A Phase 1b/2, Open Label, Dose Escalation Study of MGD007, a Humanized gpA33 × CD3 DART® Protein in Combination With MGA012, an Anti-PD-1 Antibody, in Patients With Relapsed or Refractory Metastatic Colorectal Carcinoma
Phase: PHASE1
Conditions: Colorectal Cancer Metastatic
Sponsor: MacroGenics

CLINICAL STUDY PROTOCOL: CP-MGD007-02 
22 October 2018 
A Phase 1b/2, Open Label, Dose Escalation Study of MGD007, a Humanized gpA33 × CD3 
DART® Protein in Combination with MGA012, an Anti-PD-1 Antibody, in Patients with 
Relapsed or Refractory Metastatic Colorectal Carcinoma 
NCT03531632 
Confidential
                    and Proprietary

MGD007/MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGD007-02 
Protocol Amendment 1, 22 October 2018 
CLINICAL STUDY PROTOCOL: CP-MGD007-02 
PROTOCOL AMENDMENT 1 
Study Title: 
A Phase 1b/2, Open Label, Dose Escalation Study of MGD007, a 
Humanized gpA33 × CD3 DART® Protein in Combination with 
MGA012, an Anti-PD-1 Antibody, in Patients with Relapsed or 
Refractory Metastatic Colorectal Carcinoma 
Study Number: 
CP-MGD007-02 
Study Phase: 
Phase 1b/2 
Product Numbers: 
MGD007, MGA012 (also known as INCMGA00012) 
IND Number: 
119748 
Indication: 
Relapsed or Refractory Metastatic Colorectal Carcinoma 
Coordinating 
Principal 
Investigator: 
TBD 
Sponsor: 
MacroGenics, Inc. 
9704 Medical Center Drive 
Rockville, MD 20850 
301-251-5172
Sponsor’s Medical 
Monitor: 
Refer to study contact list 
Confidentiality Statement 
This document is confidential. It contains proprietary information of MacroGenics, Inc. that 
can only be used for the purpose of reviewing or performing this study. Any use, viewing or 
disclosure of such information that is not authorized in writing by the Sponsor is strictly 
prohibited. 
REVISION HISTORY 
Status 
Date 
Original Protocol 
01 March 2018 
Original Protocol – Change Memo 1 
19 April 2018 
Protocol Amendment 1 
22 October 2018 
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MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGD007-02 
Protocol Amendment 1, 22 October 2018 
 
 
TABLE OF CONTENTS 
SPONSOR SIGNATURES ....................................................................................................... 9 
RATIONALE FOR PROTOCOL AMENDMENT 1 .............................................................. 10 
LIST OF ABBREVIATIONS ................................................................................................. 12 
1 
SYNOPSIS .................................................................................................................. 16 
2 
BACKGROUND INFORMATION ............................................................................ 21 
2.1 
Rationale for Study ............................................................................................ 21 
2.2 
Disease Background........................................................................................... 27 
2.3 
Background on MGD007 ................................................................................... 29 
2.3.1 
Background on MGD007 ......................................................................... 29 
2.3.2 
MGD007 Pharmacology .......................................................................... 30 
2.3.3 
MGD007 Pharmacokinetics and Toxicology ........................................... 32 
2.3.4 
CP-MGD007-01 Clinical Study Update .................................................. 35 
2.4 
Background on PD-1.......................................................................................... 38 
2.5 
Background on MGA012 ................................................................................... 38 
2.5.1 
MGA012 Pharmacology .......................................................................... 39 
2.5.2 
MGA012 Pharmacokinetics and Toxicology ........................................... 44 
2.5.3 
CP-MGA012-01 Clinical Study Update .................................................. 48 
2.6 
MGD007/MGA012 Combination Dose Selection ............................................. 50 
2.6.1 
Dose Selection: MGD007 ........................................................................ 50 
2.6.1.1 
MGD007 Pharmacokinetics ........................................................... 50 
2.6.2 
Dose Selection: MGA012 ........................................................................ 53 
2.6.2.1 
MGA012 Pharmacokinetics ........................................................... 53 
3 
STUDY PURPOSE AND OBJECTIVES ................................................................... 56 
3.1 
Dose Escalation Phase ....................................................................................... 56 
3.1.1 
Primary Objectives ................................................................................... 56 
3.1.2 
Secondary Objectives ............................................................................... 56 
3.1.3 
Exploratory Objectives ............................................................................ 56 
3.2 
Cohort Expansion Phase .................................................................................... 57 
3.2.1 
Primary Objective .................................................................................... 57 
3.2.2 
Secondary Objectives ............................................................................... 57 
3.2.3 
