electronic contact; information 
regarding response status and/or the occurrence of disease progression may be collected approximately every 3 months in participants who discontinued 
from study treatment due to reasons other than progressive disease, if they have not initiated any other cancer directed therapy. See Section 9.17 for details. 
1
The Screening visit should occur within 28 days prior to Day 1. 
2
Cycle 1 Day 42 and Cycle 2 Day 1 may be combined. Whether or not the visits are combined, Cycle 1 Day 42 assessments should occur before Cycle 2 Day 1 
assessments. The same applies to all consecutive cycles. 
3
Evaluations/procedures performed on Days 23, 25, 29, and 36 apply to Cycle 2 only. 
4
The EOTV should be performed within 30 days following the last dose of study drug. 
5
Participants in Module A Dose Escalation Phase will be followed for survival status until approval of Amendment 3, after which they will be discontinued 
from follow up.  
Abbreviations: CBC = complete blood cell; diff = differential; ECG = electrocardiography; ECOG PS = Eastern Cooperative Oncology Group Performance 
Status; EOI = end of infusion; EOTV = End of Treatment Visit; FUP = follow-up; INR = international normalized ratio; PLTs = platelets; PT = prothrombin time; 
TRT = treatment; TSH = thyroid-stimulating hormone. 
 
Confidential
Page
139
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Module A Cohort Expansion Phase 
EVALUATION/ 
PROCEDURE 
Screening (1) 
(Within 
28 days) 
Cycle 1  
Cycle 2 and Subsequent Cycles 
EOTV (4) 
Post 
TRT 
FUP 
Day 
1 
Day 
2 
Day 8 
(±1d) 
Day 15 
(±1d) 
Day 22 
(±1d) 
Day 42 
(±5d) 
Day 1  
(±1d) 
Day 22 
(±1d)  
Days 23, 
29, 36 
(±1d) (3) 
Study Day 
 
1 
2 
8 
15 
22 
42 
43 
64 
65, 71, 78 
 
 
STUDY DRUG ADMINISTRATION 
Administer MGC018 
 
X 
 
 
 
X 
 
X 
X 
 
 
 
ELIGIBILITY 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Baseline Tumor Imaging 
X 
 
 
 
 
 
 
 
 
 
 
 
Designate Target/ 
Non-Target Lesions  
X 
 
 
 
 
 
 
 
 
 
 
 
See Appendix 5 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Archival Tumor Specimen 
X 
 
 
 
 
 
 
 
 
 
 
 
All participants to be enrolled in the study must have an identified formalin-fixed, paraffin embedded tumor specimen and or tumor specimens sufficient for 
10 slides; see Section 9.13. The specimens will be analyzed retrospectively and will not be used to determine participant eligibility.  
Physical Exam  
X 
X 
 
 
 
 
 
X 
 
 
X 
 
If any visual signs or symptoms are noted at screening, an ophthalmologic examination will be performed. 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Body Weight 
X 
X 
 
 
 
X 
 
X 
X 
 
X 
 
Directed History/Physical 
 
 
 
 
 
X 
 
 
X 
 
 
 
SSE (mCRPC only) 
 
X 
 
 
 
X 
 
X 
X 
 
X 
 
For participants with mCRPC, complete eCRF documenting any SSEs predose of each treatment visit.  
Remote Telemedicine 
Contact  
 
 
X 
X 
X 
 
 
 
 
X 
 
 
Telemedicine contact may be by telephone or email.   
Optional tumor biopsies on 
study 
X 
 
 
 
 
 
X 
 
 
 
 
 
On-treatment tumor biopsy: Fresh tumor biopsy pre-treatment (after enrollment and prior to the Cycle 1 Day 1 dose) and in Cycle 1 Day 42 ± 5 days. 
Paired tumor biopsies if the tumor lesions are accessible for biopsy with acceptable clinical risk in the judgment of the investigator; see Section 9.14. 
Tumor biopsies of accessible lesions, pre- and post-first cycle of treatment, are strongly encouraged.  
Confidential
Page
140
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Module A Cohort Expansion Phase 
EVALUATION/ 
PROCEDURE 
Screening (1) 
(Within 
28 days) 
Cycle 1  
Cycle 2 and Subsequent Cycles 
EOTV (4) 
Post 
TRT 
FUP 
Day 
1 
Day 
2 
Day 8 
(±1d) 
Day 15 
(±1d) 
Day 22 
(±1d) 
Day 42 
(±5d) 
Day 1  
(±1d) 
Day 22 
(±1d)  
Days 23, 
29, 36 
(±1d) (3) 
Study Day 
 
1 
2 
8 
15 
22 
42 
43 
64 
65, 71, 78 
 
 
Concurrent Medications  
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
ECOG PS 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
12-lead ECG  
X 
X 
 
 
 
X 
 
X 
 
 
X 
 
To be performed in triplicate (approximately 1 minute apart). 
Assessed pre-infusion on dosing days. 
Echocardiogram/MUGA 
X 
 
 
 
 
 
 
 
 
 
 
 
Echocardiogram or MUGA scan performed at screening and other time points if clinically indicated. See Section 9.11 
Pregnancy Test (serum or 
urine) 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
Serum pregnancy test is required for eligibility. Subsequent pregnancy tests may use serum or urine. Test results must be reviewed before the study drug 
infusion on Day 1 of Cycle 1 and all subsequent cycles. If screening test is performed within 72 hours of 1st infusion, repeat of the test on Day 1 may be 
deferred. 
SAFETY/PK/MECHANISTIC STUDIES 
Protocol Procedure Related 
AEs/SAEs 
X 
 
