A Phase 1, Open-Label, Dose Escalation Study of MGA271 in Combination With Pembrolizumab and in Combination With MGA012 in Patients With Melanoma, Squamous Cell Cancer of the Head and Neck, Non-Small Cell Lung Cancer, Urothelial Cancer, and Other Cancers
Phase: PHASE1
Conditions: Melanoma, Head and Neck Cancer, Non Small Cell Lung Cancer, Urothelial Carcinoma
Sponsor: MacroGenics

MGA271
MacroGenics, Inc.
Clinical Trial Protocol: CP-MGA271-03
Amendment 6, 26 August 2020
CLINICAL TRIAL PROTOCOL: CP-MGA271-03
PROTOCOL AMENDMENT 6 
Study Title:
A Phase 1, Open-Label, Dose Escalation Study of MGA271 in 
Combination with Pembrolizumab and in Combination with MGA012 
in Patients with Melanoma, Squamous Cell Cancer of the Head and 
Neck, Non-Small Cell Lung Cancer, Urothelial Cancer, and Other 
Cancers 
Study Number:
CP-MGA271-03 
Study Phase:
Phase 1 
Product Name:
MGA271 in combination with pembrolizumab (KEYTRUDA®) and 
MGA271 in combination with MGA012 (also known as 
INCMGA00012)   
Product Numbers:
MGA271 and MGA012  
IND Number:
 
EudraCT Number
2017-001293-42 
Indication:
Melanoma, squamous cell cancer of the head and neck, non-small cell 
lung cancer, mesothelioma, urothelial cancer, clear cell renal cell 
carcinoma, ovarian cancer, thyroid cancer, triple-negative breast 
cancer, pancreatic cancer, colon cancer, soft tissue sarcoma, and 
prostate cancer 
Coordinating Principal 
Investigator:
 
Sponsor:
MacroGenics, Inc. 
9704 Medical Center Drive 
Rockville, MD 20850 
301-251-5172
Sponsor’s Medical 
Monitor:
Refer to Study Contact List 
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MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGA271-03 
Amendment 6, 26 August 2020 
 
 
 
 
 
Confidentiality Statement 
This document is confidential. It contains proprietary information of MacroGenics, Inc. that can only be used 
for the purpose of reviewing or performing this study. Any use, viewing or disclosure of such information that 
is not authorized in writing by the Sponsor is strictly prohibited. 
 
 
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MGA271 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGA271-03 
Amendment 6, 26 August 2020 
 
 
 
 
 
TABLE OF CONTENTS 
SPONSOR SIGNATURES ....................................................................................................... 9 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .......................................... 12 
1 
SYNOPSIS .................................................................................................................. 17 
2 
BACKGROUND INFORMATION ............................................................................ 36 
2.1 
Disease Background........................................................................................... 36 
2.2 
Background on B7-H3 and PD-1 ....................................................................... 39 
2.2.1 
B7-H3 ....................................................................................................... 39 
2.2.2 
PD-1 ......................................................................................................... 40 
2.3 
Study Agent Background ................................................................................... 40 
2.3.1 
MGA271 .................................................................................................. 40 
2.3.1.1 
Safety .............................................................................................. 43 
2.3.2 
Pembrolizumab ........................................................................................ 45 
2.3.2.1 
Safety .............................................................................................. 47 
2.3.3 
MGA012 .................................................................................................. 49 
2.3.3.1 
Safety .............................................................................................. 50 
2.4 
Rationale for Combining MGA271 and Pembrolizumab .................................. 51 
2.5 
Rationale for Combining MGA271 and MGA012 ............................................ 53 
2.6 
Rationale for Dose Selection ............................................................................. 54 
2.6.1 
Dose Escalation Phase ............................................................................. 54 
2.6.1.1 
Pembrolizumab............................................................................... 54 
2.6.1.2 
MGA271......................................................................................... 54 
2.6.1.3 
MGA012......................................................................................... 56 
2.6.2 
Expansion Phase ...................................................................................... 57 
3 
STUDY PURPOSE AND OBJECTIVES ................................................................... 58 
3.1 
Primary Objective .............................................................................................. 58 
3.2 
Secondary Objective(s) ...................................................................................... 58 
3.3 
Exploratory Objectives ...................................................................................... 59 
4 
TRIAL DESIGN ......................................................................................................... 60 
4.1 
Overall Study Design and Plan .......................................................................... 60 
4.1.1 
General Study Design .............................................................................. 60 
4.1.2 
Dose Escalation Phase ............................................................................. 62 
4.1.3 
Cohort Expansion Phase .......................................................................... 64 
4.1.4 
Efficacy Follow-up Period ....................................................................... 64 
4.2 
Dose Limiting Toxicity ...................................................................................... 64 
4.2.1 
Hematologic Dose Limiting Toxicity ...................................................... 65 
4.2.2 
Non-Hematologic Dose Limiting Toxicity .............................................. 65 
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MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGA271-03 
Amendment 6, 26 August 2020 
 
 
 
 
 
4.2.3 
Hepatic Non-Hematologic Dose Limiting Toxicity ................................. 66 
4.3 
Dose Escalation Rules........................................................................................ 67 
4.4 
Rules for Continuation of Study Therapy .......................................................... 68 
4.5 
Guidelines for Dose Modification ..................................................................... 69 
4.5.1 
Dose Delays ............................................................................................. 69 
4.6 
Rationale for Study Design ................................................................................ 70 
4.7 
Study Duration ................................................................................................... 70 
4.7.1 
Patient Accrual ......................................................................................... 70 
4.7.2 
Definition of End of Trial ........................................................................ 71 
5 
SELECTION AND WITHDRAWAL OF PATIENTS ................................................ 72 
5.1 
Inclusion Criteria ............................................................................................... 72 
5.2 
Exclusion Criteria .............................................................................................. 78 
5.3 
Withdrawal of Patient from the Trial or Study Drug ......................................... 80 
5.3.1 
Guidelines for Permanent Discontinuation .............................................. 80 
6 
STUDY TREATMENTS ............................................................................................ 81 
6.1 
Description of Treatments and Study Drug and Supplies .................................. 81 
6.1.1 
MGA271 .................................................................................................. 81 
6.1.2 
Pembrolizumab ........................................................................................ 81 
6.1.3 
MGA012 .................................................................................................. 82 
6.2 
Drug Preparation ................................................................................................ 82 
6.2.1 
General Guidelines and Precautions ........................................................ 82 
6.2.2 
MGA271 .................................................................................................. 83 
6.2.3 
Pembrolizumab ........................................................................................ 83 
6.2.4 
MGA012 .................................................................................................. 84 
6.2.5 
Placebo or Control ................................................................................... 85 
6.3 
Study Drug Administration ................................................................................ 85 
6.3.1 
MGA271 .................................................................................................. 85 
6.3.2 
Pembrolizumab ........................................................................................ 85 
6.3.3 
MGA012 .................................................................................................. 86 
6.4 
Selection and Timing of Dose for Each Patient ................................................. 86 
6.5 
Potential Adverse Events and Supportive Care Measures ................................. 86 
6.5.1 
Infusion Related Reactions Including Cytokine Release 
Syndrome ................................................................................................. 86 
6.5.1.1 
Grading of Infusion Reactions ....................................................... 87 
6.5.1.2 
Premedications and Prophylaxis .................................................... 88 
6.5.1.3 
Management of Observed Infusion Reactions ............................... 88 
6.5.2 
Immune-Related Adverse Events ............................................................. 92 
6.5.2.1 
Diarrhea or Colitis .......................................................................... 92 
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MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGA271-03 
Amendment 6, 26 August 2020 
 
 
 
 
 
6.5.2.2 
Hepatic Toxicity ............................................................................. 93 
6.5.2.3 
Pneumonitis .................................................................................... 95 
6.5.2.4 
Dermatologic Toxicity .................................................................... 96 
6.5.2.5 
Nephritis/Renal Failure .................................................................. 96 
6.5.2.6 
Immune-Mediated Endocrinopathies ............................................. 97 
6.6 
Method of Assigning Patients to Treatment Groups .......................................... 98 
6.7 
Blinding.............................................................................................................. 99 
6.8 
Concomitant Therapy ......................................................................................... 99 
6.9 
Restrictions ...................................................................................................... 100 
6.9.1 
Prior Therapy ......................................................................................... 100 
6.9.2 
Fluid and Food Intake ............................................................................ 100 
6.9.3 
Patient Activity Restrictions .................................................................. 100 
6.10 
Treatment Compliance ..................................................................................... 101 
6.11 
Packaging and Labeling ................................................................................... 101 
6.11.1 
MGA271 ................................................................................................ 101 
6.11.2 
Pembrolizumab ...................................................................................... 101 
6.11.3 
MGA012 ................................................................................................ 101 
6.12 
Storage and Accountability .............................................................................. 101 
6.12.1 
MGA271 ................................................................................................ 101 
6.12.2 
Pembrolizumab ...................................................................................... 102 
6.12.3 
MGA012 ................................................................................................ 102 
6.12.4 
Accounting for the Materials ................................................................. 102 
6.13 
Investigational Product Disposition at End of Study ....................................... 102 
7 
STUDY PROCEDURES .......................................................................................... 104 
7.1 
Informed Consent............................................................................................. 104 
7.2 
Medical History ............................................................................................... 104 
7.3 
Prior and Concomitant Medications ................................................................ 104 
7.4 
Physical Examination....................................................................................... 104 
7.5 
Vital Signs ........................................................................................................ 105 
7.6 
Clinical Laboratory Tests ................................................................................. 105 
7.6.1 
Laboratory Parameters ........................................................................... 105 
7.6.2 
Sample Collection, Storage, and Shipping ............................................ 106 
7.7 
Electrocardiography ......................................................................................... 107 
7.8 
Safety Assessments .......................................................................................... 107 
7.8.1 
Criteria for Evaluation ........................................................................... 107 
7.8.2 
Adverse Event: Definitions .................................................................... 108 
7.8.2.1 
Adverse Event .............................................................................. 108 
7.8.2.2 
Adverse Drug Reaction ................................................................ 108 
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MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGA271-03 
Amendment 6, 26 August 2020 
 
 
 
 
 
7.8.2.3 
Adverse Event of Special Interest ................................................ 108 
7.8.2.4 
Treatment Emergent Adverse Event ............................................. 108 
7.8.2.5 
Serious Adverse Events ................................................................ 109 
7.8.2.6 
Immediately Reportable Event ..................................................... 109 
7.8.3 
Adverse Events of Special Interest .........................................................110 
7.8.4 
Product Quality Issue with Clinical Consequences ................................110 
7.8.5 
Performing Adverse Event Assessments .................................................110 
7.8.6 
Reporting of Adverse Events to the Sponsor ..........................................112 
7.9 
Notification to the Sponsor of Events Requiring Immediate Reporting ...........113 
7.10 
Emergency Unblinding .....................................................................................114 
7.11 
Efficacy and/or Pharmacokinetic and Pharmacodynamic Assessments ...........114 
7.11.1 
Efficacy Assessments ..............................................................................114 
7.11.1.1 Treatment of Patients According to Principles of Immune-
Related Response Criteria .............................................................114 
7.11.1.2 Objective Response and Response Duration ..........................................115 
7.11.1.3 Progression-free Survival (PFS) .............................................................115 
7.11.1.4 Overall Survival (OS) .............................................................................115 
7.11.2 
Immunogenicity ......................................................................................116 
7.11.3 
Pharmacokinetics ....................................................................................116 
7.11.3.1 MGA271 and MGA012 PK ....................................................................117 
7.11.4 
Pharmacodynamics/Biomarkers .............................................................119 
7.11.4.1 Tests Performed for Both Dose Escalation and Cohort 
Expansion Patients: .......................................................................119 
7.11.4.2 Tests Performed for Cohort Expansion Patients: ....................................119 
7.11.4.3 Archival Tumor Biopsy Specimens ....................................................... 120 
7.11.4.4 Optional Paired Pre-Treatment and On-Treatment Tumor 
Biopsy Specimens ........................................................................ 120 
7.12 
Other Study Procedures ................................................................................... 121 
7.12.1 
Central Laboratory Evaluations ............................................................. 121 
7.12.2 
Sample Retention and Further Testing ................................................... 121 
7.13 
Appropriateness of Measurements ................................................................... 121 
7.13.1 
Rationale for Use of Immune Response Criteria ................................... 121 
8 
STUDY ACTIVITIES ............................................................................................... 123 
8.1 
Screening Period .............................................................................................. 123 
8.2 
Registration ...................................................................................................... 123 
8.3 
End of Treatment Visit ..................................................................................... 123 
9 
PLANNED STATISTICAL METHODS .................................................................. 124 
9.1 
General Considerations .................................................................................... 124 
9.2 
Determination of Sample Size ......................................................................... 124 
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MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGA271-03 
Amendment 6, 26 August 2020 
 
 
 
 
 
9.2.1 
Analysis Populations .............................................................................. 125 
9.3 
Demographics and Baseline Characteristics .................................................... 126 
9.4 
Safety Endpoint(s) ........................................................................................... 126 
9.4.1 
Adverse Events ...................................................................................... 126 
9.4.2 
Laboratory Values .................................................................................. 127 
9.4.3 
Other Safety Endpoints .......................................................................... 127 
9.5 
Efficacy Endpoints ........................................................................................... 127 
9.6 
Other Assessments or Analyses ....................................................................... 128 
10 
QUALITY CONTROL AND ASSURANCE ........................................................... 129 
10.1 
Monitoring, Auditing and Inspections ............................................................. 129 
10.2 
Data Entry and Computerized Systems ........................................................... 130 
11 
ADMINISTRATIVE CONSIDERATIONS.............................................................. 131 
11.1 
Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) Approval................................................................................................. 131 
11.2 
Ethical Conduct of the Study ........................................................................... 132 
11.3 
Patient Information and Consent ..................................................................... 132 
11.4 
Patient Confidentiality ..................................................................................... 133 
11.5 
Case Report Forms and Study Records ........................................................... 133 
11.6 
Access to Source Documentation .................................................................... 133 
11.7 
Retention of Data ............................................................................................. 133 
11.8 
Financial Disclosure......................................................................................... 134 
11.9 
Publication and Disclosure Policy ................................................................... 134 
11.10 
Discontinuation of the Study or Study Sites .................................................... 134 
11.10.1 
Discontinuation of Study Sites ............................................................... 134 
11.10.2 
Discontinuation of the Study ................................................................. 134 
11.11 
Identification of the Coordinating Principal Investigator ................................ 135 
12 
REFERENCE LIST .................................................................................................. 136 
 
LIST OF TABLES  
Table 1 
Enoblituzumab (MGA271) + Pembrolizumab Combination 
Benchmarks Favorably ................................................................................. 45 
Table 2 
Comparison of in vitro Potencies of MGA012 and Nivolumab and 
Pembrolizumab Replicas .............................................................................. 54 
Table 3 
MGA271 Dose Escalation Cohorts .............................................................. 62 
Table 4 
Clinical Laboratory Tests ............................................................................ 106 
Table 5 
Immunogenicity Blood Sampling Schedule for Patients Receiving 
MGA271 and Pembrolizumab .....................................................................116 
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MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGA271-03 
Amendment 6, 26 August 2020 
 
 
 
 
 
Table 6 
Pharmacokinetics Blood Sampling Schedule for Patients 
Receiving MGA271 and Pembrolizumab ...................................................118 
Table 7 
Response Rates and 95% Confidence Intervals ......................................... 125 
Table 8 
Time Window Allowances for Study Evaluations and Procedures 
for MGA271 and Pembrolizumab .............................................................. 130 
Table 9 
Time Window Allowances for Study Evaluations and Procedures 
for MGA271 and MGA012 (Cohort 4 Only) ............................................. 134 
 
LIST OF FIGURES  
Figure 1 
MGA271 (RES242) Mediates ADCC Activity Across a Spectrum 
of Cancer Types ............................................................................................ 42 
Figure 2 
MGA271 + Pembrolizumab Treatment Schema .......................................... 60 
Figure 3 
MGA271 + MGA012 Treatment Schema: Cohort 4 .................................... 61 
 
LIST OF APPENDICES  
APPENDIX 1 
TIME AND EVENTS SCHEDULE 
APPENDIX 2 
PHARMACOKINETICS, IMMUNOGENICITY, AND 
PHARMACODYNAMIC BIOMARKERS BLOOD SAMPLING 
SCHEDULE FOR MGA271+MGA012 (COHORT 4 ONLY) 
APPENDIX 3 
DEFINITION OF PFS 
APPENDIX 4 
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS 
APPENDIX 5 
RECIST 1.1 GUIDELINES 
APPENDIX 6 
IMMUNE-RELATED RECIST GUIDELINES 
APPENDIX 7 
PRINCIPAL INVESTIGATOR’S AGREEMENT 
 
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MGA271 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGA271-03 
Amendment 6, 26 August 2020 
 
 
 
 
 
SPONSOR SIGNATURES  
Study Title: 
A Phase 1, Open-Label, Dose Escalation Study of MGA271 in 
Combination with Pembrolizumab and in Combination with 
MGA012 in Patients with Melanoma, Squamous Cell Cancer of 
the Head and Neck, or Non-Small Cell Lung Cancer, Urothelial 
Cancer, and Other Cancers 
Study Number: 
 
CP-MGA271-03 
Amendment 6 
 
This clinical study protocol has been approved by the Sponsor: 
Signed: See Appended Electronic Signature Page 
Date: 
 
 
 
 
MacroGenics, Inc. 
 
 
 
 
Signed: See Appended Electronic Signature Page 
Date: 
 
 
 
 
MacroGenics, Inc. 
 
 
 
 
 
 
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MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGA271-03 
Amendment 6, 26 August 2020 
 
 
 
 
 
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MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGA271-03 
Amendment 6, 26 August 2020 
 
 
 
 
 
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MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGA271-03 
Amendment 6, 26 August 2020 
 
 
 
 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
 
ADA 
Anti-drug antibodies 
ADCC 
Antibody-dependent cell-mediated cytotoxicity 
ADR 
Adverse drug reaction 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALB 
Albumin 
ALK 
Anaplastic lymphoma kinase  
ALK-P 
Alkaline phosphatase 
ALT 
Alanine aminotransferase (SGPT) 
Anti-CTLA-4 
Cytotoxic T lymphocyte antigen 4 antibody 
Anti-PD-1 
Programmed cell death protein 1 antibody 
Anti-PD-L1 
Programmed death ligand 1antibody 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase (SGOT) 
AUC 
Area under the curve 
B7-H3 
B7 homolog 3 
BUN 
Blood urea nitrogen 
°C 
Degrees Celsius 
Ca 
Calcium 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
Cl 
Chloride 
CI 
Confidence interval 
CL 
Plasma clearance 
CNS 
Central nervous system 
cCR 
Confirmed complete response 
CR 
Complete response 
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MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGA271-03 
Amendment 6, 26 August 2020 
 
 
 
 
 
CRS 
Cytokine release syndrome 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse events 
CTL 
Cytotoxic T lymphocyte 
CTLA-4 
Cytotoxic T lymphocyte antigen 4 
DBP 
Diastolic blood pressure 
DC 
Dendritic cell 
dL 
Deciliter 
DLT 
Dose limiting toxicity 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EGFR 
Epidermal growth factor receptor  
ELISA 
Enzyme-linked immunosorbent assay 
EOI 
End of Infusion 
E:T 
Effector cell:target cell ratio 
FcγR 
Fc gamma receptor 
FDA 
Food and Drug Administration 
F/F 
Phenylalanine/phenylalanine 
FFPE 
Formalin-fixed paraffin-embedded 
FIH 
First-in-human 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
hCG 
Human chorionic gonadotropin 
Hct 
Hematocrit 
HEENT 
Head, eyes, ears, neck, throat 
Hgb 
Hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
HPV 
Human papilloma virus 
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MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGA271-03 
Amendment 6, 26 August 2020 
 
 
 
 
 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
ICF 
Informed Consent Form 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
IL 
Interleukin 
IgG 
Immunoglobulin G 
irAE 
Immune-related adverse event 
irCR 
Immune-related complete response 
irPD 
Immune-related progressive disease 
irPR 
Immune-related partial response 
irPFS 
Immune-related progression free survival 
irRC 
irRECIST 
Immune-related response criteria = Immune-related RECIST criteria 
Immune-related RECIST criteria 
IRB 
Institutional Review Board 
IRE 
Immediately Reportable Event 
IUD 
Intrauterine device 
IV 
Intravenous 
K 
Potassium 
Kg 
Kilogram 
LAG-3 
Lymphocyte-activating gene 3 
LDH 
Lactate dehydrogenase 
MAD 
Maximum administered dose 
mcg or µg 
Microgram 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram 
MHC 
Major histocompatibility class 
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MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGA271-03 
Amendment 6, 26 August 2020 
 
 
 
 
 
mIg 
Membrane-bound immunoglobulin 
mL 
Milliliter 
Mm 
Millimeter 
Msec 
Millisecond 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
Na 
Sodium 
NCI 
National Cancer Institute 
NK 
Natural Killer 
NOAEL 
No observed adverse effect level 
NSAID 
Non-steroidal anti-inflammatory drug 
NSCLC 
Non-small cell lung cancer 
NYHA 
New York Heart Association  
ORR 
Objective response rate 
OS 
Overall Survival 
Pap 
Papanicolaou 
PBMC 
Peripheral blood mononuclear cells 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamics 
PD 
Progressive disease 
PD-1 
Programmed cell death protein 1 
PD-L1 
Programmed death ligand 1 
PFS 
Progression free survival 
PK 
Pharmacokinetics 
PR 
Partial response 
PT 
Prothrombin time 
Q 
Inter-compartment clearance 
Q3W 
Every 3 weeks 
QW 
Every week 
RANK-L 
Receptor-activator of nuclear factor kappa B ligand 
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MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGA271-03 
Amendment 6, 26 August 2020 
 
 
 
 
 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RES242 
MGA271 with wild-type Fc 
SAE 
Serious adverse event 
SBP 
Systolic blood pressure 
SC 
Subcutaneous 
SCCHN 
Squamous cell cancer of the head and neck 
SD 
Stable disease 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SJS 
Stevens-Johnson syndrome 
SOC 
System Organ Class 
T1/2α 
Distribution half-life 
T1/2β 
Terminal half-life 
T4 
Thyroxine 
TcR 
T-cell antigen receptor 
TEAE 
Treatment-emergent adverse event 
TEN 
Toxic Epidermal Necrolysis 
TKI 
Tyrosine-kinase inhibitor 
Tregs 
Regulatory T-cells 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
US 
United States 
USP 
United States Pharmacopeia 
Vc 
Central volume 
V1 
Volume of distribution of the central compartment 
Vp 
Peripheral volume 
VSS 
Volume of distribution at steady state 
V/V 
Valine/valine 
WBC 
White blood cell 
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Clinical Trial Protocol: CP-MGA271-03 
Amendment 6, 26 August 2020 
 
 
 
 
 
1 
SYNOPSIS  
Sponsor: MacroGenics, Inc. 
IND Number: 
 
Name of Finished Product: MGA271 
Study Title: 
A Phase 1, Open-Label, Dose Escalation Study of MGA271 in Combination with Pembrolizumab and in 
Combination with MGA012 in Patients with Melanoma, Squamous Cell Cancer of the Head and Neck, Non-
Small Cell Lung Cancer, Urothelial Cancer, and Other Cancers 
Study Number: CP-MGA271-03 
Investigator(s)/Centers: 
This study will be executed at approximately 30-40 institutions in the United States (US) and, potentially, 
Canada, Europe (EU), Asia Pacific, and Australia experienced in cancer immunotherapy and/or the conduct 
of Phase 1 studies in patients with melanoma, squamous cell cancer of the head and neck (SCCHN), 
non-small cell lung cancer (NSCLC), urothelial cancer, and other cancers. 
Study Phase: 1 
Primary Objective(s): 
The primary objectives of this study are: 
• To characterize the safety, tolerability, dose-limiting toxicities (DLT), and maximum tolerated dose 
(MTD) or maximum administered dose (MAD) (if no MTD is defined) of MGA271 when administered 
intravenously (IV) weekly in combination with 2 mg/kg pembrolizumab administered IV every 3 weeks 
(Q3W) to patients with unresectable locally advanced or metastatic melanoma, SCCHN, NSCLC, 
urothelial cancer, and other cancers. 
• To characterize the safety, tolerability, and DLT of 15 mg/kg MGA271 when administered IV Q3W in 
combination with a flat-dose of 375 mg of MGA012 (anti-PD-1 antibody) administered IV Q3W to 
patients with unresectable locally advanced or metastatic melanoma, SCCHN, NSCLC, urothelial 
cancer, and other cancers. 
Secondary Objective(s): 
Secondary objectives of this study are: 
• To characterize the pharmacokinetics (PK) and immunogenicity of MGA271 administered IV weekly in 
combination with IV pembrolizumab Q3W, and of MGA271 in combination with MGA012, both 
administered IV every 3 weeks. 
• To characterize the pharmacodynamic (PD) activity of MGA271 when administered IV weekly in 
combination with pembrolizumab Q3W, and of MGA271 in combination with MGA012, both 
administered IV Q3W. 
• To investigate the preliminary antitumor activity of MGA271 when administered IV weekly in 
combination with IV pembrolizumab Q3W, and of MGA271 in combination with MGA012, both 
administered IV Q3W using both conventional Response Evaluation Criteria in Solid Tumors (RECIST) 
1.1 (Appendix 5) and immune-related response criteria (irRC) (i.e., irRECIST as defined in Appendix 
6).  
Study Design: 
General Study Design 
This study is a Phase 1, open-label, dose escalation and cohort expansion study designed to characterize the 
safety, tolerability, PK, PD, immunogenicity, and preliminary antitumor activity of MGA271 administered 
IV weekly in combination with pembrolizumab administered IV every 3 weeks (Q3W). Beginning with 
Amendment 5, this study will also characterize the safety and tolerability of MGA271 in combination with 
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Clinical Trial Protocol: CP-MGA271-03 
Amendment 6, 26 August 2020 
 
 
 
 
 
MGA012 (anti-PD-1 antibody), both administered by IV, Q3W, through the addition of a new cohort, 
Cohort 4. 
The study consists of a Dose Escalation Phase to determine the MTD or MAD (if no MTD is defined) of 
MGA271 administered in combination with 2 mg/kg pembrolizumab to patients with mesothelioma, 
urothelial cancer, NSCLC, SCCHN, clear cell renal cell carcinoma (ccRCC), ovarian cancer, melanoma, 
thyroid cancer, triple-negative breast cancer (TNBC), pancreatic cancer, colon cancer, soft tissue sarcoma, or 
prostate cancer, followed by a Cohort Expansion Phase in patients with melanoma, NSCLC, SCCHN, and 
urothelial cancer to further define the safety and initial efficacy of the combination with the MGA271 dose 
established in the first phase. The study treatment schema is presented in the following figure. 
a 
Patients may receive up to 5 subsequent 9-week treatment cycles of MGA271 + pembrolizumab 
depending on response to study treatments. 
* 
All patients will enter an Efficacy Follow-up Period after receipt of the last dose of study treatment to be 
followed for up to 24 weeks for survival. 
 
MGA271 will be administered as an IV infusion over 120 minutes on a once-weekly schedule. 
Pembrolizumab will be administered at 2 mg/kg as an IV infusion over 30 minutes every 3 weeks. On the 
days that both agents are administered, pembrolizumab will be administered first, followed by MGA271. 
For both the Dose Escalation and Cohort Expansion phases, patients’ first tumor assessment will be obtained 
on Cycle 1 Study Day 42 of the Initial Tumor Assessment Cycle. 
Patients who remain clinically stable and do not experience unacceptable toxicity that necessitates permanent 
discontinuation of the study drugs at the completion of the Initial (6-week) Tumor Assessment Cycle will be 
eligible to receive additional treatment with pembrolizumab and MGA271. Assuming that the patient 
remains clinically stable, maintains a response status of stable disease (SD) or better, and does not experience 
unacceptable toxicity that necessitates permanent discontinuation of the study drugs, patients may receive up 
to 5 additional 9-week treatment cycles during Subsequent Tumor Assessment Cycles, for a maximum 
total of 51 doses of MGA271 and 17 doses of pembrolizumab. 
Beginning with Amendment 5, in Cohort 4, 15 mg/kg MGA271 will be administered as an IV infusion over 
120 minutes Q3W in combination with 375 mg MGA012 administered as an IV infusion over 60 to 
75 minutes Q3W. On dosing days, MGA012 will be administered first, followed by MGA271. The study 
treatment schema is presented in the figure below. 
 
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Amendment 6, 26 August 2020 
 
 
 
 
 
 
 
Patients who remain clinically stable and do not experience unacceptable toxicity that necessitates permanent 
discontinuation of the study drugs, at the completion of the Initial (6 week) Tumor Assessment Cycle will be 
eligible to receive additional treatment with MGA271+MGA012. Assuming that the patient remains 
clinically stable, maintains a response status of SD or better, and does not experience unacceptable toxicity 
that necessitates permanent discontinuation of the study drugs, patients may receive up to 5 additional 
9-week treatment cycles during Subsequent Tumor Assessment Cycles, for a maximum total of 17 doses of 
MGA271 and 17 doses of MGA012. 
All subsequent tumor assessments will occur on Study Day 63 of each Tumor Assessment Cycle thereafter. 
Following the last dose of study drug, all patients will be followed for survival during a 6-month (24-week) 
Efficacy Follow-up Period. 
Dose Escalation Phase: 
The goal of the Dose Escalation Phase is to initially characterize the safety and tolerability of MGA271 and 
pembrolizumab administered in combination, and more specifically to describe the DLTs for each dose level 
studied and to define the MTD or MAD (if no MTD is defined) based on the frequency of occurrence of 
DLTs in each cohort. 
For the purposes of guiding decisions regarding dose escalation, the DLT Evaluation Period is defined as the 
time following administration of the first dose of pembrolizumab to the day of the third planned 
administration of pembrolizumab (i.e., Cycle 1/Initial Tumor Assessment Cycle). 
The Dose Escalation Phase of the study will enroll patients with unresectable, locally advanced or metastatic 
mesothelioma, urothelial cancer, NSCLC, SCCHN, ccRCC, ovarian cancer, melanoma, thyroid cancer, 
TNBC, pancreatic cancer, colon cancer, soft tissue sarcoma, or prostate cancer. Dose escalation will follow a 
conventional 3+3+3 design: MGA271 will be evaluated in sequential escalating doses ranging from 3 mg/kg 
to 15 mg/kg in combination with 2 mg/kg pembrolizumab in cohorts of 3 to 9 patients each. Dose levels of 
MGA271 to be evaluated include 3 mg/kg (starting dose), 10 mg/kg, and 15 mg/kg. If it is determined that 
the MTD is exceeded in the first dose cohort, a dose de-escalation cohort to evaluate a lower dose of 
MGA271 (1 mg/kg) in combination with 2 mg/kg pembrolizumab will be enrolled. 
 
 
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Clinical Trial Protocol: CP-MGA271-03 
Amendment 6, 26 August 2020 
 
 
 
 
 
The dose escalation schema is outlined below: 
Cohort 
MGA271 Dose 
Pembrolizumab Dose 
MGA012 
Cohort 1 a 
1 mg/kg 
2 mg/kg 
N/A 
Cohort 1 
3 mg/kg (starting 
dose) 
2 mg/kg 
N/A 
Cohort 2 
10 mg/kg 
2 mg/kg 
N/A 
Cohort 3 
15 mg/kg 
2 mg/kg 
N/A 
Cohort 4 
15 mg/kg 
N/A 
375 mg  
a 
To be evaluated only if the starting dose is determined to exceed the 
MTD. 
 
 
An intermediate dose of MGA271 may be explored selectively during the dose escalation portion of the 
study, based on review of the cumulative safety, efficacy, and/or PK data on the respective arms and based 
upon agreement between the investigators and the Sponsor as follows: 
• If Cohort 2 exceeds the MTD the following dose levels may be evaluated: 
◦ 
Cohort 1a: 7 mg/kg MGA271 + 2 mg/kg pembrolizumab (n=3-9 patients) 
• If Cohort 3 exceeds the MTD the following dose levels may be evaluated: 
◦ 
Cohort 2a: 12 mg/kg MGA271 + 2 mg/kg pembrolizumab (n=3-9 patients) 
Any escalation cohort, not exceeding the MTD, can be expanded to a maximum of 15 patients for further 
evaluation of safety and efficacy. 
The MTD for MGA271 will be defined as the dose level at which < 33% of patients experience a 
drug-related DLT during the DLT evaluation period. If no MTD is defined for the combination of MGA271 
and pembrolizumab after escalation to the maximum protocol-specified dose, that dose level will be 
designated as the MAD. DLTs are defined, and Dose Escalation Rules described below. 
Beginning with Amendment 5, a new cohort, Cohort 4, will be added to explore safety and tolerability of 
MGA271+MGA012 administered in combination. Since MTD was not reached for the MGA271 and 
pembrolizumab cohorts, 15 mg/kg was determined as the maximum administered dose (MAD) for MGA271. 
Patients will receive 15 mg/kg MGA271 (MAD) in combination with a flat-dose of 375 mg MGA012, with 
both study drugs administered on a Q3W schedule (see Table above) . 
For the purposes of guiding decisions regarding dose escalation, the DLT Evaluation Period is defined as the 
time following administration of the first dose of MGA271 plus MGA012 to the day of the third planned 
administration of MGA012 (i.e., Cycle 1/Initial Tumor Assessment Cycle).   
Enrollment in Cohort 4 will follow a conventional 3+3+3 design, with decision rules as outlined in 
Section 4.3. If the 15 mg/kg MGA271 +375 mg MGA012 combination dose is deemed tolerable, additional 
patients will be added for up to a total of 15 dose evaluable patients in the cohort. No higher doses of the 
combination are planned. If the 15 mg/kg MGA271+375 mg MGA012 combination dose level is found to 
exceed the MTD, de-escalation to 10 mg/kg MGA271 + 375 mg MGA012 may be explored and if that dose 
level were to exceed the MTD, a further de-escalation to 3 mg/kg MGA271 + 375 mg MGA012 may be 
explored following the same conventional 3+3+3 design.  Any of these dose levels, not exceeding the MTD, 
can be expanded up to a maximum of 15 patients for further evaluation of safety and efficacy. 
 
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Cohort Expansion Phase: 
During the Cohort Expansion Phase, additional cohorts of patients with unresectable, locally advanced or 
metastatic melanoma (up to n=16), 2 cohorts of NSCLC (n= up to 20 in each cohort), 2 cohorts of SCCHN 
(up to n=20 in each cohort) or urothelial cancer (up to n=16) will be enrolled to receive MGA271 in 
combination with pembrolizumab at the MTD (or MAD) established from the Dose Escalation Phase of the 
study. The goals for this portion of the study will be to: 
1. Further characterize the safety of MGA271 in combination with pembrolizumab at the MTD (or MAD); 
2. Further evaluate the PK, PD, and immunogenicity of MGA271 in combination with pembrolizumab; and 
3. Provide a preliminary assessment of the antitumor activity of MGA271 in combination with 
pembrolizumab in patients with advanced melanoma, NSCLC, SCCHN, or urothelial cancer. 
Efficacy Follow-up Period: 
The Efficacy Follow-up Period consists of the 6-month (24-week) period following the final dose of study 
drug (pembrolizumab or MGA271 or MGA012, whichever is last). During this time, patients will be 
followed via telephone or other electronic contact at 12-week intervals for follow-up of overall survival. 
Dose Limiting Toxicity: 
For the purposes of safety management and defining DLTs, the combination of MGA271 and 
pembrolizumab, or the combination of MGA271+ MGA012 will be treated as one entity. If a DLT is 
considered related to study drug, no distinction will be made as to which agent is the causative agent and 
administration of both agents will be stopped. One exception to this rule will be in the circumstance in which 
a DLT occurs during or immediately following the first pembrolizumab infusion or MGA012 infusion and 
before the first MGA271 administration. In this case, the toxicity will be attributed to pembrolizumab or 
MGA012 alone and will not count as a DLT of the combination of study drugs; in this case the patient will 
be replaced by another patient in the dose cohort. 
In general, for patients who experience an adverse event (AE) 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 drugs. Criteria for subsequent continuation of therapy are 
outlined below. No dose reductions of either MGA271 or pembrolizumab or MGA012 are allowed during 
the study; however, for patients being treated at a dose level subsequently determined to exceed the MTD, 
the dose of MGA271 will be reduced to the next lower dose level. 
Dose limiting toxicities will be based on treatment-emergent, drug-related AEs (or laboratory abnormalities) 
occurring following administration of the first dose of pembrolizumab to the day of the third planned 
administration of pembrolizumab (i.e., the DLT Evaluation Period). The severity of AEs will be graded 
according to the National Cancer Institute Common Terminology Criteria for Adverse Events v 4.03 
(NCI CTCAE v 4.03). 
Dose limiting toxicities are defined separately for hematologic and non-hematologic events as follows. 
Hematologic Dose Limiting Toxicity 
Hematologic DLT will be defined as follows: 
• Grade 4 neutropenia lasting > 5 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 
 
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Clinical Trial Protocol: CP-MGA271-03 
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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 
 
Non-Hematologic Dose Limiting Toxicity 
Non-hematologic DLT will be defined as any ≥ Grade 3 non-hematologic event with the following 
exceptions: 
• Grade 3 electrolyte abnormality that lasts less than 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 amylase and/or lipase elevation that is not associated with either clinical or radiographic 
evidence suggestive of pancreatitis 
• Grade 3 gastrointestinal AEs of diarrhea, constipation, abdominal pain, cramping, dyspepsia or 
dysphagia that resolves to ≤ Grade 1 within 14 days with medical therapy 
• Grade 3 fatigue that lasts < 7 days  
• Grade 3 infusion-related reaction or cytokine release syndrome that lasts < 12 hours and responds to 
medical intervention. 
• Grade 3 or 4 endocrinopathy that is adequately controlled with hormone supplementation 
• Grade 3 skin toxicity that resolves to ≤ Grade 2 within 14 days of initiation of oral corticosteroids 
• Grade 3 inflammatory reaction (e.g., with associated pain, swelling) attributed to a local antitumor 
response (e.g., inflammatory reaction at sites of metastatic disease, lymph nodes, etc.) that resolves to 
≤ Grade 2 within 7 days. 
 
Note: The following Grade 2 or greater non-hematologic AE may also be considered as DLT: 
• Grade 2 AEs that are prolonged inordinately, based upon the medical judgment of the Investigator, 
and/or lead to permanent discontinuation of MGA271 due to patient intolerance 
• Any hepatic laboratory abnormalities meeting all three Hy’s law criteria (described within hepatic non-
hematologic DLTs) 
• Any Grade 2 eye pain or reduction in visual acuity that does not respond to topical therapy and does not 
improve to Grade 1 within 14 days of the initiation of topical therapy, or that requires systemic 
treatment. 
 