Exploratory Objectives ............................................................................ 57 
4 
STUDY DESIGN ........................................................................................................ 58 
4.1 
Overall Study Design and Plan .......................................................................... 58 
4.1.1 
Dose Escalation Phase ............................................................................. 59 
4.1.2 
Cohort Expansion Phase .......................................................................... 60 
4.2 
Dose Limiting Toxicity ...................................................................................... 61 
4.2.1 
Hematologic Dose Limiting Toxicity ...................................................... 61 
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4.2.2 
Non-hematologic Dose-Limiting Toxicity ............................................... 62 
4.2.3 
Hepatic Non-hematologic Dose Limiting Toxicity .................................. 63 
4.3 
Dose Escalation Rules........................................................................................ 63 
4.4 
Guidelines for Dose Modification ..................................................................... 64 
4.4.1 
Dose Delays in Escalation and Expansion Cohorts ................................. 64 
4.5 
Study Duration ................................................................................................... 65 
4.5.1 
Patient Accrual ......................................................................................... 65 
4.5.2 
Definition of End of Study ....................................................................... 65 
4.6 
Appropriateness of Measurements ..................................................................... 66 
5 
SELECTION AND WITHDRAWAL OF PATIENTS ................................................ 67 
5.1 
Inclusion Criteria ............................................................................................... 67 
5.2 
Exclusion Criteria .............................................................................................. 69 
5.3 
Withdrawal of Patient from the Study ............................................................... 71 
5.4 
Rules for Study Treatment Discontinuation ....................................................... 72 
5.5 
Guidelines for Discontinuation of Patient from Study ...................................... 73 
6 
STUDY TREATMENTS ............................................................................................ 74 
6.1 
Method of Assigning Patients to Treatment Groups .......................................... 74 
6.2 
Blinding.............................................................................................................. 74 
6.3 
Emergency Unblinding ...................................................................................... 74 
6.4 
Study Drug and Supplies ................................................................................... 74 
6.4.1 
MGD007 .................................................................................................. 74 
6.4.2 
MGV002 Vehicle (Custom Diluent for MGD007) .................................. 75 
6.4.3 
MGA012 .................................................................................................. 75 
6.4.4 
Study Infusion Preparation ...................................................................... 76 
6.4.5 
General Guidelines and Precautions ........................................................ 76 
6.4.5.1 
MGD007......................................................................................... 76 
6.4.5.2 
MGA012......................................................................................... 77 
6.4.6 
Study Drug Preparation and Administration ............................................ 78 
6.4.6.1 
MGD007......................................................................................... 78 
6.4.6.2 
MGA012......................................................................................... 78 
6.5 
Placebo or Active Comparator ........................................................................... 79 
6.5.1 
Combination Therapy .............................................................................. 79 
6.6 
Treatment Compliance ....................................................................................... 79 
6.7 
Packaging and Labeling ..................................................................................... 79 
6.7.1 
MGD007 and MGV002 Vehicle .............................................................. 79 
6.7.2 
MGA012 .................................................................................................. 79 
6.8 
Storage and Accountability ................................................................................ 80 
6.8.1 
MGD007 and MGV002 Vehicle .............................................................. 80 
6.8.2 
MGA012 .................................................................................................. 80 
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6.9 
Investigational Product Disposition at End of Study ......................................... 80 
7 
POTENTIAL ADVERSE EVENTS AND SUPPORTIVE CARE 
MEASURES ............................................................................................................... 81 