 
 
 
 
 
 
 
 
 
 
Assess for Adverse Events 
 
Continuous 
 
Vital Signs 
X 
X 
 
 
 
X 
 
X 
X 
 
X 
 
During non-treatment visits (Screening and EOTV), vital signs will be taken once. 
Cycle 1: Day 1 and Day 22: Pre-infusion; at 15 and 30 minutes after the start of the infusion (± 5 minutes), at EOI (± 10 minutes); and at 1- and 4-hours after 
EOI (± 10 minutes). Note: Cycle 1 Day 22, the 4-hours after EOI vital signs may be deferred based on the judgement of the investigator.  
Cycle 2 and Beyond: Pre-infusion, at EOI (± 10 minutes), and at 1-hour after EOI (± 10 minutes). 
CBC, PLTs, diff; 
Chemistry Panel 2 
X 
X 
 
 
 
X 
 
X 
X 
 
X 
 
To be collected pre-infusion and prior to prophylactic pre-medications on dosing days. Day 1 laboratory blood samples can be collected up to 1 day before 
infusion. See Appendix 2 for list of assessments. 
PT or INR and PTT 2 
X 
X 
 
 
 
X 
 
X 
X 
 
X 
 
PT is preferred. INR is acceptable based on local availability. To be collected pre-infusion and prior to prophylactic pre-medications on dosing days. Day 1 
laboratory blood samples can be collected up to 1 day before infusion. See Appendix 2 for list of assessments. 
Confidential
Page
141
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Module A Cohort Expansion Phase 
EVALUATION/ 
PROCEDURE 
Screening (1) 
(Within 
28 days) 
Cycle 1  
Cycle 2 and Subsequent Cycles 
EOTV (4) 
Post 
TRT 
FUP 
Day 
1 
Day 
2 
Day 8 
(±1d) 
Day 15 
(±1d) 
Day 22 
(±1d) 
Day 42 
(±5d) 
Day 1  
(±1d) 
Day 22 
(±1d)  
Days 23, 
29, 36 
(±1d) (3) 
Study Day 
 
1 
2 
8 
15 
22 
42 
43 
64 
65, 71, 78 
 
 
Urinalysis 2 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
To be collected pre-infusion and prior to prophylactic pre-medications on dosing days. Day 1 urine samples can be collected up to 1 day before infusion. 
See Appendix 2 for list of assessments. Collect urinalysis as scheduled and as clinically indicated. Reflex test for microscopic evaluation if abnormal.   
PSA (mCRPC only) 2 
X 
X 
 
 
 
X 
 
X 
X 
 
X 
X 
PSA measurements to be performed at baseline and then repeated predose of each treatment visit, approximately 30 days after the last study treatment 
administration (EOTV), and every 12 weeks (± 7 days) during the follow-up period (per Section 9.17) until disease progression, start of another cancer 
therapy, or the study cutoff date, whichever comes first.  
Serum Testosterone 
(mCRPC only) 2 
X 
X 
 
 
 
X 
 
X 
X 
 
X 
X 
PRO 
X 
X 
 
 
 
X 
 
X 
X 
 
X 
 
Patient-reported outcome using the BPI-sf. On dosing days, assessments to be performed prior to infusion.  
Pharmacokinetics  
See Appendix 3 
 
Serum Cytokines  
See Appendix 3 
 
Flow Cytometry (Subset) 
See Appendix 3 
 
TCR repertoire (TCR) 
(Cohort Expansion only)  
See Appendix 3 
 
Serum Biomarkers (Cohort 
Expansion only) 
See Appendix 3 
 
Anti-Drug Antibody (ADA) 
See Appendix 3 
 
Tumor Assessment 
(CT/PET/MRI (bone scan 
for mCRPC) 
X 
Every 9 weeks 
X 
 
Radiographic disease assessments will occur every 9 weeks (63 days ± 3 days). Assessment will also be done at EOTV as per Section 9.16. 
Confidential
Page
142
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Module A Cohort Expansion Phase 
EVALUATION/ 
PROCEDURE 
Screening (1) 
(Within 
28 days) 
Cycle 1  
Cycle 2 and Subsequent Cycles 
EOTV (4) 
Post 
TRT 
FUP 
Day 
1 
Day 
2 
Day 8 
(±1d) 
Day 15 
(±1d) 
Day 22 
(±1d) 
Day 42 
(±5d) 
Day 1  
(±1d) 
Day 22 
(±1d)  
Days 23, 
29, 36 
(±1d) (3) 
Study Day 
 