Hepatic Non-Hematologic Dose Limiting Toxicity 
• AST or ALT > 5 x ULN or total bilirubin > 3 x ULN 
For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, 
if AST or ALT increases ≥ 50%, relative to baseline and lasts for at least 1 
week.  
Please see Section 6.5.2.2 for further management guidelines. 
• Any event meeting the criteria for Hy’s law as follows (all three features): 
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Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 3 × 
ULN 
Concurrent elevation of total bilirubin > 2 × ULN without initial evidence of 
cholestasis 
No alternative etiology can be identified 
Dose Escalation Rules 
The Dose Escalation Phase of this trial will proceed using a conventional 3 + 3 + 3 approach, and will begin 
with enrollment of 3 patients at the initial dose level of 2 mg/kg of pembrolizumab administered as an IV 
infusion once every three weeks and 3 mg/kg of MGA271 administered as an IV infusion once weekly. 
Successive dose escalation cohorts will be enrolled as outlined below. The MTD or MAD will be determined 
based on the assessment of DLTs during the DLT evaluation period. Cohort 4 will begin enrollment of 
3 patients at 15 mg/kg MGA271 and 375 mg MGA012; with no higher dose escalation cohorts to be 
explored. 
Patients who do not experience a DLT but are not evaluable for safety for the full DLT evaluation period will 
be replaced in the same dose-level cohort. 
• If 0 of the first 3 patients treated at a given dose level experience a drug-related DLT during the DLT 
evaluation period, the dose will be escalated and 3 patients will be enrolled and treated at the next higher 
dose level (up to the planned highest dose level of 15 mg/kg of MGA271). 
• If 1 of the first 3 patients treated at a given dose level experiences a drug-related DLT, then 3 additional 
patients will be enrolled at that dose level (thus making a total of 6 patients in this cohort) to further 
assess the safety of the combination of MGA271 with pembrolizumab. 
• If ≥ 2 of these 3 additional patients (i.e., ≥ 3 of the 6 patients enrolled in the cohort) experience a DLT, it 
will be concluded that the MTD has been exceeded, and 3 patients will be enrolled and treated at the 
next lower dose level. If 1 of these 3 additional patients experiences a drug-related DLT, then another 3 
additional patients (for a total of 9 patients in the cohort, 3 + 3 + 3) will be enrolled and treated at that 
dose level to further characterize the safety of the combination. If 0 of the 3 additional patients 
experiences a DLT, then the dose will be escalated, and 3 patients will be enrolled at the next higher 
dose level. 
• If ≥ 2 patients out of the first 3 patients treated at a given dose level, or ≥ 3 of 6 patients treated at a 
given dose level, or ≥ 3 out of 9 patients treated at a given dose level experience a drug-related DLT, 
then it will be concluded that the MTD for MGA271 in combination with pembrolizumab or in 
combination with MGA012 has been exceeded at that dose level, and all subsequent patients will be 
treated at the next lower dose level. 
• If 2 or more patients out of the first 6 patients 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 
MGA271/pembrolizumab or MGA271/MGA012 has been exceeded and all subsequent patients will be 
treated at the next lower dose level. 
• Note that in the circumstance in which a DLT occurs during or immediately following the first 
pembrolizumab or first MGA012 infusion and before the first MGA271 administration, the toxicity will 
be attributed to pembrolizumab or first MGA012 alone and will not count as a DLT of the combination 
of study drugs at the dose level under study. In this case the patient will be replaced by another patient in 
the dose cohort. 
 
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%. 
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Amendment 6, 26 August 2020 
 
 
 
 
 
Dose escalation to the next dose level is permitted only after the patients enrolled in the current dose cohort 
have competed the DLT evaluation period and all safety data have been reviewed by the Sponsor Medical 
Monitor and the Investigators participating in the study. 
For patients being treated at a dose level subsequently determined to exceed the MTD, the dose of MGA271 
will be immediately reduced to the next lower MGA271 dose level. 
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, PD, 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. 
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 patients for further evaluation of safety and efficacy. For the MGA271 and 
MGA012 (cohort 4), the cohort may be expanded up to a total of 15 patients. 
Rules for Continuation of Study Therapy: 
Patients who tolerate treatment with pembrolizumab and MGA271, or who tolerate treatment with 
MGA271+MGA012, may continue to receive additional treatment with the study drugs as specified above 
until any one of the following conditions are met: 
• After documentation of a confirmed complete response (cCR), MGA271 and pembrolizumab, or 
MGA271+MGA012, are continued for one more Tumor Assessment Cycle 
• Patient meets criteria for immune-related disease progression (irPD) (Appendix 6) 
• Occurrence of drug-related DLT as defined for the DLT Evaluation Period 
• The Sponsor, Investigator, or Regulatory Agency terminates the study 
• Withdrawal of patient due to an AE or serious adverse event (SAE) 
• Withdrawal of patient consent 
• Completion of protocol defined therapy 
• Investigator discretion 
• Pregnancy 
• Death 
Note: For individual patients who meet these criteria, but are otherwise considered to be experiencing 
clinical benefit by the investigator, consideration may be given to extension of therapy on a case-by-case 
basis in consultation with the Sponsor. If a patient completes 6 cycles of therapy and is experiencing clinical 
benefit as determined by the investigator, consideration may be given to extension of therapy for an 
unrestricted number of additional 9 week treatment cycles of MGA271 and pembrolizumab or 
MGA271+MGA012 on a case-by-case basis in consultation with the Sponsor. Such unrestricted treatment 
may continue until the patient either 1) meets the criteria for permanent discontinuation (see Section 5.3.1), 
or 2) a rollover protocol becomes available. 
Study Population: 
The patient population to be enrolled in the Dose Escalation Phase of this study will consist of adult patients 
with histologically–proven, unresectable locally advanced or metastatic melanoma, NSCLC, SCCHN, 
mesothelioma, urothelial cancer, ccRCC, ovarian cancer, thyroid cancer, TNBC, pancreatic cancer, colon 
cancer, soft tissue sarcoma, or prostate cancer. 
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Clinical Trial Protocol: CP-MGA271-03 
Amendment 6, 26 August 2020 
 
 
 
 
 
The number of patients enrolled in the Dose Escalation Phase cannot be precisely determined in advance, and 
could range from 9 to 45 or more patients depending on results in the course of the trial and the number of 
MG271 doses explored. This patient number does not take into account patient replacement for non-
evaluable patients or the possibility of expanding an individual escalation cohort to 15 patients to allow for 
further evaluation of safety, PK and antitumor activity of the combination of MGA271 and pembrolizumab 
at the dose level in that cohort. 
The Cohort Expansion Phase of the trial will enroll 112 patients, with a target of 16 to 20 patients into each 
of 6 cohorts: two cohorts of patients with NSCLC (up to 20 patients in each cohort), two cohorts of patients 
with SCCHN (up to 20 patients in each cohort), one cohort of patients with melanoma (up to 16 patients), 
and one cohort of patients with urothelial cancer (up to 16 patients). This number of patients does not take 
into account patients who may be replaced. During the Expansion Portion of the study, patients 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, replacement patients may be enrolled in the same dose 
level as required to complete the cohort. For planning, the maximum number of patients to be enrolled on 
this trial is anticipated to be approximately157 patients. 
Inclusion/Exclusion Criteria: 
To be eligible for study participation, patients must meet all the inclusion criteria. Patients will be excluded 
from the study if they meet any exclusion criteria. 
 
Inclusion Criteria 
General 
1. Ability to provide informed consent and documentation of informed consent prior to initiation of any 
study-related tests or procedures that are not part of standard-of-care for the patient’s disease. Patients 
must also be willing and able to comply with study procedures, including the acquisition of specified 
research specimens. 
2. Age ≥ 18 years old. 
3. Dose Escalation Phase including Cohort 4: Histologically-proven unresectable locally advanced or 
metastatic. 
a. 
Mesothelioma that has progressed during or following at least 1 and up to 3 prior systemic 
treatments for unresectable locally advanced or metastatic disease. The prior systemic chemotherapy 
must have included a pemetrexed (anti-folate)-based regimen in combination with platinum agent. 
For patients in whom pemetrexed was contraindicated or not tolerated or not an approved therapy 
(e.g., peritoneal mesothelioma), prior therapy with a first-line platinum-based regimen is required. 
b. Urothelial cancer arising in the bladder, renal pelvis, ureter, or urethra that has progressed during or 
following at least 1 and up to 5 prior systemic treatments for unresectable locally advanced or 
metastatic disease (includes anti-PD-L1, anti-PD-1, but excludes other experimental therapies). 
Patients must have received at least one platinum-containing regimen (e.g., gemcitabine/cisplatin 
[GC], dose-dense methotrexate/vinblastine/doxorubicin/cisplatin [DDMVAC], or 
carboplatinum/gemcitabine). No more than 5 prior systemic regimens allowed. 
c. 
Thyroid cancer that has progressed during or following at least 1 and up to 5 prior chemotherapy 
regimen(s). Prior therapy excludes experimental therapies given in Phase 1 trials. 
d. Pancreatic cancer that has progressed during or following at least 1 and up to 3 prior chemotherapy 
regimens. Prior therapy excludes experimental therapies given in Phase 1 trials. 
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e. 
Ovarian cancer that has progressed during or following at least 2 and up to 4 prior therapeutic 
regimens (e.g., 2 prior platinum containing regimens or if platinum resistant, a liposomal 
doxorubicin or topotecan containing regimen). Prior therapy excludes experimental therapies given 
in Phase 1 trials. 
f. 
Colon cancer that has progressed during or following at least 2 and up to 4 prior therapeutic 
regimens (e.g., fluoropyrimidine and/or irinotecan and/or oxaliplatin and/or anti-EGFR antibody 
containing regimens). Prior therapy excludes experimental therapies given in Phase 1 trials. 
g. Prostate cancer that has progressed during or following at least 1 and up to 5 prior therapeutic 
regimens (e.g., abiraterone, enzalutamide, docetaxel). Prior therapy excludes experimental therapies 
given in Phase 1 trials. 
h. Soft tissue sarcoma that has progressed during or following at least 1 and up to 5 prior therapeutic 
regimens. Prior therapy excludes experimental therapies given in Phase 1 trials. 
i. 
TNBC that has progressed during or following at least 1 and up to 5 prior therapeutic regimens. 
Prior therapy excludes experimental therapies given in Phase 1 trials. 
j. 
ccRCC that has progressed during or following at least 1 and up to 5 prior therapeutic regimens. 
Prior therapy excludes experimental therapies given in Phase 1 trials. 
k. Melanoma that has progressed during or following at least 1 and up to 5 prior systemic treatments 
for unresectable locally advanced or metastatic disease. No more than 5 prior systemic regimens 
(excludes experimental therapies) allowed. Patients who are intolerant of, or have refused treatment 
with standard cancer therapy, will be allowed to enroll. 
l. 
SCCHN that has progressed during or following at least 1 and up to 5 prior systemic treatments for 
metastatic or recurrent disease deemed to be incurable by the investigator (patients who refuse 
radical resection for recurrent disease are eligible). No more than 5 prior systemic regimens 
(excludes experimental therapies) allowed. Patients who are intolerant of, or have refused treatment 
with standard cancer therapy, will be allowed to enroll. Patients with upper esophageal or salivary 
gland tumors will not be considered as SCCHN. 
m. NSCLC that has progressed during or following at least 1 and up to 5 prior systemic therapies for 
unresectable locally advanced or metastatic disease. Patients who are intolerant of, or have refused 
treatment with standard cancer therapy, will be allowed to enroll. Patients must not have had more 
than 5 prior systemic regimens (excludes experimental therapies) for unresectable locally advanced 
or metastatic disease. 
i. 
For patients with squamous cell carcinoma, or adenocarcinoma without known activating 
mutation: the prior systemic therapy is at least one platinum analogue based therapy with or 
without a docetaxel or pemetrexed containing regimen. 
ii. 
For patients with adenocarcinoma having a previously known activating driver mutation such 
as an epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase 
(ALK) fusion: the prior systemic therapy is at least one TKI directed against the driver 
mutation. 
iii. 
Maintenance therapy following first-line therapy will not be considered a separate regimen of 
therapy. 
iv. 
Prior neoadjuvant chemotherapy for operable disease, adjuvant chemotherapy for completely 
resected disease or definitive chemoradiation therapy given for locally advanced disease will 
not be considered a separate regimen of therapy. 
Cohort Expansion Phase: Histologically-proven unresectable locally advanced or metastatic:  
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• 
Melanoma that has progressed on or after at least one anti-PD-L1 or anti-PD-1 containing 
therapy. Patients in this cohort can have their PD-L1 tumor expression levels determined before 
or after enrollment. 
• 
SCCHN, consisting of metastatic or recurrent disease (patients who refuse radical resection for 
recurrent disease are eligible); evaluated in 2 distinct cohorts, of up to 20 patients each where 
patients have progressed during or following: 
SCCHN Cohort 1: a first line, platinum-based systemic therapy without receiving prior 
anti-PD-1 or anti-PD-L1 containing therapy or 
SCCHN Cohort 2: a first-line, platinum-based systemic therapy and an anti-PD-1 or 
anti-PD-L1 containing therapy. 
In each of the 2 cohorts, at least 10 of the enrolled patients will be human papilloma virus 
(HPV) positive (HPV positivity is determined as per local institutional standards, e.g., p16 
detection by immunohistochemistry [IHC], or HPV in-situ hybridization [ISH]). Patients in 
both SCCHN cohorts can have their PD-L1 tumor expression levels determined before or after 
enrollment. 
• 
NSCLC consisting of patients with unresectable locally advanced or metastatic disease that will 
be evaluated in 2 distinct cohorts of up to 20 patients each where patients have progressed 
during or following: 
o 
NSCLC Cohort 1: a first-line systemic therapy as outlined below (i-iv, based on tumor 
histology) without receiving prior anti-PD-1 or anti-PD-L1 containing therapy. These 
patients must have PD-L1 tumor expression determined by IHC analysis at levels 
accepted by the Sponsor prior to enrollment (< 1% tumor positivity score [TPS]).  
o 
NSCLC Cohort 2: a first line systemic therapy as outlined below (i-iv, based on tumor 
histology) and an anti-PD-1 or anti-PD-L1 containing therapy. Patients in this cohort 
can have the PD-L1 tumor expression levels determined before or after enrollment. 
i. 
For patients with squamous cell carcinoma, or adenocarcinoma without known activating 
mutation: the prior systemic therapy is a platinum analogue based therapy with or without a 
docetaxel or pemetrexed containing regimen. 
ii. 
For patients with adenocarcinoma having a previously known activating driver mutation 
such as an epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma 
kinase (ALK) fusion: the prior systemic therapy is a TKI directed against the driver 
mutation. 
iii. 
Maintenance therapy following first-line therapy will not be considered a separate regimen 
of therapy. 
iv. 
Prior neoadjuvant chemotherapy for operable disease, adjuvant chemotherapy for 
completely resected disease or definitive chemoradiation therapy given for locally advanced 
disease will not be considered a separate regimen of therapy. 
• 
Urothelial cancer consisting of transitional cell or mixed transitional/nontransitional 
(predominantly transitional) cell cancer of the renal pelvis, ureter, bladder, or urethra, in a 
cohort of up to 16 patients. Patients must have received at least one platinum-containing 
regimen, either as neo-adjuvant, adjuvant, or for metastatic disease, and progressed on an anti-
PD-L1 or anti-PD-1 containing therapy. Patients in this cohort can have the PD-L1 tumor 
expression levels determined before or after enrollment. 
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Appendix 4). 
5. Life expectancy ≥ 12 weeks. 
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6. Measurable disease as per RECIST 1.1 criteria (Appendix 5) and documented by computed tomography 
(CT) and/or magnetic resonance imaging (MRI). Patients must have measurable disease to be enrolled 
on this study. Note: Lesions to be used as measurable disease for the purpose of response assessment 
must either a) not reside in a field that has been subjected to prior radiotherapy, b) have demonstrated 
clear evidence of radiographic progression since the completion of prior radiotherapy and prior to study 
enrollment. 
7. Prospective determination of B7-H3 expression is not required to define eligibility for this study; 
however, tumor expression of B7-H3 will still be evaluated for all patients enrolled on the study, so 
patients must have sufficient tissue/slides for B7-H3 testing identified in order to be eligible. Patients 
should have a formalin-fixed, paraffin embedded (FFPE) tumor specimen or unstained slides identified 
for analysis, to enable determination of the expression of B7-H3 within tumor specimens using IHC 
staining. If an archived tumor specimen is not available, patients who undergo a fresh tumor biopsy 
(Section 7.11.4.3) can have B7-H3 expression evaluated from a FFPE sample obtained from the fresh 
tumor biopsy. In this case, the biopsy should be obtained prior to initiating study therapy. In cases in 
which an archived sample and fresh tumor sample are both available, B7-H3 expression can be 
confirmed with either FFPE sample.  
8. All patients in the Expansion Phase will have the PD-L1 tumor expression levels assessed using an IHC 
method deemed acceptable by the Sponsor and based either on archival or new tissue biopsy samples, 
submitted as formalin-fixed paraffin-embedded tissue samples.  
a) Note: Patients in the NSCLC cohort who have not received prior anti-PD-1 or anti-PD-L1 therapy 
will need to have the PD-L1 IHC expression levels determined prior to enrollment to determine 
eligibility. All other patients can have PD-L1 tumor expressions determined prior to or after 
enrollment.  
9. Patients enrolling in the study without prior documented PD-L1 tumor expression levels (determined by 
a Sponsor-approved method) should have a formalin-fixed, paraffin-embedded tumor specimen or 
unstained slides identified and available for analysis, to assess PD-L1 tumor expression levels, 
determined by a method selected by the Sponsor.  
Laboratory Features 
10. Acceptable laboratory parameters as follows: 
a. 
Platelet count  100 × 103/µL without transfusion within 28 days prior to the initiation of study 
drug. 
b. Absolute neutrophil count  1.5 × 103/ µL in the absence of any growth factor support within 28 
days prior to the initiation of study drug. 
c. 
ALT/ AST  3.0 × ULN; for patients with hepatic metastases, ALT and AST ≤ 5 × ULN. 
d. Total bilirubin  1.5 × ULN, except patients with Gilbert’s syndrome, who may enroll if the 
conjugated bilirubin is within normal limits. 
e. 
Creatinine < 2 mg/dL, or a calculated or measured creatinine clearance > 50 mL/min. 
 
Reproductive Features 
11. Female patients of childbearing potential (not surgically sterilized and between menarche and 1 year 
postmenopause) must have a negative urine pregnancy test performed within 72 hours prior to the 
initiation of study drug administration. Further, female patients of childbearing potential must agree to 
either remain abstinent or use acceptable contraceptive measures from the time of consent through 
120 days after discontinuation of study drug administration. For female patients, two forms of 
contraception must be utilized and may include oral, transdermal, injectable or implantable 
contraceptives, intrauterine device (IUD), female condom, diaphragm with spermicide, cervical cap, use 
of a condom by the sexual partner or a sterile sexual partner. Periodic abstinence (e.g., calendar, 
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ovulation, symptothermal and post-ovulation methods) and withdrawal are not considered acceptable 
forms of contraception in this study. 
12. Male patients with partners of childbearing potential must use barrier contraception. In addition, male 
patients should also have their partners use another method of contraception from the time of consent 
through 120 days after discontinuation of study drug administration. 
13. Female patients must not be breastfeeding. 
 
Tumor Biopsy 
14. Patients in the Cohort Expansion Phase who have one lesion considered to be potentially amenable to 
biopsy have the option of providing consent for paired pre-treatment and on-treatment biopsy samples. 
Tumor lesions used for biopsy should not be lesions used as RECIST target lesions, unless there are no 
other lesions suitable for biopsy. If a RECIST target lesion is used for biopsy, the lesion must be ≥ 2 cm 
in longest diameter. Tumor biopsies should be obtained only from lesions that are felt to be accessible 
with acceptable clinical risk, in the judgment of the investigator. 
 
Previous Checkpoint Inhibitor Therapy 
15.  Patients who have previously received an immune checkpoint inhibitor (e.g., programmed-death ligand 
1 antibody [anti-PD-L1], programmed cell death protein 1 antibody [anti-PD-1], cytotoxic T-
lymphocyte-associated protein 4 antibody [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. 
This excludes patients who experienced the following immune checkpoint inhibitor-related AEs (i.e., the 
following AEs make the patient 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. 
 
Exclusion Criteria: 
1. Patients with symptomatic central nervous system (CNS) metastases must have been treated, be 
asymptomatic, and meet the following at the time of enrollment: 
a. 
No concurrent treatment for the CNS disease (e.g., surgery, radiation, corticosteroids ≥ 10 mg 
prednisone/day or equivalent). 
b. No progression of CNS metastases on MRI or CT for at least 14 days after last day of prior therapy 
for the CNS metastases. 
c. 
No concurrent leptomeningeal disease or cord compression. 
 
2. Patients with any history of known or suspected autoimmune disease with the specific exceptions of 
vitiligo, resolved childhood atopic dermatitis, psoriasis not requiring systemic treatment (within the past 
2 years) and patients with a history of Grave’s disease that are now euthyroid clinically and by 
laboratory testing. 
3. History of prior allogeneic bone marrow, stem-cell or solid organ transplantation. 
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4. Treatment with any systemic anti-neoplastic therapy, or investigational therapy within the 4 weeks prior 
to the initiation of study drug administration. 
5. Treatment with radiation therapy within 2 weeks prior to the initiation of study drug administration. 
6. Treatment with 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. Steroids for topical, 
ophthalmic, inhaled or nasal administration are allowed. 
7. History of clinically significant cardiovascular disease including but not limited to:  
a. Myocardial infarction or unstable angina within the 12 weeks prior to the initiation of study drug. 
b. Uncontrolled hypertension: systolic blood pressure (SBP) >180 mmHg, diastolic blood pressure 
(DBP) >100 mmHg. 
c. QTcB prolongation > 480 msec. 
d. Congestive heart failure (New York Heart Association [NYHA] class III-IV). 
 
8. Clinically-significant gastrointestinal disorders including: 
a. 
Any history of gastrointestinal perforation unless the affected area has been deemed by the 
investigator to no longer be a risk for perforation. 
b. History of clinically significant gastrointestinal bleeding within 4 weeks prior to the initiation of 
study drug. 
c. 
History of acute pancreatitis within 4 weeks prior to the initiation of study drug  
d. Diverticulitis that is clinically significant in the opinion of the Investigator based on the extent or 
severity of known disease and/or the occurrence of clinically-significant disease flares within 4 
weeks prior to the initiation of study drug administration. 
 
9. Evidence of active viral, bacterial, or systemic fungal infection requiring parenteral treatment within 7 
days prior to the initiation of study drug. Patients 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. 
10. Known positive testing for human immunodeficiency virus or history of acquired immune deficiency 
syndrome. 
11. 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 (PCR). 
12. Second primary invasive malignancy that has not been in remission for greater than 2 years. Exceptions 
that do not require a 2-year remission include: related 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. 
13. History of trauma or major surgery within 4 weeks prior to the initiation of study drug administration. 
14. Any serious underlying medical or psychiatric condition that would impair the ability of the patient to 
receive or tolerate the planned treatment at the investigational site. 
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15. Known hypersensitivity to recombinant proteins, 
 or any excipient contained in the drug 
or vehicle formulation for MGA271, pembrolizumab, or MGA012 (Section 6.1). 
16. Vaccination with any live virus vaccine within 4 weeks prior to the initiation of study drug 
administration. Inactivated annual influenza vaccination is allowed. 
17. Dementia or altered mental status that would preclude understanding and rendering of informed consent. 
18. Employees of MacroGenics, Inc. 
19. Prisoners or other individuals who are involuntarily detained. 
20. Any issue that in the opinion of the investigator, would contraindicate the patient’s participation in the 
study or confound the results of the study. 
Study Drugs: 
MGA271: 
 
 
  
MGA271 will be administered by IV infusion over 120 minutes.
 
 
 
Pembrolizumab: Pembrolizumab is supplied in two configurations: a “pembrolizumab for injection” 
configuration that is a single-use vial containing 50 mg lyophilized powder for reconstitution with 2.3 mL 
sterile water for injection resulting in a 25mg/mL solution (see Section 6.2.3) or “pembrolizumab injection” 
configuration that is a single-use vial containing pembrolizumab solution at a concentration of 100 mg/4mL 
(i.e., 25 mg/mL). 
Pembrolizumab for injection is a sterile, preservative-free, white to off-white lyophilized powder in single-
use vials. Each vial is reconstituted and diluted for intravenous infusion. Each 2 mL of reconstituted solution 
contains 50 mg of pembrolizumab and is formulated in L-histidine (3.1 mg), polysorbate 80 (0.4 mg), and 
sucrose (140 mg). May contain hydrochloric acid/sodium hydroxide to adjust pH to 5.5. 
Pembrolizumab injection is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly 
yellow solution that requires dilution for IV infusion. Each vial contains 100 mg of pembrolizumab in 4 mL 
of solution. Each 1 mL of the 100 mg/4mL solution contains 25 mg of pembrolizumab and is formulated in: 
L-histidine (1.55 mg), polysorbate 80 (0.2 mg), sucrose (70 mg), and Water for Injection, USP. 
Pembrolizumab will be administered by IV infusion over 30 minutes through an IV line containing a sterile, 
non-pyrogenic, low-protein binding 0.2 micron to 5 micron in-line or add-on filter by IV infusion. 
MGA012: 
 
 
 
 
 
Duration of Treatment and Study Duration: 
MGA271 will be administered on a once weekly schedule for up to 51 doses and pembrolizumab 
administered once every 3 weeks for a total of up to 17 doses (i.e., up to 6 cycles). With Amendment 5, in 
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Cohort 4, MGA271 will be administered on a Q3W schedule for up to 17 doses of MGA271 and MGA012 
administered once every 3 weeks for a total of up to 17 doses (i.e., up to 6 cycles). As per Rules for 
Continuation of Study Therapy, an unrestricted number of additional cycles may be permitted on a case-by-
case basis in consultation with the Sponsor.  
It is expected that enrollment of the dose escalation portion of the study will occur over approximately 
12 months, and that enrollment of the cohort expansion portion of the study will take approximately 9 – 
12 months. 
The total time for conduct of the trial is expected to be approximately 72 months (which includes 24 weeks 
of efficacy follow-up). These estimates of the timing for study conduct may vary from that observed in the 
actual conduct of the trial. 
Treatment Schedule (Procedure): 
See Time and Events (Appendix 1) 
Criteria for Evaluation: 
Safety Assessments: 
• The safety assessment will be based on the evaluation of treatment-emergent AEs that occur from the 
time of initiation of administration of either study drug through the End of Treatment Visit or 28 days 
after the last dose of study drug (whichever is later) and will be determined based on signs, symptoms, 
physical examination findings and/or laboratory test results from enrolled patients as appropriate 
• AEs and SAEs will be collected from the time the patient receives the first dose of study drug until the 
End of Treatment Visit or 28 days after the last dose of study drug (whichever is later). Protocol-related 
AEs and SAEs will be collected from the time the patient has consented to study participation. 
• AEs reported between the time the patient signed the informed consent and the administration of the first 
dose of study drug will be captured as medical history. 
• SAEs considered related to study drug may be reported at any time, even after the patient’s final visit. 
• Progression of the underlying neoplasm resulting in hospitalization or death (e.g., patient hospitalized 
for or dies from progressive disease [PD] only, without any other SAE) will be documented as an 
antitumor activity outcome and not as an SAE. If an SAE occurs in a patient and it is unclear whether 
the event is related to PD, the SAE should be reported. 
• The reporting of laboratory/vital signs abnormalities as both laboratory findings and AEs should be 
avoided. They should not be reported as AEs unless any one of the following are met: 
Any criterion for an SAE is fulfilled 
The laboratory/vital signs abnormality causes the patient to discontinue from the 
study treatment 
The laboratory/vital signs abnormality causes the patient to interrupt the study 
treatment 
The laboratory/vital signs abnormality causes the patient to modify the dose of 
study treatment 
The laboratory/vital signs abnormality requires intervention 
 
Efficacy Assessments: 
Tumor assessments will be obtained at screening using CT and/or MRI scans at time intervals as specified in 
the Appendix 1 (Time and Events Table). The study is divided into 6 Tumor Assessment Cycles; the first is 
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a 6-week cycle called the Initial Tumor Assessment Cycle, and Cycles 2 through 6 are 9-week cycles. The 
tumor assessment takes place at the end of each cycle. Treatment will continue until patients have completed 
study therapy and required follow-up, experienced disease progression, or have been withdrawn from the 
study. At each optional on-treatment tumor assessment time point, the objective response status will be 
determined. 
Efficacy Assessments: 
Objective Response and Response Duration 
Target and non-target lesions will be designated and evaluated using both conventional RECIST 1.1 criteria 
(Appendix 5) and immune-related response criteria (Appendix 6) for the purposes of statistical analysis. 
Objective responses will be categorized as Complete Response (CR), Partial Response (PR), Stable Disease 
(SD), or Progressive Disease (PD) for conventional RECIST 1.1 criteria and immune-related (ir) CR, irPR, 
irSD, and irPD for the immune-related response criteria. Determination of the objective response rate will be 
calculated based on the proportion of response evaluable patients achieving CR or PR using the respective 
criteria, when such responses are confirmed by a subsequent scan obtained at least 28 days after the initial 
documentation of objective response. Response evaluable patients will include those patients who have 
measurable disease and have had a baseline tumor assessment and at least 1 optional on-treatment tumor 
assessment (see Appendix 1). Objective responses that are not subsequently documented with a 
confirmatory CT or MRI scan (e.g. unconfirmed responses) will not be included as an objective response for 
the purpose of calculating overall objective response rates. Response duration will be calculated from the 
time of initial response (CR or PR) documentation (in patients who have a subsequent confirmation of 
objective response) to the time of progressive disease or death, whichever occurs first. A patient’s response 
duration will be censored if at the time of last antitumor assessment response is ongoing. Patients who 
discontinue study treatment for a reason other than progressive disease may be followed for efficacy until 1 
of the following occurs: the patient progresses, withdraws consent for follow up, or initiates other anti-cancer 
therapy, or the overall trial is closed. 
Progression-free survival (PFS) 
PFS will be calculated as the time from the first dose of study drug until documented disease progression or 
death from any cause, whichever occurs first (Appendix 3). A patient’s PFS will be censored if at the time of 
last assessment for progression, the patient remains progression free. PFS will be determined using both 
conventional RECIST 1.1 and immune-related response criteria. 
Overall survival (OS) 
OS will be calculated as the time from the first dose of study drug until death due to any cause or last 
observation or contact, whichever occurs first. A patient’s OS will be censored if at the time of last contact, 
the patient remains alive. In addition, landmark 6-month OS rate will be determined. 
Pharmacokinetic Assessments: 
Serum concentrations of MGA271 and MGA012 will be monitored using a quantitative sandwich enzyme-
linked immunosorbent assays (ELISA). Single and multiple dose PK parameters for MGA271 and MGA012, 
Cmax, Tmax, AUCtau, Ctrough, CL, Vss, and t1/2 will be derived from MGA271 and MGA012 serum concentration 
versus time data. Population PK analyses may be conducted using data from this study alone or combined 
with data from other studies. 
Immunogenicity Assessments: 
The generation of anti-drug antibodies (ADA) directed against MGA271 and MGA012 will be assayed using 
ELISA or Electrochemiluminescence method. 
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Pharmacodynamics/Biomarkers: 
Tests Performed for both Dose Escalation and Cohort Expansion Patients: 
• Characterization of alterations in serum cytokine levels including, but not limited to, IL-2, IL-6, IL-10, 
and TNF-α 
• Enumeration of lymphocyte subsets, NK cells and activation status over time via multi-parameter flow 
cytometry on whole blood; evaluation of the regulatory T cell population over time 
• Determination of B7-H3 and PD-L1 expression as well as immune cell infiltration into the tumor (e.g. 
CD8+ and CD4+ T cell infiltration) will be explored via IHC staining or other method of archival tumor 
biopsy specimens (unless fresh tumor sample submitted and used to determine B7-H3 expression and no 
archived sample obtained) 
• Soluble B7-H3 over time analyzed by ELISA; in addition to other potential circulating serum 
biomarkers indicative of potential tumor response 
 
 
Tests Performed for Cohort Expansion Patients: 
• Determination of B7-H3 tumor cell and tumor vasculature expression, PD-L1 tumor cell membranous 
expression, and immune cell infiltration into the tumor bed via IHC staining (or other method for 
immune cell infiltration) of archival tissue and/or of optional paired pre- and on-treatment tumor biopsy 
specimens when available. The optional pre-treatment and on-treatment tumor biopsies will be carried 
out for cohort expansion patients who elect to undergo pre- and on-treatment biopsy. 
• Characterization of T cell repertoire using T cell receptor (TCR) spectratyping of PBMCs on selected 
samples may be carried out depending on observed anti-tumor activity. 
• An assessment of the ability of patient’s PBMCs to support MGA271-mediated antibody dependent 
cellular cytotoxicity (ADCC) activity in pre- and on-treatment samples using a non-isotopic assay with 
the patient’s PBMCs as effector cells and B7-H3 expressing tumor cell lines as target cells may be 
carried out depending on observed anti-tumor activity. 
 