1 
2 
8 
15 
22 
42 
43 
64 
65, 71, 78 
 
 
Survival Follow-up 
 
 
X  
Survival follow-up collected every 3 months (90 days ± 7 days) by clinic visit, telephone, paper mail, or other electronic contact for 2 years; information 
regarding response status and/or the occurrence of disease progression may be collected approximately every 3 months in participants who discontinued 
from study treatment due to reasons other than progressive disease, if they have not initiated any other cancer directed therapy. See Section 9.17 for details. 
1
The Screening visit should occur within 28 days prior to Day 1. 
2
All laboratory tests and body weight may be performed up to 24 hours prior to each treatment visit.  
3
For ≥ Cycle 2 Visits on Days 23, 29, and 36 are remote telemedicine visits only.  
4
The EOTV should be performed within 30 days following the last dose of study drug. 
Abbreviations: ADA = anti-drug antibody; AE = adverse event; CBC = complete blood count; CT = computed tomography; diff = differential; ECG = electrocardiography; ECOG 
PS = Eastern Cooperative Oncology Group Performance Status; EOI = end of infusion; EOTV = End of Treatment Visit; FUP = follow-up; INR = international normalized ratio; 
mCRPC = metastatic castration-resistant prostate carcinoma; MRI = magnetic resonance imaging; MUGA = multigated acquisition (scan); PET = positron emission tomography; 
PLTs = platelets; PRO = patient-reported outcome; PT = prothrombin time; PTT = partial thromboplastin time; SAE = serious adverse event; SSE = symptomatic skeletal event; 
TCR = T-cell repertoire; TRT = treatment. 
  
 
Confidential
Page
143
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Module B Dose Escalation and Cohort Expansion Phases 
EVALUATION/ 
PROCEDURE 
Screening (1) 
 
(Within 28 days) 
Cycle 1  
Cycle 2 and subsequent Cycles(3) 
End of 
Treatment 
Visit (4) 
Post 
TRT 
FUP 
Day 
1 
Days 2 
and 4 
Day 8 
(±1d) 
Day 
15 
Day 
22 
(±1d) 
Day 
42 (2) 
(±3d) 
Day 
1 
(±1d) 
Day 22 
(±1d) 
Days 
23, 25, 
29, 36 
(±1d) 
Day 
42 
(±3d) 
STUDY DRUG ADMINISTRATION 
 
Administer MGA012 
 
 
 
 
 
X 
 
X 
X 
 
 
 
 
Administer MGC018 
 
X 
 
 
 
X 
 
X 
X 
 
 
 
 
ELIGIBILITY 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline Tumor Imaging 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Designate Target/ 
Non-Target Lesions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
See Appendix 5 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Archival Tumor Specimen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
All participants to be enrolled in the study must have an identified formalin-fixed, paraffin embedded tumor specimen and or tumor specimens sufficient for 
10 slides; see Section 9.13. The specimens will be analyzed retrospectively and will not be used to determine participant eligibility. 
Physical Exam  
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weight  
X 
X 
 
 
 
X 
 
X 
X 
 
 
X 
 
Directed History/Physical  
 
 
 
X 
 
X 
 
 
X 
 
 
 
 
Optional tumor biopsies 
on study 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
On treatment tumor biopsy: Fresh tumor biopsy pre-treatment (after enrollment and prior to the Cycle 1 Day 1 dose) and at Cycle 1 D42 ± 5 days. 
Paired tumor biopsies if the tumor lesions are accessible for biopsy with acceptable clinical risk in the judgment of the investigator; see Section 9.14. 
Tumor biopsies of accessible lesions, pre- and post-first cycle of treatment, are strongly encouraged for participants in Cohort Expansion. 
Concurrent Medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG PS 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
12-lead ECG 
X 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
To be performed in triplicate (approximately 1 minute apart).  
During non-treatment visits (Screening and EOTV), ECG will be taken at 1 time point. 
Cycle 1 Day 1: Pre-infusion of MGC018 (within -30 minutes), EOI of MGC018 (within 30 minutes after EOI), and Hour 4 after EOI (± 10 minutes).  
Cycle 1 Day 22 and Day 1 of all subsequent cycles:  12-lead ECG is recorded pre-infusion (within -30 minutes) and EOI (within 30 minutes after EOI).   
Confidential
Page
144
of
169

MGC018, MGA012
MacroGenics, Inc.
Clinical Trial Protocol: CP-MGC018-01
Amendment 6, 16 August 2021
Module B Dose Escalation and Cohort Expansion Phases
EVALUATION/
PROCEDURE
Screening (1)
(Within 28 days)
Cycle 1 
Cycle 2 and subsequent Cycles(3) 
End of 
Treatment
Visit (4) 
Post 
TRT 
FUP
Day 
1
Days 2 
and 4
Day 8
(±1d)
Day 
15
Day 
22 
(±1d)
Day 
42 (2) 
(±3d)
Day 
1
(±1d)
Day 22
(±1d)
Days 
23, 25, 
29, 36 
(±1d)
Day 
42
(±3d)
Echocardiogram/MUGA 
X 
X 
X 
Echocardiogram or MUGA scan performed at screening, approximately every 12 weeks [at the end of C2, C4, C6…(± 7 days)], at the end of treatment 
visit and at other time points if clinically indicated See Section 9.11 
Ophthalmic Exam 
X 
X 
X 
Ophthalmic examinations including visual acuity testing (with correction), fundoscopic examination, and tonometry are performed at screening, at Cycle 
2 Day 42 (± 7 days), End of Treatment, and at other time points if clinically indicated.  Other directed studies (e.g., optical coherence tomography) will 
be performed as clinically indicated.  See Section 9.12 
Pregnancy Test (serum or 
urine) 
X 
X 
X 
X 
Serum pregnancy test is required for eligibility. Subsequent pregnancy tests may use serum or urine. Test results must be reviewed before the study drug 
infusion on Day 1 of Cycle 1 and all subsequent cycles. If screening test is performed within 72 hours of 1st infusion, repeat of the test on Day 1 may be 
deferred. 
Eligibility Checklist and 
Register Participant 
X 
SAFETY/PK/MECHANISTIC STUDIES
Protocol Procedure 
Related AEs/SAEs 
X 
Assess for Adverse Events 
Continuous 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
During non-treatment visits (Screening, Day 8, and EOTV), vital signs will be taken once. 
Cycle 1:  
Day 1: Pre-infusion of MGC018 (within -30 minutes); at 15 and 30 minutes after the start of infusion (± 5 minutes), at EOI (± 10 minutes); and at 1- and 
4-hours after EOI (± 10 minutes).
Day 22: Pre-infusion of MGA012 (within -30 minutes); at 15 and 30 minutes after the start of MGA012 infusion (± 5 minutes), at EOI of MGA012
(± 10 minutes); at EOI of MGC018 (± 10 minutes), and at 1 hour after MGC018 EOI (± 10 minutes).
Cycle 2 and Beyond: Pre-infusion of MGA012 (within -30 minutes); at EOI of MGA012 (± 10 minutes); at EOI of MGC018 (± 10 minutes), and at 1 hour
after MGC018 EOI (± 10 minutes).
Confidential
Page
145
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Module B Dose Escalation and Cohort Expansion Phases 
EVALUATION/ 
PROCEDURE 
Screening (1) 
 
(Within 28 days) 
Cycle 1  
Cycle 2 and subsequent Cycles(3) 
End of 
Treatment 
Visit (4) 
Post 
TRT 
FUP 
Day 
1 
Days 2 
and 4 
Day 8 
(±1d) 
Day 
15 
Day 
22 
(±1d) 
Day 
42 (2) 
(±3d) 
Day 
1 
(±1d) 
Day 22 
(±1d) 
Days 
23, 25, 
29, 36 
(±1d) 
Day 
42 
(±3d) 
CBC, PLTs, diff; 
Chemistry Panel  
X 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
 
To be collected pre-infusion and prior to prophylactic pre-medications on dosing days. Day 1 laboratory blood samples can be collected up to 1 day before 
infusion. See Appendix 2 for list of assessments. 
PT or INR   
X 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
 
PT is preferred. INR is acceptable based on local availability. To be collected pre-infusion and prior to prophylactic pre-medications on dosing days. Day 1 
laboratory blood samples can be collected up to 1 day before infusion. Collect as scheduled, and as clinically indicated. 
Free T4 and TSH 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
Sample to be drawn at Screening, Cycle 2 Day 1, and then on Day 1 every other cycle, i.e., Cycle 4, Cycle 6, etc. 
Urinalysis   
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
To be collected pre-infusion and prior to prophylactic pre-medications on dosing days. Day 1 urine samples can be collected up to 1 day before infusion. See 
Appendix 2 for list of assessments. Collect as scheduled and as clinically indicated. Reflex test for microscopic evaluation if abnormal. 
PSA (mCRPC only) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
PSA measurements to be performed at baseline and then repeated predose on Day 1 of each cycle, approximately 30 days after the last study treatment 
administration (EOTV), and every 12 weeks (± 7 days) during the follow-up period until disease progression, start of another cancer therapy, or the study 
cutoff date, whichever comes first. 
Pharmacokinetics  
See Appendix 3 
 
Serum Cytokines  
See Appendix 3 
 
Flow Cytometry 
(Occupancy) 
See Appendix 3 
 
Flow Cytometry (Subset) 
See Appendix 3 
 
TCR repertoire (TCR) 
(Cohort Expansion only)  
See Appendix 3 
 
Serum Biomarkers 
(Cohort Expansion only) 
See Appendix 3 
 
Anti-Drug Antibody 
(ADA)  
See Appendix 3 
 
Confidential
Page
146
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Module B Dose Escalation and Cohort Expansion Phases 
EVALUATION/ 
PROCEDURE 
Screening (1) 
 
(Within 28 days) 
Cycle 1  
Cycle 2 and subsequent Cycles(3) 
End of 
Treatment 
Visit (4) 
Post 
TRT 
FUP 
Day 
1 
Days 2 
and 4 
Day 8 
(±1d) 
Day 
15 
Day 
22 
(±1d) 
Day 
42 (2) 
(±3d) 
Day 
1 
(±1d) 
Day 22 
(±1d) 
Days 
23, 25, 
29, 36 
(±1d) 
Day 
42 
(±3d) 
Tumor Assessment 
(CT/PET/MRI)  
X 
 
 
 
 
 
X 
 
 
 
X 
X 
 
Radiographic disease assessments will occur on Day 42 ± 3 days for the first four cycles, and every other cycle thereafter. Assessment will also be done at 
EOTV. 
Survival Follow-up 
 