Analysis Populations: 
Two general populations will be used for the purposes of this analysis - the Safety Population and the 
Response Evaluable Population as defined below: 
• Safety Population: All patients who received at least one dose of either MGA271 or pembrolizumab or 
MGA012. Safety Population will be used to summarize baseline data, safety data and for assessment of 
OS and PFS. Patients who receive at least one dose of MGA271 or MGA012 will be included in PK, 
PD, and immunogenicity analyses. 
• Response Evaluable Population: All patients who received both MGA271 and pembrolizumab or 
MGA271 +MGA012  and had at least 1 post-infusion radiographic tumor assessments. Patients who 
meet these criteria will be eligible for the determination of best overall response and will be included in 
the response evaluable population used for the calculation of ORRs using both conventional RECIST 1.1 
(Appendix 5) and irRC (i.e., irRECIST as defined in Appendix 6) criteria. 
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Statistical Methods: 
Summary statistics will consist of absolute and relative frequencies of each category of discrete variables, 
and of means, standard deviations, medians, minimum, and maximum values of continuous variables. Safety 
and antitumor activity summaries will be provided for each dose level cohort in the dose escalation portion of 
the study, and for all dose level cohorts combined. Response rates may be calculated for specific disease sub-
groups, if appropriate. 
Response duration will be calculated for responders as the time from initial response (CR or PR) to the time 
of PD or death, whichever occurs first. Response rates will be determined using both conventional criteria 
using RECIST 1.1 (Appendix 5) as well as by irRC (i.e., irRECIST as defined in Appendix 6. Two-sided 
exact confidence intervals (CIs) will be constructed around the objective response rates. 
Kaplan-Meier methods will be used to estimate response duration over time and the median response 
duration. Responders who complete the study without documented PD will be censored at the date of their 
last tumor assessment. PFS and irPFS will be calculated as the time from the initial infusion of 
pembrolizumab or MGA271 until documented disease progression, death from any cause, whichever occurs 
first. Patients with no PFS event (disease progression or death from any cause) will be censored at the date of 
their last tumor assessment. In addition, PFS and irPFS rates will be calculated at 3 months and 6-month time 
points from the first dose of study drug. Kaplan-Meier methods will be used to estimate PFS over time and 
the median duration of PFS. The method of Brookmeyer and Crowley (9) will be used to construct 95% CIs 
around PFS estimates of the median and other quartiles for each expansion cohort. 
Overall survival is defined as the time from the initial infusion of pembrolizumab or MGA271 to death from 
any cause. Kaplan-Meier methods will be used to estimate the overall survival function. Patients who do not 
die will be censored at the date that the patient was last known to be alive. In addition, OS rate will be 
calculated at 6 months from the first dose of study drug. 
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2 
BACKGROUND INFORMATION  
2.1 
Disease Background  
In this clinical trial, patients with locally advanced unresectable or metastatic, melanoma, 
squamous cell cancer of the head and neck (SCCHN), non-small cell lung cancer (NSCLC), 
urothelial cancer and other cancers (i.e., mesothelioma, clear cell renal cell carcinoma 
(ccRCC), ovarian cancer, thyroid cancer, triple-negative breast cancer (TNBC), pancreatic 
cancer, colon cancer, soft tissue sarcoma, or prostate cancer) will be enrolled in the Dose 
Escalation Phase. The Cohort Expansion Phase will enroll patients with melanoma, SCCHN, 
NSCLC, and urothelial cancer. The rationale for selecting these distinct types of cancer is 
based on 3 factors: 1) the high level of unmet medical need for patients with these advanced 
diseases, 2) the relatively high level of B7 homolog 3 (B7-H3) expression observed in 
clinical specimens from these cancers, and 3) the rapidly accumulating evidence (conclusive 
for melanoma) that immune modulation with checkpoint inhibitors can have substantial 
antitumor activity in these tumors. 
Melanoma: In 2014, it is estimated that approximately 76,100 patients will be diagnosed 
with melanoma, with an estimated 9,710 deaths due to melanoma in the United States (US) 
(3). 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. There have been significant inroads towards 
the treatment of advanced melanoma that have occurred over the past 5 years with the 
approval of immune checkpoint inhibitors directed against cytotoxic T lymphocyte- 
associated protein 4 (CTLA-4) or programmed cell death protein 1 (PD-1) (ipilimumab 
[2011], pembrolizumab [2014] and nivolumab [2014]), cytokines (peginterferon alfa-2b 
[2011], and tyrosine kinase inhibitors (TKIs) including B-RAF enzyme inhibitors 
(vemurafenib [2011] and dabrafenib [2013]), and MEK1 and MEK2 inhibitors (dabrafenib 
[2013]) in the US. Despite the 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 progression-free survival (PFS) for patients 
with advanced melanoma on pembrolizumab was approximately 5.5 months (median overall 
survival [OS] not reached at 12 months) (45), and with ipilimumab treatment, the median OS 
and median PFS are approximately 10 months and 2.9 months, respectively (28). Thus 
although current treatment options such as ipilimumab monotherapy have provided a survival 
benefit in advanced disease, there remains a medical need for continued improved treatment 
in advanced cases. 
Melanoma serves as the index cancer for immune modulation as 5 immune modulators, 
including the PD-1 checkpoint inhibitors nivolumab and pembrolizumab, have now been 
approved in the US for the treatment for patients with advanced melanoma (high dose 
interleukin 2 is also approved to treat melanoma in addition to those listed above). In 
addition, the combination of CTLA-4 blockade (with ipilimumab) and blockade of the B7 
family checkpoint inhibitor PD-1 (with nivolumab) demonstrated a 42% objective response 
rate (ORR) in patients with advanced melanoma (58). An objective response rate of 42% 
with the ipilimumab/nivolumab combination is greater than that reported with either agent 
alone, approximately 11% and 28% respectively (28;61). Therefore, continued efforts to 
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utilize the immune system against melanoma with new checkpoint inhibitor targets or 
combinations of agents are attractive and may well continue to yield improved results over 
single agent approaches. 
In addition to the above, a high percentage of melanoma tumors demonstrate membranous 
surface expression of B7-H3, where nevi have either no or low levels of membranous 
expression (Investigator’s Brochure) (59;65). In addition, the level of B7-H3 expression on 
melanoma is 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 
(59;65). 
Squamous Cell Cancer of the Head and Neck: It is estimated that in 2014, approximately 
55,070 patients in the US will be diagnosed with cancer of the head and neck with an 
estimated 12,000 deaths from this cancer (3). Cancers of the head and neck constitute a 
collection of tumors that begin in the squamous cells lining the mucosal surfaces of the head 
and neck, referred to as SCCHN, and are categorized by the area of the head or neck in which 
they begin: Oral cavity, pharynx (includes nasopharynx, oropharynx, and hypopharynx), 
paranasal sinuses, and nasal cavity, and salivary glands. 
Although cancers originating in the salivary glands are usually classified as part of head and 
neck cancers, salivary gland cancers can arise from multiple types of cells within a gland and 
therefore have a heterogeneous histological pathology compared to the other head and neck 
cancers arising from a squamous cell lining. Therefore, patients with salivary gland cancers 
will not be evaluated in this study. 
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 (12;25). In the US the incidence of 
oropharyngeal cancers caused by HPV infection is increasing, while the incidence of 
oropharyngeal cancers related to other causes is falling (12). 
When SCCHN is detected in its earliest stages and treated, it is curable with excellent long 
term OS, however, locally recurrent and metastatic disease remains very poorly treatable 
with a median OS of 178 days (64). Thus there remains a tremendous medical need for 
improved treatment in advanced cases. 
Monoclonal antibodies targeting the T-cell immune checkpoint inhibitors PD-1 and PD-L1 
have recently demonstrated antitumor activity in patients with advanced SCCHN. 
Pembrolizumab was evaluated in a cohort of 60 patients with both HPV-positive and 
HPV-negative SCCHN (52). Of the 56 evaluable patients, 51% had a reduction in tumor 
volume, with 19.6% having either a partial response (PR) or complete response (CR) that 
was equally distributed between the HPV-positive and negative -patients. In addition, 
MEDI4736, a humanized monoclonal antibody targeting PD-L1, demonstrated a 32% 
objective response rate in a cohort of 22 patients with advanced SCCHN (51). 
B7-H3 has also been found to be expressed on a high percentage of SCCHN tumors  
(Investigator’s Brochure) (31;42). In addition to the high percentage of tumors expressing 
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membranous B7-H3 in SCCHN tumors, 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 (31). 
Non-Small Cell Lung Cancer: In the US, it is estimated that in 2014 approximately 
224,210 patients will be diagnosed with lung cancer and 80 to 85% of these cases will be one 
of the NSCLC histologies (3). The diagnosis of NSCLC is most often made when the disease 
is advanced or metastatic (Stage IIIB/IV), beyond the time when it can be controlled with 
localized therapies, leaving only systemic treatment options. The current first-line systemic 
treatment options for Stage IIIB/IV NSCLC patients are limited, with cisplatin-based doublet 
chemotherapy being the basis for most first-line treatment, with TKIs used for tumors with 
identified driver mutations. Despite these approaches, therapy for patients with advanced 
disease remains largely non-curative. The OS rate in Stage IIIB/IV disease remains poor with 
1 year survival rates of 30-40% and 5 year survival rate < 5% despite maximal conventional 
therapy (41). Given the continued poor prognosis of patients with NSCLC, and substantial 
unmet medical need, new therapeutic approaches are required. 
NSCLC, like melanoma, is a tumor where multiple immune checkpoint inhibitors have 
demonstrated antitumor activity including the PD-1 inhibitors nivolumab and pembrolizumab 
(23;24), demonstrating overall ORRs (regardless of PD-L1 status) of approximately 20% and 
30% respectively. In addition, the PD-L1 inhibitor MEDI4736 (8) demonstrated an ORR of 
approximately 13%, regardless of PD-L1 status. 
Like melanoma and SCCHN, membranous B7-H3 is expressed on a high percentage of 
NSCLC tumors with a trend towards a higher percentage of squamous carcinomas than 
adenocarcinoma expressing B7-H3 (Investigator’s Brochure) (6). In addition, the number 
of tumor infiltrating T-cells in tumor tissue was found to be substantially lower in B7-H3 
expressing tumors than in those tumors not expressing B7-H3, and higher expression of 
B7-H3 on the primary tumor was associated with a higher likelihood of metastatic disease 
(57). 
Urothelial Cancer: In the U.S., it is estimated that in 2016 approximately 143,190 patients 
will be diagnosed with cancer of the urinary system, of which 76,960 will arise from the 
urinary bladder and 3,530 from the ureter and other urinary organs (American Cancer 
Society. Cancer Facts & Figures. American Cancer Society pamphlet 2016). Prognosis and 
treatment varies depending on the category at diagnosis: non-muscle-invasive, muscle-
invasive, and metastatic (NCCN Guidelines Version 2.2015 Bladder Cancer). Approximately 
70% of patients have non-muscle-invasive disease at the time of diagnosis, but about 31 to 
78% will experience recurrence or new tumors within 5 years. One of the first 
immunotherapies -- bacillus Calmette-Guerin (BCG) -- has been used extensively as 
prophylactic or adjuvant therapy for bladder cancer post-surgery; however, the duration of 
maintenance is typically 3 years, with significant local and systemic toxicity. Chemotherapy 
with cisplatin, taxanes, and gemcitabine is recommended as first-line treatment for advanced 
disease; however, the benefit is limited for poor-risk patients and toxicity can be significant. 
Five-year overall survival has been demonstrated as 13% with gemcitabine and cisplatin 
(GC) and 15.3% with dose dense methotrexate, vinblastine, doxorubicin and cisplatin 
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(ddMVAC). There remains a significant unmet need for better, and less toxic, treatment 
options for patients with advanced disease. 
Recent advances with new immunotherapies have occurred with the development of PD-
1/PD-L1 inhibitors. Pembrolizumab demonstrated antitumor activity in a Phase 1b study of 
patients with recurrent or metastatic PD-L1-positive urothelial cancer (43). In 28 patients 
with measurable disease, the ORR was 25% (11% CR and 14% PR) with a 12-month PFS 
rate of 19%. The ORR in patients with PD-L1-positive tumors was 38%. 
Advanced melanoma, NSCLC, SCCHN, and urothelial cancer are good candidates to 
evaluate with a combination of pembrolizumab and MGA271. All four tumor types have 
been shown to express membranous B7-H3 in a high percentage of cases and all four have 
demonstrated susceptibility to immune modulation with monotherapy checkpoint inhibitors. 
Finally, despite recent advances in the treatment of each disease, there remains a tremendous 
unmet need for better therapy in patients with these advanced diseases. 
2.2 
Background on B7-H3 and PD-1  
2.2.1 
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 (17). B7 homolog 3 (B7-H3) is a novel member of 
the B7 family. B7-H3 has been implicated in the delivery of both co-stimulatory and co-
inhibitory signals (29). The apparent contrasting activities of B7-H3 may be attributed to 
multiple factors. While the murine B7-H3 molecule exists as a 2-Ig form, the human 
counterpart has undergone gene duplication and exists primarily as a 4-Ig molecule (54). 
Further, as with other members of the B7 family, B7-H3 may bind, on different cells, to 
multiple receptors that remain to be identified. 
B7-H3 is an attractive target for tumor immunotherapy without regard to its immunological 
properties. Tissue expression studies have demonstrated that B7-H3 protein is not expressed 
in most normal tissues, rather its expression is inducible on certain antigen presenting cells 
(11;55) and vasculature, exists on certain endocrine tissues (most notably in the cytoplasm of 
epithelial cells of the adrenal cortex), and is over-expressed in a wide range of cancers 
(including cultured cancer stem-like cells). B7-H3 is broadly over-expressed on many 
malignant neoplasms, including SCCHN (MacroGenics unpublished observation); bladder 
cancer (MacroGenics unpublished observation) (7); prostate cancer (13;48;60;71), where 
expression of B7-H3 is associated with metastatic behavior and poor outcome; renal cell 
carcinoma (18), where B7-H3 is broadly expressed in tumor vasculature; ovarian cancer (66); 
colorectal cancer (56); gastric cancer (70); non-small cell lung cancer (57) (MacroGenics 
unpublished observation); glioblastoma (39); melanoma (MacroGenics unpublished 
observation); and certain small round blue cell tumors of childhood including neuroblastoma 
and rhabdomyosarcoma (10;26). 
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2.2.2 
PD-1  
PD-1 is an immune-modulatory receptor expressed on activated T-cells. The physiological 
role of PD-1 is to limit the inflammatory response to infection and prevent autoimmunity by 
limiting the activity of T cells in the periphery (5;21;32). 
The basis for this physiology is that the ligands for PD-1, namely PD-L1 (B7-H1) and PD-L2 
(B7-DC), are up-regulated on many cell types — hematopoietic, endothelial and epithelial — 
in response to pro-inflammatory cytokines, notably interferon gamma. In addition, B7-
DC/PD-L2 is up-regulated on dendritic cells and macrophages in response to different pro-
inflammatory cytokines such as IL-4 (53;67). 
Cancer cells, to avoid antitumor response, co-opt the normal physiology of the PD-1 pathway 
used to prevent collateral normal tissue damage that would occur in an unchecked 
inflammatory immune response. Expression of B7-H1/ PD-L1 as an adaptive response to 
antitumor immunity likely occurs because this ligand is induced on most epithelial cancers in 
response to interferon-gamma, similarly to epithelial and stromal cells in normal tissues (61). 
In addition, PD-1 is highly expressed on induced regulatory T-cells (T-regs), and PD-1: 
PD-L1 interactions appear to promote the induction, conversion and maintenance of T-regs, 
suggesting an additional mechanism for immunosuppression in a tumor microenvironment 
rich in PD-1 ligands (2;20). 
2.3 
Study Agent Background  
2.3.1 
MGA271  
MGA271 is a humanized monoclonal antibody that binds the B7-H3 immunoligand with 
high affinity (35). The antibody has been engineered to have enhanced binding to the 
activating FcR, CD16A, and especially the low affinity allele of CD16A, CD16A-158F. 
Since most patients carry the low-affinity allele of CD16A, the enhanced binding of the Fc-
optimized version is expected to impart binding improvement that benefits the whole patient 
population, not just those patients who are homozygous for the high-binding allele of CD16A 
(valine/valine (V/V) genotype, approximately 15% of the population). MGA271 also exhibits 
reduced binding to the low-affinity inhibitory receptor, CD32B. 
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Antibody dependent cellular cytotoxicity (ADCC) has been shown to be an important 
mechanism of action for several monoclonal antibodies including rituximab (16;66) and 
trastuzumab (16;40) and is likely an important mechanism of action for MGA271. 
The ability of MGA271 (or RES242 [MGA271 with a wild-type Fc]) to mediate ADCC 
activity was evaluated across multiple cancer types expressing varying levels of B7-H3 as 
determined by flow cytometry. The cancer types tested included: melanoma (A375, UACC-
62), lung cancer (SK-MES-1, A549), prostate cancer (LnCAP), breast cancer (JIMT-1, 
MDA-MB-468), bladder cancer (SW780, HT-1197), and renal cancer (ACHN) cell lines. 
MGA271-mediated ADCC activity against all tumor lines that express B7-H3 at detectable 
levels. Furthermore, MGA271 showed enhanced ADCC potency compared to the related 
version of the antibody with wild type Fc domains, chBRCA84D or RES240, against all the 
tumor cell lines examined (see Figure 1). Consistent with the studies described above, the 
greatest enhancement in ADCC activity against the B7-H3 expressing prostate cancer cell 
line LnCAP was observed with effector populations obtained from individuals homozygous 
for the weak binding allele of CD16A (phenylalanine/phenylalanine [F/F]). In contrast, 
MGA271 did not mediate ADCC against Raji B-cell lymphoma cells, which do not express 
detectable cell surface B7-H3. 
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2.3.1.1 
Safety  
2.3.1.1.1 
Nonclinical Data  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.3.1.1.2 
Clinical Trial Experience  
MGA271 is currently being evaluated in patients with cancer in 4 ongoing, Phase 1, 
MacroGenics-sponsored clinical studies. Clinical trial experience is presented for 
MGA271+pembrolizumab combination therapy for the current study (CP-MGA271-03) and 
MGA271 monotherapy for Study CP-MGA271-01. Data from remaining 2 studies are not 
included, 1 explores MGA271 treatment in a pediatric population and the other explores 
combination MGA271 and ipilimumab treatment.  
Safety 
As of the cutoff date of 13 April 2019, safety data are available for 133 patients exposed to 
MGA271+Pembrolizumab in Study CP-MGA271-03 and for 179 patients exposed to 
MGA271 in Study CP-MGA271-01. A discussion of safety for each study is presented below. 
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Study CP-MGA271-03  
Adverse events considered related to MGA271+pembrolizumab treatment were reported in 
116 patients (87.2%). The most common treatment-related adverse events (TRAEs) reported 
in ≥ 5% of patients exposed to MGA271+pembrolizumab in decreasing order of frequency 
were as follows: infusion-related reaction (54.1%); fatigue (27.8%); nausea (9.8%); pyrexia 
(9.0%); lipase increased (8.3%); arthralgia (7.5%); events of diarrhea, rash maculo-papular, 
and decreased appetite (6.8%, each); events of hypothyroidism and pneumonitis 
(6.0%, each); events of chills, anemia, lymphocyte count decreased, and pruritus 
(5.3% each). Greater than or equal to Grade 3 TRAEs were reported in 38 patients (28.6%). 
Of these, the most commonly reported in ≥ 5% of patients was infusion-related reaction 
(6.8%) and lipase increased (6.0%).  
Forty-eight patients (36.1%) experienced at least 1 serious adverse event (SAE). The most 
common SAEs, reported in ≥ 2% of patients in decreasing order of frequency were: 
infusion-related reaction (6.8%), pneumonitis (4.5%), and dyspnea (2.3%). Twenty-three 
patients (17.3%) experienced SAEs considered related to MGA271+pembrolizumab; the 
majority of these events were ≤ Grade 3 in severity (20/23 patients [87%]). The most 
common SAEs considered related were infusion-related reaction (6.8%) and pneumonitis 
(4.5%). Fourteen patients (10.5%) experienced at least 1 ≥ Grade 3 SAE that was considered 
related to MGA271+pembrolizumab; with the exception of infusion-related reaction 
(6 patients [4.5%]) and pneumonitis (3 patients [2.3%]), the events were singularly reported. 
Study CP-MGA271-01  
Adverse events considered related to MGA271 monotherapy treatment have been reported in 
146 patients (81.6%). The most common related AEs reported in ≥ 5% of patients exposed to 
MGA271 in decreasing order of frequency were as follows: infusion-related reaction 
(39.7%), fatigue (31.8%), nausea (19.6%), chills (14.0%), vomiting (12.8%), pyrexia (9.5%), 
diarrhea (8.4%), decreased appetite (7.3%), pruritus (6.1%), influenza-like illness (5.6%), 
and headache (5.0%). These events were generally mild (Grade 1) or moderate (Grade 2) in 
severity, but thirteen patients (7.3%) reported ≥ Grade 3 AEs considered related to MGA271 
treatment.  
Eleven patients (6.1%) experienced SAEs considered related to MGA271 treatment. The 
most common SAEs considered related were infusion-related reaction (3.4%) and pyrexia 
(1.1%]). The SAEs considered related to MGA271 treatment were generally mild (Grade 1) 
or moderate (Grade 2) in severity; few patients (5 patients [2.8%]) experienced at least 1 ≥ 
Grade 3 SAE considered to be related, with the most commonly reported as infusion-related 
reaction (1.7%).  
Overall, MGA271 administration as a monotherapy has been generally well-tolerated, with 
infusion-related reactions, typically mild or moderate, being the primary safety concern. 
Previously implemented premedication guidelines have been continued to help mitigate the 
occurrence of these events. Observed infusion-related reactions have been manageable, 
resolving without sequelae. Patients who experienced Grade 3 infusion-related reactions have 
fully recovered following brief interruption in dosing and after receiving treatment based 
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upon symptomatology. Other AEs expected with administration of MGA271 include nausea, 
vomiting, and pyrexia. 
2.3.1.1.2.1 
Summary  
In conclusion, the data from the clinical studies CP-MGA271-03 and CP-MGA271-01 as of 
13 April 2019 suggest that MGA271 at doses up to 15 mg/kg combined with 2 mg/kg 
Pembrolizumab weekly by IV and MGA271 monotherapy at doses up to 15 mg/kg 
administered weekly by IV, is generally well tolerated with toxicities manageable by standard 
medical therapy for patients with advanced cancer. 
 
  
Efficacy: 
As of 12 October 2018 (1), 133 patients have been treated in this study. Combination 
MGA271 and pembrolizumab dose escalation and expansion cohorts are closed to further 
enrollment; patients enrolled in these cohorts have completed combination treatment; no 
MTD was defined. The MGA271 + pembrolizumab combination treatment demonstrated an 
acceptable safety profile. In the anti-PD-1/PD-L1 naïve patients treated with 
MGA271 + pembrolizumab, the objective response rates benchmarked favorably with 
historical experience with anti-PD-1 monotherapy: SCCHN (post-platinum chemotherapy) 
was 33.3% and NSCLC (PD-L1 < 1%) was 35.7%; see Table 1. 
Table 1 
Enoblituzumab (MGA271) + Pembrolizumab Combination 
Benchmarks Favorably  
 
 
2.3.2 
Pembrolizumab  
Pembrolizumab (KEYTRUDA®) is a humanized IgG4 kappa monoclonal antibody that 
blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2 (38). Pembrolizumab 
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is produced in recombinant Chinese hamster ovary cells (CHO). Pembrolizumab was initially 
approved by the US Food and Drug Administration (FDA) in 2014. Pembrolizumab 
(KEYTRUDA®) currently has approval (as of February 2019) for the following indications: 
Melanoma:  
• For the treatment of patients with unresectable or metastatic melanoma 
• For the adjuvant treatment of patients with melanoma with involvement of lymph 
node(s) following complete resection. 
Non-Small Cell Lung Cancer: 
• In combination with pemetrexed and platinum chemotherapy, as first-line 
treatment of patients with metastatic nonsquamous NSCLC, with no EGFR or 
ALK genomic tumor aberrations. 
• In combination with carboplatin and either paclitaxel or nabpaclitaxel as first-line 
treatment of patients with metastatic squamous NSCLC. 
• As a single agent for the first-line treatment of patients with metastatic NSCLC 
whose tumors have high PD-L1 expression (Tumor Proportion Score [TPS] ≥ 
50%) as determined by an FDA approved test, with no EGFR or ALK genomic 
tumor aberrations. 
• As a single agent for the treatment of patients with metastatic NSCLC whose 
tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with 
disease progression on or after platinum-containing chemotherapy. Patients with 
EGFR or ALK genomic tumor aberrations should have disease progression on 
FDA-approved therapy for these aberrations prior to receiving KEYTRUDA. 
Head and Neck Squamous Cell Cancer (HNSCC): 
• For the treatment of patients with recurrent or metastatic HNSCC with disease 
progression on or after platinum-containing chemotherapy. 
Urothelial Carcinoma: 
• For the treatment of patients with locally advanced or metastatic urothelial 
carcinoma who are not eligible for cisplatin-containing chemotherapy and whose 
tumors express PD-L1 (Combined Positive Score [CPS] ≥10) as determined by an 
FDA-approved test, or in patients who are not eligible for any platinum-
containing chemotherapy regardless of PD-L1 status.  
• For the treatment of patients with locally advanced or metastatic urothelial 
carcinoma who have disease progression during or following platinum-containing 
chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with 
platinum-containing chemotherapy. 
The recommended dosage for these indications is 200 mg IV over 30 minutes every 3 weeks. 
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2.3.2.1 
Safety  
Pembrolizumab (KEYTRUDA®) can cause immune-mediated toxicities, some of which can 
be life-threatening and possibly lead to death.  
• Immune-Mediated Pneumonitis: Pneumonitis occurred in 94 (3.4%) of 
2799 patients receiving KEYTRUDA, including Grade 1 (0.8%), Grade 2 (1.3%), 
Grade 3 (0.9%), Grade 4 (0.3%), and Grade 5 (0.1%) pneumonitis. The median 
time to onset was 3.3 months (range: 2 days to 19.3 months), and the median 
duration was 1.5 months (range: 1 day to 17.2+ months). Sixty-three (67%) of the 
94 patients received systemic corticosteroids, with 50 of the 63 receiving high-
dose corticosteroids for a median duration of 8 days (range: 1 day to 10.1 months) 
followed by a corticosteroid taper. Pneumonitis occurred more frequently in 
patients with a history of prior thoracic radiation (6.9%) than in patients who did 
not receive prior thoracic radiation (2.9%). Pneumonitis led to discontinuation of 
KEYTRUDA in 36 (1.3%) patients. Pneumonitis resolved in 55 (59%) of the 94 
patients. 
• Immune-Mediated Colitis: Colitis occurred in 48 (1.7%) of 2799 patients 
receiving KEYTRUDA, including Grade 2 (0.4%), Grade 3 (1.1%), and Grade 4 
(<0.1%) colitis. The median time to onset was 3.5 months (range: 10 days to 16.2 
months), and the median duration was 1.3 months (range: 1 day to 8.7+ months). 
Thirty-three (69%) of the 48 patients received systemic corticosteroids, with 27 of 
the 33 requiring high-dose corticosteroids for a median duration of 7 days (range: 
1 day to 5.3 months) followed by a corticosteroid taper. Colitis led to 
discontinuation of KEYTRUDA in 15 (0.5%) patients. Colitis resolved in 41 
(85%) of the 48 patients. 
• Renal Failure and Immune-Mediated Nephritis: Nephritis occurred in 9 (0.3%) 
of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), Grade 3 
(0.1%), and Grade 4 (<0.1%) nephritis. The median time to onset was 5.1 months 
(range: 12 days to 12.8 months), and the median duration was 3.3 months (range: 
12 days to 8.9+ months). Eight (89%) of the 9 patients received systemic 
corticosteroids, with 7 of the 8 receiving high-dose corticosteroids for a median 
duration of 15 days (range: 3 days to 4.0 months) followed by a corticosteroid 
taper. Nephritis led to discontinuation of KEYTRUDA in 3 (0.1%) patients. 
Nephritis resolved in 5 (56%) of the 9 patients. Nephritis occurred in 1.7% of 405 
patients receiving KEYTRUDA in combination with pemetrexed and 11 platinum 
in the KEYNOTE-189 study, including Grade 3 (1%) and Grade 4 (0.5%) 
nephritis. The median time to onset was 3.2 months (range: 16 days to 11.1 
months) and the duration ranged from 1.6 to 16.8+ months. Six (86%) of the 7 
patients received systemic corticosteroids, with all 6 receiving high-dose 
corticosteroids for a median duration of 3 days (range: 1 to 17 days) followed by a 
corticosteroid taper. Nephritis led to discontinuation of KEYTRUDA in 5 (1.2%) 
patients. Nephritis resolved in 2 (29%) of the 7 patients. 
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• Immune-Mediated Hepatitis: Hepatitis occurred in 19 (0.7%) of 2799 patients 
receiving KEYTRUDA, including Grade 2 (0.1%), Grade 3 (0.4%), and Grade 4 
(<0.1%) hepatitis. The median time to onset was 1.3 months (range: 8 days to 
21.4 months), and the median duration was 1.8 months (range: 8 days to 
20.9+ months). Thirteen (68%) of the 19 patients received systemic 
corticosteroids, with 12 of the 13 receiving high-dose corticosteroids for a median 
duration of 5 days (range: 1 to 26 days) followed by a corticosteroid taper. 
Hepatitis led to discontinuation of KEYTRUDA in 6 (0.2%) patients. Hepatitis 
resolved in 15 (79%) of the 19 patients. 
• Immune-Mediated Endocrinopathies: 
Hypophysitis  
Hypophysitis occurred in 17 (0.6%) of 2799 patients receiving KEYTRUDA, 
including Grade 2 (0.2%), Grade 3 (0.3%), and Grade 4 (<0.1%) hypophysitis. 
The median time to onset was 3.7 months (range: 1 day to 11.9 months), and the 
median duration was 4.7 months (range: 8+ days to 12.7+ months). Sixteen (94%) 
of the 17 patients received systemic corticosteroids, with 6 of the 16 receiving 
high-dose corticosteroids. Hypophysitis led to discontinuation of KEYTRUDA in 
4 (0.1%) patients. Hypophysitis resolved in 7 (41%) of the 17 patients.  
Thyroid Disorders:  
Hyperthyroidism occurred in 96 (3.4%) of 2799 patients receiving KEYTRUDA, 
including Grade 2 (0.8%) and Grade 3 (0.1%) hyperthyroidism. The median time 
to onset was 1.4 months (range: 1 day to 21.9 months), and the median duration 
was 2.1 months (range: 3 days to 15.0+ months). Hyperthyroidism led to 
discontinuation of KEYTRUDA in 2 (<0.1%) patients. Hyperthyroidism resolved 
in 71 (74%) of the 96 patients. 
Hypothyroidism occurred in 237 (8.5%) of 2799 patients receiving KEYTRUDA, 
including Grade 2 (6.2%) and Grade 3 (0.1%) hypothyroidism. The median time 
to onset was 3.5 months (range: 1 day to 18.9 months), and the median duration 
was not reached (range: 2 days to 27.7+ months). Hypothyroidism led to 
discontinuation of KEYTRUDA in 1 (<0.1%) patient. Hypothyroidism resolved in 
48 (20%) of the 237 patients. The incidence of new or worsening hypothyroidism 
was higher in patients with HNSCC occurring in 28 (15%) of 192 patients 
receiving KEYTRUDA, including Grade 3 (0.5%) hypothyroidism. Of these 28 
patients, 15 had no prior history of hypothyroidism. 
Thyroiditis occurred in 16 (0.6%) of 2799 patients receiving KEYTRUDA, 
including Grade 2 (0.3%) thyroiditis. The median time of onset was 1.2 months 
(range: 0.5 to 3.5 months). 
• Type 1 Diabetes mellitus: KEYTRUDA can cause type 1 diabetes mellitus, 
including diabetic ketoacidosis, which have been reported in 6 (0.2%) of 
2799 patients receiving KEYTRUDA. 
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• Immune-Mediated Skin Adverse Reactions: Immune-mediated rashes, 
including Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN) 
(some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, 
can occur. Monitor patients for suspected severe skin reactions and exclude other 
causes. 
 
The following clinically significant, immune-mediated adverse reactions occurred in less 
than 1% of 2799 patients treated with KEYTRUDA: arthritis (1.5%), uveitis, myositis, 
Guillain-Barre syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, 
sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other 
trials and post-marketing use. 
The most common adverse reactions reported in ≥ 20% of patients were:  
• KEYTRUDA as a single agent: fatigue, musculoskeletal pain, decreased appetite, 
pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain and 
abdominal pain.  
• KEYTRUDA in combination with chemotherapy: fatigue/asthenia, nausea, 
constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, 
pyrexia, alopecia, and peripheral neuropathy.  
 
A high level of awareness for the possibility that an AE may be an immune-related AE (irAE) 
is necessary in the management of patients receiving pembrolizumab because the 
presentations of an irAE can be subtle, and other causes must be ruled out. An irAE can 
occur at any point during treatment with pembrolizumab. It is imperative to establish the 
correct diagnosis promptly, determining severity based on Common Terminology Criteria for 
Adverse Events (CTCAE) grading and initiating treatment with steroids, if necessary, and 
holding further pembrolizumab treatment is essential (38). Refer to Section 6.5 for a detailed 
description of toxicity management. See also current KEYTRUDA® Prescribing Information. 
2.3.3 
MGA012  
MGA012 (also known as INCMGA00012) is a humanized, hinge-stabilized, IgG4κ 
monoclonal antibody (mAb) that recognizes human PD-1. 
 
 
 
 
  
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2.3.3.1 
Safety  
2.3.3.1.1 
MGA012 Nonclinical Experience  
 
 
 
 
 
 
 
 
 
 
2.3.3.1.2 
MGA012 Clinical Experience  
Phase 1 dose-finding results in participants with advanced cancer (N = 37) have been 
presented (34). MGA012 demonstrated acceptable tolerability with no dose-limiting toxicity 
observed at doses ranging from 1 to 10 mg/kg every 2 weeks (Q2W), Q4W administration 
was also studied. A maximum tolerated dose was not reached. 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 non small-cell 
lung carcinoma (NSCLC), endometrial cancer, cervical cancer, and sarcoma cohorts, with 
subsequent evaluation of flat dosing in tumor-agnostic and microsatellite instability (MSI) 
high uterine cancer cohorts.  
Interim results for the expansion cohorts have recently been presented (37). A total of 
132 patients were enrolled into the disease-specific expansion cohorts and another 30 in the 
tumor agnostic flat dosing cohorts at 500 and 750 mg Q4W. Patients were predominantly 
Caucasian and female; the median age ranged from 44 for the sarcoma cohort to 64 for the 
endometrial cancer cohort. The most frequently reported treatment-emergent adverse events 
(TEAEs) (> 10%) in patients receiving body-weight based dosing were fatigue, diarrhea, and 
dyspnea. The most frequently reported TEAEs (≥ 20%) in patients 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%) patients exposed to 
MGA012 in the study have experienced immune-related adverse events (irAEs). Most irAEs 
were transient, except for endocrine-related irAEs. Non endocrine irAEs that 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 (e.g., MSI or PD-L1 status). Specifically, 
5/27 (19%) evaluable NSCLC patients had confirmed RECIST responses, as did 4/29 (14%) 
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cervical cancer patients, 4/23 (17%) endometrial cancer patient, and 1 sarcoma patient. ORR 
and median duration of responses have not yet been established.  
MGA012 is currently being developed for the treatment of metastatic Merkel-cell carcinoma 
and squamous cell carcinoma of the anal canal and as both a monotherapy and in 
combination with other potentially immunomodulatory agents (including chemotherapy) for 
a broad spectrum of solid tumors.   
2.4 
Rationale for Combining MGA271 and Pembrolizumab  
Despite current treatment options for patients with melanoma, NSCLC, SCCHN, or 
urothelial cancer, substantial unmet medical need remains for patients with advanced disease. 
This study evaluates a novel combination of immunotherapies in patients with advanced 
cancer and is designed to investigate whether combined administration of MGA271 and 
pembrolizumab to coordinately block two distinct B7 pathways can further potentiate the 
potentially promising antitumor activity observed with pembrolizumab alone.  
The blockade of individual immune checkpoints has demonstrated antitumor activity in a 
variety of cancers and has been validated in melanoma with ipilimumab and pembrolizumab. 
Nonetheless, the vast majority of tumors eventually progress, escaping immune detection and 
destruction. Therefore, strategies that combine immune checkpoint blockade through non-
redundant immune checkpoints, and/or other mechanisms are being actively investigated and 
are beginning to demonstrate even greater potential antitumor activity than monotherapy 
based treatments (58). 
The simultaneous blockade of B7-H3 with MGA271 and PD-1 with pembrolizumab 
represents an opportunity to potentially enhance and focus the immune system against cancer 
cells to mediate antitumor effects more pronounced than either single agent alone. Aside 
from coordinately targeting the distinct functions mediated by B7-H3 and PD-1/PD-L1 with 
combined administration of MGA271 and pembrolizumab, several additional lines of 
evidence suggest that these agents may be combined to more effectively enhance the 
antitumor response compared to either agent alone, including the following: 
Pembrolizumab and MGA271 may enhance the immune response against tumors 
though reduction of T regulatory cell (T-regs) immunosuppression. 
Both PD-1 and B7-H3 are reported to have roles in amplifying the impact of T-regs in the 
tumor bed, and these mechanisms could play a substantial role in the ability of each pathway 
to mediate immune suppression that allows tumors to escape immune mediated destruction. 
Therefore, a coordinated blockade of PD-1 and B7-H3 may have a substantial impact on 
reducing the effects of T-regs in the tumor bed and sharply reduce immune suppression. 
Below is a brief synopsis of the role that each receptor has in potentiating the effects of 
regulatory T cells. 
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PD-1 
PD-1 is highly expressed on induced regulatory T cells and activation of the PD-1/ PD-L1 
axis promotes the induction, conversion and maintenance of T-regs (20). Native CD4 T-
helper cells were induced to become T-regs on exposure to PD-L1 coated beads in-vitro, and 
PD-L1 enhanced and sustained Foxp3 expression. The induced T-regs were shown to have 
immune suppressive function both in in-vitro and in-vivo murine models (20). In another set 
of experiments it was demonstrated that the induction of T-regs by PD-L1 could be abolished 
by blocking PD-1 on the T-helper cells (2) These experiments suggest that the interaction of 
PD-1 and PD-L1 could provide an additional mechanism for immunosuppression through de 
novo generation of T-regs in a tumor microenvironment rich in PD-1 ligands. 
B7-H3 
Expression of B7-H3 on antigen presenting dendritic cells (DC) in the tumor bed has been 
linked to an enhanced suppressive function of T-regs cells in murine models and in human 
lung cancer (36;49;50). In a study evaluating NSCLC tumor specimens for expression of B7 
checkpoint inhibitors on tumor infiltrating lymphocytes, B7-H3 expression was significantly 
up-regulated on tumor infiltrating DC whereas the expression of other B7 molecules, B7-DC 
(PD-L2), B7-1, B7-2, B7-H1 (PD-L2), remained unchanged compared to DC derived from 
healthy lung tissue (49). T-regs and B7-H3 expressing DC work together in a feedback loop 
as T-regs induce further B7-H3 expression on DC and B7-H3 expressing DC further induce 
T-regs in the tumor bed. Thus, B7-H3 expressing dendritic cells, have an overall 
immunosuppressive effect by increasing the number of T-regs in the tumor. In addition, DC 
that express B7-H3 have decreased T-effector cell simulative effects compared to non-B7-H3 
expressing DC. Therefore, blockade of B7-H3 signaling by MGA271on DC may indirectly 
reduce the immune-suppressive function of T-regs in the tumor bed and the combined 
inhibition on the effects of T-regs immunosuppression by adding pembrolizumab may 
synergize to substantially degrade T-reg-mediated immunosuppression. 
Coordinate engagement of both innate and adaptive immunity by combining agents 
that potentiate ADCC with agents that modulate T-cell function may yield synergistic 
antitumor activity. 
In addition to its potential T-cell regulatory properties, MGA271 is an Fc-enhanced 
monoclonal antibody modified to increase its Fc stimulatory activity and thus enhance 
potential ADCC immune attack on B7-H3 expressing tumor cells. The immune response is 
considered to be a major determinant of monoclonal antibody antitumor directed ADCC 
activity (33). Combining the 2 distinct mechanisms of action of ADCC and release of the 
PD-1 checkpoint inhibition against T-effector cells may synergize for increased ant-tumor 
activity than observed with MGA271 or pembrolizumab, alone. 
The limited B7-H3 expression on normal cells may potentiate immune targeting of 
tumor cells while limiting self-immune reactivity. 
Coordinate engagement of multiple immune-stimulatory mechanisms directed against tumors 
with an improved safety profile based on limited expression of B7-H3 in normal tissue, 
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reduces the potential for breaking tolerance against normal organs and immune-related AEs 
with the MGA271/pembrolizumab combination compared to combinations consisting of anti-
CTLA-4 (i.e., ipilimumab or tremilimumab) and anti-PD-1 (i.e., pembrolizumab or 
nivolumab) antibodies. 
Combinatorial immune checkpoint blockade may provide antitumor activity where 
either one or both agents has limited activity on its own in certain tumors. 
In some cases, with immune checkpoints, blockade of a single checkpoint may demonstrate 
little to no antitumor activity in certain tumor types, but when a second immune checkpoint is 
blocked in combination with the first, substantial activity is observed. Lymphocyte-activation 
gene 3 (LAG-3) is a ligand expressed on T-cells that is substantially expressed on tumor 
infiltrating T cells, including T-effector and T-regs. The ligand for LAG-3 is major 
histocompatibility complex class II (MHC II) expressed on antigen presenting cells (27). In a 
murine model of established fibrosarcoma or colon cancer xenografts, murine anti-PD-1 and 
anti- LAG-3 antibodies had a limited to moderate effect on the growth of the tumors, 
respectively. Of the mice treated with anti-LAG-3, 10% and 0% were tumor free at Day 50 in 
the fibrosarcoma and colon cancer inoculated mice, respectively. Similarly, for the anti-PD-1 
treated mice, 20% and 40% were tumor free at Day 50. In striking contrast, 70% and 80% of 
the mice inoculated with fibrosarcoma and colon cancer cells, respectively, were tumor-free 
after 50 days following combinatorial anti-LAG-3 plus anti-PD-1 immunotherapy (69). 
2.5 
Rationale for Combining MGA271 and MGA012  
Beginning with Amendment 5, a new cohort (Cohort 4) will be enrolled to explore the safety 
and tolerability of MGA271+MGA012 treatment. The properties of MGA012 are 
comparable to those observed with replicas of the approved anti-PD-1 mAbs, nivolumab and 
pembrolizumab (Table 2). MGA012 also blocks the PD-1/PD-L1 inhibitory axis (measured 
with a luciferase reporter assay system) in a dose-dependent manner that is comparable to 
those observed with the nivolumab and pembrolizumab replicas (Table 2).  
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Table 2 
Comparison of in vitro Potencies of MGA012 and Nivolumab 
and Pembrolizumab Replicas           
Property 
EC50 (or IC50) Values (µg/mL) 1 
Mean ± SEM 
 
Nivolumab replica 
Pembrolizumab 
replica 
Binding to PD-1-expressing NS0/PDCD1 cells 
 
0.158 ± 0.058 
0.140 ± 0.048 
Inhibition of sPD-L1 binding to PD-1 
expressing NS0/PDCD1 cells 
 
0.016 ± 0.005 
0.014 ± 0.001 
Inhibition of sPD-L2 binding to PD-1 
expressing NS0/PDCD1 cells 
 
0.028 ± 0.004 
0.028 ± 0.003 
Inhibition of PD-1/PD-L1 Signaling in 
luciferase reporter assay 
 
0.171 ± 0.017 
0.103 ± 0.016 
1 
EC50, effective concentration at 50% of maximal activity; IC50 =effective concentration at 50% inhibition 
of activity. 
 