 
X  
Survival follow-up collected every 3 months (90 days ± 7 days) by clinic visit, telephone, paper mail, or other electronic contact for 2 years; information 
regarding response status and/or the occurrence of disease progression may be collected approximately every 3 months in participants who discontinued 
from study treatment due to reasons other than progressive disease, if they have not initiated any other cancer directed therapy. See Section 9.17 for details. 
1
The Screening visit should occur within 28 days prior to Day 1. 
2
Cycle 1 Day 42 and Cycle 2 Day 1 may be combined. Regardless if the visits are combined or not, Cycle 1 Day 42 assessments should occur before Cycle 2 
Day 1 assessments. The same applies to all consecutive cycles.  
3
Evaluations/procedures performed on Days 23, 25, 29, and 36 apply to Cycle 2 only. 
4
The EOTV should be performed within 30 days following the last dose of study drug. 
Abbreviations: ADA = anti-drug antibody; AE = adverse event; CBC = complete blood count; CT = computed tomography; diff = differential; 
ECG = electrocardiography; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EOI = end of infusion; EOTV = End of Treatment Visit; 
FUP = follow-up; INR = international normalized ratio; mCRPC = metastatic castration-resistant prostate carcinoma; MRI = magnetic resonance imaging; 
MUGA = multigated acquisition (scan); PET = positron emission tomography; PLTs = platelets; PSA = prostate-specific antigen; PT = prothrombin time; 
SAE = serious adverse event; SSE = symptomatic skeletal event; TCR = T-cell repertoire; TRT = treatment; TSH = thyroid stimulating hormone. 
 
I 
I 
I 
Confidential
Page
147
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Appendix 2 
Clinical Laboratory Tests  
Pregnancy test: 
Blood or Urine Human chorionic gonadotropin (hCG) 
 
Hematology (CBC with differential): 
Hemoglobin  
Hematocrit  
Platelet count 
White blood cell count 
Absolute neutrophils, lymphocytes, and eosinophils 
 
Serum chemistry: 
Albumin  
Alkaline phosphatase 
Alanine aminotransferase  
Aspartate aminotransferase 
Bicarbonate 
Bilirubin (Total and Direct) 
Blood urea nitrogen 
Calcium  
Chloride  
Creatinine 
Glucose 
Magnesium 
Phosphate 
Potassium 
Sodium 
Uric acid 
Coagulation: 
Prothrombin time (PT) – preferred, or INR is 
acceptable 
International normalised ratio (INR) 
Partial thromboplastin time (PTT) 
 
Endocrine tests: 
Free thyroxine (Module A Dose Escalation and 
Module B Dose Escalation and Module B Cohort 
Expansion) 
Thyroid-stimulating hormone (Module A Dose 
Escalation and Module B Dose Escalation and Module 
B Cohort Expansion) 
Serum testosterone (mCRPC Module A Cohort 
Expansion and Module B Cohort Expansion) 
 
Urinalysis: 
Protein 
Occult blood 
If abnormal protein or occult blood, perform reflex 
test for microscopic evaluation 
 
Tumor marker: 
Prostate specific antigen (PSA) for mCRPC only 
 
 
 
 
Confidential
Page
148
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Appendix 3 
Pharmacokinetics, Immunogenicity, and Pharmacodynamic 
Biomarkers Blood Sampling Schedule for Module A and B  
Blood samples for PK, ADA, and pharmacodynamic biomarkers will be collected per Table 12, 
Table 13, and Table 14. Please note: 
•
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 collection of the blood sample for immunogenicity assessment.  
•
Both planned and actual start and end of infusion date and times and blood sample 
collection date and times will be recorded on the eCRFs. 
 
Confidential
Page
149
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Table 12 
Module A: Pharmacokinetic, Immunogenicity, and Pharmacodynamic Biomarkers Blood Sampling 
Schedule: MGC018 Monotherapy Q3W Dose Escalation Phase       
Cycle 
Day 
Window 
Time Point 
MGC018 PK 
(Total and ADC) 
Serum 
MGC018 PK 
(SYD986) 
Plasma 
ADA 
(for 
MGC018) 
Cytokines 
Flow 
Cytometry 
Subsets 
Cycle 1 
 
01 
N/A 
Pre MGC018 
Infusion 
X 
X 
X 
X 
X 
± 5 min 
EOI MGC018 
Infusion  
X 
X 
 
X 
 
± 10 min 
1 h after EOI 
MGC018 
X 
X 
 
X 
 
± 10 min 
4 h after EOI 
MGC018 
X 
X 
 
X 
 
02 
N/A 
Day 02 
X 
X 
 
X 
X 
04 
N/A 
Day 04 
X 
X 
 
X 
 
08 
N/A 
Day 08 
X 
X 
 
 
X 
15 
N/A 
Day 15 
X 
X 
 
 
 
22 
N/A 
Pre MGC018 
Infusion 
X 
X 
X 
 
X 
± 5 min 
EOI MGC018 
Infusion 
X 
X 
 
 
 
Cycle 2 
01 
N/A 
Pre MGC018 
Infusion 
X 
X 
X 
 
X 
± 5 min 
EOI MGC018 
Infusion 
X 
X 
 
 
 
22 
N/A 
Pre MGC018 
Infusion 
X 
X 
 
 
X 
± 5 min 
EOI MGC018 
Infusion 
X 
X 
 
 
 
± 10 min 
1 h after EOI 
MGC018 
X 
X 
 
 
 
± 10 min 
4 h after EOI 
MGC018 
X 
X 
 
 
 
23 
N/A 
Day 23 
X 
X 
 
 
X 
25 
N/A 
Day 25 
X 
X 
 
 
 
29 
N/A 
Day 29 
X 
X 
 
 
X 
36 
N/A 
Day 36 
X 
X 
 
 
X 
Confidential
Page
150
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Table 12 
Module A: Pharmacokinetic, Immunogenicity, and Pharmacodynamic Biomarkers Blood Sampling 
Schedule: MGC018 Monotherapy Q3W Dose Escalation Phase       
Cycle 
Day 
Window 
Time Point 
MGC018 PK 
(Total and ADC) 
Serum 
MGC018 PK 
(SYD986) 
Plasma 
ADA 
(for 
MGC018) 
Cytokines 
Flow 
Cytometry 
Subsets 
Cycle 3 
01 
N/A 
Pre MGC018 
Infusion 
X 
X 
X 
 
X 
± 5 min 
EOI MGC018 
Infusion 
X 
X 
 
 
 
Cycle 4 
and 
Beyond 
01 
N/A 
Pre MGC018 
Infusion 
X 
X 
X 
 
 
± 5 min 
EOI MGC018 
Infusion 
X 
X 
 
 
 
IRR/ 
CRS 
 
N/A 
IRR/CRS 
X 
X 
 
X 
 
EOTV 
 
N/A 
EOTV 
X 
X 
X 
 
X 
Abbreviations: ADA = anti-drug antibody; ADC = antibody-drug conjugate; CRS = cytokine release syndrome; EOI = end of infusion; EOTV = End of Treatment Visit; NA = not 
applicable; IRR = infusion-related reaction. 
 
 
Confidential
Page
151
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Table 13 
Module A: Pharmacokinetic, Immunogenicity, and Pharmacodynamic Biomarkers Blood Sampling 
Schedule: MGC018 Monotherapy Q3W Cohort Expansion Phase       
Cycle 
Day 
Window 
Time Point 
MGC018 
PK 
(Total 
and 
ADC) 
Serum 
MGC018 
PK 
(SYD986) 
Plasma 
ADA 
(for 
MGC018) 
Cytokines 
Flow 
Cytometry 
Subsets 
Serum 
Biomarkers 
 
T-cell 
Repertoire 
 
Cycle 1 
01 
N/A 
Pre MGC018 
Infusion 
X 
X 
X 
X 
X 
X 
X 
+ 5 min 
EOI MGC018 
Infusion  
X 
X 
 
X 
 
 
 
± 10 min 
1 h after EOI 
MGC018 
X 
X 
 
X 
 
 
 
± 10 min 
4 h after EOI 
MGC018 
X 
X 
 
X 
 
 
 
22 
N/A 
Pre MGC018 
Infusion 
X 
X 
X 
X 
X 
X 
 
+ 5 min 
EOI MGC018 
Infusion 
X 
X 
 
X 
 
 
 
42 
± 5 Days 
Biopsy 
 
 
 
 
X a 
X a 
X a  
Cycle 2 
01 
N/A 
Pre MGC018 
Infusion 
X 
X 
X 
X 
X 
X 
 
X 
+ 5 min 
EOI MGC018 
Infusion 
X 
X 
 
X 
 
 
 
22 
N/A 
Pre MGC018 
Infusion 
X 
X 
 
X 
X 
X 
 
+5 min 
EOI MGC018 
Infusion 
X 
X 
 
X 
 
 
 
Cycle 3 
01 
N/A 
Pre MGC018 
Infusion 
X 
X 
X 
X 
X 
X 
X 
+ 5 min 
EOI MGC018 
Infusion 
X 
X 
 
X 
 
 
 
Cycle 4 
01 
N/A 
Pre MGC018 
Infusion 
X 
X 
X 
X 
 
 
 
+ 5 min 
EOI MGC018 
Infusion 
X 
X 
 
X 
 
 
 
Confidential
Page
152
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Table 13 
Module A: Pharmacokinetic, Immunogenicity, and Pharmacodynamic Biomarkers Blood Sampling 
Schedule: MGC018 Monotherapy Q3W Cohort Expansion Phase       
Cycle 
Day 
Window 
Time Point 
MGC018 
PK 
(Total 
and 
ADC) 
Serum 
MGC018 
PK 
(SYD986) 
Plasma 
ADA 
(for 
MGC018) 
Cytokines 
Flow 
Cytometry 
Subsets 
Serum 
Biomarkers 
 
T-cell 
Repertoire 
 
Cycle 5 
and 
Beyond 
01 
N/A 
Pre MGC018 
Infusion 
X 
X 
X 
 
 
 
 
 
+ 5 min 
EOI MGC018 
Infusion 
X 
X 
 
 
 
 
 
IRR/ 
CRS 
 
N/A 
IRR/CRS 
X 
X 
 
X 
 
 
 
EOTV 
 
N/A 
EOTV 
X 
X 
X 
X 
X 
 
 
Abbreviations: ADA = anti-drug antibody; ADC = antibody-drug conjugate; CRS = cytokine release syndrome; EOI = end of infusion; EOTV = End of Treatment Visit; NA = not 
applicable; IRR = infusion-related reaction 
a
Blood sample drawn from participants that consent to undergo a biopsy. 
Confidential
Page
153
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Table 14 
Module B: Pharmacokinetic, Immunogenicity, and Pharmacodynamic Biomarkers Blood Sampling 
Schedule: MGC018 and MGA012 Combination Therapy Q3W       
Cycle 
Day 
Window 
Time Point 
MGC018 PK 
(Total and ADC) 
Serum 
MGC018 PK 
(SYD986) 
Plasma 
MGA012 PK 
Serum 
ADA (for 
MGA012 and 
MGC018) 
Cytokines 
Flow Cytometry 
Occupancy 
Flow Cytometry 
Subsets 
Serum 
Biomarkers 
(Expansion only) 
T-Cell 
Repertoire 
(Expansion only) 
Cycle 1 
01 
N/A 
Pre MGC018 Infusion 
X 
X 
 