The safety, tolerability and preliminary efficacy of MGA012 has been explored in a Phase 1 
study, CP-MGA012-01, as described in Section 2.3.1.1.2. 
2.6 
Rationale for Dose Selection  
2.6.1 
Dose Escalation Phase  
2.6.1.1 
Pembrolizumab  
The dose of pembrolizumab administered during the study will be 2 mg/kg given once every 
3 weeks via 30-minute IV infusion. This is the FDA-approved dose and schedule that was 
found to have clinical benefit in patients with advanced melanoma. In addition, the 2 mg/kg 
dose has also demonstrated antitumor activity in NSCLC (23;46) and pembrolizumab has 
received accelerated approval for NSCLC by the US FDA. 
2.6.1.2 
MGA271  
The dose for MGA271 in the escalation phase will begin at 3 mg/kg IV (120-minute 
infusion), with proposed escalations to 10 mg/kg and then 15 mg/kg, given on a once weekly 
schedule. There will be a dose de-escalation to 1 mg/kg of MGA271 if the starting dose of 
3 mg/kg in combination with pembrolizumab is found to exceed the maximum tolerated dose 
(MTD). In addition, MGA271 dose de-escalations of 7 mg/kg and 12 mg/kg may be 
evaluated depending on the toxicity profile of the MGA271/pembrolizumab combination 
observed with MGA271 doses of 10 and 15 mg/kg, respectively. 
The initial dose proposed for MGA271 in the Dose Escalation Phase, 3 mg/kg, is based on 
the pharmacokinetic and safety profile of MGA271 from the ongoing CP-MGA271-01 
Phase 1 study. In the CP-MGA271-01 study, dose escalation was carried out from 
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0.01 mg/kg to 15 mg/kg without a DLT observed at any dose level. As 15 mg/kg was the 
highest protocol specified dose, 15 mg/kg was determined as the maximum administered 
dose (MAD), and that dose carried into the expansion phase of that study. The safety profile 
of MGA271 based on a total of 51 patients exposed to MGA271 demonstrated that the 
majority of AEs were mild (CTCAE Grade 1 or 2), with toxicities manageable by standard 
medical therapy. One patient has discontinued MGA271 for a drug related toxicity that was 
considered to be a drug-related SAE. See Section 2.3.1 for a more detailed description of the 
safety profile from Study CP-MGA271-01. 
Preliminary population PK modeling of data from 78 adult subjects from 
Study CP-MGA271-01 and 9 pediatric subjects from Study CP-MGA271-04 who 
received weekly MGA271 IV infusion of 0.15, 0.5, 1.5, 5, 10, or 15 mg/kg delivered 
over a period of 120 minutes indicated that MGA271 PK in adult and pediatric patients 
can be well described by the quasi-steady-state approximation of the 2-compartment 
target-mediated drug disposition model. The model parameters were in agreement with the 
values expected for the monoclonal antibodies. Due to the small sample size of the study, no 
covariates except of weight were included in the final model. For a typical 75 kg subject, 
clearance, central volume, inter-compartment clearance, and peripheral volume were 
estimated as CL=0.157 L/day, V1=3.33 L, Q=0.779 L/day, and V2= 3.33 L, respectively. The 
terminal half-life and distribution half-life of the linear part of elimination (that is dominant 
at high concentrations) was estimated at t1/2term= 30.96 days and t1/2dist = 1.41 days, 
respectively. QSS constant KSS was estimated at KSS=566 ng/mL. Maximum elimination 
rate via the target mediated pathway (equal to KSYN=BASE*KDEG) was estimated at 
3.46 mg/L/day. 
Although the 15 mg/kg dose of MGA271 demonstrates a mild toxicity profile, and is now 
used as the dose in the CP-MGA271-01 monotherapy expansion cohorts, a 5-fold lower dose, 
3 mg/kg, will be used as the starting dose in the Dose Escalation Phase in the current study. 
Even though the proposed 3 mg/kg starting dose does not likely saturate the B7-H3 receptors, 
as suggested by the target-mediated drug disposition in the PK modeling, this 5-fold lower 
starting dose allows for adequate safety margin for initial testing of the combination. 
Beginning with Amendment 5, MGA271 will be dosed at 15 mg/kg every 3 weeks, Q3W. 
Based on population PK modeling and simulation of MGA271, at 15 mg/kg dose, the 
estimated average Cmin_SS was 787.6 µg/ml (276.8-1548.1 µg/ml) when the doses were 
administered weekly (QW) and 160.5 µg/ml (26.9-412.2 µg/ml) when the doses would be 
administered Q3W. As expected, the decrease in dosing frequency would decrease the 
average Cmin_SS in subjects; 
 
 
 
 
 
 
 
 
 
 
 
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 (see Section 2.3.1). 
2.6.1.3 
MGA012  
The dose for MGA012 will be administered as a flat-dose of 375 mg, Q3W. MGA012 is 
administered in Study INCMGA00012-101 as both a weight-based dose (ranging from 
1 mg/kg to 10 mg/kg) and at fixed doses of 500 mg and 750 mg. Treatment has been well 
tolerated over the entire dosing range and a maximum tolerated dose has not been reached 
(34). 
The monotherapy recommended Phase 2 dose of 500 mg Q4W is based on clinical data from 
the ongoing first-in-human monotherapy study (INCMGA00012-101; NCT03059823). This 
dose-escalation study of MGA012 was performed and evaluated 37 patients at the following 
doses: 1 mg/kg Q2W, 3 mg/kg Q2W, 3 mg/kg Q4W, 10 mg/kg/Q2W, and 10 mg/kg Q4W. 
While supra dose proportionality was observed for AUC and Cmax for the first dose from 
1 mg/kg to 10 mg/kg, linear PK was shown from 3 mg/kg to 10 mg/kg.  
A population PK (PPK) analysis was performed on patients in the INCMGA00012-101 study 
to characterize the effect of body weight on the PK of MGA012. The plasma concentrations 
of MGA012 can be adequately described by a 2-compartment model with first-order 
elimination. Higher clearance of MGA012 was estimated for the 1 mg/kg dose than for other 
dose groups. Body weight dependence of clearance was characterized by a power 
relationship with an exponent of 0.911.  
A simulation was conducted to investigate the use of weight-based dosing and flat dosing for 
MGA012, with the aim of targeting a steady-state trough concentration of approximately 
21 mcg/mL, the median trough concentration for pembrolizumab (22) providing flexibility 
for combinations with different schedules. The median MGA012 exposure and its 
distribution around the median at 500 mg Q4W were similar to 7 mg/kg Q4W in the 
simulated population, which justified clinical exploration in an expansion cohort of the study. 
The median steady-state concentration at 500 mg Q4W is 24.8 mcg/mL, and 58% of 
participants have trough concentrations greater than the target concentration. The median 
steady-state concentration at 350 mg every 3 weeks (Q3W) is 27.6 mcg/mL. Though not 
simulated, the 375 mg Q3W dose was selected to maintain dose-linearity in clinical trials.  
Pharmacokinetic data were obtained from 15 patients who received MGA012 at 500 mg 
Q4W in the Cohort Expansion Phase of Study INCMGA00012-101. The observed AUC0-∞ 
for 500 mg Q4W is close to the steady-state AUC0-t based on the PPK analysis of weight 
based dosing, as is the estimated clearance. The estimated t1/2 (333 hours) is slightly shorter 
than that from the previous estimate of 409 hours. The mean trough plasma concentration on 
Cycle 2 was 17.1 mcg/mL, and the mean projected minimum plasma concentration at steady 
state is 23.1 mcg/mL (which meets or slightly exceeds the targeted concentration based on 
pembrolizumab data) with mean accumulation index of 1.50. Overall, the 500 mg Q4W dose 
had very similar PK properties to the 3 mg/kg Q2W dosing and has approximately a 77% 
probability for steady-state trough plasma concentration ≥ 10 mcg/mL, which is associated 
with maximum target engagement and greatest probability of efficacy. Based on these 
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observations, 500 mg Q4W was selected as the recommended Phase 2 dose for monotherapy. 
Fifteen patients are enrolled in an additional expansion cohort of Study INCMGA00012-101 
that will test the 375 mg Q3W regimen. Preliminary safety experience with this dosing 
regimen is also favorable (Incyte Corporation, data on file). Based on these observations, a 
flat dose regimen of MGA012 375 mg Q3W is considered an acceptable alternative where 
flexibility in dosing is needed.  
The Q3W recommended dose of MGA012 is 375 mg, based on a demonstration of clinical 
safety and favorable pharmacology in the dose-finding 0012-101 study (37, 14,15) 
2.6.2 
Expansion Phase  
The doses used in the Expansion Phase will be the MTD or MAD for the combination of 
MGA271 and pembrolizumab determined during the Dose Escalation Phase. 
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3 
STUDY PURPOSE AND OBJECTIVES  
This study is an open-label, dose escalation, Phase 1 study designed to characterize the 
safety, tolerability, PK, pharmacodynamics (PD), immunogenicity, and preliminary antitumor 
activity of IV MGA271 administered IV weekly in combination with 2 mg/kg 
pembrolizumab administered IV every 3 weeks in patients with unresectable locally 
advanced or metastatic melanoma, NSCLC, SCCHN, urothelial cancer, and other cancers. 
With Amendment 5, a new cohort (Cohort 4) will be initiated to explore the safety, 
tolerability, PK, PD, and immunogenicity of MGA271 + MGA012, both administered Q3W, 
in patients with unresectable locally advanced or metastatic melanoma, NSCLC, SCCHN, 
urothelial cancer, and other cancers, as stipulated in Section 5.1, Inclusion Criteria. 
3.1 
Primary Objective  
The primary objectives of this study are:  
• To characterize the safety, tolerability, DLT, and MTD, or MAD (if no MTD is 
defined) of MGA271 when administered IV weekly in combination with 2 mg/kg 
pembrolizumab administered IV every 3 weeks (Q3W) to patients with 
unresectable locally advanced or metastatic melanoma, SCCHN, NSCLC, 
urothelial cancer, and other cancers.  
• To characterize the safety, tolerability, and DLT of 15 mg/kg MGA271 when 
administered IV Q3W in combination with a flat-dose of 375 mg of MGA012 
(anti-PD-1 antibody) administered IV Q3W to patients with unresectable locally 
advanced or metastatic melanoma, SCCHN, NSCLC, urothelial cancer, and other 
cancers as stipulated in inclusion criteria.  
 
3.2 
Secondary Objective(s)  
Secondary objectives of this study are: 
• To characterize the PK and immunogenicity of MGA271 administered IV weekly 
in combination with IV pembrolizumab Q3W, and of MGA271 in combination 
with MGA012, both administered IV every 3 weeks.  
• To characterize the PD activity of MGA271 when administered IV weekly in 
combination with pembrolizumab Q3W, and of MGA271 in combination with 
MGA012, both administered IV Q3W.  
• To investigate the preliminary antitumor activity of MGA271 when administered 
IV weekly in combination with IV pembrolizumab Q3W, and of MGA271 in 
combination with MGA012, both administered IV Q3W using both conventional 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (Appendix 5) and 
immune-related response criteria (irRC) (i.e., irRECIST as defined in Appendix 
6).  
 
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3.3 
Exploratory Objectives  
• To explore the relationships between PK, PD, patient safety and antitumor activity 
of MGA271 when administered in combination with pembrolizumab.  
• To investigate the immune-regulatory activity of MGA271 in combination with 
pembrolizumab and of MGA271 in combination with MGA012 in vivo, including 
various measures of T cell activation in peripheral blood and/or tumor biopsy 
specimens. 
• To determine the relationships between membranous expression of B7-H3 and 
PD-L1 on tumor cells, immune cell infiltration within biopsy specimens 
(including but not limited to CD4+ and CD8+ T cells), B7-H3 and PD-L1 
expression on the immune cell infiltrate, and clinical response via IHC staining of 
optional paired pre- and on-treatment tumor biopsy specimens. 
 
 
 
 
 
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4 
TRIAL DESIGN  
4.1 
Overall Study Design and Plan  
4.1.1 
General Study Design  
This study is a Phase 1, open-label, dose escalation and cohort expansion study designed to 
characterize the safety, tolerability, PK, PD, immunogenicity, and preliminary antitumor 
activity of MGA271 administered IV weekly in combination with pembrolizumab 
administered IV every 3 weeks (Q3W). Beginning with Amendment 5, this study will 
also characterize the safety and tolerability of MGA271 in combination with MGA012 (anti–
PD-1 antibody), both administered by IV, Q3W, through the addition of a new cohort, 
Cohort 4. 
The study consists of a Dose Escalation Phase to determine the MTD or MAD (if no MTD 
is determined) of MGA271 administered in combination with 2 mg/kg pembrolizumab, 
followed by a Cohort Expansion Phase to further define the safety and initial efficacy of the 
combination with the MGA271 dose established in the first phase. The study treatment 
schema is presented in Figure 2. 
Figure 2 
MGA271 + Pembrolizumab Treatment Schema  
 
a 
Patients may receive up to 5 subsequent 9-week treatment cycles of MGA271 + pembrolizumab depending 
on response to study treatments 
*All patients will enter an Efficacy Follow-up Period after receipt of the last dose of study treatment to be 
followed for up to 24 weeks for survival. 
 
MGA271 will be administered as an IV infusion over 120 minutes on a once-weekly 
schedule. Pembrolizumab will be administered at 2 mg/kg as an IV infusion over 30 minutes 
every 3 weeks. On the days that both agents are administered, pembrolizumab will be 
administered first, followed by MGA271. 
For both the Dose Escalation and Cohort Expansion phases, patients’ first tumor assessment 
will be obtained on Cycle 1 Study Day 42 of the Initial Tumor Assessment Cycle. 
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Patients who remain clinically stable and do not experience unacceptable toxicity that 
necessitates permanent discontinuation of the study drugs, at the completion of the Initial (6-
week) Tumor Assessment Cycle will be eligible to receive additional treatment with 
pembrolizumab and MGA271. Assuming that the patient remains clinically stable, maintains 
a response status of SD or better, and does not experience unacceptable toxicity that 
necessitates permanent discontinuation of the study drugs, patients may receive up to 
5 additional 9-week treatment cycles during Subsequent Tumor Assessment Cycles, for a 
maximum total of 51 doses of MGA271 and 17 doses of pembrolizumab. 
Beginning with Amendment 5, in Cohort 4: 15 mg/kg MGA271 will be administered as an 
IV infusion over 120 minutes Q3W in combination with 375 mg MGA012 administered as 
an IV infusion over 60 to 75 minutes Q3W. On dosing days, MGA012 will be administered 
first, followed by MGA271. The study treatment schema is presented in Figure 3. 
Figure 3 
MGA271 + MGA012 Treatment Schema: Cohort 4  
 
 
 
 
 
 
 
MGA271 Administration+ MGA012 Administration     Tumor Evaluation 
a 
Patients may receive up to 5 subsequent 9-week treatment cycles of MGA271 + MGA012 depending 
on response to study treatments 
      All patients will enter an Efficacy Follow-up Period after receipt of the last dose of study treatment to 
be followed for up to 24 weeks for survival. 
 
Patients who remain clinically stable and do not experience unacceptable toxicity that 
necessitates permanent discontinuation of the study drugs, at the completion of the Initial 
(6-week) Tumor Assessment Cycle, will be eligible to receive additional treatment with 
MGA271+MGA012. Assuming that the patient remains clinically stable, maintains a 
response status of SD or better, and does not experience unacceptable toxicity that 
necessitates permanent discontinuation of the study drugs, patients may receive up to 
5 additional 9-week treatment cycles during Subsequent Tumor Assessment Cycles, for a 
maximum total of 17 doses of MGA271 and 17 doses of MGA012. 
Initial Tumor Assessment 
Cycle (6 weeks) 
Subsequent Tumor   
Assessment Cycle (9 weeks) 
Subsequent 9-week Tumor 
Assessment Cycle (9 weeks) a 
Cycle 1 
Cycle 2 
Cycle X 
Day 
Week 
1
22 
1
4 
42/1 
1 
22 
4 
43 
7 
63/1 
1 
1
1
22 
4 
43 
7 
63/1 
1 
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All tumor assessments performed following the Initial Tumor Assessment Cycle will occur 
on Study Day 63 of each Subsequent Tumor Assessment Cycle thereafter. Following the last 
dose of study drug, all patients will be followed for survival during a 6-month (24-week) 
Efficacy Follow-up Period. Patients who discontinue study treatment for a reason other than 
progressive disease may be followed for efficacy and survival beyond the 6-month (24-week) 
period until 1 of the following occurs: the patient progresses, withdraws consent for follow 
up, or initiates other anti-cancer therapy, or the overall trial is closed. 
4.1.2 
Dose Escalation Phase  
The goal of the Dose Escalation Phase is to initially characterize the safety and tolerability 
of MGA271 and pembrolizumab administered in combination, and more specifically to 
describe the DLTs for each dose level studied and to define the MTD or MAD (if no MTD is 
defined) based on the frequency of occurrence of DLTs in each cohort. Patients with 
mesothelioma, urothelial cancer, NSCLC, SCCHN, ccRCC, ovarian cancer, melanoma, 
thyroid cancer, TNBC, pancreatic cancer, colon cancer, soft tissue sarcoma, or prostate 
cancer will be enrolled in the Dose Escalation Phase. 
For the purposes of guiding decisions regarding dose escalation, the DLT Evaluation Period 
is defined as the time following administration of the first dose of pembrolizumab to the day 
of the third planned administration of pembrolizumab (i.e., Cycle 1/Initial Tumor Assessment 
Cycle). 
Dose escalation will follow a conventional 3+3+3 design: MGA271 will be evaluated in 
sequential escalating doses ranging from 3 mg/kg to 15 mg/kg in combination with 2 mg/kg 
pembrolizumab in cohorts of 3 to 9 patients each. Dose levels of MGA271 to be evaluated 
include 3 mg/kg (starting dose), 10 mg/kg, and 15 mg/kg. If it is determined that the MTD is 
exceeded in the first dose cohort, a dose de-escalation cohort to evaluate a lower dose of 
MGA271 (1 mg/kg) in combination with 2 mg/kg pembrolizumab will be enrolled. 
Table 3 
MGA271 Dose Escalation Cohorts  
Cohort 
MGA271 Dose 
Pembrolizumab Dose 
MGA012 
Cohort 1a 
1 mg/kg 
2 mg/kg 
N/A 
Cohort 1 
3 mg/kg (starting dose) 
2 mg/kg 
N/A 
Cohort 2 
10 mg/kg 
2 mg/kg 
N/A 
Cohort 3 
15 mg/kg 
2 mg/kg 
N/A 
Cohort 4 
15 mg/kg 
N/A 
375 mg  
a 
To be evaluated only if the starting dose is determined to exceed the MTD. 
 
An intermediate dose of MGA271 may be explored selectively during the dose escalation 
portion of the study, based on review of the cumulative safety, efficacy, and/or PK data on the 
respective arms and based upon agreement between the investigators and the Sponsor as 
follows: 
• If Cohort 2 exceeds the MTD the following dose level may be evaluated: 
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o Cohort 1a: 7 mg/kg MGA271 + 2 mg/kg pembrolizumab (n=3-9 patients) 
• If Cohort 3 exceeds the MTD the following dose levels may be evaluated: 
o Cohort 2a: 12 mg/kg MGA271 + 2 mg/kg pembrolizumab (n=3-9 patients) 
 
Any escalation cohort, not exceeding the MTD, can be expanded to a maximum of 
15 patients for further evaluation of safety and efficacy. 
The MTD for MGA271 will be defined as the dose level at which < 33% of patients 
experience a drug-related DLT during the DLT evaluation period. If no MTD is defined for 
the combination of MGA271 and pembrolizumab after escalation to the maximum protocol-
specified dose, that dose level will be designated as the MAD. Dose limiting toxicities are 
defined in Section 4.2 and Dose Escalation Rules described in Section 4.3. 
Beginning with Amendment 5, a new cohort, Cohort 4, will be added to explore safety and 
tolerability of MGA271+MGA012 administered in combination. Since MTD was not 
reached for the MGA271+pembrolizumab cohorts, 15 mg/kg was determined as the 
maximum administered dose (MAD) for MGA271. Patients will receive 15 mg/kg MGA271 
(MAD) in combination with a flat-dose of 375 mg MGA012, with both study drugs 
administered on a Q3W schedule (see Table 3). 
For the purposes of guiding decisions regarding dose escalation, the DLT Evaluation Period 
is defined as the time following administration of the first dose of MGA271 plus MGA012 to 
the day of the third planned administration of MGA012 (i.e., Cycle 1 /Initial Tumor 
Assessment Cycle).  
Enrollment in Cohort 4 will follow a conventional 3+3+3 design with decision rules as 
outlined in Section 4.3. If the 15 mg/kg MGA271 + 375 mg MGA012 combination dose is 
deemed tolerable, additional patients may be added for up to a total of 15 dose evaluable 
patients in the cohort. No higher doses of the combination are planned. If the 15 mg/kg 
MGA271 +375 mg MGA012 combination dose level is found to exceed the MTD, 
de-escalation to 10 mg/kg MGA271+375 mg MGA012 may be explored and if that dose 
level were to exceed the MTD, a further de-escalation to 3 mg/kg MGA271+375 mg 
MGA012 may be explored following the same conventional 3+3+3 design. Any of these dose 
levels, not exceeding the MTD, can be expanded up to a maximum of 15 patients for further 
evaluation of safety and efficacy.  
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4.1.3 
Cohort Expansion Phase  
During the Cohort Expansion Phase, additional cohorts of patients with unresectable, locally 
advanced or metastatic melanoma (up to n=16), 2 cohorts of NSCLC (up to n=20 in each 
cohort), 2 cohorts of SCCHN (up to n=20 in each cohort) or urothelial cancer (up to n=16) 
will be enrolled to receive MGA271 in combination with pembrolizumab at the MTD (or 
MAD) established from the Dose Escalation Phase of the study. The goals for this portion of 
the study will be to: 
1. Further characterize the safety MGA271 in combination with pembrolizumab at 
the MTD (or MAD); 
2. Further evaluate the PK, PD, and immunogenicity of MGA271 in combination 
with pembrolizumab; and  
3. Provide a preliminary assessment of the antitumor activity of MGA271 in 
combination with pembrolizumab in patients with advanced melanoma, NSCLC, 
SCCHN, or urothelial cancer. 
 
4.1.4 
Efficacy Follow-up Period  
The Efficacy Follow-up Period consists of the 6-month (24-week) period following the final 
dose of study drug (pembrolizumab or MGA271 or MGA012, whichever is last) where 
patients will be followed for survival via telephone or other electronic contact at 12-week 
intervals from the start of the period. Patients who discontinue study treatment for a reason 
other than progressive disease may be followed for efficacy and survival until 1 of the 
following occurs: the patient progresses, withdraws consent for follow up, or initiates other 
anti-cancer therapy, or the overall trial is closed.  
4.2 
Dose Limiting Toxicity  
For the purposes of safety management and defining DLTs, the combination of MGA271 and 
pembrolizumab, or the combination of MGA271+MGA012 will be treated as one entity. If a 
DLT is considered related to study drug, no distinction will be made as to which agent is the 
causative agent and administration of both agents will be stopped. One exception to this rule 
will be in the circumstance in which a DLT occurs during or immediately following the first 
pembrolizumab infusion or MGA012 infusion and before the first MGA271 administration. 
In this case, the toxicity will be attributed to pembrolizumab or MGA012 alone and will not 
count as a DLT of the combination of study drugs; in this case the patient will be replaced by 
another patient in the dose cohort. 
In general, for patients who experience an AE 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 drugs. Criteria for 
subsequent continuation of therapy are outlined below. No dose reductions of either 
MGA271 or pembrolizumab or MGA012 are allowed during the study. 
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Dose limiting toxicities will be based on treatment-emergent drug-related AEs (or laboratory 
abnormalities) occurring during the DLT Evaluation Period (defined as the time following 
administration of the first dose of pembrolizumab to the day of the third planned 
administration of pembrolizumab [i.e., Cycle 1/Initial Tumor Assessment Cycle.]) The 
severity of AEs will be graded according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. 
Dose limiting toxicities are defined separately for hematologic and non-hematologic events 
as outlined below. 
4.2.1 
Hematologic Dose Limiting Toxicity  
Hematologic DLT will be defined as follows: 
• Grade 4 neutropenia lasting > 5 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 
 
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 will be defined as any ≥ Grade 3 non-hematologic event with the 
following exceptions: 
• Grade 3 electrolyte abnormality that lasts less than 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 amylase and/or lipase elevation that is not associated with either clinical 
or radiographic evidence suggestive of pancreatitis 
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• Grade 3 gastrointestinal AEs of diarrhea, constipation, abdominal pain, cramping, 
dyspepsia or dysphagia that resolves to ≤ Grade 1 within 14 days with medical 
therapy 
• Grade 3 fatigue that lasts < 7 days 
• Grade 3 infusion-related reaction or cytokine release syndrome that lasts < 12 
hours and responds to medical intervention. 
• Grade 3 or 4 endocrinopathy that is adequately controlled with hormone 
supplementation 
• Grade 3 skin toxicity that resolves to ≤ Grade 2 within 14 days of initiation of oral 
corticosteroids 
• Grade 3 inflammatory reaction (e.g., with associated pain, swelling) attributed to 
a local antitumor response (e.g., inflammatory reaction at sites of metastatic 
disease, lymph nodes, etc.) that resolves to ≤ Grade 2 within 7 days. 
 
Note: The following Grade 2 or greater non-hematologic AE may also be considered as DLT: 
• Grade 2 AEs that are prolonged inordinately, based upon the medical judgment of 
the Investigator, and/or lead to permanent discontinuation of MGA271 due to 
patient intolerance. 
• Any hepatic laboratory abnormalities meeting all three Hy’s law criteria 
(described within Section 4.2.3 below). 
• Any Grade 2 eye pain or reduction in visual acuity that does not respond to 
topical therapy and does not improve to Grade 1 within 14 days of the initiation of 
topical therapy, or that requires systemic treatment. 
 
4.2.3 
Hepatic Non-Hematologic Dose Limiting Toxicity  
• AST or ALT > 5 × ULN or total bilirubin > 3 × ULN 
o For patients with liver metastasis who begin treatment with Grade 2 AST 
or ALT, if the AST or ALT increases by ≥50%, relative to baseline and 
lasts for at least 1 week. 
o Please see Section 6.5.2.2 for further management guidelines. 
• Any event meeting the criteria for Hy’s law as follows (all three features): 
o Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT)  
> 3 × ULN. 
o Concurrent elevation of total bilirubin > 2 × ULN without initial evidence 
of cholestasis. 
o No alternative etiology can be identified. 
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4.3 
Dose Escalation Rules  
The Dose Escalation Phase of this trial will proceed using a conventional 3 + 3 + 3 approach, 
and will begin with enrollment of 3 patients at the initial dose level of 2 mg/kg of 
pembrolizumab administered as an IV infusion once every three weeks and 3 mg/kg of 
MGA271 administered as an IV infusion once weekly. Successive dose escalation cohorts 
will be enrolled as outlined below. The MTD or MAD will be determined based on the 
assessment of DLTs during the DLT evaluation period. Cohort 4 will begin enrollment of 
3 patients at 15 mg/kg MGA271 and 375 mg MGA012; with no higher dose escalation 
cohorts to be explored.  
Patients who do not experience a DLT but are not evaluable for safety for the full DLT 
evaluation period will be replaced in the same dose-level cohort. 
• If 0 of the first 3 patients treated at a given dose level experience a drug-related 
DLT during the DLT evaluation period, the dose will be escalated and 3 patients 
will be enrolled and treated at the next higher dose level (up to the planned 
highest dose level of 15 mg/kg of MGA271). 
• If 1 of the first 3 patients treated at a given dose level experiences a drug-related 
DLT, then 3 additional patients will be enrolled at that dose level (thus making a 
total of 6 patients in this cohort) to further assess the safety of the combination of 
MGA271 with pembrolizumab. 
• If ≥ 2 of these 3 additional patients (i.e., ≥ 3 of the 6 patients enrolled in the 
cohort) experience a DLT, it will be concluded that the MTD has been exceeded, 
and 3 patients will be enrolled and treated at the next lower dose level. If 1 of 
these 3 additional patients experiences a drug-related DLT, then another 3 
additional patients (for a total of 9 patients in the cohort, 3 + 3 + 3) will be 
enrolled and treated at that dose level to further characterize the safety of the 
combination. If 0 of the 3 additional patients experiences a DLT, then the dose 
will be escalated, and 3 patients will be enrolled at the next higher dose level. 
• If ≥ 2 patients out of the first 3 patients treated at a given dose level, or ≥ 3 of 
6 patients treated at a given dose level, or ≥ 3 out of 9 patients treated at a given 
dose level experience a drug-related DLT, then it will be concluded that the MTD 
for MGA271 in combination with pembrolizumab or in combination with 
MGA012 has been exceeded at that dose level, and all subsequent patients will be 
treated at the next lower dose level. 
• If 2 or more patients out of the first 6 patients 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 MGA271 / pembrolizumab or 
MGA271/MGA012 has been exceeded and all subsequent patients will be treated 
at the next lower dose level. 
• Note that in the circumstance in which a DLT occurs during or immediately 
following the first pembrolizumab or first MGA012 infusion and before the first 
MGA271 administration, the toxicity will be attributed to pembrolizumab or 
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MGA012 alone and will not count as a DLT of the combination of study drugs at 
the dose level under study. In this case the patient will be replaced by another 
patient in the dose cohort. 
 
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%. 
Dose escalation to the next dose level is permitted only after the patients enrolled in the 
current dose cohort have competed the DLT evaluation period and all safety data have been 
reviewed by the Sponsor Medical Monitor and the Investigators participating in the study. 
For patients being treated at a dose level subsequently determined to exceed the MTD, the 
dose of MGA271 will be immediately reduced to the next lower MGA271 dose level. 
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, PD, 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. 
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 patients for further evaluation of safety and efficacy. 
For the MGA271 + MGA012(Cohort 4), the cohort may be expanded up to a total of 15 
patients. 
4.4 
Rules for Continuation of Study Therapy  
Patients who tolerate treatment with pembrolizumab and MGA271, or who tolerate treatment 
with MGA271+MGA012, may continue to receive additional treatment with the study drugs 
as specified in the protocol (see Section 4.1.1), until any one of the following conditions are 
met: 
• After documentation of a confirmed complete response (cCR), MGA271 and 
pembrolizumab, or MGA271+MGA012, are continued for one more Tumor 
Assessment Cycle 
• Patient meets criteria for immune-related disease progression (irPD) (Appendix 
6) 
• Occurrence of drug-related DLT as defined for the DLT Evaluation Period 
• The Sponsor, Investigator, or Regulatory Agency terminates the study 
• Withdrawal of patient due to an AE or SAE 
• Withdrawal of patient consent 
• Completion of protocol defined therapy 
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• Investigator discretion 
• Pregnancy 
• Death 
 
Note: For individual patients who meet these criteria, but are otherwise considered to be 
experiencing clinical benefit by the investigator, consideration may be given to extension of 
therapy on a case-by-case basis in consultation with the Sponsor. If a patient completes 6 
cycles of therapy and is experiencing clinical benefit as determined by the investigator, 
consideration may be given to extension of therapy for an unrestricted number of additional 
9-week treatment cycles of MGA271 and pembrolizumab or MGA271+MGA012 on a case-
by-case basis in consultation with the Sponsor. Assessments and procedures for Cycles 7 and 
beyond will be done according to those for Cycle 6 (see Appendix 1). Such unrestricted 
treatment may continue until the patient either 1) meets the criteria for permanent 
discontinuation (see Section 5.3.1), or 2) a rollover protocol becomes available. 
4.5 
Guidelines for Dose Modification  
No intra-patient dose escalation will be allowed. No dose reductions will be allowed with 
exception of 1) reduction of infusion rate during re-challenge for patients experiencing an 
infusion reaction (Section 6.5.1) or 2) reduction of dose in patients receiving MGA271 at a 
dose that is subsequently determined to exceed the MTD (Section 4.3). For patients who 
experience DLT that is considered related to either study drug, no further pembrolizumab or 
MGA271 or MGA012 will be administered. 
4.5.1 
Dose Delays  
Patients who experience toxicity that is potentially dose-limiting should have study drug held 
pending assessment, management and resolution of the toxicity. For patients in whom the 
toxicity is assessed to be unrelated to study drug or for whom the toxicity does not meet the 
criteria for DLT, therapy may be re-instituted at the same dose and schedule that was 
administered prior to the event, presuming the toxicity has resolved to ≤ Grade 1 in severity. 
Reinstitution of therapy shall be conducted as follows: 
For patients in whom the toxicity is assessed to be related to study drug, dose interruptions of 
up to 14 days are allowed for drug related toxicity. This may include up to one missed dose 
of pembrolizumab and up to 2 consecutively missed doses of MGA271. For the 
MGA271+MGA012 combination, Cohort 4, this would allow for a maximum of one dose 
each of MGA271 and MGA012. The procedures at the original scheduled missed visit should 
be performed as soon as possible with treatment reinstituted as if no delay had occurred, 
picking up at the day where the interruption occurred, and patients receive the full 
complement of pembrolizumab and MGA271 or MGA271+MGA012 or as outlined in The 
Time and Event Schedule (Appendix 1). Patients with infusion delays > 14 days due to drug 
related toxicity will discontinue both study drugs, complete the End of Treatment visit, and 
then enter the Efficacy Follow-up Period. 
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4.6 
Rationale for Study Design 
As described in Sections 2.4 and 2.5, there is a strong rationale to evaluate the antitumor 
activity of the MGA271 and pembrolizumab/MGA012 combination in advanced melanoma, 
NSCLC, SCCHN, and urothelial cancer. The study is designed to determine the MTD or 
MAD of the combination in the Dose Escalation Phase of the study in multiple tumor types. 
In Cohort 4, the combination of MGA271+MGA012 will be explored in patients with the 
same tumor types explored in the MGA271+pembrolizumab dose escalation cohorts, i.e., 
mesothelioma, urothelial cancer, NSCLC, SCCHN, ccRCC, ovarian cancer, melanoma, 
thyroid cancer, TNBC, pancreatic cancer, colon cancer, soft tissue sarcoma, or prostate 
cancer; justification provided in Section 2.5. The DLT Evaluation period occurs within the 
first Tumor Assessment Cycle; patients who do not experience a DLT or other unacceptable 
toxicity will then be allowed to continue receiving MGA271 and pembrolizumab or 
MGA271+MGA012 for up to 5 additional 9-week Tumor Assessment Cycles. Once an MAD 
or MTD is defined, patients will be enrolled into an Expansion Phase.
4.7 
Study Duration 
MGA271 will be administered on a once weekly schedule for up to 51 doses and 
pembrolizumab administered once every 3 weeks for a total of up to 17 doses (i.e., up to 6 
cycles). Beginning with Amendment 5, MGA271 will be administered on a Q3W schedule 
for up to 17 doses of MGA271 and MGA012 administered once every 3 weeks for a total of 
up to 17 doses (i.e., up to 6 cycles). As per Rules for Continuation of Study Therapy (Section 
4.4), an unrestricted number of additional cycles may be permitted on a case-by-case basis in 
consultation with the Sponsor.
It is expected that enrollment of the dose escalation portion of the study will occur over 
approximately 12 months, and that enrollment of the cohort expansion portion of the study 
will take approximately 9 - 12 months.
The total time for conduct of the trial is expected to be approximately 72 months (which 
includes 24 weeks of efficacy follow-up). These estimates of the timing for study conduct
may vary from that observed in the actual conduct of the trial.
4.7.1 
Patient Accrual 
The number of patients enrolled in the Dose Escalation Phase cannot be precisely determined 
in advance, and could range from 9 to 45 or more patients depending on results in the course 
of the trial and the number of MG271 doses explored. This patient number does not take into 
account patient replacement for non-evaluable patients or the possibility of expanding an 
individual escalation cohort to 15 patients to allow for further evaluation of safety, PK and 
antitumor activity of the combination of MGA271 and pembrolizumab at the dose level in 
that cohort.
The Cohort Expansion Phase of the trial will enroll 112 patients, with a target of 16 to 
20 patients into each of 6 cohorts: two cohorts of patients with NSCLC (up to 20 patients in 
each cohort), two cohorts of patients with SCCHN (up to 20 patients in each cohort), one 
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cohort of patients with melanoma (up to 16 patients), and one cohort of patients with 
urothelial cancer (up to 16 patients). This number of patients does not take into account 
patients who may be replaced. During the Expansion Portion of the study, patients 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, replacement patients 
may be enrolled in the same dose level as required to complete the cohort.  
For planning, the maximum number of patients to be enrolled on this trial is anticipated to be 
approximately 157 patients. 
4.7.2 
Definition of End of Trial  
The end of study will occur after the last patient has met off-study criteria and the data 
collection process is complete (time of study database lock). 
 
 
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5 
SELECTION AND WITHDRAWAL OF PATIENTS  
Inclusion and exclusion criteria are designed to properly define the target population for 
study participation and to identify those patients who may not be appropriate candidates for 
study participation based on specific co-morbidities or other clinicopathologic features of 
their disease. Patients must meet all the inclusion criteria; patients will be excluded from the 
study if they meet any exclusion criteria. No exceptions to these criteria will be granted by 
the Sponsor. 
The patient population to be enrolled in this study will consist of adult patients with 
histologically–proven, unresectable locally advanced or metastatic melanoma, NSCLC, 
SCCHN tumors, urothelial cancer, or other cancers. 
5.1 
Inclusion Criteria  
General: 
1. Ability to provide informed consent and documentation of informed consent prior 
to initiation of any study-related tests or procedures that are not part of standard-
of-care for the patient’s disease. Patients must also be willing and able to comply 
with study procedures, including the acquisition of specified research specimens. 
2. Age ≥ 18 years old. 
3. Dose Escalation Phase including Cohort 4: Histologically-proven unresectable 
locally advanced or metastatic: 
a. Mesothelioma that has progressed during or following at least 1 
and up to 3 prior systemic treatments for unresectable locally 
advanced or metastatic disease. The prior systemic chemotherapy 
must have included a pemetrexed (anti-folate)-based regimen in 
combination with platinum agent. For patients in whom 
pemetrexed was contraindicated or not tolerated or not an 
approved therapy (e.g., peritoneal mesothelioma), prior therapy 
with a first-line platinum-based regimen is required. 
b. Urothelial cancer arising in the bladder, renal pelvis, ureter, or 
urethra that has progressed during or following at least 1 and up to 
5 prior systemic treatments for unresectable locally advanced or 
metastatic disease (includes anti-PD-L1, anti-PD-1, but excludes 
other experimental therapies). Patients must have received at least 
one platinum-containing regimen (e.g., gemcitabine/cisplatin [GC], 
dose-dense methotrexate/vinblastine/doxorubicin/cisplatin 
[DDMVAC], or carboplatinum/gemcitabine). No more than 5 prior 
systemic regimens allowed. 
c. Thyroid cancer that has progressed during or following at least 1 
and up to 5 prior chemotherapy regimen(s). Prior therapy excludes 
experimental therapies given in Phase 1 trials. 
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d. Pancreatic cancer that has progressed during or following at least 1 
and up to 3 prior chemotherapy regimens. Prior therapy excludes 
experimental therapies given in Phase 1 trials. 
e. Ovarian cancer that has progressed during or following at least 2 
and up to 4 prior therapeutic regimens (e.g., 2 prior platinum 
containing regimens or if platinum resistant, a liposomal 
doxorubicin or topotecan containing regimen). Prior therapy 
excludes experimental therapies given in Phase 1 trials. 
f. Colon cancer that has progressed during or following at least 2 and 
up to 4 prior therapeutic regimens (e.g., fluoropyrimidine and/or 
irinotecan and/or oxaliplatin and/or anti-EGFR antibody containing 
regimens). Prior therapy excludes experimental therapies given in 
Phase 1 trials. 
g. Prostate cancer that has progressed during or following at least 1 
and up to 5 prior therapeutic regimens (e.g., abiraterone, 
enzalutamide, docetaxel). Prior therapy excludes experimental 
therapies given in Phase 1 trials. 
h. Soft tissue sarcoma that has progressed during or following at least 
1 and up to 5 prior therapeutic regimens. Prior therapy excludes 
experimental therapies given in Phase 1 trials. 
i. TNBC that has progressed during or following at least 1 and up to 
5 prior therapeutic regimens. Prior therapy excludes experimental 
therapies given in Phase 1 trials. 
j. ccRCC that has progressed during or following at least 1 and up to 
5 prior therapeutic regimens. Prior therapy excludes experimental 
therapies given in Phase 1 trials. 
k. Melanoma that has progressed during or following 1 or up to 5 
prior systemic treatments for unresectable locally advanced or 
metastatic disease, with no more than 5 prior systemic regimens 
(excludes experimental therapies) allowed. Patients who are 
intolerant of, or have refused treatment with standard cancer 
therapy, will be allowed to enroll. 
l. SCCHN that has progressed during or following 1 or up to 5 prior 
systemic treatments for metastatic or recurrent disease deemed to 
be incurable by the investigator (patients who refuse radical 
resection for recurrent disease are eligible) with no more than 5 
prior systemic regimens (excludes experimental therapies) 
allowed. Patients who are intolerant of, or have refused treatment 
with standard cancer therapy, will be allowed to enroll. Patients 
with upper esophageal or salivary gland tumors will not be 
considered as SCCHN. 
m. NSCLC that has progressed during or following 1 or up to 5 prior 
systemic therapies for unresectable locally advanced or metastatic 
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disease. Patients who are intolerant of, or have refused treatment 
with standard cancer therapy, will be allowed to enroll. Patients 
must not have had more than 5 prior systemic regimens (excludes 
experimental therapies) for unresectable locally advanced or 
metastatic disease. 
i. 
For patients with squamous cell carcinoma, or 
adenocarcinoma without known activating mutation: the prior 
systemic therapy is at least one platinum analogue based 
therapy with or without a docetaxel or pemetrexed containing 
regimen. 
ii. 
For patients with adenocarcinoma having a previously known 
activating driver mutation such as an epidermal growth factor 
receptor (EGFR) mutation or anaplastic lymphoma kinase 
(ALK) fusion: the prior systemic therapy is at least one TKI 
directed against the driver mutation. 
iii. 
Maintenance therapy following first-line therapy will not be 
considered a separate regimen of therapy. 
iv. 
Prior neoadjuvant chemotherapy for operable disease, 
adjuvant chemotherapy for completely resected disease or 
definitive chemoradiation therapy given for locally advanced 
disease will not be considered a separate regimen of therapy. 
Cohort Expansion Phase: Histologically-proven unresectable locally advanced or metastatic: 
• Melanoma that has progressed on or after at least one anti-PD-L1 or anti-PD-1 
containing therapy. Patients in this cohort can have their PD-L1 tumor expression 
levels determined before or after enrollment. 
• SCCHN, consisting of metastatic or recurrent disease (patients who refuse radical 
resection for recurrent disease are eligible); evaluated in 2 distinct cohorts, of up 
to 20 patients each where patients have progressed during or following: 
SCCHN Cohort 1: a first line, platinum-based systemic therapy 
without receiving prior anti-PD-1 or anti-PD-L1 containing therapy or 
SCCHN Cohort 2: a first-line, platinum-based systemic therapy and an 
anti-PD-1 or anti-PD-L1 containing therapy. 
In each of the 2 cohorts, at least 10 of the enrolled patients will be human 
papilloma virus (HPV) positive (HPV positivity is determined as per local 
institutional standards, e.g., p16 detection by immunohistochemistry [IHC], or 
HPV in-situ hybridization [ISH]). Patients in both SCCHN cohorts can have their 
PD-L1 tumor expression levels determined before or after enrollment. 
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• NSCLC consisting of patients with unresectable locally advanced or metastatic 
disease that will be evaluated in 2 distinct cohorts of up to 20 patients each where 
patients have progressed during or following: 
o NSCLC Cohort 1: a first-line systemic therapy as outlined below (i-iv, 
based on tumor histology) without receiving prior anti-PD-1 or anti-PD-
L1 containing therapy. These patients must have PD-L1 tumor expression 
determined by IHC analysis at levels accepted by the Sponsor prior to 
enrollment (< 1% tumor positivity score [TPS]).  
o NSCLC Cohort 2: a first line systemic therapy as outlined below (i-iv, 
based on tumor histology) and an anti-PD-1 or anti-PD-L1 containing 
therapy. Patients in this cohort can have the PD-L1 tumor expression 
levels determined before or after enrollment. 
i. For patients with squamous cell carcinoma, or adenocarcinoma 
without known activating mutation: the prior systemic therapy is a 
platinum analogue based therapy with or without a docetaxel or 
pemetrexed containing regimen. 
ii. For patients with adenocarcinoma having a previously known 
activating driver mutation such as an epidermal growth factor receptor 
(EGFR) mutation or anaplastic lymphoma kinase (ALK) fusion: the 
prior systemic therapy is a TKI directed against the driver mutation. 
iii. Maintenance therapy following first-line therapy will not be 
considered a separate regimen of therapy. 
iv. Prior neoadjuvant chemotherapy for operable disease, adjuvant 
chemotherapy for completely resected disease or definitive 
chemoradiation therapy given for locally advanced disease will not be 
considered a separate regimen of therapy. 
• Urothelial cancer consisting of transitional cell or mixed 
transitional/nontransitional (predominantly transitional) cell cancer of the renal 
pelvis, ureter, bladder, or urethra, in a cohort of up to 16 patients. Patients must 
have received at least one platinum-containing regimen, either as neo-adjuvant, 
adjuvant, or for metastatic disease, and progressed on an anti-PD-L1 or anti-PD-1 
containing therapy. Patients in this cohort can have the PD-L1 tumor expression 
levels determined before or after enrollment. 
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
(Appendix 4). 
5. Life expectancy ≥ 12 weeks. 
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6. Measurable disease as per RECIST 1.1 criteria (Appendix 5) and documented by 
computed tomography (CT) and/or magnetic resonance imaging (MRI). Patients 
must have measurable disease to be enrolled on this study. Note: Lesions to be 
used as measurable disease for the purpose of response assessment must either a) 
not reside in a field that has been subjected to prior radiotherapy, b) have 
demonstrated clear evidence of radiographic progression since the completion of 
prior radiotherapy and prior to study enrollment. 
7. Prospective determination of B7-H3 expression is not required to define eligibility 
for this study; however, tumor expression of B7-H3 will still be evaluated for all 
patients enrolled on the study, so patients must have sufficient tissue/slides for 
B7-H3 testing identified in order to be eligible. Patients should have a FFPE 
tumor specimen or unstained slides identified for analysis, to enable 
determination of the expression of B7-H3 within tumor specimens using IHC 
staining. If an archived tumor specimen is not available, patients who undergo a 
fresh tumor biopsy (Section 7.11.4.3) can have B7-H3 expression evaluated from 
an FFPE sample obtained from the tumor biopsy. In this case, the biopsy should 
be obtained prior to initiating study therapy. In cases in which an archived sample 
and fresh tumor sample are both available, B7-H3 expression can be confirmed 
with either FFPE sample.    
8. All patients in the Expansion Phase will have the PD-L1 tumor expression levels 
assessed using an IHC method deemed acceptable by the Sponsor and based 
either on archival or new tissue biopsy samples, submitted as FFPE tissue 
samples.  
a. Note: Patients in the NSCLC cohort who have not received prior anti-PD-
1 or anti-PD-L1 therapy will need to have the PD-L1 IHC expression 
levels determined prior to enrollment to determine eligibility. All other 
patients can have PD-L1 tumor expressions determined prior to or after 
enrollment.  
9. Patients enrolling in the study without prior documented PD-L1 tumor expression 
levels (determined by a Sponsor-approved method) should have a formalin-fixed, 
paraffin-embedded tumor specimen or unstained slides identified and available for 
analysis, to assess PD-L1 tumor expression levels, determined by a method 
selected by the Sponsor.  
 
Laboratory Features: 
10. Acceptable laboratory parameters as follows: 
a. Platelet count  100 × 103/µL without transfusion within 28 days prior to 
the initiation of study drug. 
b. Absolute neutrophil count  1.5 × 103/ µL in the absence of any growth 
factor support within 28 days prior to the initiation of study drug. 
c. ALT/AST  3.0 × ULN; for patients with hepatic metastases, ALT and 
AST ≤ 5 × ULN. 
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d. Total bilirubin  1.5 × ULN, except patients with Gilbert’s syndrome, who 
may enroll if the conjugated bilirubin is within normal limits. 
e. Creatinine < 2 mg/dL, or a calculated or measured creatinine clearance 
> 50 mL/min. 
 
Reproductive Features: 
11. Female patients of childbearing potential (not surgically sterilized and between 
menarche and 1 year postmenopause) must have a negative urine pregnancy test 
performed within 72 hours prior to the initiation of study drug administration. 
Further, female patients of childbearing potential must agree to either remain 
abstinent or use acceptable contraceptive measures from the time of consent 
through 120 days after discontinuation of study drug administration. For female 
patients, two forms of contraception must be utilized and may include oral, 
transdermal, injectable or implantable contraceptives, intrauterine device (IUD), 
female condom, diaphragm with spermicide, cervical cap, use of a condom by the 
sexual partner or a sterile sexual partner. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal and postovulation methods) and withdrawal are not 
considered acceptable forms of contraception in this study. 
12. Male patients with partners of childbearing potential must use barrier 
contraception. In addition, male patients should also have their partners use 
another method of contraception from the time of consent through 120 days after 
discontinuation of study drug administration. 
13. Female patients must not be breast-feeding. 
Tumor Biopsy 
14. Patients in the Cohort Expansion Phase who have one lesion considered to be 
potentially amenable to biopsy have the option of providing consent for paired 
pre-treatment and on-treatment biopsy samples. Tumor lesions used for biopsy 
should not be lesions used as RECIST target lesions, unless there are no other 
lesions suitable for biopsy. If a RECIST target lesion is used for biopsy, the lesion 
must be ≥ 2 cm in longest diameter. Tumor biopsies should be obtained only from 
lesions that are felt to be accessible with acceptable clinical risk, in the judgment 
of the investigator. 
Previous Checkpoint Inhibitor Therapy 
15. Patients 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. 
This excludes patients who experienced the following immune checkpoint 
inhibitor-related AEs (i.e., the following AEs make the patient ineligible despite 
the AE resolving to ≤ Grade 1 or baseline): 
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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. 
 
5.2 
Exclusion Criteria  
1. Patients with symptomatic central nervous system (CNS) metastases must have 
been treated, be asymptomatic, and meet the following at the time of enrollment: 
a. No concurrent treatment for the CNS disease (e.g. surgery, radiation, 
corticosteroids ≥ 10 mg prednisone/day or equivalent). 
b. No progression of CNS metastases on MRI or CT for at least 14 days after 
last day of prior therapy for the CNS metastases. 
c. No concurrent leptomeningeal disease or cord compression. 
 
2. Patients with any history of known or suspected autoimmune disease with the 
specific exceptions of vitiligo, resolved childhood atopic dermatitis, psoriasis not 
requiring systemic treatment (within the past 2 years) and patients with a history 
of Grave’s disease that are now euthyroid clinically and by laboratory testing. 
3. History of prior allogeneic bone marrow, stem-cell or solid organ transplantation. 
4. Treatment with any systemic anti-neoplastic therapy, or investigational therapy 
within the 4 weeks prior to the initiation of study drug administration. 
5. Treatment with radiation therapy within 2 weeks prior to the initiation of study 
drug administration. 
6. Treatment with 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. Steroids for topical, ophthalmic, inhaled or nasal administration 
are allowed. 
7. History of clinically significant cardiovascular disease including but not limited 
to:  
a. Myocardial infarction or unstable angina within the 12 weeks prior to the 
initiation of study drug. 
b. Uncontrolled hypertension: systolic blood pressure (SBP) >180 mmHg, 
diastolic blood pressure (DBP) >100 mmHg. 
c. QTcB prolongation > 480 msec. 
d. Congestive heart failure (New York Heart Association [NYHA] class III-
IV) 
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8. Clinically-significant gastrointestinal disorders including: 
a. Any history of gastrointestinal perforation unless the affected area has 
been deemed by the investigator to no longer be a risk for perforation by 
the investigator. 
b. History of clinically significant gastrointestinal bleeding within 4 weeks 
prior to the initiation of study drug. 
c. History of acute pancreatitis within 4 weeks prior to the initiation of study 
drug  
d. Diverticulitis that is clinically significant in the opinion of the Investigator 
based on the extent or severity of known disease and/or the occurrence of 
clinically-significant disease flares within 4 weeks prior to the initiation of 
study drug administration. 
9. Evidence of active viral, bacterial, or systemic fungal infection requiring 
parenteral treatment within 7 days prior to the initiation of study drug. Patients 
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. 
10. Known positive testing for human immunodeficiency virus or history of acquired 
immune deficiency syndrome. 
11. 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 (PCR). 
12. Second primary invasive malignancy that has not been in remission for greater 
than 2 years. Exceptions that do not require a 2 year remission include: related 
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. 
13. History of trauma or major surgery within 4 weeks prior to the initiation of study 
drug administration. 
14. Any serious underlying medical or psychiatric condition that would impair the 
ability of the patient to receive or tolerate the planned treatment at the 
investigational site. 
15. Known hypersensitivity to recombinant proteins, 
 any excipient 
contained in the drug or vehicle formulation for MGA271, pembrolizumab  or 
MGA012 (Section 6.1). 
16. Vaccination with any live virus vaccine within 4 weeks prior to the initiation of 
study drug administration. Inactivated annual influenza vaccination is allowed. 
17. Dementia or altered mental status that would preclude understanding and 
rendering of informed consent. 
18. Employees of MacroGenics, Inc. 
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19. Prisoners or other individuals who are involuntarily detained. 
20. Any issue that in the opinion of the investigator, would contraindicate the 
patient’s participation in the study or confound the results of the study. 
 
5.3 
Withdrawal of Patient from the Trial or Study Drug  
5.3.1 
Guidelines for Permanent Discontinuation  
Patients who meet the following criteria should be permanently withdrawn from study 
therapy. Patients will continue to be followed as appropriate and consistent with protocol 
guidelines, but should receive no further study therapy with MGA271 or pembrolizumab or 
MGA012. 
• The patient experiences adverse events that necessitate discontinuation of either 
study drug. 
• The Investigator assesses that the patient's safety is adversely impacted by 
continuing study therapy. 
• Uncontrolled intercurrent illness unrelated to cancer that renders continuing study 
treatment unsafe or regular study visits impossible. 
• The Sponsor, Investigator, or Regulatory Agency terminates the study. 
• The patient requests to be discontinued from the study, i.e. withdraws consent. 
• Noncompliance with study medication or protocol-required evaluations. 
• The patient exhibits progression of disease [according to irRC (i.e., irRECIST)]. 
• If the patient becomes pregnant during the study, the patient must discontinue 
study treatment immediately. Reports of pregnancy will be requested until 
delivery or termination in order to monitor the pregnancy outcome. 
• A violation of enrollment criteria or other significant protocol violation is 
discovered after a patient has been enrolled and treated such that continued 
treatment would not be in the best interests of the patient. 
 
If the Investigator decides that the patient should be  withdrawn from the study or from 
dosing for any reason other than disease progression, the Sponsor or its designee must be 
alerted within 24 hours via an Immediately Reportable Event form (Section 7.9). 
Patients who withdraw before Study Day 42 for a reason unrelated to drug toxicity may be 
considered to have inadequate data to support dose escalation. In this case, replacement 
patients may be enrolled in the same dose level. 
Procedures for handling patients who fail to appear for study visits and criteria regarding 
when to consider patients lost-to-follow-up will be defined in the Study Procedures Manual. 
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6 
STUDY TREATMENTS  
6.1 
Description of Treatments and Study Drug and Supplies  
Study drugs will be administered as an open-label IV solution, followed by observation. 
Under no circumstances is the Investigator allowed to release these clinical supplies for use 
by another physician not named on Form FDA 1572 or to administer study drug to a patient 
who is not enrolled in this study. Study drug must be dispensed at an institution specified on 
Form FDA 1572. 
Requests to MacroGenics, Inc. for additional study drug should be made at least 2 weeks in 
advance. 
6.1.1 
MGA271  
The MGA271 drug product is a
 
 
 
 
 
 
 
MGA271 is supplied as a 
 
 
 
 
 
. MGA271 must not be 
administered as an IV push or bolus. 
6.1.2 
Pembrolizumab  
Pembrolizumab (marketed as KEYTRUDA by Merck & Co., Inc., Whitehouse Station, NJ 
08889 U.S. License No. 1713) is a humanized monoclonal antibody that blocks the 
interaction between PD-1 and its ligands, PD-L1 and PD-L2. Pembrolizumab is an IgG4 
kappa immunoglobulin with an approximate molecular weight of 149 kDa. 
Pembrolizumab is supplied in two configurations: a “pembrolizumab for injection” 
configuration that is a single-use vial containing 50 mg lyophilized powder for reconstitution 
with 2.3 mL sterile water for injection resulting in a 25mg/mL solution (see Section 6.2.3) or 
“pembrolizumab injection” configuration that is a single-use vial containing pembrolizumab 
solution at a concentration of 100 mg/4mL (i.e., 25 mg/mL). 
Pembrolizumab for injection is a sterile, preservative-free, white to off-white lyophilized 
powder in single-use vials. Each vial is reconstituted and diluted for intravenous infusion. 
Each 2 mL of reconstituted solution contains 50 mg of pembrolizumab and is formulated in 
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L-histidine (3.1 mg), polysorbate 80 (0.4 mg), and sucrose (140 mg). May contain 
hydrochloric acid/sodium hydroxide to adjust pH to 5.5. 
Pembrolizumab injection is a sterile, preservative-free, clear to slightly opalescent, colorless 
to slightly yellow solution that requires dilution for IV infusion. Each vial contains 100 mg of 
pembrolizumab in 4 mL of solution. Each 1 mL of the 100 mg/4mL solution contains 25 mg 
of pembrolizumab and is formulated in: L-histidine (1.55 mg), polysorbate 80 (0.2 mg), 
sucrose (70 mg), and Water for Injection, USP. Pembrolizumab will be administered by IV 
infusion over 30 minutes through an IV line containing a sterile, non-pyrogenic, low-protein 
binding 0.2 micron to 5 micron in-line or add-on filter by IV infusion. 
6.1.3 
MGA012  
MGA012 is 
 
 
 
 
 
 
6.2 
Drug Preparation  
6.2.1 
General Guidelines and Precautions  
The calculated dose for MGA271 and pembrolizumab will be administered based on the 
patient’s actual weight at Day 1. Significant (≥ 10%) change in body weight from baseline 
should prompt recalculation of dose. Refer to the Pharmacy Manual for further instructions 
on allowable parameters for dose rounding of MGA271 and pembrolizumab. 
For patients with weight > 120 kg, MGA271 dose calculations will be based on Ideal Body 
Weight (IBW) rather than actual weight using the following formula: 
Estimated ideal body weight in (kg): 
Males: IBW = 50 kg + 2.3 kg for each inch over 5 feet. 
Females: IBW = 45.5 kg + 2.3 kg for each inch over 5 feet. 
Infusion or allergic reactions may occur with the infusion of monoclonal antibodies and other 
protein-based therapeutics. Precautions for anaphylaxis should be observed during both 
MGA271 and pembrolizumab and 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 6.5.1 for specific guidelines regarding the management of infusion reactions. 
Supportive care measures consistent with optimal patient care will be provided throughout 
the study according to institutional standards. 
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When both study drugs are administered on the same day, separate infusion bags must be 
used for each infusion. Pembrolizumab or MGA012 is to be administered first. 
An effort should be made to begin the MGA271 infusion between 30 minutes to 120 minutes 
after the completion of the pembrolizumab or MGA012 infusion. It is understood that this 
window may not always be attainable, but is the preferred window of time to administer 
MGA271. 
6.2.2 
MGA271  
• Inspect parenteral drug products visually for particulate matter and discoloration 
prior to administration. Some visible, proteinaceous MGA271 particles may be 
present. Discard vial if solution is cloudy, there is pronounced discoloration 
(
), or there is foreign particulate matter.  
• The desired amount of MGA271 should be withdrawn from the vial(s) and diluted 
to the appropriate final concentration with 0.9% Sodium Chloride Injection USP, 
according to the instructions provided in the Pharmacy Manual. 
• The infusion bag containing MGA271 should be gently inverted to mix the 
solution. THE BAG MUST NOT BE SHAKEN; excessive agitation may cause 
aggregate formation. DO NOT FREEZE. 
• Discard partially used vials of MGA271. 
• Administration of study drug should begin immediately after preparation but 
 
 
 
 
, to allow dose solution to reach room 
temperature. Precautions should be taken to minimize the time between dose 
preparation and IV infusion administration. If there is a delay in administration of 
study drug such that it will not be administered on the day of preparation, the 
Medical Monitor should be notified immediately. Instructions on how to proceed 
will be provided. 
 
6.2.3 
Pembrolizumab  
Reconstitution instructions for pembrolizumab for injection lyophilized powder: 
• Add 2.3 mL of Sterile Water for Injection, USP by injecting the water along the 
walls of the vial and not directly on the lyophilized powder (resulting 
concentration 25 mg/mL). 
• Slowly swirl the vial. Allow up to 5 minutes for the bubbles to clear. Do not shake 
the vial. 
Preparation for intravenous infusion: 
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• Visually inspect the reconstituted solution for particulate matter and discoloration 
prior to administration. The solution is clear to slightly opalescent, colorless to 
slightly yellow solution. Discard the vial of visible particulates are observed. 
• Dilute pembrolizumab injection (solution) or reconstituted lyophilized powder 
prior to intravenous administration. 
• Withdraw the required volume from the vial(s) of pembrolizumab and transfer 
into an IV bag containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose 
Injection, USP. Mix diluted solution by gentle inversion. The final concentration 
of the diluted solution should be between 1 mg/mL to 10 mg/mL. 
• Discard any unused portion left in the vial. 
 
The product does not contain a preservative. 
Store the reconstituted and diluted solutions from the pembrolizumab 50 mg vial either: 
• At room temperature for no more than 6 hours from the time of reconstitution. 
This includes room temperature storage of reconstituted vials, storage of the 
infusion solution in the IV bag, and the duration of infusion. 
 
Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of 
reconstitution. If refrigerated, allow the diluted solution to come to room temperature prior to 
administration. 
Do not freeze. 
Store the diluted solution from the pembrolizumab 100 mg/4 mL vial either: 
• At room temperature for no more than 6 hours from the time of reconstitution. 
This includes room temperature storage of the infusion solution in the IV bag, and 
the duration of infusion. 
• Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from 
the time of dilution. If refrigerated, allow the diluted solution to come to room 
temperature prior to administration. 
• Do not freeze. 
 
6.2.4 
MGA012  
• Visual inspection of drug product vials for solution clarity, foreign particulate 
matter and discoloration is required prior to use. If solution cloudiness or foreign 
particulate matter or pronounced discoloration is observed (solution may have 
 the drug product should not be used for dose preparation.  
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• 
. 
 
 
 
 
 to allow dose solution to reach room temperature. 
Precautions should be taken to minimize the time between dose preparation and 
IV infusion administration. 
• Instructions on the preparation of each study drug are detailed in the Pharmacy 
Manual. If there is a delay in administration of study drug such that it will not be 
administered on the day of preparation, the Medical Monitor should be notified 
immediately. Instructions on how to proceed will be provided.  
 
6.2.5 
Placebo or Control  
There will be neither placebo nor active control drug for this study. 
6.3 
Study Drug Administration  
6.3.1 
MGA271  
• Do not mix MGA271 with, or administer as an infusion with, other medicinal 
products. 
• Administer the diluted solution over 120 minutes through an intravenous line 
using an infusion pump.  
• 
 
 
• Do NOT use non-polyolefin IV infusion bags. 
• For cohorts with weekly MGA271 administration, an interval of at least 6 days 
should occur since the previous administration. 
• For Cohort 4, MGA271 is administered Q3W ± 3 days. An interval of at least 
18 days should occur since the previous administration. 
• MGA271 must not be administer as an IV push or bolus. 
 
6.3.2 
Pembrolizumab  
• Administer infusion solution intravenously over 30 minutes through an 
intravenous line containing a sterile, non-pyrogenic, low-protein binding 0.2 
micron to 5 micron in-line or add-on filter using an infusion pump. 
• Do not co-administer other drugs through the same infusion line. 
• Dose rounding within 10% of the originally calculated dose is allowed 
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6.3.3 
MGA012  
• MGA012 will be administered at a fixed dose of 375 mg, regardless of body 
weight or body surface area. 
• All doses of MGA012 must be diluted in a 100-mL or 250-mL infusion bag 
containing 0.9% Sodium Chloride Injection, USP (normal saline), prior to dose 
administration. 
 
. The dose solution should be 
administered over 60 to 75 minutes through an IV administration set with a 
commercially available infusion pump.  
• Do not mix MGA012 with, or administer as an infusion with, other medicinal 
products. All IV infusions of MGA012 must be administered separately. Do not 
infuse MGA012 as an IV push or bolus.  
• Study treatments are administered Q3W ± 3 days. An interval of at least 18 days 
should occur since the previous administration. 
 
6.4 
Selection and Timing of Dose for Each Patient  
Patients will be assigned to successive dose cohorts as described in Section 4.1.2 and 
Section 4.1.3. 
6.5 
Potential Adverse Events and Supportive Care Measures  
6.5.1 
Infusion Related Reactions Including Cytokine Release 
Syndrome  
MGA271, pembrolizumab, and MGA012 are immune modulating agents that may lead to 
T-cell activation and killing of the tumor cell. Activation of T cells is associated with the 
production of various cytokines. 
Infusion reactions (including cytokine release syndrome [CRS]) associated with either 
MGA271, pembrolizumab, or MGA012 administration should be managed according to the 
standard practice of medicine. General guidelines for the management of such reactions are 
provided in this section. However, severe reactions may require more intensive interventions 
(e.g., steroids, anti-TNF antibodies, and/or IL-6 inhibitors). 
Patients should be monitored closely for the development of infusion-related reactions during 
the pembrolizumab and MGA271 and MGA271+MGA012 infusions. Medications and 
supportive measures for the treatment of severe hypersensitivity reactions should be available 
for immediate use for an infusion reaction during study drug administration and may include, 
but are not limited to: subcutaneous (SC) epinephrine (0.3 to 0.5 mL of a 1:1000 solution), 
antihistamines (e.g., diphenhydramine 25 to 50 mg IV), corticosteroids (e.g., hydrocortisone 
50-100 mg IV push or equivalent), IV fluids, vasopressors, oxygen, bronchodilators, and 
antipyretics. Resuscitation equipment and other supplies for the emergency management of 
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an allergic/toxic reaction must be available. The patient should be treated according to the 
best available local practices and procedures. All supportive measures consistent with 
optimal patient care will be provided throughout the study according to institutional 
standards. 
Should symptoms of fever or chills develop it may be difficult to distinguish among potential 
causes of the symptoms including emerging infection, or infusion reaction. Patients should be 
evaluated carefully for the presence of infection, 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 6.5.1.3 for guidance regarding the management of 
infusion reactions. 
If a patient has a Grade 1 or 2 infusion reaction with pembrolizumab or with MGA012 and 
the investigator considers it unsafe for the patient to receive MGA271 at the scheduled 
infusion time, the MGA271 dose may be administered on the following day (the day after the 
pembrolizumab infusion). For Grade 3 infusion reactions with pembrolizumab or with 
MGA012 that resolve completely or to Grade 1 within 12 hours, the scheduled dose of 
MGA271 may be administered the following day with premedications as listed below. 
6.5.1.1 
Grading 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 patient tolerates (see Section 
6.5.1.3); 
• 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]; prophylactic medications indicated for  
24 hours; 
• 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; 
• Grade 5: death. 
 
The above grading scale is the CTCAE v 4.03 grading scale for CRS, which is nearly 
identical to the CTCAE v 4.03 grading scale for infusion reaction and allergic reaction, and 
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. 
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6.5.1.2 
Premedications and Prophylaxis  
No specific prophylactic pre-infusion regimen is recommended for pembrolizumab unless a 
patient has an infusion reaction with pembrolizumab or MGA271 infusion (see below). For 
MGA271, the following suggested guidelines (which may be modified by the investigator) 
are measures to be followed to avoid potential infusion reactions. 
Prior to first infusion (guidelines to be followed): 
• Acetaminophen 650 mg 
• Diphenhydramine 50 mg or appropriate dose of equivalent H1 antagonist 
• Ranitidine 300 mg or appropriate dose of equivalent H2 antagonist at the 
discretion of the investigator 
• Hydrocortisone 50 to 100 mg suggested or doses up to 10-20 mg dexamethasone 
may be administered (dose selected at the discretion of the Investigator) 
 
Prior to subsequent MGA271 infusion, investigators may use the following premedications 
as considered indicated (suggested guidelines): 
• Acetaminophen 650 mg 
• Diphenhydramine 50 mg or appropriate dose of equivalent H1 antagonist 
• Ranitidine 300 mg or appropriate dose of equivalent H2 antagonist 
• Optional hydrocortisone not typically needed after first dose. However, for 
patients who had infusion reactions not adequately or only moderately controlled 
with acetaminophen, diphenhydramine, or ranitidine, subsequent doses may be 
tapered at the discretion of the Investigator.  
 
6.5.1.3 
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 infusion reactions. Note that 
these apply to MGA271, pembrolizumab, and MGA012: 
Grade 1 
• Slow the infusion rate by 50%. 
• Monitor the patient for worsening of condition. 
• Continue rate at 50% reduction and increase dose rate to the original rate by 
doubling the infusion rate after 30 minutes, as tolerated to the initial rate. 
Consideration can be given to beginning all subsequent infusions at 50% rate and 
increasing as tolerated. 
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Amendment 6, 26 August 2020 
 
 
 
 
 
• On days when both pembrolizumab and MGA271 or MGA271 and MGA012 are 
given on the same day and a patient has an infusion reaction with pembrolizumab 
or MGA012, the MGA271 infusion can be given (without prophylactic 
medications) on the same day if the infusion reaction resolves within 3 hours. For 
scheduling purposes, the MGA271 infusion may be given the next day if the 
reaction lasts greater than 3 hours. 
• If a patient has an infusion reaction with pembrolizumab or MGA012, 
prophylactic preinfusion medications should be given prior to all subsequent 
pembrolizumab or MGA012 infusions as written below for Grade 1 infusion 
reactions. 
• If a patient has an infusion reaction with MGA271 on either day when it is 
administered after pembrolizumab, or after MGA012, or given alone, prophylactic 
preinfusion medications should be given prior to all subsequent MGA271 
infusions as written below. 
• The following prophylactic preinfusion medications are recommended prior to 
future infusions of MGA271 and/or pembrolizumab, and/or MGA012 for patients 
who experience Grade 1 infusion reactions: diphenhydramine 50 mg (or 
equivalent) and/or acetaminophen 650 mg at least 30 minutes before additional 
study drug administrations. 
 
Grade 2 
• Stop the infusion. 
• Administer diphenhydramine hydrochloride 25-50 mg IV, acetaminophen 650 mg 
orally for fever, and 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. 
• When both pembrolizumab and MGA271 or MGA012 and MGA271 are given on 
the same day and a patient has an infusion reaction with pembrolizumab or with 
MGA012: 
• The MGA271 infusion can be administered on the same day if the infusion 
reaction resolves within 3 hours. The MGA271 infusion may be given the next 
day if the infusion reaction last longer than 3 hours. 
• Premedication of diphenhydramine hydrochloride 25-50 mg IV and 
acetaminophen 650 mg orally should be administered 30 minutes prior to the 
MGA271 dose. If no corticosteroids where given for the pembrolizumab or 
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MGA012 infusion reaction, hydrocortisone 50-100 mg IV or equivalent may be 
considered prior to MGA271 administration. 
• Prophylactic pre-infusion medications should be given prior to all subsequent 
pembrolizumab or MGA012 infusions. Patients who experience Grade 2 infusion 
reaction should be pre-medicated with diphenhydramine hydrochloride 25-50 mg 
IV and acetaminophen 650 mg orally for subsequent doses of pembrolizumab. 
• If a patient has an infusion reaction with MGA271 on any of the days that it is 
administered after pembrolizumab or after MGA012, or given alone, prophylactic 
preinfusion medications should be given prior to all subsequent MGA271 
infusions. 
• For patients with Grade 2 infusion reactions despite premedication with 
diphenhydramine and acetaminophen, corticosteroids (hydrocortisone 50-100 mg 
IV or equivalent) should be considered for acute management of the event and 
should be added to the premedication regimen for subsequent dosing of 
pembrolizumab and/or MGA271 or subsequent dosing of MGA012 and/or 
MGA271. 
 
Grade 3 
• STOP THE INFUSION AND DISCONNECT THE INFUSION TUBING FROM 
THE PATIENT. 
• TO AVOID EXACERBATION OF INFUSION REACTION OR CRS: DO NOT 
FLUSH THE TUBING – ASPIRATE RESIDUAL DRUG FROM THE PORT 
LUMEN. 
• Administer diphenhydramine hydrochloride 25-50 mg IV, hydrocortisone 25-
100 mg IV (or equivalent), and other medications/treatment as medically 
indicated. Higher doses of corticosteroids (i.e. methylprednisolone 2 -4 mg/kg IV) 
may also be considered for acute management. 
• IV fluids, supplemental oxygen and bronchodilators should be considered as 
appropriate. 
• Grade 3 infusion reaction with MGA271: If symptoms have resolved to 
baseline within 12 hours, a re-challenge may be considered at the next scheduled 
dose, with a 50% reduction of infusion rate. In addition, patients should be pre-
medicated for this re-challenge and for any subsequent doses of MGA271 with 
the following: diphenhydramine hydrochloride 25-50 mg IV, oral acetaminophen 
625 mg and hydrocortisone 25-100 mg IV. Patients who have a Grade 3 infusion 
reaction that does not resolve within 12 hours despite medical management 
should not receive further MGA271, pembrolizumab, or MGA012 treatment. 
• Grade 3 infusion reaction with pembrolizumab or MGA012: If the grade 3 
infusion reaction occurs with pembrolizumab or with MGA012, both MGA271 
and pembrolizumab or MGA271 and MGA012 will be discontinued for that day’s 
dose. If symptoms have resolved to baseline within 12 hours, a pembrolizumab or 
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MGA012 re-challenge at the next scheduled infusion day may be considered, with 
a 50% reduction of infusion rate. In addition, patients should be pre-medicated for 
this re-challenge and for any subsequent doses of pembrolizumab or MGA012 
with the following: diphenhydramine hydrochloride 25-50 mg IV, oral 
acetaminophen 625 mg and hydrocortisone 25-100 mg IV. MGA271 dosing can 
be resumed with at the next scheduled infusion day if the pembrolizumab or 
MGA012 grade 3 infusion reaction resolved to grade 1 within 12 hours. Patients 
who have a Grade 3 infusion reaction that does not resolve within 12 hours 
despite medical management should not receive further MGA271, 
pembrolizumab, or MGA012 treatment. 
• Patients who experience a second Grade 3 infusion reaction at the time of re-
challenge of MGA271 or pembrolizumab or MGA012 (irrespective of duration of 
first Grade 3 reaction), will permanently discontinue MGA271, and 
pembrolizumab and MGA012. 
• Report as an Immediately Reportable Event (IRE) within 24 hours. 
• Report the event as a SAE, if appropriate. 
 
Grade 4 
• STOP THE INFUSION AND DISCONNECT THE INFUSION TUBING FROM 
THE PATIENT. 
• TO AVOID EXACERBATION OF INFUSION REACTION OR CRS: DO NOT 
FLUSH THE TUBING. 
• Administer diphenhydramine hydrochloride 50 mg IV, methylprednisolone 2-
4 mg/kg 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. 
• Report as an IRE within 24 hours. 
• Report the event as an SAE. 
• Patients who have a Grade 4 infusion reaction will not receive further MGA271 
or pembrolizumab or MGA012. 
Grade 5 
• Report as an IRE within 24 hours. 
• Report the event as an SAE. 
 
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All changes in the infusion of either MGA271 or pembrolizumab or MGA012, including 
interruption of the infusion and its duration as well as reductions in infusion rate and duration 
must be recorded. 
6.5.2 
Immune-Related Adverse Events  
Immune checkpoint blockade has been associated with several syndromes resulting from the 
breaking of immunological tolerance in normal tissues (28;47;62). These syndromes include 
but are not limited to: pneumonitis, colitis, autoimmune hepatitis, arthritis, 
glomerulonephritis, dermatological toxicities including toxic epidermal necrolysis (TEN) and 
Stevens-Johnson Syndrome (SJS), myocarditis and cardiomyopathy, hypophysitis, 
thyroiditis, or other autoimmune endocrinopathies. The occurrence of any of these syndromes 
dictates interruption, and potentially discontinuation of study drug administration pending 
further evaluation and reporting them to the Sponsor as adverse events of special interest 
(AESIs). Most low grade irAEs can be managed symptomatically. Persistent low grade or 
moderate toxicities may require treatment with corticosteroids or in refractory cases 
other immune suppressing agents such as mycophenolate or infliximab. High grade 
immune-related toxicities will, in almost all cases require treatment with corticosteroids. 
For the purposes of the safety management, no distinction should be made as to which drug 
is the causative agent and both agents stopped (temporarily held or discontinued). Signs or 
symptoms of inflammation should be considered drug related and immune mediated, unless 
an alternate etiology is identified. 
Temporary interruptions of MGA271, pembrolizumab, or MGA012 may be required in the 
event of treatment-related toxicity. General guidelines for specific toxicity regarding dosing 
and treatment are provided below. All toxicities will be graded according to NCI CTCAE 
v4.03. 
6.5.2.1 
Diarrhea or Colitis  
Diarrhea that develops in patients while receiving pembrolizumab may reflect immune 
reactivity against normal colonic epithelium and careful monitoring for potential 
immune-related colitis should be instituted; see Section 2.3.2.1 for summary of 
pembrolizumab safety profile.  
Patients should be monitored closely for evidence of diarrhea or other change in bowel habits 
as well as other signs and symptoms suggestive of colitis. Patients who develop signs or 
symptoms including abdominal pain, bloating, nausea, vomiting, diarrhea or blood in the 
stools should be evaluated carefully for potential colitis. 
Grade 1 diarrhea 
• Closely monitor the diarrhea until resolution. 
Grade 2 diarrhea 
• Increase frequency of monitoring until resolution 
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• Consider holding the next dose of pembrolizumab or MGA012, and/or MGA271. 
• Symptomatic management 
• Loperamide/diphenoxylate 
• Consider budesonide 9 mg once per day or divided three times per day. 
• Consider management as per Grade 3 diarrhea with prolonged event > 5 to7 days 
or relapsed diarrhea. 
Grade 3 diarrhea 
• Hospitalize patient promptly for further evaluation and management including: 
• Hold pembrolizumab or MGA012, and/or MGA271 
• Bowel rest 
• Supplemental IV fluids with close monitoring of fluid and electrolyte status. 
• Monitoring of frequency of bowel movements 
• Consider imaging to rule out bowel obstruction or perforation 
• Consideration of colonoscopy as appropriate 
• Implementation of initial empiric immune suppression consisting of IV 
corticosteroids using methylprednisolone at a dosage of 2 mg/kg/day divided 
twice daily. As tolerated, patients may be converted to oral corticosteroids (i.e., 
prednisone 2 mg/kg/day divided twice daily) and tapered as appropriate guided by 
the patients’ clinical status. Taper corticosteroids as clinically indicated. 
• For patients with severe colitis, or those who do not respond to corticosteroids, 
additional immune suppression with anti-TNF-α antibodies (i.e., infliximab) 
should be considered early in the course. 
• Consider restarting pembrolizumab or MGA012, and MGA271, if: 
• It is determined there is no colitis and an alternative cause of diarrhea is found 
• Diarrhea resolves to ≤ CTCAE Grade 1 within 14 days 
Grade 4 diarrhea  
• Discontinue pembrolizumab or MGA012, and MGA271 
• Treat as for Grade 3 
 
6.5.2.2 
Hepatic Toxicity  
6.5.2.2.1 
Elevations in Transaminases  
Section 2.3.2.1 provides a summary of the pembrolizumab safety profile. Management 
guidelines for patients experiencing hepatic toxicity are as follows: 
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Grade 1 elevations 
• No specific therapy required 
Grade 2 elevations 
• For elevations in transaminases 3 to 5 × ULN (Grade 2), rule out viral and other 
etiologies, consider immediate oral steroids such as prednisone 60 mg /day 
divided twice daily, and hold MGA271 and pembrolizumab or MGA012. 
• 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 
• Resume pembrolizumab or MGA012, and/or MGA271, at next scheduled dose if: 
• No more than one dose of pembrolizumab or MGA012 was missed and no more 
than 2 doses of MGA271 were missed 
• If improvement to ≤ Grade 1does not occur within 14 days discontinue 
pembrolizumab or MGA012, and MGA271 
Grade 3 elevations 
• Permanently discontinue MGA271 and pembrolizumab or MGA012, for AST or 
ALT greater than 5 times ULN unless patient has liver metastasis and began 
treatment with Grade 2 AST or ALT 
• For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, 
permanently discontinue if AST or ALT increases by greater than or equal to 50% 
relative to baseline and lasts for at least 1 week 
• Initiate IV steroids; suggest methylprednisolone at a dosage of 2 mg/kg/day 
divided twice daily. 
• If no response to corticosteroid therapy within 3 to 5 days is observed, consider 
adding immune suppression therapy with mycophenolate. Infliximab is not 
recommended because of a potential for autoimmune hepatitis (30). 
• Monitor liver function testing 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. 
Grade 4 elevations 
• Discontinue pembrolizumab or MGA012, and MGA271 
• Treat as for Grade 3 elevation 
 
6.5.2.2.2 
Elevations in Total Bilirubin  
Management guidelines for patients experiencing elevations in total bilirubin are as follows: 
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Grade 1 elevations 
• No specific therapy required 
Grade 2 elevations 
• Hold MGA271 and pembrolizumab or MGA012, until improvement to ≤ Grade 1 
• Consider oral steroids 
• If improvement to ≤ Grade 1 does not occur within 14 days, discontinue MGA271 
and pembrolizumab or MGA012, and begin oral steroids  
Grade 3 elevations 
• For elevations in total bilirubin > 3× ULN, permanently discontinue MGA271 
and pembrolizumab or MGA012, and  
• Initiate IV steroids; suggest methylprednisolone at a dosage of 2 mg/kg/day 
divided twice daily. 
• If no response to corticosteroid therapy within 3 to 5 days is observed, consider 
adding immune suppression therapy with mycophenolate. Infliximab is not 
recommended because of a potential for autoimmune hepatitis (30). 
• Monitor liver function testing 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. 
Grade 4 elevations 
• Discontinue pembrolizumab or MGA012, and MGA271 
• Treat as for Grade 3 elevation 
 
6.5.2.3 
Pneumonitis  
Section 2.3.2.1 provides a summary of pembrolizumab safety profile. Management 
guidelines for patients experiencing pneumonitis are as follows: 
Grade 1 pneumonitis 
• No specific therapy required, close monitoring of lung function and imaging 
Grade 2 pneumonitis 
• Hold MGA271 and pembrolizumab or MGA012 
• Begin corticosteroids: 1 to 2 mg/kg of oral prednisone or equivalent, per day 
divided twice daily 
• Taper over 4 weeks as clinically indicated 
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• Resume MGA271 and pembrolizumab or MGA012 administration at next 
scheduled dose, if:     
• Pneumonitis resolves to ≤ Grade 1 within 3 days with or without treatment 
Grade 3 and 4 pneumonitis 
• Hospitalize 
• Permanently discontinue MGA271 and pembrolizumab or MGA012 
• Initiation of maximal supportive care including IV corticosteroids, suggest 
methylprednisolone at 2- 4 mg/kg/day divided twice daily. Higher doses may be 
used in consultation with the Sponsor’s medical monitor 
• If no response to corticosteroid therapy is observed within 3-5 days, consider 
adding immune suppression therapy (i.e., infliximab, etc.) 
 