X 
X 
X 
X 
X 
X 
± 5 
min 
EOI MGC018 
Infusion 
X 
X 
 
 
X 
 
 
 
 
± 10 
min 
1 h after EOI 
MGC018 
X 
X 
 
 
X 
 
 
 
 
± 10 
min 
4 h after EOI 
MGC018 
X 
X 
 
 
X 
 
 
 
 
02 
N/A 
Day 02 
X 
X 
 
 
X 
 
X 
 
 
04 
N/A 
Day 04 
X 
X 
 
 
X 
 
 
 
 
08 
N/A 
Day 08 
X 
X 
 
 
 
 
X 
X 
 
15 
N/A 
Day 15 
X 
X 
 
 
 
 
 
 
 
22 
N/A 
Pre MGA012 Infusion 
 
 
X 
X 
 
X 
X 
X 
 
± 5 
min 
EOI MGA012 
Infusion  
X 
X 
X 
 
 
X 
X 
 
 
± 5 
min 
EOI MGC018 
Infusion 
X 
X 
 
 
 
 
 
 
 
42 
± 5 
Days 
Biopsy 
(SCCHN only) 
 
 
 
 
 
 
X a 
X a 
X a 
Cycle 2 
01 
N/A 
Pre MGA012 Infusion 
 
 
X 
X 
 
X 
X 
X 
X 
± 5 
min 
EOI MGA012 
Infusion 
X 
X 
X 
 
 
X 
 
 
 
± 5 
min 
EOI MGC018 
Infusion 
X 
X 
 
 
 
 
 
 
 
22 
N/A 
Pre MGA012 Infusion 
 
 
X 
 
 
X 
X 
X 
 
± 5 
min 
EOI MGA012 
Infusion 
X 
X 
X 
 
 
X 
 
 
 
± 5 
min 
EOI MGC018 
Infusion 
X 
X 
 
 
 
 
 
 
 
Confidential
Page
154
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Table 14 
Module B: Pharmacokinetic, Immunogenicity, and Pharmacodynamic Biomarkers Blood Sampling 
Schedule: MGC018 and MGA012 Combination Therapy Q3W       
Cycle 
Day 
Window 
Time Point 
MGC018 PK 
(Total and ADC) 
Serum 
MGC018 PK 
(SYD986) 
Plasma 
MGA012 PK 
Serum 
ADA (for 
MGA012 and 
MGC018) 
Cytokines 
Flow Cytometry 
Occupancy 
Flow Cytometry 
Subsets 
Serum 
Biomarkers 
(Expansion only) 
T-Cell 
Repertoire 
(Expansion only) 
± 10 
min 
1 h after EOI 
MGC018 
X 
X 
 
 
 
 
 
 
 
± 10 
min 
4 h after EOI 
MGC018 
X 
X 
 
 
 
 
 
 
 
23 
N/A 
Day 23 
X 
X 
 
 
 
 
X 
 
 
25 
N/A 
Day 25 
X 
X 
 
 
 
 
 
 
 
29 
N/A 
Day 29 
X 
X 
 
 
 
 
X 
 
 
36 
N/A 
Day 36 
X 
X 
 
 
 
X 
X 
 
 
Cycle 3 
01 
N/A 
Pre MGA012 
Infusion 
 
 
X 
X 
 
X 
X 
X 
X 
± 5 
min 
EOI MGA012 
Infusion 
X 
X 
X 
 
 
X 
 
 
 
± 5 
min 
EOI MGC018 
Infusion 
X 
X 
 
 
 
 
 
 
 
Cycle 4 and 
Beyond 
01 
N/A 
Pre MGA012 
Infusion 
 
 
X 
X 
 
 
 
 
 
± 5 
min 
EOI MGA012 
Infusion 
X 
X 
X 
 
 
 
 
 
 
± 5 
min 
EOI MGC018 
Infusion 
X 
X 
 
 
 
 
 
 
 
IRR/CRS 
 
N/A 
IRR/CRS 
X 
X 
X 
 
X 
 
 
 
 
EOTV 
 
N/A 
EOTV 
X 
X 
X 
X 
 
 
X 
 
 
Abbreviations: ADA = anti-drug antibody; ADC = antibody-drug conjugate; CRS = Cytokine Release Syndrome; EOI = end of infusion; EOTV = End of Treatment Visit; 
N/A = not applicable; IRR = infusion-related reaction. 
a
Blood sample drawn from participants in the Cohort Expansion Phase that consent to and undergo a biopsy.  
Confidential
Page
155
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Appendix 4 
Eastern Cooperative Oncology Group (ECOG) 
Performance Status  
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity, but ambulatory and able to carry out work of a 
light or sedentary nature (e.g., light house work or office work) 
2 
Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and 
about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry-on any self-care. Totally confined to bed or chair. 
5 
Dead 
 
 
 