6.5.2.4 
Dermatologic Toxicity  
Section 2.3.2.1 provides a summary of pembrolizumab safety profile. Management 
guidelines for patients experiencing dermal toxicities are as follows: 
In general, Grade 1 or 2 skin reactions can be treated symptomatically with low-dose topical 
corticosteroids (betamethasone 0.1% or hydrocortisone 1%) or with antihistamines, such as 
diphenhydramine. Persistent Grade 1 or 2 rash should be managed with higher dose topical 
corticosteroids and/or oral prednisone (1-2 mg/kg/day) if there is no improvement with 
topical therapies or the rash is associated with other dermal toxicities such as pruritus. 
Grade 3 or 4 rashes require initiation of oral corticosteroids (oral prednisone 1 – 
2 mg/kg/day) and temporary holding of study drugs with Grade 3 toxicity and permanent 
discontinuation for Grade 4 toxicity. Grade 3 skin toxicity that does not resolve to ≤ CTCAE 
Grade 2 within 14 days of initiation of oral corticosteroids requires permanent 
discontinuation of study therapy. Strong consideration should be given to start IV 
corticosteroids (methylprednisolone 1-2 mg/kg/day) for Grade 4 dermatologic toxicities with 
tapering on resolution to < Grade 2 over 30 days. 
6.5.2.5 
Nephritis/Renal Failure  
Section 2.3.2.1 provides a summary of pembrolizumab safety profile. Management 
guidelines for patients experiencing nephritis/renal failure are as follows: 
Grade 1 nephritis 
• No specific therapy required, close monitoring of renal function 
Grade 2 nephritis 
• Hold MGA271 and pembrolizumab or MGA012 
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• Consider nephrology consultation and renal biopsy to confirm interstitial 
nephritis. 
• Begin corticosteroids: 1 to 2 mg/kg of oral prednisone or equivalent, per day 
divided twice daily 
o Taper over 4 weeks as clinically indicated 
• Resume MGA271 and pembrolizumab or MGA012 administration at next 
scheduled dose, if: 
o Nephritis resolves to ≤ Grade 1 within 14 days with or without treatment 
Grade 3 and 4 nephritis 
• Consider hospitalization, nephrology consultation and renal biopsy to confirm 
interstitial nephritis 
• Begin corticosteroids: 2 to 4 mg/kg of oral or IV prednisone or equivalent, per 
day divided twice daily 
o Taper over 4 weeks as clinically indicated 
• Permanently discontinue MGA271, pembrolizumab, or MGA012 for Grade 3/4 
nephritis. 
 
6.5.2.6 
Immune-Mediated Endocrinopathies  
Section 2.3.2.1 provides a summary of pembrolizumab safety profile. Management 
guidelines for patients experiencing endocrinopathies are as follows: 
6.5.2.6.1 
Hypophysitis  
In cases of symptomatic (Grade 2 or 3) hypophysitis documented on MRI: 
• Hold pembrolizumab or MGA012 and MGA271 
• Consult endocrinologist 
• Consider hospitalization  
• Begin short course of high dose IV corticosteroids: e.g. methylprednisolone 2-4 
mg/kg IV (or equivalent) divided twice daily  
• Initiate hormonal replacement as indicated  
• Pembrolizumab or MGA012 and/or MGA271 may be resumed as allowed by 
protocol when 
o Endocrinopathy is controlled with appropriate replacement therapy 
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o Corticosteroid dose reduced to ≤ 10 mg prednisone or equivalent per day 
• Repeat brain MRI as clinically indicated 
 
Discontinue MGA271 and pembrolizumab or MGA012 for Grade 4 hypophysitis 
6.5.2.6.2 
Thyroid Toxicity  
Hyperthyroidism/Hypothyroidism:  
There have been no reported cases of endocrine toxicities in the Phase 1 dose escalation and 
expansion trial of MGA271. 
Thyroid disorders can occur at any time during treatment with pembrolizumab. Monitor 
patients for changes in thyroid function (at the start of treatment, periodically during 
treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms 
of thyroid disorders. Isolated hypothyroidism may generally be managed with replacement 
therapy without treatment interruption and without corticosteroids and a suggested treatment 
guideline for hyperthyroidism is described below: 
Grade 1 hyperthyroidism 
• No specific therapy required 
Grade 2 hyperthyroidism 
• Hold pembrolizumab or MGA012 and MGA271 
• Resume pembrolizumab or MGA012 and/or MGA271 if stable on hormone 
replacement therapy (if necessary) 
Grade 3 or 4 hyperthyroidism 
• Hold pembrolizumab or MGA012 and/or MGA271 
• Consider hospitalization and consulting endocrinologist 
• Initiate hormonal replacement as necessary  
 
May consider restarting pembrolizumab or MGA012 and MGA271 with complete resolution 
or stable on hormone replacement therapy 
6.6 
Method of Assigning Patients to Treatment Groups  
Patients will be assigned sequentially to the dose escalation cohorts and cohort expansion 
portions of the study. 
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6.7 
Blinding  
This is an open-label study and no blinding will be employed. 
6.8 
Concomitant Therapy  
MGA271, pembrolizumab, and MGA012 are the only cancer drugs to be administered 
routinely in this study. No concomitant anti-cancer therapy will be given. 
All concomitant medications and blood products administered during the patient’s 
participation in the study until the post treatment follow-up visit must be recorded in the 
source document and on the electronic Case Report Form (eCRF). All changes in infusions, 
including interruptions and their duration as well as reductions in rate and duration must be 
recorded. 
The following rules concerning concurrent treatment(s) will apply in this study: 
• Any other anti-neoplastic therapies including but not limited to chemotherapy or 
other small molecules, biologics, or radiotherapy are not allowed. For patients 
who require palliative radiotherapy (i.e., cumulative dose less than 3000 rads, 
limited field of distribution) for reasons other than disease progression, therapy 
with MGA271 and pembrolizumab may be interrupted for up to 4 weeks. 
Palliative radiotherapy may not be given concurrently with either MGA271 or 
pembrolizumab or MGA012. Treatment with palliative therapy should be initiated 
at least 24 hours after receiving either MGA271 or pembrolizumab or MGA012, 
and re-initiation of MGA271 or pembrolizumab or MGA012 can begin one day 
after the completion of palliative radiotherapy if there were no complications 
associated with the radiotherapy. Palliative radiotherapy fields also should not 
overlap tumor lesions that have previously been designated as target lesions. In 
the event that this is medically necessary for palliative purposes, the patient may 
continue on study, but will no longer be evaluable for objective response from the 
time palliative radiotherapy is initiated. 
• Patients may not receive other investigational drugs during the period of study 
participation. 
• Because MGA271, pembrolizumab, and MGA012 have a mechanism of action 
dependent upon the engagement of T lymphocytes, the use of corticosteroids 
should be limited to the extent possible. Chronic doses of corticosteroids in excess 
of 10 mg daily of prednisone or equivalent is prohibited other than for the 
management of drug-related adverse experiences. Steroids may be employed in 
the treatment of suspected MGA271- or pembrolizumab- or 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 adverse event. 
• Use of granulocyte colony stimulating factor, granulocyte-macrophage colony 
stimulating factor or other growth factors is prohibited. 
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• Live vaccines within 4 weeks prior to the first dose of MGA012 and while 
participating in the study are prohibited. Examples of live vaccines include, but 
are not limited to, the following: measles, mumps, rubella, chicken pox, yellow 
fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for 
injection are generally recombinant vaccines and are allowed any time after the 
DLT period is completed. However, intranasal influenza vaccines (e.g., FluMist®) 
are live attenuated vaccines and are not allowed. Similarly, Shingrix® vaccine for 
shingles is permitted after the DLT period, but Zostavax® is prohibited. 
 
Patients 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 and should be documented on the 
concomitant medication form. 
• Use of bisphosphonates or receptor activator of nuclear factor kappa-B ligand 
(RANK-L) inhibitors is allowed 
 
6.9 
Restrictions  
6.9.1 
Prior Therapy  
Prior therapy restrictions are described in the inclusion/exclusion criteria specified in 
Section 5. 
6.9.2 
Fluid and Food Intake  
There are no requirements for fasting and no restrictions for fluid and food intake by the 
patients during the study, although it is recommended that, to the extent possible, patients 
have a fluid intake of  2 liters on days associated with PK sampling, and that 
electrocardiograms will be obtained pre-meal. 
6.9.3 
Patient Activity Restrictions  
There are no restrictions on patient activities and no requirement for patient confinement 
during the study. 
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6.10 
Treatment Compliance  
MGA271 and pembrolizumab will be administered by healthcare professionals under the 
supervision of the Investigators. Records of MGA271 and pembrolizumab 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 investigational site visits and at the completion of the study. 
6.11 
Packaging and Labeling  
6.11.1 
MGA271  
MGA271 will be supplied in open-label, single-dose vials. All investigational product will be 
labelled with a minimum of the protocol number, directions for use, storage conditions, 
expiry date (if applicable), batch number, the statements “For clinical trial use only,” and/or 
“CAUTION: New Drug – Limited by Federal (United States) Law to Investigational Use,” 
and the Sponsor's name and address. Please see the Pharmacy Manual for detailed 
information about the packaging and labeling of the study drug. 
6.11.2 
Pembrolizumab  
Pembrolizumab will be obtained by the site from commercial supply for patients with 
melanoma. Pembrolizumab will be provided in the commercial packaging. Please see the 
Pharmacy Manual for detailed information about the packaging and labeling of 
pembrolizumab. 
6.11.3 
MGA012  
MGA012 will be supplied 
 
 
 
 
Please see the Pharmacy Manual for detailed information about the packaging and 
labeling of the study drug. 
6.12 
Storage and Accountability  
6.12.1 
MGA271  
The vials containing study drug should be 
 and must not be 
frozen or shaken. Protect from sunlight. To ensure compliance with storage conditions, 
temperature logs will be maintained. 
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 designee. When the study is completed, copies of study 
drug accountability records must be sent to the Sponsor. The original drug accountability 
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records must be maintained with the rest of the documentation in accordance with 
Section 10.1 of the protocol. 
Additional details regarding storage, handling, and accountability can be found in the 
Pharmacy Manual. 
6.12.2 
Pembrolizumab  
Pembrolizumab is marketed as KEYTRUDA by Merck & Co., Inc., Whitehouse Station, NJ 
08889. 
Pembrolizumab is supplied in the following configurations: 
• KEYTRUDA (pembrolizumab) injection (lyophilized powder): carton containing 
one 50 mg single-use vial (NDC 0006-3029-02). 
• KEYTRUDA (pembrolizumab) injection (solution): carton containing one 100 
mg/4 mL (25 mg/mL), single-use vial (NDC 0006-3026-02) 
 
Store vials under refrigeration at 2°C to 8°C (36°F to 46°F) in original carton to protect from 
light. Do not freeze. Do not shake. 
6.12.3 
MGA012  
Vials containing MGA012 should 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. 
6.12.4 
Accounting for the Materials  
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. When the study is 
completed, copies of all study drug accountability records must be provided to the Sponsor. 
Original drug accountability records must be maintained with the rest of the 
documentation for inspection by the study monitors. Additional details regarding storage, 
handling, and accountability can be found in the Pharmacy Manual. 
6.13 
Investigational Product Disposition at End of Study  
Upon completion or termination of the study, all unopened vials of study medication must be 
returned to MacroGenics or its representative, unless the site has received written 
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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. 
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7 
STUDY PROCEDURES  
This section provides a general description of the procedures and assessments associated with 
this study. Time and Events Schedule (Appendix 1) details the schedule of assessments by 
study day. 
Note: On days where multiple procedures are required at the same time point, the PK sample 
should be collected first. 
7.1 
Informed Consent  
The Investigator is responsible for ensuring that the patient or his/her legal representative 
provides informed consent prior to performing any study related assessments, evaluations, or 
procedures. 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 patient and the original maintained according to 
institutional procedures. The patient’s medical records will include documentation of the 
informed consent process. Informed consent will be obtained prior to any study screening 
procedures being performed. 
7.2 
Medical History  
A complete medical history should be obtained during the screening visit. All concurrent 
medical conditions in the last 60 days and any significant medical conditions (e.g., 
hospitalizations, surgeries, prior cancer history) should be collected. During the screening 
period (prior to first dose of pembrolizumab, MGA012, or MGA271), any untoward event 
that occurs should be recorded as medical history and not as an adverse event, unless it is due 
to a protocol-related procedure. Thereafter (i.e., after the time of study drug administration), 
any untoward event should be collected as an AE. 
7.3 
Prior and Concomitant Medications  
All concomitant medications and blood products administered during the patient’s 
participation in the study until the End of Treatment Visit 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. 
7.4 
Physical Examination  
The Investigator will perform physical examination of all patients. Physical examination will 
include height (screening only), weight, and examination of skin, HEENT (head, eyes, ears, 
nose, and throat), lymph nodes, heart, chest, lungs, abdomen, extremities, and neurologic 
system as specified in Appendix 1. 
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Weight will be measured during screening, Day 1, and then before each dose of 
pembrolizumab, MGA012, or MGA271. 
7.5 
Vital Signs  
Vital signs include temperature, pulse, blood pressure, and respiratory rate and are obtained 
as specified in Table 8 for MGA271 and pembrolizumab or Table 9 for MGA271 and 
MGA012. 
7.6 
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 will be 
performed locally. Safety labs should be performed and reviewed before study drug 
administration. 
Please consult the Laboratory Manual for specific directions on collection and processing 
samples. 
7.6.1 
Laboratory Parameters  
Clinical laboratory tests to be performed locally will include the following: 
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Table 4 
Clinical Laboratory Tests  
Pregnancy test: 
Urine Human chorionic gonadotropin (hCG) 
 
Hematology: 
Hematocrit (Hct) 
Hemoglobin (Hgb) 
Mean corpuscular hemoglobin (MCH) 
Mean corpuscular hemoglobin concentration 
(MCHC) 
Mean corpuscular volume (MCV) 
Platelet count 
Red blood cell (RBC) count  
White blood cell (WBC) count with differential 
counts 
 
Serum Chemistry: 
Albumin (ALB) 
Alkaline phosphatase (ALK-P) 
Alanine aminotransferase (ALT; SGPT) 
Aspartate aminotransferase (AST; SGOT) 
Bicarbonate 
Blood urea nitrogen (BUN) 
Calcium (Ca) 
Chloride (Cl) 
Creatinine 
Glucose 
Magnesium 
Phosphorus 
Potassium (K) 
Sodium (Na) 
Total protein 
Uric acid 
Special Chemistry: 
Amylase 
Lipase 
Bilirubin (Total and Direct) 
 
Coagulation: 
Prothrombin time (PT) 
Activated Partial Thromboplastin Time (APTT) 
 
Endocrine tests: 
Free thyroxine (T4) 
Thyroid-stimulating hormone (TSH) 
 
Urinalysis: 
Appearance 
Bilirubin 
Color 
Glucose 
Ketones 
Microscopic examination of sediment  
Nitrite  
Occult blood 
pH 
Protein 
Specific gravity 
 
 
Other tests (PK, anti-drug antibody [ADA], cytokines, determination of leukocyte subsets, 
evaluation of T cell activation status, expression of markers of T cells, determination of T cell 
infiltration, and tumor B7-H3 expression) will be carried out at Sponsor-specified central 
laboratories (refer to the Laboratory Manual). 
7.6.2 
Sample Collection, Storage, and Shipping  
Clinical laboratory testing described in Section 7.6.1 will be performed locally. Details on 
local and central laboratory specimen collection, storage, and shipping will be provided in 
the Laboratory Manual. 
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7.7 
Electrocardiography  
Twelve-lead electrocardiograms (ECGs) (in triplicate, approximately 1 minute apart) will be 
obtained according to the (Appendix 1) in order to evaluate the potential cardiac effects of 
the combination of MGA271 and pembrolizumab and of MGA271+MGA012, including QT 
interval. There are no requirements for fasting and no restrictions for fluid and food intake by 
the patients during the study, although it is recommended that, to the extent possible, ECGs 
be obtained pre-meal at approximately the same time of the day to minimize diurnal 
variations. However, this may not be possible because of infusion times and clinic logistics. 
To account for intrinsic variability, all ECGs should be obtained in triplicate (3 ECGs per 
time point at approximately 1-minute intervals). Central interpretation will be used for data 
analysis purposes; note for Cohort 4 only, ECGs will be read locally. ECGs are to be obtained 
as specified in Table 8 for MGA271 and pembrolizumab and in Table 9 for MGA271 and 
MGA012. 
7.8 
Safety Assessments  
7.8.1 
Criteria for Evaluation  
• The safety assessment will be based on the evaluation of treatment-emergent AEs 
that occur from the time of initiation of administration of either study drug 
through the End of Treatment Visit or 28 days after the last dose of study drug 
(whichever is later) and will be determined based on signs, symptoms, physical 
examination findings and/or laboratory test results from enrolled patients as 
appropriate. 
• AEs and SAEs will be collected from the time the patient receives the first dose of 
study drug until the End of Treatment visit or 28 days after the last dose of study 
drug (whichever is later). Protocol-related AEs and SAEs will be collected from 
the time the patient has consented to study participation. 
• AEs reported between the time the patient signed the informed consent and the 
administration of the first dose of study drug will be captured as medical history. 
• SAEs considered related to study drug may be reported at any time, even after the 
patient’s final visit. 
• Progression of the underlying neoplasm resulting in hospitalization or death (e.g., 
patient hospitalized for or dies from progressive disease [PD] only, without any 
other SAE) will be documented as an antitumor activity outcome and not as an 
SAE. If an SAE occurs in a patient and it is unclear whether the event is related to 
PD, the SAE should be reported. 
• The reporting of laboratory/vital signs abnormalities as both laboratory findings 
and AEs should be avoided. They should not be reported as AEs unless any one of 
the following are met: 
o Any criterion for an SAE is fulfilled 
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o The laboratory/vital signs abnormality causes the patient to discontinue 
from the study treatment 
o The laboratory/vital signs abnormality causes the patient to interrupt the 
study treatment 
o The laboratory/vital signs abnormality causes the patient to modify the 
dose of study treatment 
o The laboratory/vital signs abnormality requires intervention 
 
7.8.2 
Adverse Event: Definitions  
7.8.2.1 
Adverse Event  
An adverse event is any untoward medical occurrence in a subject or clinical investigation 
patient administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
An adverse event will also be considered to be any untoward effect of a study-related 
procedure, which is conducted after signed informed consent and prior to study drug 
administration. 
7.8.2.2 
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 (i.e., the relationship cannot be ruled out). 
7.8.2.3 
Adverse Event of Special Interest  
An AESI is an event of scientific and medical interest or concern to the Sponsor’s product or 
program, for which ongoing monitoring and rapid communication to the Sponsor could be 
appropriate. It may be a serious or non-serious AE, which may require further investigation 
in order to characterize and understand it. 
7.8.2.4 
Treatment Emergent Adverse Event  
An event that is temporally associated with administration of study product is defined as a 
treatment-emergent adverse event (TEAE). Events meeting this definition will be those 
occurring during or after administration of the first dose of study drug. Events that existed 
before the first administration of study product and then increased in severity during or after 
the first administration of study product will also be considered treatment emergent. Such 
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events will be captured on the eCRF as new events, with the onset date as the date of the 
increase in severity. 
7.8.2.5 
Serious Adverse Events  
A SAE is any adverse event that results in any of the following outcomes: 
• Death 
• Life-threatening (immediate risk of death) 
• Inpatient hospitalization 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 that may not result in death, be life-threatening, or 
require hospitalization may be considered SAEs when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home; blood dyscrasias or 
convulsions that do not result in inpatient hospitalization or the development of 
drug dependency or drug abuse. 
 
7.8.2.6 
Immediately Reportable Event  
IREs are events that must be reported immediately to MacroGenics Product Safety within 
24 hours of being identified. IREs include but are not limited to: 
• SAEs 
• AEs leading to permanent discontinuation of study drug in an individual patient. 
• Pregnancy in a study patient or partner of a study patient. [Note: If the female 
partner of a male patient 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.] 
• The following AESIs (Section 7.8.3): 
o Grade 3 infusion-related reactions or CRS (see Section 6.5.1) 
o irAE (see Section 6.5.2) 
• Administration of a dose significantly greater than the planned dose of either 
MGA271, pembrolizumab, or MGA012 resulting in an event of clinical 
consequence. 
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• Withdrawal of the patient from study drug administration for any reason other 
than disease progression. 
• 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 without any alternate etiology 
 
In those cases, in which the IRE is considered related to study drug, the study drug may be 
discontinued and the patient will continue participation in the study for observational safety 
and analysis (except for cases where the patient is withdrawn from the study by the 
Investigator). At any time after completion of the study, if an Investigator becomes aware of 
a serious adverse event that s/he suspects is related to study drug, the Investigator should 
report the event to MacroGenics, Inc. Product Safety. 
7.8.3 
Adverse Events of Special Interest  
AESI will include the following: 
• Infusion reactions including cytokine release syndrome 
• Immune-related AE of Grade 3 or greater suggestive of an autoimmune process, 
including but not limited to: pneumonitis, colitis, autoimmune hepatitis, arthritis, 
glomerulonephritis, myocarditis and cardiomyopathy, hypophysitis, thyroiditis, 
myositis, uveitis, neurotoxicity, or other autoimmune endocrinopathies, 
pericarditis, or dermatologic toxicity.  
 
7.8.4 
Product Quality Issue with Clinical Consequences  
If a product quality issue results in an event of clinical consequences, from the use of study 
product, it must be immediately reported to the Sponsor/designee as an IRE. The Sponsor 
will collect the information and evaluate accordingly to protect the safety of the study 
patients. 
7.8.5 
Performing Adverse Event Assessments  
A physician’s assessment of the event is expected to be completed in conjunction with 
reporting an IRE to the MacroGenics Product Safety/designee. 
Medical evaluation and classification of the adverse event must be performed by the 
Investigator who is qualified to review AE information. The determination of seriousness, 
severity and causality must be made according to the following criteria: 
Assessment of Seriousness: Event seriousness will be determined according to the 
definition of an SAE in Section 7.8.2. Seriousness serves as a guide for defining regulatory 
reporting obligations for AEs. 
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Assessment of Severity: Event severity will be assigned according to the Investigator’s 
assessment using the CTCAE Version 4.03 (for described events and syndromes). For events 
not contained in CTCAE, the Investigator may assign severity according to the following 
scale: 
• Grade 1= Mild 
• Grade 2 = Moderate AE 
• Grade 3 = Severe AE 
• Grade 4 = Life-threatening or disabling AE 
• Grade 5 = Death related to AE 
 
Any event or laboratory value judged as Grade 4 severity should be separately evaluated to 
determine whether it also meets the serious criterion of “immediately life threatening.” 
Note: Severity is not synonymous with seriousness. The term "severe" is often used to 
describe the intensity (severity) of a specific event. The event itself, however, may be of 
relatively minor medical significance (such as severe headache). This is not the same as 
"serious," which is based on patient/event outcome or action criteria usually associated with 
events that pose a threat to a patient's life or functioning. 
Assessment of Causality: The Investigator is required to provide an assessment of causality 
or relationship of AEs to the study drug based on 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 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 patient’s medical record). 
Unlikely: The event is unlikely to be related to the study drug and likely to be related to 
factors other than study drug. 
If an SAE is considered "unlikely" or "unrelated" to study drug, the Investigator should offer 
his/her clinical opinion as to what factor(s), agent(s), or process(es) were the likely causative 
mechanism for the event. 
Causality assessments that are considered related to study drug: 
Possible: There is an association between the event and the administration of the study drug 
and there is a plausible mechanism for the event to be related to study drug; but there may 
also be alternative etiology, such as characteristics of the patient’s clinical status or 
underlying disease. 
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Probable: There is an association between the event and the administration of study drug, a 
plausible mechanism for the event to be related to the study drug and the event could not be 
reasonably explained by known characteristics of the patient’s clinical status or an alternative 
etiology is not apparent. 
Definite: There is an association between the event and the administration of study drug; a 
plausible mechanism for the event to be related to the study drug and causes other than the 
study drug has been ruled out and/or the event re-appeared on re-exposure to the study drug. 
Assessment of Expectedness: As part of the regulatory reporting requirements, the Sponsor 
must perform an assessment of expectedness (expected/unexpected from the perspective of 
previously observed, not on the basis of what might be anticipated from the pharmacological 
properties of a medicinal product) for AEs. Adverse reactions will be considered unexpected 
if the nature, seriousness, severity or outcome of the reaction(s) is not consistent with the 
reference information (e.g., the Adverse Drug Reaction section of the Investigator’s 
Brochure) for the study product. 
7.8.6 
Reporting of Adverse Events to the Sponsor  
Adverse events will be collected and followed from the time the patient provides informed 
consent for the study until the End of Treatment visit or 28 days after the last dose of study 
drug. If a patient experiences an AE after the informed consent document is signed and prior 
to treatment with study drug, it should be captured as medical history; however, if the 
Investigator believes the AE may have been caused by a protocol-related procedure it will be 
recorded as an AE and entered onto the eCRF. 
Adverse events occurring after the patient undergoes early termination or completes the trial 
(completes the End of Treatment visit), need not be reported unless the event is serious and 
the Investigator believes that the event may have been caused by the study drug or a protocol 
procedure. 
To identify the occurrence of any new medical complaints or worsening of previous 
complaints, non-leading questioning should be posed to the patient. 
Events related to disease progression/worsening of underlying disease (including those with a 
fatal outcome) will be collected as efficacy endpoints, and not documented as AEs/SAEs. 
These events may not qualify for expedited reporting to regulatory agencies if consistent with 
expected rates of progression for the underlying disease. However, if an SAE occurs in a 
patient and it is unclear if the event is due to progressive disease, the SAE should be 
reported. 
If a patient reports signs and symptoms that represent a single medical syndrome, diagnosis, 
or concept, the syndrome/diagnosis/concept should be documented (e.g., cough, runny nose, 
fever = Upper Respiratory Tract Infection) in the eCRF. 
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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. 
Adverse events occurring after the patient completes the trial or after early termination need 
not be reported unless the event is serious and the Investigator believes that the event may 
have been caused by the study drug or a protocol procedure. 
Clinical Laboratory Changes: Safety laboratory assessments will be carried out locally and 
evaluated by the Investigator to ensure patient safety. The Investigator is responsible for 
reviewing the results of all laboratory tests as they become available. Laboratory tests will be 
graded according to CTCAE v 4.03. 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. 
If the Investigator determines the laboratory value is an abnormal change from baseline and 
is of clinical significance for that patient, it is considered an AE. Generally, Grade 1 
laboratory findings need not be reported as AEs unless clinically significant. The Investigator 
will evaluate laboratory findings of ≥ Grade 2 or higher classification to determine their 
clinical significance and if an AE has occurred. Consistent with the CTCAE designation of 
Grade 3 events as severe or medically significant and Grade 4 events as life-threatening, 
Grade 3 and Grade 4 laboratory findings should be reported as AEs or SAEs, as appropriate. 
Grade 2 laboratory findings may be reported as AEs if, in the opinion of the Investigator, the 
event exhibits clinical significance. If clinically relevant abnormal laboratory values are 
associated with clinical symptom(s), or consistent with a diagnosis, the diagnosis should be 
reported as the AE (e.g., hemoglobin 9 g/dL in an adult female = anemia). If these clinically 
relevant abnormal laboratory values do not result in a diagnosis, the test result or finding 
should be reported as the AE assuming that it does not represent a laboratory error. Repeat 
testing may be indicated. Such laboratory values should generally be recorded as “increased” 
or “decreased” (e.g., change from baseline hemoglobin of 13 g/dL to 11g/dL = hemoglobin 
decreased). 
7.9 
Notification to the Sponsor of Events Requiring Immediate 
Reporting  
Throughout the study, the Investigator must document all AEs on the eCRF in a timely 
manner. IREs, as defined in Section 7.8.2, are events that must be reported immediately to 
MacroGenics Product Safety or designee within 24 hours of being identified. 
The Investigator must immediately complete and fax/email the Immediately Reportable 
Event (IRE) Report Form within 24 hours of identifying the event to MacroGenics Product 
Safety/designee. The IRE Report Form and IRE Report Form Completion Guidelines are 
found in the Study Procedures Manual. 
For pregnancy, the MacroGenics Pregnancy Exposure Form must also be completed and 
faxed/emailed. The Investigator must attempt to follow the pregnancy to term or termination 
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in order to report on outcome and health status of mother and child. The Pregnancy Exposure 
Form is found in the Study Procedures Manual. 
7.10 
Emergency Unblinding  
Not applicable. This is an open-label study. 
7.11 
Efficacy and/or Pharmacokinetic and Pharmacodynamic 
Assessments  
7.11.1 
Efficacy Assessments  
7.11.1.1 
Treatment of Patients According to Principles of Immune-
Related Response Criteria  
Tumor assessments will be obtained at screening using CT and/or MRI scans at time intervals 
as specified in the Appendix 1 (Time and Events Table). The study is divided into 6 Tumor 
Assessment Cycles; the first is a 6-week cycle called the Initial Tumor Assessment Cycle and 
Cycles 2 through 6 are 9-week cycles. The tumor assessment takes place at the end of each 
cycle. Treatment will continue until patients have completed study therapy and required 
follow-up, experienced disease progression, or have been withdrawn from the study (see 
Section 4.4 and Section 5.3). At each on-treatment tumor assessment time point, the 
objective response status will be determined. In the context of the statistical analysis for this 
trial, objective response determination and the assessment of best overall response (BOR) 
will be defined using both conventional RECIST1.1 criteria (Appendix 5) as well as an 
adaptation of these criteria, designated as immune-related response criteria (irRC) 
(i.e., irRECIST as defined in Appendix 6). Patient management decisions, however, will be 
made solely based on the immune-related response criteria (Appendix 6). 
For patients who demonstrate acceptable tolerability of treatment with MGA271, and an 
objective response assessment of irCR, irPR or irSD, or unconfirmed clinically-stable irPD, 
therapy may be continued (see Section 4.4 and Section 5.3). 
For patients who are otherwise clinically stable, but have met conventional criteria for PD, 
therapy may be continued at the discretion of the investigator pending confirmation of 
progression at the next scheduled tumor assessment. This approach allows for limited 
treatment of patients beyond the initial radiographic documentation of disease progression, 
assuming that patients are tolerating therapy adequately, that patients remain otherwise 
clinically stable despite this initial radiographic evidence of disease progression and that the 
Investigator feels the patient may still derive benefit from continuation of therapy. Treatment 
of patients according to irRC (i.e., irRECIST) principles is supported by well-documented 
evidence that in some patients treated with T cell directed, immune-modulatory agents, their 
tumors can evolve to an objective response after an initial period characterized by either 
apparent radiographic growth of target lesions or the development of new target lesions that 
would otherwise meet the criteria for disease progression using conventional response 
criteria (67) 
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For patients in whom progression is confirmed at the next scheduled tumor assessment, the 
criteria for immune-related PD (irPD) will have been met, and treatment with MGA271, 
pembrolizumab, or MGA012 should be discontinued. The patient should be removed from 
study participation after completion of protocol specified follow-up (see Section 8.3 and 
Appendix 1). For patients who experience an objective response of immune-related complete 
response (irCR) or immune-related partial response (irPR), 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. 
7.11.1.2 
Objective Response and Response Duration  
Target and non-target lesions will be designated and evaluated using both conventional 
RECIST 1.1 criteria (Appendix 5) and immune-related response criteria (Appendix 6) as 
noted above for the purposes of statistical analysis. Objective responses will be categorized 
as CR, PR, SD, or PD for conventional RECIST 1.1 criteria and irCR, irPR, irSD, and irPD 
for the immune-related response criteria. Determination of the objective response rate will be 
calculated based on the proportion of response evaluable patients achieving CR or PR using 
the respective criteria, when such responses are confirmed by a subsequent scan obtained at 
least 28 days after the initial documentation of objective response. Response-evaluable 
patients will include those patients who have measurable disease and have had a baseline 
tumor assessment and at least 1 on-treatment tumor assessments (see Appendix 1). Objective 
responses that are not subsequently documented with a confirmatory CT or MRI scan (e.g., 
unconfirmed responses) will not be included as an objective response for the purpose of 
calculating overall objective response rates. Response duration will be calculated from the 
time of initial response (CR or PR) documentation (in patients who have a subsequent 
confirmation of objective response) to the time of progressive disease or death, whichever 
occurs first.  
A patient’s response duration will be censored if at the time of last antitumor assessment 
response is ongoing. Patients who discontinue study treatment for a reason other than 
progressive disease may be followed for efficacy until 1 of the following occurs: the patient 
progresses, withdraws consent for follow up, or initiates other anti-cancer therapy, or the 
overall trial is closed.  
7.11.1.3 
Progression-free Survival (PFS)  
PFS will be calculated as the time from the date of the first dose of study drug until the date 
of any documented PD; the date of death from any cause, or date of last assessment for tumor 
progression, whichever occurs first (Appendix 3). A patient’s PFS will be censored if at the 
time of last assessment for progression, the patient remains progression free. PFS will be 
determined using both conventional RECIST 1.1 and irRC (i.e., irRECIST) criteria.  
7.11.1.4 
Overall Survival (OS)  
OS will be calculated as the time from the first dose of study drug until death due to any 
cause or last observation or contact. A patient’s OS will be censored if at the time of last 
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contact, the patient was alive. In addition, landmark 6-month OS rate will be determined. OS 
will be monitored as described in the Study Manual.  
7.11.2 
Immunogenicity  
For patients receiving MGA271 and pembrolizumab, blood samples for MGA271 
immunogenicity assessments (i.e., ADA) will be collected at the time points in Table 5; 
Electrochemiluminescence will be used for MGA271 ADA assay.  
For patients receiving MGA271 and MGA012 (Cohort 4), MGA271 and MGA012 ADA 
blood samples will be collected per Appendix 2; ELISA method will be used for the 
MGA012 ADA assay. 
Table 5 
Immunogenicity Blood Sampling Schedule for Patients Receiving 
MGA271 and Pembrolizumab  
Tumor 
Assessment 
Cycle 
Study Day 
Treatment 
Day of 
Cycle 
Dose Number a,b 
MGA271 
(Pembrolizumab) 
ADA Sampling 
Time 
(h) 
ADA Sample 
Collection for 
MGA271 
Initial (1st) 
1 
1 
1 (1) 
0 (Predose) c 
X 
22 
22 
4 (2) 
0 (Predose) d 
X 
2nd 
43 
1 
7 (3) 
0 (Predose) d 
X 
3rd 
106 
1 
16 (6) 
0 (Predose) d 
X 
4th 
169 
1 
25 (9) 
0 (Predose) d 
X 
5th 
232 
1 
34 (12) 
0 (Predose) d 
X 
6th 
337 
43 
49 (17) 
0 (Predose) d 
X 
NA e 
NA 
NA 
28 Days After the 
Last Dose of 
MGA271 
NA 
X 
a 
Pembrolizumab dose and MGA271 dose administered as 0.5 hour (30 min) and 2 hours (120 min) 
infusions, respectively. 
b 
On days when MGA271 is administered after pembrolizumab, MGA271 may be administered the next day 
for safety reasons or scheduling purposes. 
c 
Predose ADA sample on Study Day 1 (Treatment Day 1 of Initial [1st] Cycle) will be collected prior to 
pembrolizumab infusion. 
d 
All other ADA samples will be collected prior pembrolizumab and prior to the MGA271 infusion when 
MGA271 is given alone; the start of infusion is designated as time = 0 hour. 
e 
Not applicable; however, ADA sample will be collected simultaneously with PK sample. 
NOTE: Both planned and actual start and end of infusion times and ADA sample collection times will be 
recorded on the eCRFs. The window of time for obtaining ADA samples is provided in the Study Procedures 
Manual. 
 
7.11.3 
Pharmacokinetics  
Serum concentrations of MGA271 and MGA012 will be monitored using a quantitative 
sandwich ELISA. Single and multiple dose PK parameters for MGA271 and MGA012, Cmax, 
Tmax, AUCtau, Ctrough, CL, Vss, and t1/2 will be derived from MGGA271 and MGA012 serum 
concentration versus time data. 
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7.11.3.1 
MGA271 and MGA012 PK  
For patients receiving MGA271 and pembrolizumab, blood samples for MGA271 PK will be 
collected at the following time points given in Table 6 and for patients receiving MGA271 
and MGA012 blood samples for MGA271 and MGA012 per Appendix 2. Blood samples 
will be collected from the arm contralateral to the site of IV infusion. If an indwelling 
catheter is used, the fluid in the catheter will be removed and discarded prior to the collection 
of blood sample for ADA or PK assessment. 
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Table 6 
Pharmacokinetics Blood Sampling Schedule for Patients Receiving 
MGA271 and Pembrolizumab  
Tumor 
Assessment 
Cycle 
Study 
Day 
Treatment 
Day of 
Cycle 
MGA271 
(Pembrolizumab) 
Dose Number a,b 
PK Sampling Time 
After the Start of 
Infusion (h) 
PK Sample 
Collection for 
MGA271 
Initial (1st) 
1 
1 
1 (1) 
0 (Predose) c 
X 
 
 
 
2 (EOI) d 
X 
 
 
 
 
3 
X 
 
 
 
 
5 
X 
 
 
 
 
8 (optional) g 
X 
 
2 
2 
 
24 
X 
 
3 
3 
 
48 
X 
 
8 
8 
2 
0 (Predose) e 
X 
 
 
 
 
2 (EOI) d 
X 
 
22 
22 
4 (2) 
0 (Predose) e 
X 
 
 
 
 
2 (EOI) d 
X 
2nd 
43 
1 
7 (3) 
0 (Predose) e 
X 
 
 
 
 
2 (EOI) d 
X 
 
 
 
 
3 
X 
 
 
 
 
5 
X 
 
 
 
 
8 (optional) g 
X 
 
44 
2 
 
24 
X 
 
45 
3 
 
48 
X 
 
50 
8 
8 
0 (Predose) e 
X 
3rd 
106 
1 
16 (6) 
0 (Predose) e 
X 
4th 
169 
1 
25 (9) 
0 (Predose) e 
X 
5th 
232 
1 
34 (12) 
0 (Predose) e 
X 
6th 
337 
43 
49 (17) 
0 (Predose) e 
X 
NA f 
NA 
NA 
28 days after the last 
dose of study drug 
NA 
X 
a 
Pembrolizumab dose and MGA271 dose administered as 0.5 hour (30 min) and 2 hour (120 min) infusions, 
respectively. 
b 
On days when MGA271 is administered after pembrolizumab, MGA271 may be administered the next day 
for safety reasons or scheduling purposes. 
c 
Predose PK sample on Study Day 1 (Treatment Day 1 of Initial [1st] Cycle) will be collected prior to 
pembrolizumab infusion; the start of infusion is designated as time = 0 hour; ADA sample will be collected 
simultaneously with PK sample. 
d 
EOI= end of MGA271 infusion; sample will be collected within 5 min prior to the end of infusion. 
e 
All predose PK samples will be collected prior to pembrolizumab on days when MGA271 is given after 
pembrolizumab, and prior to MGA271 infusion on days when MGA271 is given alone; the start of 
MGA271 infusion is designated as time = 0 hour; ADA sample will be collected simultaneously with PK 
sample. 
f 
Not applicable; however, PK sample will be collected simultaneously with ADA sample. 
g 
8 hour PK is optional in cases where obtaining this sample is logistically not feasible for the patient 
NOTE: Both planned and actual start and end of infusion times and PK sample collection times will be recorded 
on the CRFs. The window for PK sample collection time is provided in the Study Procedures Manual. 
If MGA271 infusion is interrupted, PK time points for 120 minutes (EOI), 3, 5, 8, 24 and 48 hours after the start 
of infusion will be recalculated as per the actual EOI and 1, 3, 6, 22 and 46 hours post end of MGA271 infusion. 
 
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7.11.4 
Pharmacodynamics/Biomarkers  
Procedures for the acquisition, handling and processing of pharmacodynamic biomarker 
specimens will be provided in the Laboratory Manual. 
7.11.4.1 
Tests Performed for Both Dose Escalation and Cohort 
Expansion Patients:  
• Characterization of alterations in serum cytokine levels to include, but not limited 
to, IL-2, IL-6, IL-10 and TNF-α 
• Enumeration of lymphocyte subsets, NK cells and activation status over time via 
multi-parameter flow cytometry on whole blood; evaluation of the regulatory T 
cell population over time 
• Determination of B7-H3 and PD-L1 expression as well as immune cell infiltration 
into the tumor (e.g., CD4+ and CD8+ T cell infiltration) will be explored via IHC 
staining or other method of archival tumor biopsy specimens (unless fresh tumor 
sample submitted and used to determine B7-H3 expression and no archived 
sample obtained) 
• Soluble B7-H3 over time analyzed by enzyme-linked immunosorbent assay 
(ELISA); in addition to other potential circulating serum biomarkers indicative of 
potential tumor response 
 
Note: Cohort 4 will not have PD-L1 testing. 
7.11.4.2 
Tests Performed for Cohort Expansion Patients:  
• Determination of B7-H3 tumor cell and tumor vasculature expression, PD-L1 
tumor cell membranous expression, and immune cell infiltration into the tumor 
bed via IHC staining (or other method for immune cell infiltration) of archival 
tissue and/or of optional paired pre- and on-treatment tumor biopsy specimens 
when available. The optional pre-treatment and on-treatment tumor biopsies will 
be carried out for cohort expansion patients who elect to undergo pre- and on-
treatment biopsy. 
• Assessment of PD-L1 tumor expression levels.  
• Characterization of T cell repertoire using T cell receptor (TCR) spectratyping of 
PBMCs on selected samples may be carried out depending on observed anti-
tumor activity. 
• An assessment of the ability of patient’s PBMCs to support MGA271-mediated 
antibody dependent cellular cytotoxicity (ADCC) activity in pre- and on-
treatment samples using a non-isotopic assay with the patient’s PBMCs as 
effector cells and B7-H3 expressing tumor cell lines as target cells may be carried 
out depending on observed anti-tumor activity.  
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7.11.4.3 
Archival Tumor Biopsy Specimens  
Patients who have not had tumor B7-H3 expression levels previously determined using IHC 
analysis performed at the Sponsor-designated central laboratory will be required to have 
identified an archival tumor specimen (FFPE) or 5 unstained slides for the determination of 
B7-H3 expression within tumor specimens using an IHC staining assay. Tumor specimens 
should be sufficient to provide a minimum of 5 slides to enable determination of B7-H3 
expression using IHC staining. If a tumor biopsy is performed at baseline with resulting 
sample adequate to make 5 slides, the archived sample requirement will be waived, but it is 
still strongly encouraged to obtain the archived sample so that comparisons in B7-H3 
staining can be made between FFPE slides from archived and FFPE slides from fresh tissue. 
Additional archival slides will be required for assessment of PD-L1 expression if the patient 
has not already had the level of PD-L1 expression assessed.  
7.11.4.4 
Optional Paired Pre-Treatment and On-Treatment Tumor 
Biopsy Specimens  
Patients in the Cohort Expansion Phase who have one lesion considered to be potentially 
amenable to biopsy have the option of providing consent for paired biopsy samples. Baseline 
and on-treatment biopsy samples are to be done during the screening period and Day 42 ± 
3 days, respectively. Tumor lesions used for biopsy should be lesions that are felt to be 
accessible with acceptable clinical risk in the judgment of the investigator and should not be 
lesions used as RECIST target lesions, unless there are no other lesions suitable for biopsy. If 
a RECIST target lesion is used for biopsy, the lesion must be ≥ 2 cm in longest diameter. 
Lesions to be biopsied should not have been previously irradiated, unless the lesion has 
grown in size beginning at least 14 days since the last radiation dose. Note that multiple 
lesions may be used to obtain the biopsy sample. 
Lesions to be biopsied should be of sufficient size to enable acquisition of at least 2 tumor 
biopsy cores using a 16-gauge biopsy needle. Exceptions to the gauge of the needle may be 
considered after consultation with the Sponsor’s Medical Monitor. Up to 2 additional biopsy 
cores may be obtained if this can be performed with acceptable clinical risk in the judgment 
of the Investigator. Punch biopsies or 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. Additional unscheduled tumor biopsies may be 
obtained at interim or follow-up time points at the Investigator’s discretion and in 
consultation with the Sponsor Medical Monitor if clinically indicated and/or to assess 
changes in tumor histopathology over time. 
Additional instructions for the acquisition, processing, and storage of tumor biopsy 
specimens will be provided in the Laboratory Manual. The paired tumor biopsy specimens 
will be obtained to enable investigation of the pharmacodynamic effects of MGA271 within 
the local tumor microenvironment of patients with melanoma. Studies to be performed will 
include assessment of local T cell infiltration and the expression of tumor apoptosis markers. 
Tissue samples will be stored as described in Section 7.12.2 by the Sponsor for potential 
retesting after the end of the study. 
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7.12 
Other Study Procedures  
7.12.1 
Central Laboratory Evaluations  
MacroGenics or its designee will provide blood sampling supplies such as polypropylene 
transport tubes, labels, and log sheets. Serum tubes should be labeled with the patient’s 
number, date, and time of sampling. The Investigator will maintain a log with the same data. 
Specimens must be appropriately prepared, divided if appropriate, frozen, and shipped (while 
often retaining certain replicate samples at the site) according to the instructions in the 
Laboratory Manual. 
7.12.2 
Sample Retention and Further Testing  
Samples acquired for protocol-specified assays (except for the tissue sample from the biopsy 
as described in Section 7.11.4.4 that will be stored indefinitely) may be retained up to 2 years 
after last approval of a marketing application in an International Conference on 
Harmonisation (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. Samples may also be 
used for additional future research use (including assay development/optimization) and may 
be retained up to 15 years from the end of study for these future research purposes; however, 
patients must provide consent for additional future research uses. 
7.13 
Appropriateness of Measurements  
Routine laboratory evaluations including hematology, chemistry, special chemistry, 
coagulation, 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 elucidate certain AEs. 
Serum concentrations of MGA271 will be monitored using an ELISA based assay. Standard 
bridging ELISAs will be carried out in the Sponsor’s designated central laboratory to 
characterize the immunogenicity of MGA271. Analysis of PK data will be carried out using 
industry standard software. Population PK modeling may be performed and an appropriate 
model and model parameters may be described. 
7.13.1 
Rationale for Use of Immune Response Criteria  
Patients will be managed according to irRC (i.e., irRECIST) principles. This approach allows 
for limited treatment of patients beyond the initial radiographic documentation of disease 
progression, assuming that patients are tolerating therapy adequately, that patients remain 
otherwise clinically stable despite this initial radiographic evidence of disease progression 
and that the Investigator considers that the patient may still derive benefit from continuation 
of therapy. Treatment of patients according to irRC (i.e., irRECIST) principles is supported 
by well-documented evidence that in some patients treated with T cell directed, immune-
modulatory agents, their tumors can evolve to an objective response after an initial period 
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characterized by either growth of target lesions or the development of new target lesions that 
would otherwise meet the criteria for disease progression using conventional response 
criteria (68) (see also Appendix 6). Further details regarding the application of this approach 
are described in Section 7.11.1. 
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8 
STUDY ACTIVITIES  
A table of study activities including screening, on-study and end-of study visits is presented 
in Appendix 1, Time and Events Table. 
8.1 
Screening Period  
At the screening visit, patients will enter the study upon signing the informed consent 
document. No screening activities outside of usual standard-of-care should be performed 
prior to obtaining informed consent from the patient. Only those patients who meet all 
inclusion/ exclusion criteria specified in Section 5 will be entered into this study. 
8.2 
Registration  
Each patient must be registered with MacroGenics prior to enrollment. The following 
information should be provided during registration: 
• Date of birth 
• Date of signed informed consent 
• Planned date of first of pembrolizumab and MGA271 or of MGA271+MGA012 
administration 
 
The instructions for the registration process are provided in the Study Manual. 
8.3 
End of Treatment Visit  
A list of evaluations to be performed for the End of Treatment visit is provided in Appendix 
1. Criteria for triggering the End of Treatment visit are specified in Section 5.3. The End of 
Treatment Visit should be performed after the patient has met off-study criteria or has been 
followed for at least 28 days after the last dose of study drug depending on ability to follow 
the patient and duration and severity of ongoing AEs. It is recognized that certain patients 
(such as those experiencing progression of disease) may be cared for in facilities other than 
the participating investigational site, may proceed to receive other cancer therapy, and/or may 
elect not to return to the investigational site. Therefore, this visit is considered optional, but 
should be carried out whenever possible. 
 
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9 
PLANNED STATISTICAL METHODS  
9.1 
General Considerations  
This Phase 1 study is primarily observational and, thus, the majority of the statistical 
summaries will be descriptive. Summary statistics will consist of absolute and relative 
frequencies of each category of discrete variables and of means, standard deviations, 
medians, minimums and maximums for continuous variables. 
Safety and efficacy summaries will be provided for each dose level cohort during dose 
escalation and for all dose level cohorts combined, as well as for each expansion cohort 
(melanoma, SCCHN, NSCLC, and urothelial cancer) and all expansion cohorts combined. 
Response rates may be calculated for specific disease sub-groups, if appropriate. 
Baseline will be considered the closest value obtained prior to first dose. Data that are 
reported as missing will be treated as missing in all data summaries. Incomplete dates will be 
imputed and defined in the Statistical Analysis Plan. In descriptive summaries for safety, 
observations that are spurious (extreme relative to the majority of the data) will not be altered 
or removed from the summary. 
9.2 
Determination of Sample Size  
This study plans to enroll approximately up to 157 patients (up to approximately 45 in the 
dose escalation phase and 112 in the MTD expansion cohorts). This sample size is considered 
sufficient to evaluate the primary objective of this study (toxicity). In addition, 
 
 
 
 in select solid tumors. 
Additional patients may be enrolled in study groups to meet sample size requirements if 
discontinuations unrelated to treatment-emergent signs and symptoms occur. 
For the Cohort Expansion Phase, up to 16 patients each will be enrolled into melanoma and 
urothelial expansion cohorts, respectively, and up to 20 patients will be enrolled into each of 
2 cohorts for NSCLC and SCCHN, respectively. The sample size is primarily based on 
providing preliminary estimation of responses. 
 
 
 
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9.2.1 
Analysis Populations  
Two populations will be used for analysis, the Safety Population and the Response 
Evaluable Population, as defined below: 
• Safety Population: All patients who received at least one dose of either MGA271 
or pembrolizumab or MGA012. Safety Population will be used to summarize 
baseline data, safety data and for assessment of OS and PFS. Patients who receive 
at least one dose of MGA271 or MGA012 will be included in PK, PD, and 
immunogenicity analyses. 
• Response Evaluable Population: All patients who received MGA271 and 
pembrolizumab or MGA271 +MGA012 and had at least 1 post-infusion 
radiographic tumor assessments. Patients who meet these criteria will be eligible 
for the determination of best overall response and will be included in the response 
evaluable population used for the calculation of ORRs using both conventional 
RECIST 1.1 (Appendix 5) and irRC (i.e., irRECIST as defined in Appendix 6) 
criteria. 
 
Patients who withdraw before receiving all protocol-specified treatment before completion of 
the DLT evaluation period, for a reason unrelated to drug toxicity will be considered to have 
inadequate data to support dose escalation. In this case, replacement patients may be enrolled 
at the same dose level and schedule as necessary to complete the cohort. 
  
           
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
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9.3 
Demographics and Baseline Characteristics  
Patient disposition, demographics, baseline characteristics, disease history, medical history, 
concomitant medications, and study drug exposure data will be summarized using descriptive 
statistics. 
9.4 
Safety Endpoint(s)  
9.4.1 
Adverse Events  
Adverse events will be coded to the Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary. Only treatment-emergent AEs, as defined in Section 7.8.2, will be summarized in 
tables. Events prior to treatment (e.g., due to study-related procedure) will be listed in an 
appendix to the final study report. 
The following tables of adverse event data will be created to summarize the number and 
percent of patients who experience at least one event of each of the following types: 
• All AEs by CTCAE grade 
• Drug related AEs by CTCAE grade 
• AEs with CTCAE Grade severity Grade  3 
• All drug related AEs by CTCAE Grade severity Grade  3 
• All SAE (this may be a listing if there are few events) 
• Drug related SAE 
• Fatal AEs (this may be a listing if there are few events) 
• AESIs 
• AEs that result in study discontinuation 
• AEs which lead to dose interruption 
• AEs that lead to withdrawal of study drug 
 
All of these tables will display the number and percent of patients that experience the given 
event and will display events by MedDRA System Organ Class (SOC) and Preferred Term. 
Events will be displayed alphabetically for SOC and Preferred Term. An overall summary of 
AEs will display the number and percent of patient/patients who experience at least one event 
of each of the following types: 
• All AEs 
• Drug Related AEs 
• AEs with CTCAE severity  Grade 3 
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• Drug-related AE with CTCAE severity Grade ≥ 3 
• All SAE 
• Drug-related SAE 
• AEs that lead to dose interruption 
• AE that results in study or study drug discontinuation 
• Fatal AEs 
• AESIs 
 
9.4.2 
Laboratory Values  
Summaries of laboratory values will display descriptive statistics for numerically quantified 
labs. Summaries will be grouped by laboratory panel (e.g., hematology, blood chemistry, and 
urinalysis) and will be displayed by visit for each laboratory parameter. 
A list of repeated labs including original values and repeat values will be included. 
Graphs of mean values over time may also be generated. 
9.4.3 
Other Safety Endpoints  
ECGs will be collected and analyzed for evidence of cardiac toxicity, especially prolongation 
of QT interval. Vital signs will be summarized with descriptive statistics at each visit and 
time point where they are collected. 
9.5 
Efficacy Endpoints  
Response will be categorized as CR, PR, SD, or PD and evaluated using RECIST 1.1 criteria 
(Appendix 5) and as irCR, irPR, irSD, or irPD using the immune-related response criteria 
(i.e., irRECIST as defined in Appendix 6). The ORR will be the proportion of patients in the 
response evaluable population achieving CR or PR when such responses are confirmed at 
least 28 days after the initial observation of an objective response. A two-sided 95% exact 
binomial confidence interval will be calculated around the ORR for each expansion cohort. 
Response duration will be calculated for responders as the time from initial response (CR or 
PR) to the time of PD or death, whichever occurs first. Kaplan-Meier methods will be used to 
estimate response duration over time and the median response duration. Responders who 
complete the study without documented PD will be censored at the date of their last tumor 
assessment.  
PFS and irPFS will be calculated as the time from the initial infusion of pembrolizumab or 
MGA271 until documented disease progression, or death from any cause. Patients with no 
PFS event (disease progression or death from any cause) will be censored at the date of their 
last tumor assessment. In addition, PFS and irPFS rates will be calculated at 3-month and 6-
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month time points from the first dose of study drug. Kaplan-Meier methods will be used to 
estimate PFS over time and the median duration of PFS. The method of Brookmeyer and 
Crowley (9) will be used to construct 95% CIs around PFS estimates of the median and other 
quartiles for each expansion cohort. 
Incomplete and missing data can complicate interpretation of PFS. Appendix 3 describes the 
handling of these data for the PFS analysis.  
Overall survival is defined as the time from the initial infusion of pembrolizumab or 
MGA271 to death from any cause. Kaplan-Meier methods will be used to estimate the 
overall survival function. Patients who do not die will be censored at the date that the patient 
was last known to be alive. In addition, OS will be calculated at 6 months from the first dose 
of study drug. 
9.6 
Other Assessments or Analyses  
Pharmacokinetic Analysis: Summary statistics will be tabulated for PK parameters by 
MGA271 dose. Geometric means and percent coefficients of variation will be reported for 
Cmax, AUCtau, and Ctrough; arithmetic means and standard deviations will be reported for 
terminal half-life (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. Population PK 
analyses may be conducted using data from this study alone or combined with data from 
other studies. 
Immunogenicity Analysis: The proportion of patients who are negative for MGA271 ADA 
at baseline and become positive in this assay, the proportion of patients who are negative at 
baseline and remain negative, and those who have positive ADA at baseline that increases or 
decreases in titer over the course of treatment will be summarized. 
Pharmacodynamic Analysis: Summary statistics for pharmacodynamics parameters such 
as, but not limited to, those listed under section, “Pharmacodynamics/Biomarkers/Tumor 
Biopsy” (Section 7.11.4) and corresponding changes from baseline, will be summarized 
and/or may also be presented graphically as will possible associations between changes in 
pharmacodynamics measures of interest and MGA271 dose and exposure may be explored. 
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10 
QUALITY CONTROL AND ASSURANCE  
Quality review activities will be undertaken to ensure accurate, complete, and reliable data. 
MacroGenics, Inc. and/or its representatives will do the following: 
• Provide instructional material to the study sites, as appropriate. 
• Sponsor a start-up training session (Investigator Meeting or Study Initiation Visit) 
to instruct the Investigators and study coordinators. This session will give 
instruction on the protocol, the completion of the eCRFs, and study procedures. 
• Make periodic visits to the study site to monitor protocol compliance and general 
Good Clinical Practice GCP compliance. 
• Be available for consultation and stay in contact with the study site personnel by 
mail, e-mail, telephone, and/or fax. 
• Review and evaluate eCRF data and use standard computer checks to detect and 
query errors in data collection. 
• Conduct a quality review of the database. 
 
10.1 
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 patient medical records in the patient files as source documents for 
the study (refer to Section 11.5 for additional information on source documents). 
MacroGenics, Inc. 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 a sample of the patient data recorded on eCRFs against source documents at the 
study site. The Investigator will also ensure that the monitor is given access to all the above 
noted study-related documents, source documents (regardless of media) and study-related 
facilities (e.g., investigational pharmacy, etc.), and has adequate space to conduct the 
monitoring visit. Queries may be raised if any datum is unclear or contradictory. The 
Investigator and site personnel must address all queries in a timely manner. 
Participation as an Investigator in this study implies acceptance of the potential for inspection 
by the study Sponsor/Representatives, US or non-US government regulatory authorities, 
IRB/IEC and applicable compliance and quality assurance offices. The Investigator will 
permit study-related audits and inspections and will provide access to all study-related 
documents (e.g., source documents, regulatory documents, data collection instruments, study 
data etc.). The Investigator will ensure the capability for inspections of applicable study-
related facilities (e.g., pharmacy, diagnostic laboratory, etc.). 
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10.2 
Data Entry and Computerized Systems  
An electronic data capture system will be used in this trial. Other data assessments, such as 
central laboratory assays, immunochemistry, and ECG data, will be managed by central 
vendors for transfer to MacroGenics, Inc. or representative for use in the study analysis 
database. 
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11 
ADMINISTRATIVE CONSIDERATIONS  
11.1 
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 patient recruitment, payment or 
compensation procedures, or information from the Sponsor will be submitted to the IRB/IEC. 
The IRB/IEC’s written unconditional approval of the study protocol and the informed 
consent forms (ICFs) will be in the possession of the Investigator and the Sponsor before the 
study drug is initiated at the Investigator’s site. The Investigator will transmit the IRB/IEC’s 
unconditional approval statement to the Sponsor. This approval must include the date of 
review, and refer to the study by protocol title and/or study number and version number and 
refer to the ICFs by version number or date. If the IRB/IEC or institution uses its own unique 
number for the protocol instead of the Sponsor’s number, that unique number should be 
noted on the approval statement. If approval of the ICFs is stamped on the forms (instead of 
documented in the IRB/IEC approval statement) the date of approval and/or expiration must 
be included. 
Protocol modifications or changes may not be initiated without approval from the Sponsor 
and prior written IRB/IEC approval (when required), except when necessary to eliminate 
immediate hazards to the patients. Such modifications will be submitted to the IRB/IEC; 
written verification that the modification was submitted should be obtained. 
The Investigator must, where required by local regulations, submit 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 patients or potential patients (e.g., recruitment materials, 
diary cards) and the plan for distribution/use. 
• Revisions of other documents originally submitted for review or for notification. 
• Serious and/or unexpected AEs occurring during the study. 
• New information that may adversely affect the safety of patients or conduct of the 
study. 
• At minimum, an annual update and/or request for re-approval of study, unless 
otherwise specified by IRB/IEC. 
• Protocol violations or deviations 
• Notification when the study has been completed. 
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• Proof of indemnity/liability insurance. 
• Other documents required by the IRB/IEC 
 
11.2 
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. 
The protocol and the informed consent document will be reviewed and approved by the 
IRB/IEC of each participating center before study initiation. Serious adverse events, 
regardless of causality, will be reported to the Sponsor/designee and to the IRB/IEC, if 
required by local regulations. The Investigator will keep the IRB/IEC informed regarding the 
progress of the study. 
11.3 
Patient Information and Consent  
It is the responsibility of the Investigator to obtain and document written informed consent 
from the patient. Informed consent in compliance with the principles of informed consent in 
ICH E6 and all applicable local regulations should be obtained before any protocol-specified 
procedures or interventions are conducted. The Sponsor reserves the right to delay initiation 
of the study at a site where ICFs do not meet the standards of applicable local regulations or 
ICH E6. 
Information should be given to the patient in both oral and written form, and patients must be 
given ample opportunity to inquire about details of the study. 
The consent form generated by the Investigator must be approved by the IRB/IEC. The 
Investigator will provide the Sponsor with a copy of the IRB/IEC-approved consent forms 
and a copy of the IRB/IEC’s written approval before the start of the study. 
Consent forms must be written (and appropriately translated in the patient’s native language 
or language in which the patient has fluency) so as to be understood by the prospective 
patient. Informed consent will be documented by the use of a written consent form approved 
by the IRB/IEC. The form must be signed and dated by the patient, and by the person who 
conducted the discussion of the informed consent. 
All versions of each patient’s signed ICF must be kept on file by the Investigator for possible 
inspection by regulatory authorities and/or authorized MacroGenics’ monitoring and 
regulatory compliance persons. The patient should receive a copy of the signed and dated 
written ICF and any other written information provided to the patients. 
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11.4 
Patient Confidentiality  
To maintain confidentiality of patients, all laboratory specimens, evaluation forms, reports, 
and other records will be identified by a coded number. Clinical information will not be 
released without written permission of the patient, except as necessary for monitoring by the 
relevant regulatory authorities, the Sponsor of the clinical trial, 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. 
11.5 
Case Report Forms and Study Records  
Source data in a clinical trial are the original records or certified copies where clinical 
observations are first recorded, which may include, but are not limited to, the patient’s 
medical file, original laboratory reports, histology, and pathology reports (as applicable). The 
Investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information will be entered onto CRFs designed to capture all observations 
and other data pertinent to the clinical investigation. Data should be recorded on source 
documents and entered onto eCRFs. Electronic CRFs should be filled out completely 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. 
11.6 
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. 
The Investigator may be subjected to a field audit by MacroGenics, Inc. (or designee) and/or 
regulatory inspectors in order to validate the participation of patients in the study and to 
verify the data reported on the eCRFs on file at MacroGenics, Inc. MacroGenics should be 
notified immediately of any audits scheduled by any regulatory authorities. Copies of audit 
reports, findings and/or correspondence from regulatory authorities for audits conducted on a 
MacroGenics-sponsored study should be promptly forwarded to MacroGenics. 
11.7 
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, Inc. is 
required to maintain study records for longer periods (e.g., applicable local regulations); 
therefore, MacroGenics, Inc. should be contacted before study records are removed from the 
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control of the investigational site for any reason. The Investigator must obtain written 
permission from MacroGenics, Inc. prior to destruction of study documents. 
11.8 
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: 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 MGA271; 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 (as defined in Section 4.7.2). 
In consideration of participation in the study, MacroGenics, Inc. 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. 
11.9 
Publication and Disclosure Policy  
Data collected in this clinical study belong to the study Sponsor which will formulate a 
policy on the use of study data. This policy will be codified in the Clinical Trial Agreement. 
This includes authorship issues: scheduling and prioritizing analyses for reports, publications, 
and presentations; and developing a review and approval process. 
11.10 
Discontinuation of the Study or Study Sites  
11.10.1 
Discontinuation of Study Sites  
Participation may be discontinued if MacroGenics, Inc., the Investigator, a regulatory 
authority, or the IRB/IEC of the study sites deems it necessary for any reason. 
11.10.2 
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. 
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11.11 
Identification of the Coordinating Principal Investigator  
A Coordinating Principal Investigator will be appointed by the Sponsor Medical Monitor 
prior to the end of the study. 
As part of his or her responsibilities, the Coordinating Principal Investigator will review the 
final CSR. Agreement with the final CSR will be documented by the dated signature of the 
Coordinating Principal Investigator. 
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12 
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(NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapy 
in advanced melanoma (MEL). J Clin Oncol 2014;32(5s). 
58. Tekle C, Nygren MK, Chen YW, Dybsjord I, Nesland JM, Maelandsmo GM, et al. 
B7-H3 contributes to the metastatic capacity of melanoma cells by modulation of known 
metastasis-associated genes. Int J Cancer 2012 May 15;130(10):2282-90. 
59. Thompson RH, Kwon ED, Allison JP. Inhibitors of B7-CD28 costimulation in urologic 
malignancies. Immunotherapy 2009 Jan;1(1):129-39. 
60. Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to 
activate anti-tumor immunity. Curr Opin Immunol 2012 Apr;24(2):207-12. 
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Clinical Trial Protocol: CP-MGA271-03 
Amendment 6, 26 August 2020 
 
 
 
 
 
61. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. 
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 
2012 Jun 28;366(26):2443-54. 
62. Vermorken JB, Trigo J, Hitt R, Koralewski P, Diaz-Rubio E, Rolland F, et al. Open-
label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of 
cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell 
carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin 
Oncol 2007 Jun 1;25(16):2171-7. 
63. Wang, D D, Zhang, S, Zhao, H, Men, A Y, and Parivar, K. Fixed dosing versus body 
size-based dosing of monoclonal antibodies in adult clinical trials. J Clin Pharmacol, 
2009. 49(9): p. 1012-24  
64. Wang L, Kang FB, Shan BE. B7-H3 mediated tumor immunology: Friend or foe? Int J 
Cancer 2013 Sep 7. 
65. Weng WK, Levy R. Two immunoglobulin G fragment C receptor polymorphisms 
independently predict response to rituximab in patients with follicular lymphoma. J Clin 
Oncol 2003 Nov 1;21(21):3940-7. 
66. Wilke CM, Wei S, Wang L, Kryczek I, Kao J, Zou W. Dual biological effects of the 
cytokines interleukin-10 and interferon-gamma. Cancer Immunol Immunother 2011 
Nov;60(11):1529-41. 
67. Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbe C, et al. Guidelines for 
the evaluation of immune therapy activity in solid tumors: immune-related response 
criteria. Clin Cancer Res 2009 Dec 1;15(23):7412-20. 
68. Woo SR, Turnis ME, Goldberg MV, Bankoti J, Selby M, Nirschl CJ, et al. Immune 
inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote 
tumoral immune escape. Cancer Res 2012 Feb 15;72(4):917-27. 
69. Wu CP, Jiang JT, Tan M, Zhu YB, Ji M, Xu KF, et al. Relationship between co-
stimulatory molecule B7-H3 expression and gastric carcinoma histology and prognosis. 
World J Gastroenterol 2006 Jan 21;12(3):457-9. 
70. Zang X, Sullivan PS, Soslow RA, Waitz R, Reuter VE, Wilton A, et al. Tumor 
associated endothelial expression of B7-H3 predicts survival in ovarian carcinomas. Mod 
Pathol 2010 May 21. 
71. 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 Dec 4;104(49):19458-
63.
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Clinical Trial Protocol: CP-MGA271-03 
Amendment 6, 26 August 2020 
 
 
 
 
 
Appendix 1 
Time and Events Schedule  
Time and Events Schedule: MGA271 and Pembrolizumab 
Cycle 
 
Initial Tumor Assessment Cycle 
Cycle 2 and beyond 
 
Treatment Day of the Cycle 
(Visits occur ± 3 days of scheduled visit, unless 
otherwise noted)  
-28 
1 
2 
3 
8 
15 
22 
29 
36 
42 
1 
8 
15 
29 
36 
50 
57 
22 
 
43 
63 
EOTV 
Evaluation or Procedure 20 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY DRUG ADMINISTRATION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pembrolizumab  
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
 
 
MGA271 
 
X 1 
 
 
X 
X 
X 1 
X 
X 
 
X 1 
X 
X 1 
X 1 
 
 
ELIGIBILITY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent (obtained prior to registration; no 
time constraint)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient registration18 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Identify available archival tissue samples for B7-H3 
and PD-L1 testing or consent to a fresh biopsy 2  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmed PD-L1 Expression < 1% (for NSCLC 
Cohort 1 only) 2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG PS 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
ECG 20 
X 3 
X 3 
X 3 
 
X 3 
X 3 
X 
3 
 
 
 
X 15 
 
 
 
 
 
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Clinical Trial Protocol: CP-MGA271-03 
Amendment 6, 26 August 2020 
 
 
 
 
 
Time and Events Schedule: MGA271 and Pembrolizumab 
Cycle 
 
Initial Tumor Assessment Cycle 
Cycle 2 and beyond 
 
Treatment Day of the Cycle 
(Visits occur ± 3 days of scheduled visit, unless 
otherwise noted)  
-28 
1 
2 
3 
8 
15 
22 
29 
36 
42 
1 
8 
15 
29 
36 
50 
57 
22 
 
43 
63 
EOTV 
Evaluation or Procedure 20 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-hCG pregnancy test  
X 4 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Pre-Treatment Tumor Biopsy  
(Cohort Expansion Phase Only)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional On-Treatment Tumor Biopsy  
(Cohort Expansion Phase Only)  
 
 
 
 
 
 
 
 
 
X 5 
 
 
 
 
 
 
SAFETY & PD EVALUATION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 6, 20 
X 
X 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Monitor for AEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with differential, platelet count 8, 20 
X 
X 
 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
Chemistry panel 8, 9, 20 
X 
X 
 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
Special Chemistry 8,10, 20 
X 
X 
 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
Free T4 and TSH 8, 20 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Prothrombin time;  
Activated partial thromboplastin time 8, 20 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Urinalysis 8, 20 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
Flow Cytometry: Lymphocyte subsets, NK cells and 
activation markers 7, 20 
 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
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Clinical Trial Protocol: CP-MGA271-03 
Amendment 6, 26 August 2020 
 
 
 
 
 
Time and Events Schedule: MGA271 and Pembrolizumab 
Cycle 
 
Initial Tumor Assessment Cycle 
Cycle 2 and beyond 
 
Treatment Day of the Cycle 
(Visits occur ± 3 days of scheduled visit, unless 
otherwise noted)  
-28 
1 
2 
3 
8 
15 
22 
29 
36 
42 
1 
8 
15 
29 
36 
50 
57 
22 
 
43 
63 
EOTV 
Evaluation or Procedure 20 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PBMC Collection: T-cell Repertoire/ADCC 
(Expansion only) 7, 20 
 
X 
 
 
 
 
X 
 
 
 
 
 
X19 
 
 
 
Soluble B7-H3 and other soluble proteins 7, 20 
 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
Serum Cytokine Sampling 11, 20 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 20 (pulse, respirations, blood pressure, 
temp)  
X 12 
X 12 
X 12 
 
X 12 
X 12 
X 
12 X 12 
X 12 
 
X 16 X 16 
X 16 
X 16 
X 16 
 
THERAPEUTIC ACTIVITY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease assessment by RECIST and irRECIST: 
CT/MRI Chest, Abdomen and Pelvis 20   
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
CT/MRI Brain 13, 20 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
PK/IMMUNOGENICITY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MGA271 PK sampling 14, 20 
 
X 
X 
X 
X 
 
X 
 
 
 
See Table 6 for Cycles 2 - 6 
X 
ADA blood sample (anti-MGA271 Antibodies20 
 
X 7 
 
 
 
 
X 7 
 
 
 
X 17 
 
 
X 17 
 
X 
1. On days when both pembrolizumab and MGA271 are to be administered, pembrolizumab must be administered first. An effort should be made to begin 
the MGA271 infusion between 30 minutes to 120 minutes after the completion of the pembrolizumab infusion. It is understood that this window may 
not always be attainable, but it is the preferred window of time to administer MGA271. On days when MGA271 is administered after pembrolizumab, 
MGA271 may be administered the next day for safety reasons or scheduling purposes. The start and stop time of each pembrolizumab and MGA271 
infusion must be documented. A minimum of 6-day interval should occur between doses of MGA271 when given on a weekly schedule. 
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Clinical Trial Protocol: CP-MGA271-03 
Amendment 6, 26 August 2020 
 
 
 
 
 
2. Tissue samples or slides for B7-H3 testing should be identified before initiating therapy, but do not need to be submitted or resulted in advance of 
initiating therapy and may be submitted by C1 D43. B7-H3 expression is not required for eligibility in this study; however, tumor expression of B7-H3 
will be evaluated for all patients. Patients should have a formalin-fixed, paraffin embedded (FFPE) tumor specimen or unstained slides identified for 
analysis, to enable determination of the expression of B7-H3 within tumor specimens using IHC staining. If an archived tumor specimen is not 
available, patients who undergo a fresh tumor biopsy (Section 7.11.4.3) can have B7-H3 expression evaluated from a FFPE sample obtained from the 
fresh tumor biopsy. In this case, the biopsy should be obtained prior to initiating study therapy. In cases in which an archived sample and fresh tumor 
sample are both available, B7-H3 expression can be confirmed with either FFPE sample. PD-L1 tumor expression status for NSCLC Cohort 1 to be 
obtained before registration (no time constraint) either by historical documented IHC expression, or if no prior PD-L1 expression level available, 
obtained by IHC PD-L1 testing on archival or new tumor sample. PD-L1 testing for all other Cohort Expansion Phase cohorts can have PD-L1 tumor 
expressions determined prior to or after enrollment. All PD-L1 testing to be done with a sponsor approved method. Tumor immune cell infiltration 
evaluation will be determined prior to or after enrollment for all patients if enough sample is available for testing.  
3. Pembrolizumab infusion on Days 1 and 22: ECGs will be obtained immediately before the pembrolizumab infusion (pre-dose) and at 30 minutes (end of 
infusion).  
MGA271 infusion on Day 1 (intensive PK day): ECGs will be taken immediately before MGA271 infusion (pre-dose); at 120 minutes (end of infusion); at 3 
hours and 24 hours after the start of infusion. If infusion is interrupted, ECGs will be done based on the time of re-starting infusion. MGA271 infusion on Days 8, 
15 and 22: ECGs will be taken immediately before MGA271 infusion (pre-dose) and at 120 minutes (end of infusion). 
4. For women of childbearing potential, to be obtained within 72 hours prior to initial dose of pembrolizumab. 
5. Can be done +/- 3 days from Day 42. 
6. Includes height (screening only) and weight. Note that full physical exams to be done on screening, Day 1 (baseline), and at the EOTV. All other 
physical exams will be directed physical exams based on patient symptoms, tumor location and as clinically indicated. 
7. Day 1 sample will be collected prior to pembrolizumab infusion; all other days, prior to MGA271 infusion. See Table 5 for ADA sample Days and 
times.  
8. Samples will be drawn prior to infusion and analyzed by the LOCAL laboratory. Day 1 of Cycle 1 safety labs do not need to be repeated if done within 3 
days of Day 1. 
9. Includes ALB, ALK-P, ALT, AST, bicarbonate, BUN, Ca, Cl, creatinine, glucose, magnesium, phosphorus, K, Na, total protein, uric acid. 
10. Includes amylase, total and direct bilirubin, lipase. 
11. For Cytokine samples: Day 1 sample will be collected prior to pembrolizumab infusion and then collected with the 5 hours after start of MGA271 
infusion PK sample, and with the PK sample on Days 2 and 3, and with the PK end of infusion sample on Day 8. Additional samples may be obtained 
selectively at additional timepoints in patients who experience signs and symptoms of cytokine release. 
12. Initial Tumor Assessment Cycle: Vital signs include temperature, pulse, blood pressure, and respiratory rate and are obtained as follows: 
Pembrolizumab infusion on Days 1 and 22: Vital signs will be taken immediately before the pembrolizumab infusion (pre-dose); at 15 minutes after the start of 
infusion; at 30 minutes (end of infusion); and at 90 minutes after start of infusion if the MGA271 dose has not already commenced. 
MGA271 infusion on Days 1, 8, 15, 22, 29 and 36: Vital signs will be taken immediately before MGA271 infusion (pre-dose); at 60 minutes after the start of 
infusion; at end of infusion; and at 3 hours after the start of infusion. If infusion is interrupted, vitals will be based on time of restarted infusion. NOTE: The vital 
signs taken at 3 hours after the start of the infusion (i.e., 1 hour after the end of the infusion) and may be deferred if continued monitoring is not clinically 
indicated. Vital signs will also be taken at 24 hours after the start of infusion on Day 1 (PK day).  
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Clinical Trial Protocol: CP-MGA271-03 
Amendment 6, 26 August 2020 
 
 
 
 
 
13. A CT or MRI of the brain will be performed in cases where clinically indicated (e.g., suspicion of brain metastases) and repeat brain scans will only be 
performed if the Screening brain scan was positive or as clinically indicated. 
14. Pharmacokinetic sampling to be performed according to Table 6. 
15. Treatment Tumor Assessment Cycles 2 and beyond.  
ECGs will be obtained prior to the first pembrolizumab infusion on the first day of each cycle (Day 1). For Cycle 2, Day 1 only, (intensive PK day): ECGs will 
be taken immediately before MGA271 infusion (pre-dose) and at 120 minutes (end of infusion). 
16. Treatment Assessment Cycles 2 and beyond: Vital signs include temperature, pulse, blood pressure, and respiratory rate and are obtained as follows: 
Pembrolizumab infusion days: Vital signs including temperature, pulse, blood pressure and respiratory rate will be taken immediately before the pembrolizumab 
infusion (pre-dose); at 15 minutes after the start of infusion; at 30 minutes (end of infusion). 
MGA271 infusion (both on days with and without pembrolizumab infusion): Vital signs will be taken immediately before MGA271 infusion (pre-dose); at 60 
minutes after the start of infusion; and at end of infusion; and at 3 hours after the start of infusion. NOTE: The vital signs taken at 3 hours after the start of the 
infusion (i.e., 1 hour after the end of the infusion) and may be deferred if continued monitoring is not clinically indicated. Vital signs will also be taken at 24 
hours after the start of infusion on Day 1 (PK day).  
17. ADA samples will be obtained on Day 1 of Cycles 2, 3, 4, and 5. The ADA sample will be obtained on Day 43 of Cycle 6. See Table 5 for ADA sample 
Days and times. 
18. To be done within 3 days of Day 1. 
19. Cycles 2 and 3 only. 
20. For time window allowances for specific evaluations or procedures, refer to the Table 8. 
 