Confidential
Page
156
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Appendix 5 
RECIST v1.1 Guidelines  
Adapted from Eisenhauer 2009 (22). 
All participants 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
157
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
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 participant, 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 
Confidential
Page
158
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
lesions, documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken since it is more objective and may also be reviewed at 
the end of the study. 
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 
Confidential
Page
159
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
the case that, on occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesions which can be measured reproducibly should be 
selected. 
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 x 30 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
160
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
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 case report form. If it 
is the opinion of the radiologist that the lesion has likely disappeared, the measurement should be 
recorded as 0 mm. If the lesion is believed to be present and is faintly seen but too small to 
measure, a default value of 5 mm should be assigned (Note: It is less likely that this rule will be 
used for lymph nodes since they usually have a definable size when normal and are frequently 
surrounded by fat such as in the retroperitoneum; however, if a lymph node is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should be assigned 
in this circumstance as well). This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness). The measurement of these lesions is 
potentially non-reproducible, therefore providing this default value will prevent false responses 
or progressions based upon measurement error. However, if the radiologist is able to provide an 
actual measure, that should be recorded, even if it is below 5 mm. 
Lesions that split or coalesce on treatment. When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesions. If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the ‘coalesced lesion’. 
2.3.3 
Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they 
need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol. 
Confidential
Page
161
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
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
162
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
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 best overall response is the best response recorded from the start of the study treatment until 
the end of treatment taking into account any requirement for confirmation. The patient’s best 
overall response assignment will depend on the findings of both target and non-target disease and 
will also take into consideration the appearance of new lesions. 
2.4.1 
Time point response 
It is assumed that at each protocol specified time point, a response assessment occurs. Table A-1 
on the next page provides a summary of the overall response status calculation at each time point 
for patients who have measurable disease at baseline. 
2.4.2 
Missing assessments and inevaluable designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. If only a subset of lesion measurements is made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not change 
the assigned time point response. This would be most likely to happen in the case of PD. For 
example, if a patient had a baseline sum of 50 mm with three measured lesions and at follow-up 
only two lesions were assessed, but those gave a sum of 80 mm, the patient will have achieved 
PD status, regardless of the contribution of the missing lesion. 
2.4.3 
Best overall response: all time points 
The best overall response is determined once all the data for the patient is known. 
Confidential
Page
163
of
169

MGC018, MGA012
MacroGenics, Inc.
Clinical Trial Protocol: CP-MGC018-01
Amendment 6, 16 August 2021
Table A-1
Time point response: patients with target (+/- non-target) disease 
Target lesions
Non-target lesions
New lesions
Overall response
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = inevaluable. 
Best response determination in trials where confirmation of complete or partial response IS 
required: Complete or partial responses may be claimed only if the objective response is 
confirmed on a follow-up scan obtained no less than 4 weeks after the initial scan demonstrating 
an objective response. In this circumstance, the best overall response can be interpreted as in 
Table A-2.
Table A-2
Best overall response when confirmation of CR and PR required 
Overall response
First time point
Overall response
Subsequent time point
BEST overall response
CR 
CR 
CR 
CR 
PR 
SD, PD or PR a 
CR 
SD 
SD 
CR 
PD 
SD 
CR 
NE 
SD 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise, NE 
NE 
NE 
NE 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = inevaluable. 
a
If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR criteria 
relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best response would 
depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed when subsequent scans 
suggest small lesions were likely still present and in fact the patient had PR, not CR at the first time point. Under these 
circumstances, the original CR should be changed to PR and the best response is PR. 
Confidential
Page
164
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ 
size (< 10 mm), they may still have a measurement reported on scans This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes. As noted earlier, this means that patients with CR may not 
have a total sum of ‘zero’ on the case report form (CRF). 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration”. Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy. The objective response status of 
such patients is to be determined by evaluation of target and non-target disease as shown in 
Table A-1 and Table A-2. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at 
the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 
2.5 
Confirmation/Duration of response 
2.5.1 
Confirmation 
Objective responses should be confirmed by CT and/or MRI scans obtained no less than 4 weeks 
after the original scan. 
2.5.2 
Duration of overall response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded on study). The duration of overall complete response is measured from the time 
measurement criteria are first met for CR until the first date that recurrent disease is objectively 
documented. 
2.5.3 
Duration of stable disease 
Stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest sum on study (if the baseline sum is the smallest, this is the 
reference for calculation of PD). 
 
Confidential
Page
165
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Appendix 6 
Brief Pain Inventory-Short Form (BPI-sf)  
Confidential
Page
166
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Confidential
Page
167
of
169

MGC018, MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGC018-01 
Amendment 6, 16 August 2021 
 
 
Appendix 7 
Principal Investigator’s Agreement  
Study Title: 
A Phase 1/2, First-in-Human, Open-Label, Dose-Escalation Study of 
MGC018 (Anti–B7-H3 Antibody Drug Conjugate) Alone and in 
Combination with MGA012 (Anti–PD-1 Antibody) in Patients with 
Advanced Solid Tumors 
Study Number: 
CP-MGC018-01 
 
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
168
of
169

CP-MGC018-01 Protocol Amendment 6 (16-Aug-2021)
This is the electronic signature page for the above referenced document.
User Task: eSignatories Approval
 
ic
Research Approval (Intended or Designee)
16-Aug-2021 20:46:08 GMT+0000
User Task: eSignatories Approval
 
i
 Data Management/Statistics Approval
(Intended or Designee)
17-Aug-2021 02:28:00 GMT+0000
Confidential
Page
169
of
169