 
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MGA271 
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Clinical Trial Protocol: CP-MGA271-03 
Amendment 6, 26 August 2020 
 
 
 
 
 
Time and Events Schedule: MGA271+MGA012 (Cohort 4 Only) 
Cycle 
 
Initial Tumor Assessment Cycle 
Cycle 2 and beyond 
 
Treatment Day of the Cycle 
(Visits occur ± 3 days of scheduled visit, unless otherwise 
noted)  
-28 
1 
2 
4 
8 
15 
22 
42 
1 
2 
4 
8 
15 
22 
43 
63 
EOTV 
Evaluation or Procedure 11 
STUDY DRUG ADMINISTRATION 
MGA012  
 
X 
 
 
 
 
X 
 
X 
 
 
 
 
X 
X 
 
 
MGA271  
 
X 1 
 
 
 
 
X 1  
 
X 1 
 
 
 
 
X 1 
X 1 
 
 
ELIGIBILITY 
Informed Consent (obtained prior to registration; no time 
constraint)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient registration  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Identify available archival tissue samples for B7-H3 testing or 
consent to a fresh biopsy 2  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG PS 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
ECG 3, 11 
X3  
X3  
 
 
 
 
X
3  
 
X3  
 
 
 
 
 
 
 
 
-hCG pregnancy test  
X4 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
SAFETY & PD EVALUATION 
Physical examination 5, 11, 12 
X 
X 
 
 
 
 
X 
 
X 
 
 
 
 
X 
X 
X 
X 
Monitor for AEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with differential, platelet count 6, 11, 12 
X 
X 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
X 
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MGA271 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGA271-03 
Amendment 6, 26 August 2020 
 
 
 
 
 
Time and Events Schedule: MGA271+MGA012 (Cohort 4 Only) 
Cycle 
 
Initial Tumor Assessment Cycle 
Cycle 2 and beyond 
 
Treatment Day of the Cycle 
(Visits occur ± 3 days of scheduled visit, unless otherwise 
noted)  
-28 
1 
2 
4 
8 
15 
22 
42 
1 
2 
4 
8 
15 
22 
43 
63 
EOTV 
Evaluation or Procedure 11 
Chemistry panel 6, 7, 11, 12  
X 
X 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
X 
Special Chemistry 6, 8, 11, 12 
X 
X 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
Free T4 and TSH 6, 11, 12 
 
X 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
Prothrombin time;  
Activated partial thromboplastin time 6, 11 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Urinalysis 6, 11, 12 
X 
X 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
X 
Flow Cytometry Occupancy  
See Appendix 2 and Table 9 
Flow Cytometry subsets  
See Appendix 2 and Table 9 
Soluble B7-H3 and other soluble proteins  
See Appendix 2 and Table 9 
Serum Cytokine Sampling  
See Appendix 2 and Table 9 
Vital signs (pulse, respirations, blood pressure, temp) 9, 11  
X  
X 
 
 
 
 
X  
 
X  
 
 
 
 
X  
X  
X  
 
THERAPEUTIC ACTIVITY 
Disease assessment by RECIST and irRECIST: CT/MRI Chest, 
Abdomen and Pelvis 11 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
CT/MRI Brain 10, 11 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
PK sampling  
See Appendix 2 and Table 9 
ADA blood sample  
See Appendix 2 and Table 9 
1. An effort should be made to begin the MGA271 infusion between 30 minutes to 120 minutes after the completion of the MGA012 infusion. It is 
understood that this window may not always be attainable, but it is the preferred window of time to administer MGA271.  MGA271 may be 
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Clinical Trial Protocol: CP-MGA271-03 
Amendment 6, 26 August 2020 
 
 
 
 
 
administered the next day for safety reasons or scheduling purposes. The start and stop time of each MGA012 and MGA271 infusion must be 
documented. MGA271 is administered Q3W ± 3 days. An interval of at least 18 days should occur since the previous administration.  
2. B7-H3 expression are not required for eligibility in this study; however, tumor expression of B7-H3 will be evaluated for all patient tissue samples or 
slides for B7-H3 and tissue should be identified before initiating therapy, but do not need to be submitted or resulted in advance of initiating therapy and 
may be submitted by C1 D43. Patients should have a formalin-fixed, paraffin embedded (FFPE) tumor specimen or unstained slides identified for 
analysis, to enable determination of the expression of B7-H3 within tumor specimens using IHC staining. If an archived tumor specimen is not 
available, patients who undergo a fresh tumor biopsy (Section 7.11.4.3) can have B7-H3 expression evaluated from a FFPE sample obtained from the 
fresh tumor biopsy. In this case, the biopsy should be obtained prior to initiating study therapy. In cases in which an archived sample and fresh tumor 
sample are both available, B7-H3 expression can be confirmed with either FFPE sample. 
3. MGA012 infusion on Days 1 and 22: ECGs will be obtained before both the MGA012 and MGA271 infusions, at the end of both MGA012 and 
MGA271 infusions. C1D1: 3 hours after start of MGA271 infusion. C2 and beyond: D1 pre-infusion MGA012. If infusion is interrupted, ECGs will be 
done based on the time of re-starting infusion.  
4. For women of childbearing potential, to be obtained within 72 hours prior to initial dose of MGA012. 
5. Includes height (screening only) and weight. Note that full physical exams to be done on screening, Day 1 (baseline), and at the EOTV. All other 
physical exams will be directed physical exams based on patient symptoms, tumor location and as clinically indicated. 
6. Samples will be drawn prior to infusion and analyzed by the LOCAL laboratory. Day 1 of Cycle 1 safety labs do not need to be repeated if done within 3 
days of Day 1. 
7. Includes ALB, ALK-P, ALT, AST, bicarbonate, BUN, Ca, Cl, creatinine, glucose, magnesium, phosphorus, K, Na, total protein, uric. 
8. Includes amylase, total and direct bilirubin, lipase. 
9. The 2 hour after start of MGA012 infusion and 3 hour after start of MGA271 infusion vital signs measurements may be deferred if continuing 
monitoring is not clinically indicated.  If infusion is interrupted, vital signs will start from the beginning when infusion resumes. 
10. A CT or MRI of the brain will be performed in cases where clinically indicated (e.g., suspicion of brain metastases) and repeat brain scans will only be 
performed if the Screening brain scan was positive or as clinically indicated. 
11. For time window allowances for specific evaluations or procedures, refer to Table 9. 
12. Assessments are shared between Day 63 and Day 1 of the subsequent cycle and do not need to be repeated if Day 1 occurs within 3 days of Day 63. If 
two scheduled visits have shared data (i.e., the visits occur on the same date because overlapping window allowances permit combined visits), enter all 
required assessments and procedures in the forms for the earlier scheduled visit first. Any additional assessments and procedures unique to the later visit 
should be entered in that visit. Do not enter duplicate forms (e.g., laboratory results) in both scheduled visits. 
 
 
 
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Clinical Trial Protocol: CP-MGA271-03 
Amendment 6, 26 August 2020 
 
 
 
 
 
Table 8 
Time Window Allowances for Study Evaluations and Procedures for MGA271 and Pembrolizumab          
Procedure 
Study Day 
Time Point 
Window Allowance 
Cytokines 
C1D1 
Pre-Infusion 
 
-1 hour to 0 min before SOI 
 
5 hours after Start of MGA271 Infusion 
+/-30 min  
(must match PK time) 
  
C1D2 
24 hours after Start of MGA271 Infusion 
+/-3 hours  
(must match PK time) 
  
C1D3 
48 hours after Start of MGA271 Infusion 
+/-3 hours  
(must match PK time) 
  
C1D8 
End of Infusion (MGA271) 
-10 min to 0 min (EOI) (must match PK 
time) 
ECG 
C1D1, C1D22 
Pre-Infusion (pembrolizumab) 
-1 hour to 0 min before SOI 
 
C1D1, C1D22 
End of Infusion (pembrolizumab) 
 0 min to +20 min after EOI 
 
C1D1 
Pre-Infusion (MGA271) 
-1 hour to 0 min before SOI (Note: must be 
taken after post pembrolizumab ECG) 
 
C1D1 
End of Infusion (MGA271) 
0 min to +20 min 
 
C1D1 
3 hours after Start of MGA271 Infusion 
+/- 30 min 
 
C1D2 
24 hours after Start of MGA271 Infusion 
+/- 3 hour 
 
C1: D8, 15, 22 
Pre-Infusion (MGA271) 
-1 hour to 0 min before SOI 
 
C1: D8, 15, 22 
End of Infusion (MGA271) 
0 min to +20 min after EOI 
 
C2D1 
Pre-Infusion (pembrolizumab) 
-1 hour to 0 min before SOI 
 
C2D1 
Pre-Infusion (MGA271) 
-1 hour to 0 min before SOI (Note: must be 
taken after post pembrolizumab ECG) 
 
C2D1 
End of Infusion (MGA271) 
0 min to +20 min 
 
C2 and beyond: D1 
Pre-Infusion (pembrolizumab) 
-1 hour to 0 min before SOI 
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Clinical Trial Protocol: CP-MGA271-03 
Amendment 6, 26 August 2020 
 
 
 
 
 
  
C1D1, D22 
Pre-Infusion (pembrolizumab) 
Any time before dosing on visit day (dosing 
day) or day before (must match PK time) 
Flow cytometry, 
sB7-H3 
C1D2 
24 hours after Start of MGA271 Infusion 
+/-3 hours  
(must match PK time) 
  
C1D1, D8, D22; C2D1; C3-5D1; 
C6D43 
Pre-Infusion  
Any time before dosing on visit day (dosing 
day) or day before  
PK 
C1D1, D8, D22; C2D1 
End of MGA271 Infusion 
-10 min to 0 min (EOI) 
 
C1D1; C2D1 
3 hours after Start of MGA271 Infusion 
 +/-30 min 
 
C1D1; C2D1 
5 hours after Start of MGA271 Infusion 
 +/-30 min 
 
C1D1; C2D1 
8 hours after Start of MGA271 Infusion 
 +/-30 min 
 
C1D2; C2D2 
24 hours after Start of MGA271 Infusion 
+/-3 hours 
 
C1D3; C2D3 
48 hours after Start of MGA271 Infusion 
+/-3 hours 
  
C1: D1, 22 
Pre-Infusion (pembrolizumab) 
-15 min to 0 min before SOI 
Vital Signs 
  
15 minutes after Start of Pembrolizumab 
Infusion 
+/-5 min 
 
  
End of Infusion (pembrolizumab) 
0 min to +15 min after EOI 
 
  
90 minutes after Pembrolizumab Infusion 
+/-15 min 
  
C1: D1, 8, 15, 22, 29, 36 
Pre-Infusion (MGA271) 
-15 min to 0 min before SOI (Note: must be 
taken after post pembrolizumab vitals) 
 
  
60 minutes after Start of MGA271 Infusion 
+/-15 min 
 
  
End of Infusion (MGA271) 
0 min to +15 min 
 
  
3 hours after Start of MGA271 Infusion 
+/-30 min 
 
C1D2 
24 hours after Start of MGA271 Infusion 
+/-3 hour 
 
C2 and beyond: D1, 22, 43 
Pre-Infusion (pembrolizumab) 
-15 min to 0 min before SOI 
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15 minutes after Start of Pembrolizumab 
Infusion 
+/-5 min 
 
  
End of Infusion (pembrolizumab) 
0 min to +15 min after EOI 
 
  
Pre-Infusion (MGA271) 
 -15 min to 0 min before SOI (Note: must be 
taken after post pembrolizumab vitals) 
 
  
60 minutes after Start of MGA271 Infusion 
+/-15 min 
 
  
End of Infusion (MGA271) 
0 min to +15 min 
 
  
3 hours after Start of MGA271 Infusion 
+/-30 min 
 
C2 and beyond: D1, 8, 15, 29, 36, 
50, 57 
Pre-Infusion (MGA271) 
-15 min to 0 min before SOI  
 
  
60 minutes after Start of MGA271 Infusion 
+/-15 min 
 
  
End of Infusion (MGA271) 
0 min to +15 min 
 
  
3 hours after Start of MGA271 Infusion 
+/-30 min 
 
C1D1, C1D22, C2-5: D1, C6D43 
Pre-Infusion (pembrolizumab) 
Any time before dosing on visit day (dosing 
day) or day before 
  
C1: D1, 8, 15, 22, 29, 36; C2 and 
beyond: D1, 8, 15, 22, 29, 36, 43, 
50, 57, 63 
Pre-Infusion  
-3 to 0 days prior to dosing 
ADA 
C1: D42; C2 and beyond: D63 
Pre-Infusion  
-3 to 0 days prior to dosing 
Physical Examination 
C1: D1, 8, 15, 22, 36; C2 and 
beyond: D1, 22, 63 
Pre-Infusion  
-3 to 0 days prior to dosing 
Disease Assessment 
C1: D1, 8, 15, 22, 36; C2 and 
beyond: D1, 22, 63 
Pre-Infusion  
-3 to 0 days prior to dosing 
CBC with differential, 
platelet count 
C1: D1, 8, 15, 22, 36; C2 and 
beyond: D1, 22, 63 
Pre-Infusion 
-3 to 0 days prior to dosing 
Chemistry panel 
C1: D1, 22; C2 and beyond: D1 
Pre-Infusion 
-3 to 0 days prior to dosing 
Special chemistry 
C1: D1; C2 and beyond: D1 
Pre-Infusion  
-3 to 0 days prior to dosing 
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Free T4 and TSH 
C1: D1, 22; C2 and beyond: D1, 
22, 63 
Pre-Infusion 
-3 to 0 days prior to dosing 
Prothrombin time; 
Activated partial 
thromboplastin time 
C1: D1, 8, 15, 22, 29, 36; C2 and 
beyond: D1, 8, 15, 22, 29, 36, 43, 
50, 57 
Pre-Infusion 
+10 min 
Urinalysis 
C1: D1, 22; C2 and beyond: D1, 
22, 63 
Pre-Infusion 
-3 to 0 days prior to dosing 
Study Drug Infusion 
Duration 
C1: D1, 8, 15, 22, 29, 36; 
C2 and beyond: D1, 8, 15, 22, 29, 
36, 43, 50, 57 
NA 
+10 min 
Abbreviations: ADA= Anti-drug antibodies; C=cycle; D=day; min=minutes; EOI=end of infusion; NA=not applicable; SOI=start of infusion; 
 
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Table 9 
Time Window Allowances for Study Evaluations and Procedures for MGA271 and MGA012 (Cohort 4 
Only)           
Procedure 
Study Day 
Time Point 
Window Allowance 
Cytokines 
C1D1, C2D1 
Pre-Infusion MGA012 
-1 hour to 0 min before SOI 
 
 
C1D1, C2D1 
5 hours after start of MGA271 Infusion 
 +/-30 min (must match PK time) 
  
C1D2, C2D2 
No specific timepoint 
No specific window 
ECG 
C1D1, C1D22 
Pre-Infusion MGA012 
-1 hour to 0 min before SOI 
C1D1, C1D22 
End of Infusion MGA012 
 0 min to +20 min after EOI 
C1D1, C1D22 
Pre-Infusion MGA271 
-1 hour to 0 min before SOI (Note: must be 
taken after post MGA012 ECG) 
C1D1, C1D22 
End of Infusion MGA271 
0 min to +20 min after EOI 
C1D1 
3 hours after Start of MGA271 Infusion 
+/- 30 min 
  
C2 and beyond: D1 
Pre-Infusion MGA012 
-1 hour to 0 min before SOI 
Flow cytometry, 
Occupancy 
C1D1, C1D22 
C2D1, C2D22, 
C3 and beyond: D1 and 
D22 
Pre-Infusion MGA012 
Any time before dosing on visit day (dosing 
day) or day before (must match PK time) 
 
C1D1, C2D1 
5 hours after start of MGA271 infusion 
+/-30 min (must match PK time) 
  
C1D2, C2D2 
C1D8, C2D8 
C1D15, C2D15 
No specific timepoint 
No specific window 
 
C1D22, C2D22, C3 and 
beyond: D1 and D22 
End of MGA271 Infusion 
-10 min to 0 min (EOI) 
Flow Cytometry Subsets 
C1D1, C2D1 
C1D22, C2D22 
C3 and beyond: D1 and 
D22 
Pre-Infusion MGA012 
Any time before dosing on visit day (dosing 
day) or day before (must match PK time) 
 
C1D1, C2D1 
5 hours after start of MGA271 infusion 
+/-30 min (must match PK time) 
 
C1D2, C2D2 
C1D15, C2D15 
No specific timepoint 
No specific window 
Soluble B7 H3 and Other 
Soluble Proteins 
C1D1, C2D1 
C1D22, C2D22 
Pre-Infusion MGA012 
Any time before dosing on visit day (dosing 
day) or day before (must match PK time) 
 
C1D8, C2D8 
No specific timepoint 
No specific window 
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Amendment 6, 26 August 2020 
 
 
 
 
 
Table 9 
Time Window Allowances for Study Evaluations and Procedures for MGA271 and MGA012 (Cohort 4 
Only)           
Procedure 
Study Day 
Time Point 
Window Allowance 
PK 
C1D1, C1D22  
C2D1, C2D22 
C3 and beyond: D1 and 
D22 
Pre-Infusion MGA012  
Any time before dosing on visit day (dosing 
day) or day before  
 
C1D1, C1D22  
C2D1, C2D22 
C3 and beyond: D1 and 
D22 
End of MGA012 infusion 
-10 min to 0 min (EOI) 
C1D1, C1D22 
C2D1, C2D22 
C3 and beyond: D1 and 
D22 
End of MGA271 Infusion 
-10 min to 0 min (EOI) 
C1D1, C2D1 
5 hours after Start of MGA271 Infusion 
 +/-30 min 
 
C1D2, C1D4, C1D8, 
C1D15 
No specific timepoint 
 No specific window 
C2D2, C2D4, C2D8, 
C2D15 
No specific timepoint 
 No specific window 
Vital Signs 
C1D1, C1D22 
Pre-Infusion MGA012 
-15 min to 0 min before SOI 
  
30 minutes after Start of MGA012 Infusion 
+/-15 min 
 
  
End of Infusion (MGA012) 
0 min to +15 min after EOI 
  
2 hours after Start of MGA012 Infusion 
+/-15 min 
C1D1, C1D22 
Pre-Infusion MGA271 
-15 min to 0 min before SOI (Note: must be 
taken after post MGA012 vitals) 
  
60 minutes after Start of MGA271 Infusion 
+/-15 min 
  
End of Infusion MGA271 
0 min to +15 min 
 
  
3 hours after Start of MGA271 Infusion 
+/-30 min 
 
C2 and beyond: D1, D22, 
D43 
Pre-Infusion MGA012 
-15 min to 0 min before SOI 
 
  
30 minutes after Start of MGA012 Infusion 
+/-15 min 
  
End of Infusion MGA012 
0 min to +15 min after EOI 
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Amendment 6, 26 August 2020 
 
 
 
 
 
Table 9 
Time Window Allowances for Study Evaluations and Procedures for MGA271 and MGA012 (Cohort 4 
Only)           
Procedure 
Study Day 
Time Point 
Window Allowance 
 
 
2 hours after Start of MGA012 Infusion 
+/-15 min 
  
Pre-Infusion MGA271 
 -15 min to 0 min before SOI (Note: must be 
taken after post MGA012 vitals) 
  
60 minutes after Start of MGA271 Infusion 
+/-15 min 
  
End of Infusion MGA271 
0 min to +15 min 
  
3 hours after Start of MGA271 Infusion 
+/-30 min 
ADA 
Days 1 and 22 all Cycles 
Pre-Infusion (MGA012) 
Any time before dosing on visit day (dosing 
day) or day before 
Physical Examination 
C1: D1, 22, C2 and beyond: 
D1, 22, 43 
Pre-Infusion  
-3 to 0 days prior to dosing 
Disease Assessment 
C1: D42; C2 and beyond: 
D63 
Pre-Infusion  
-3 to 0 days prior to dosing 
CBC with differential, 
platelet count 
C1: D1, 22, C2 and beyond: 
D1, 22 
Pre-Infusion  
-3 to 0 days prior to dosing 
Chemistry panel 
C1: D1, 22, C2 and beyond: 
D1, 22 
Pre-Infusion  
-3 to 0 days prior to dosing 
Special chemistry 
C1: D1, 22, C2 and beyond: 
D1, 22 
Pre-Infusion 
-3 to 0 days prior to dosing 
Free T4 and TSH 
C1: D1, 22; C2 and beyond: 
D1 
Pre-Infusion 
-3 to 0 days prior to dosing 
Prothrombin time; 
Activated partial 
thromboplastin time 
C1: D1; C2 and beyond: D1 
Pre-Infusion  
-3 to 0 days prior to dosing 
Urinalysis 
C1: D1, 22; C2 and beyond: 
D1, 22 
Pre-Infusion 
-3 to 0 days prior to dosing 
Study Drug Infusion 
Duration 
C1: D1, 22, C2 and beyond: 
D1, 22, 43  
NA 
+10 min 
Abbreviations: ADA= Anti-drug antibodies; C=cycle; D=day; min=minutes; EOI=end of infusion; NA=not applicable; SOI=start of infusion; 
 
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Appendix 2 
Pharmacokinetics, Immunogenicity, and Pharmacodynamic Biomarkers Blood Sampling 
Schedule for MGA271+MGA012 (Cohort 4 Only)  
Tumor 
Assessment 
Cycle 
Day 
Time Points 
PK 
MGA271 
And 
MGA012  
ADA 
MGA271 
and 
MGA012   
 
Cytokines 
Flow Cytometry 
Occupancy 
Flow 
Cytometry 
Subsets 
Soluble 
B7-H3 and 
Other Soluble 
Proteins  
Cycle 1 and 
2 
1 
Pre MGA012  
x 
x 
x 
x 
x 
x 
EOI MGA012  
x 
 
 
 
 
 
EOI MGA271 
x 
 
 
 
 
 
1 
5 hr. after start of MGA271 
infusion  
x 
 
x 
x 
x 
 
2 
No specific time point 
x 
 
x 
x 
x 
 
4 
No specific time point 
x 
 
 
 
 
 
8 
No specific time point 
x 
 
 
x 
 
x 
15 
No specific time point 
x 
 
 
x 
x 
 
22 
Pre MGA012 
x 
x 
 
x 
x 
x 
22 
EOI MGA012 
x 
 
 
 
 
 
22 
EOI MGA271 
x 
 
 
x 
 
 
Cycle 3 and 
Beyond 
1 
Pre MGA012 
x 
x 
 
x 
x 
 
EOI MGA012 
x 
 
 
 
 
 
EOI MGA271 
x 
 
 
x 
 
 
22 
Pre MGA012 
x 
x 
 
x 
x 
 
EOI MGA012 
x 
 
 
 
 
 
EOI MGA271 
x 
 
 
x 
 
 
IRR/CRS 
 
No specific time point 
 
 
x 
 
 
 
EOTV 
 
No specific time point 
x 
x 
 
 
x 
x 
• 
Actual start and end of infusion times and PK sample collection times will be recorded on the CRFs. 
• 
All Pre-dose samples will be collected prior to MGA012 infusion. ADA samples will be collected simultaneously with pre-infusion PK samples. 
• 
Flow cytometry samples (occupancy and subset) will be collected through Cycle 4. 
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• 
Cytokine samples will be performed according to the table above.  Additional samples should be obtained selectively at additional time points in 
patients who experience signs and symptoms of cytokine release at the time of the adverse event, with the goal to obtain a cytokine sample 
immediately at the time of onset of adverse event; specific dates and times of blood draws must be recorded. 
Abbreviations: ADA= Anti-drug antibodies; C=cycle; D=day; min=minutes; EOI=end of infusion; NA=not applicable; SOI=start of infusion; 
 
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Appendix 3 
Definition of PFS  
Situation 
Date 
Outcome 
No baseline tumor assessments  
Date of 1st dose  
Censored 
Death prior to the 1st scheduled 
tumor assessment 
Date of death 
Progressed 
No post-baseline tumor 
assessments in absence of death 
prior to the 1st scheduled tumor 
assessment 
Date of 1st dose 
Censored 
Documented disease progression 
Date of disease progression 
Progressed 
Initiation of alternative anti-
cancer treatments in absence of 
PD 
Date of last tumor assessment prior 
to initiation of such treatment 
Censored 
Death or progression 
immediately after missing two or 
more consecutive scheduled 
tumor assessments 
Date of last tumor assessment prior 
to missed assessments 
Censored 
 
 
 
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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 
 
 
 
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Appendix 5 
RECIST 1.1 Guidelines  
(Adapted from Eisenhauer 2009 (19) ) 
All patients with be required to have at least 1 measurable lesion to be considered as having 
measurable disease at baseline for the determination of eligibility for this study. Measurable 
lesions are defined below. 
MEASURABILITY OF TUMOR AT BASELINE  
DEFINITIONS 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
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. 
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. 
Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment: 
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Bone lesions: 
• Bone scan, PET scan or plain films are not considered adequate imaging 
techniques to measure bone lesions. However, these techniques can be used to 
confirm the presence or disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 
CT or MRI can be considered as measurable lesions if the soft tissue component 
meets the definition of measurability described above. 
• Blastic bone lesions are non-measurable. 
 
Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts. 
• ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
 
Lesions with prior local treatment: 
• Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are not considered measurable unless there has been 
demonstrated progression in the lesion prior to study enrollment. 
 
SPECIFICATIONS BY METHODS OF MEASUREMENTS  
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. 
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. 
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Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial and ≥10 mm diameter as assessed using calipers (e.g. skin nodules). For the case 
of skin lesions, documentation by color photography including a ruler to estimate the size of 
the lesion is suggested. As noted above, when lesions can be evaluated by both clinical exam 
and imaging, imaging evaluation should be undertaken since it is more objective and may 
also be reviewed at the end of the study. 
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. 
TUMOR RESPONSE EVALUATION  
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). 
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 
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organs should be identified as target lesions and will be recorded and measured at baseline. 
For example, in instances where patients have only one or two organ sites involved, a 
maximum of two and four lesions respectively will be recorded). Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be representative of all 
involved organs, but in addition should be those that lend themselves to reproducible 
repeated measurements. It may be the case that, on occasion, the largest lesion does not lend 
itself to reproducible measurement in which circumstance the next largest lesions which can 
be measured reproducibly should be selected.  
Lymph nodes merit special mention since they are normal anatomical structures which may 
be visible by imaging even if not involved by tumor. As noted above, pathological nodes 
which are defined as measurable and may be identified as target lesions must meet criterion 
of a short axis of ≥ 15 mm by CT scan. Only the short axis of these nodes will contribute to 
the baseline sum. The short axis of the node is the diameter normally used by radiologists to 
judge if a node is involved by solid tumor. Nodal size is normally reported as two dimensions 
in the plane in which the image is obtained (for CT scan this is almost always the axial plane; 
for MRI the plane of acquisition may be axial, sagittal or coronal). The smaller of these 
measures is the short axis. For example, an abdominal node which is reported as being 20 
mm x30 mm has a short axis of 20 mm and qualifies as a malignant, measurable node. In this 
example, 20 mm should be recorded as the node measurement. All other pathological nodes 
(those with short axis ≥10 mm but < 15 mm) should be considered non-target lesions. Nodes 
that have a short axis < 10 mm are considered non-pathological and should not be recorded 
or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes 
are to be included in the sum, then as noted above, only the short axis is added into the sum. 
The baseline sum diameters will be used as reference to further characterize any objective 
tumor regression in the measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified 
as non-target lesions and should also be recorded at baseline. Measurements are not required 
and these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression. In addition, it is possible to record multiple non-target lesions involving the 
same organ as a single item on the case record form (e.g. ‘multiple enlarged pelvic lymph 
nodes’ or ‘multiple liver metastases’). 
RESPONSE CRITERIA  
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions. 
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. 
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Partial Response (PR): at least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters.  
Progressive Disease (PD): at least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is 
also considered progression). 
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. 
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 
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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’. 
Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine the tumor response for 
the group of non-target lesions. While some non-target lesions may actually be measurable, 
they need not be measured and instead should be assessed only qualitatively at the time 
points specified in the protocol. 
Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be 
non-pathological in size (<10mm 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).  
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. 
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New Lesions 
The appearance of new malignant lesions denotes disease progression. There are no specific 
criteria for the identification of new radiographic lesions; however, the finding of a new 
lesion should be unequivocal: i.e. not attributable to differences in scanning technique, 
change in imaging modality or findings thought to represent something other than tumor (for 
example, some ‘new’ bone lesions may be simply healing or flare of pre-existing lesions). 
This is particularly important when the patient’s baseline lesions show partial or complete 
response. For example, necrosis of a liver lesion may be reported on a CT scan report as a 
‘new’ cystic lesion, which it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this 
is the patient who has visceral disease at baseline and while on study has a CT or MRI brain 
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.  
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. 
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. 
Missing assessments and unevaluable 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. 
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Best overall response: all time points 
The best overall response is determined once all the data for the patient is known. 
Table A-1 
Time point response: patients with target (+/- non-target) 
disease           
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = 
inevaluable. 
 
Best response determination in trials where confirmation of complete or partial response IS 
required: Complete or partial responses may be claimed only if the objective response is 
confirmed on a follow-up scan obtained no less than 4 weeks after the initial scan 
demonstrating an objective response. In this circumstance, the best overall response can be 
interpreted as in Table A-2. 
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Table A-2 
Best overall response when confirmation of CR and PR required   
Overall response 
First time point 
Overall response 
Subsequent time point 
BEST overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PR a 
CR 
SD 
SD  
CR 
PD 
SD  
CR 
NE 
SD  
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise, NE 
NE 
NE 
NE 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = 
inevaluable. 
a 
If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease 
meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have 
reappeared after CR). Best response would depend on whether minimum duration for SD was met. 
However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely still 
present and in fact the patient had PR, not CR at the first time point. Under these circumstances, the 
original CR should be changed to PR and the best response is PR. 
 
Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to 
‘normal’ size (<10 mm), they may still have a measurement reported on scans This 
measurement should be recorded even though the nodes are normal in order not to overstate 
progression should it be based on increase in size of the nodes. As noted earlier, this means 
that patients with CR may not have a total sum of ‘zero’ on the case report form (CRF). 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration”. Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy. The objective response status of 
such patients is to be determined by evaluation of target and non-target disease as shown in 
Table A-1 and Table A-2. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
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assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
CONFIRMATION/DURATION OF RESPONSE  
Confirmation 
Objective responses should be confirmed by CT and/or MRI scans obtained no less than 4 
weeks after the original scan. 
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. 
Duration of stable disease 
Stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest sum on study (if the baseline sum is the smallest, this is 
the reference for calculation of PD). 
 
 
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Appendix 6 
Immune-Related RECIST Guidelines  
(Adapted from Wolchok 2009 (67)) 
All patients with be required to have at least 1 measurable lesion to be considered as having 
measurable disease at baseline for the determination of eligibility for this study. Measurable 
lesions are defined below.  
MEASURABILITY OF TUMOR AT BASELINE  
DEFINITIONS  
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
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 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. 
Non-measurable 
All other lesions, including small lesions (longest diameter < 10mm 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. 
Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment: 
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Bone lesions: 
• Bone scan, PET scan or plain films are not considered adequate imaging 
techniques to measure bone lesions. However, these techniques can be used to 
confirm the presence or disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 
CT or MRI can be considered as measurable lesions if the soft tissue component 
meets the definition of measurability described above. 
• Blastic bone lesions are non-measurable. 
 
Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts. 
• ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
 
Lesions with prior local treatment: 
• Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are not considered measurable unless there has been 
demonstrated progression in the lesion prior to study enrollment. 
 
SPECIFICATIONS BY METHODS OF MEASUREMENTS  
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. 
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. 
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Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial and ≥10 mm diameter as assessed using calipers (e.g., skin nodules). For the case 
of skin lesions, documentation by color photography including a ruler to estimate the size of 
the lesion is suggested. As noted above, when lesions can be evaluated by both clinical exam 
and imaging, imaging evaluation should be undertaken since it is more objective and may 
also be reviewed at the end of the study. 
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 will not be used to assess objective tumor response. 
TUMOR RESPONSE EVALUATION  
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). 
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 
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organs should be identified as target lesions and will be recorded and measured at baseline. 
For example, in instances where patients have only one or two organ sites involved, a 
maximum of two and four lesions respectively will be recorded). Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be representative of all 
involved organs, but in addition should be those that lend themselves to reproducible 
repeated measurements. It may be the case that, on occasion, the largest lesion does not lend 
itself to reproducible measurement in which circumstance the next largest lesions which can 
be measured reproducibly should be selected. 
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 previously, pathological nodes 
which are defined as measurable and may be identified as target lesions must meet criterion 
of a short axis of ≥ 15 mm by CT scan. Only the short axis of these nodes will contribute to 
the baseline sum. The short axis of the node is the diameter normally used by radiologists to 
judge if a node is involved by solid tumor. Nodal size is normally reported as two dimensions 
in the plane in which the image is obtained (for CT scan this is almost always the axial plane; 
for MRI the plane of acquisition may be axial, sagittal or coronal). The smaller of these 
measures is the short axis. For example, an abdominal node which is reported as being 20 
mm x30 mm has a short axis of 20 mm and qualifies as a malignant, measurable node. In this 
example, 20 mm should be recorded as the node measurement. All other pathological nodes 
(those with short axis ≥10 mm but < 15 mm) should be considered non-target lesions. Nodes 
that have a short axis <10 mm are considered non-pathological and should not be recorded or 
followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes 
are to be included in the sum, then as noted above, only the short axis is added into the sum. 
The baseline sum diameters will be used as reference to further characterize any objective 
tumor regression in the measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified 
as non-target lesions and should also be recorded at baseline. Measurements are not required 
and these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression’. In addition, it is possible to record multiple non-target lesions involving the 
same organ as a single item on the case record form (e.g., ‘multiple enlarged pelvic lymph 
nodes’ or ‘multiple liver metastases’). 
RESPONSE CRITERIA  
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions by immune-related response criteria (i.e., irRECIST). 
Evaluation of target lesions 
Immune-Related Complete Response (irCR): Disappearance of all target lesions. Any 
pathological lymph nodes (whether target or non-target) must have reduction in short axis to 
<10 mm. 
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Immune-Related Partial Response (irPR): at least a 30% decrease in the sum of diameters of 
target lesions, taking as reference the baseline sum diameters. 
Immune-related Progressive Disease (irPD): at least a 20% increase in the sum of diameters 
of target lesions, taking as reference the smallest sum on study (this includes the baseline sum 
if that is the smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. 
Unlike conventional RECIST criteria, the appearance of new measurable lesions does not 
automatically denote disease progression under immune-related response criteria. Rather the 
dimensions of new measurable lesions are added to overall sum of tumor diameters for 
determination of objective response status. Patients will not be considered as having 
progression unless the new overall sum of diameters has increased by > 20% from the 
smallest sum of tumor diameters achieved while on study. 
Immune-Related Stable Disease (irSD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
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 irCR, each node must achieve a short axis <10 mm. 
For irPR, irSD and irPD, 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 
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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’. 
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. 
Immune-Related Complete Response (irCR): Disappearance of all non-target lesions. All 
lymph nodes must be non-pathological in size (<10mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesions(s) 
Immune-Related Progressive Disease (irPD): Unlike conventional RECIST 1.1, new 
measurable lesions or increases in the size of non-target lesions do not define PD in isolation 
in the immune-related response criteria. Rather, immune-related PD is established if the sum 
of diameters is > 20% of the nadir of the sum of diameters for a given patient. 
New Lesions 
The appearance of new malignant lesions alone does not denote disease progression. Instead, 
the diameter of new lesions is added to the sum of diameters for target and non-target lesions. 
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. 
Time point response 
It is assumed that at each protocol specified timepoint, a response assessment occurs. For 
patients experiencing irCR or irPR, a confirmatory scan obtained no less than 4 weeks after 
the original scan is required to confirm the objective response. For patients experiencing 
irPD, but who demonstrate acceptable tolerability of treatment as evaluated by the 
Investigator, a confirmatory scan obtained no less than 4 weeks after the original scan is 
required for the confirmation of irPD. 
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Immune-Related Complete Response (irCR): Complete disappearance of all target and 
non-target lesions and no new lesions. The short axis of all lymph nodes must be < 10 mm. 
Immune-Related Partial Response (irPR): The sum of diameters has decreased > 30% 
from the baseline, but does not meet the criteria for irCR. 
Immune-Related Stable Disease (irSD): The patient does not meet criteria for irCR, irPR or 
irPD. 
Immune-Related Progressive Disease (irPD): The sum of diameters for target lesions and 
new measurable lesions has increased by > 20% from the nadir sum of diameters  
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. 
Best overall response: all time points 
The best overall response is determined once all the data for the patient is known. 
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. Absent this subsequent radiographic confirmation, irCR or irPR 
designations will be considered as unconfirmed responses. 
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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 irCR 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 1. 
CONFIRMATION/DURATION OF RESPONSE  
Confirmation 
Objective responses should be confirmed by CT and/or MRI scans obtained no less than 4 
weeks after the original scan. 
Duration of overall response 
The duration of overall response is measure from the time measurement criteria are first met 
for irCR/irPR (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 irCR until the first date that recurrent 
disease is objectively documented. 
Duration of stable disease 
Stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest sum on study (if the baseline sum is the smallest, this is 
the reference for calculation of irPD). 
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Appendix 7 
Principal Investigator’s Agreement  
Study Title: 
A Phase 1, Open-Label, Dose Escalation Study of MGA271 in 
Combination with Pembrolizumab and in Combination with 
MGA012 in Patients with Melanoma, Squamous Cell Cancer of 
the Head and Neck, Non-Small Cell Lung Cancer, Urothelial 
Cancer, and Other Cancers 
Study Number: 
CP-MGA271-03 
 
I have read the protocol described above. 
I have fully discussed the objectives of this trial 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 trial 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 trial 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 trial, I will communicate my 
intention immediately in writing to the Sponsor. 
 
Signed: 
 
 
Date: 
 
PI Name (printed): 
 
PI Affiliation: 
 
PI Address: 
 
PI Phone Number: 
 
 
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CP-MGA271-03 Protocol Amendment 6 (26-Aug-2020)
This is the electronic signature page for the above referenced document.
User Task: eSignatories Approval
– Data Management/Statistics Approval
(Intended or Designee)
27-Aug-2020 17:11:49 GMT+0000
User Task: eSignatories Approval
roval (Intended or Designee)
27-Aug-2020 18:00:44 GMT+0000
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