7.1 
Premedication and Prophylaxis.......................................................................... 81 
7.1.1 
Rationale for Premedication and Prophylaxis .......................................... 82 
7.2 
Infusion-Related Reactions Including Cytokine Release Syndrome ................. 82 
7.2.1 
Grading and Management of Infusion Reactions .................................... 83 
7.2.2 
Management of Observed Infusion Reactions ......................................... 84 
7.3 
Management of Diarrhea or Colitis ................................................................... 87 
7.3.1 
Diarrhea Occurring Before Addition of MGA012 to 
MGD007 or Early (within 72 Hours) After Administration of 
the MGD007/MGA012 Combination ...................................................... 88 
7.3.2 
Diarrhea with Onset > than 72 Hours After Administration of 
the Combination of MGD007/MGA012 or Clinical 
Manifestations Suggestive of Colitis ....................................................... 89 
7.4 
Nausea/Emesis ................................................................................................... 90 
7.5 
Immune-Related Adverse Events ....................................................................... 90 
7.5.1 
Hepatic Toxicity ....................................................................................... 91 
7.5.1.1 
Elevations in Transaminases .......................................................... 91 
7.5.2 
Elevations in Total Bilirubin .................................................................... 92 
7.5.3 
Pneumonitis .............................................................................................. 93 
7.5.4 
Dermatologic Toxicity ............................................................................. 94 
7.5.5 
Nephritis ................................................................................................... 95 
7.5.6 
Immune-mediated Hypophysitis .............................................................. 95 
7.5.7 
Thyroid Toxicity ...................................................................................... 96 
8 
CONCOMITANT THERAPY AND RESTRICTIONS ............................................. 98 
8.1 
Concomitant Therapy ......................................................................................... 98 
8.1.1 
Prohibited Therapy ................................................................................... 98 
8.1.2 
Permitted Therapies ................................................................................. 99 
8.2 
Restrictions ........................................................................................................ 99 
8.2.1 
Fluid and Food Intake .............................................................................. 99 
8.2.2 
Patient Activity Restrictions .................................................................... 99 
9 
STUDY PROCEDURES .......................................................................................... 100 
9.1 
Informed Consent............................................................................................. 100 
9.2 
Screening Period .............................................................................................. 100 
9.3 
Registration ...................................................................................................... 100 
9.4 
Medical History ............................................................................................... 100 
9.5 
Prior and Concomitant Medications ................................................................ 101 
9.6 
Physical Examination....................................................................................... 101 
9.6.1 
Vital Signs .............................................................................................. 101 
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9.7 
ECOG Performance Status .............................................................................. 101 
9.8 
Clinical Laboratory Tests ................................................................................. 101 
9.8.1 
Central Laboratory Assays ..................................................................... 101 
9.8.2 
Pharmacokinetics ................................................................................... 102 
9.8.3 
Pharmacodynamics/Biomarkers ............................................................ 102 
9.8.4 
Sample Collection, Storage, and Shipping ............................................ 102 
9.9 
Radiographic, CT, or MRI Assessments .......................................................... 102 
9.10 
Electrocardiography ......................................................................................... 102 
9.11 
End of Treatment Visit ..................................................................................... 103 
9.12 
Post-treatment Follow-Up Visits ...................................................................... 103 
10 
ASSESSMENT OF PHARMACOKINETICS AND 
PHARMACODYNAMICS....................................................................................... 104 
10.1 
Pharmacokinetics Assessments ........................................................................ 104 
10.2 
Pharmacodynamic/Biomarker Assessments .................................................... 104 
10.2.1 
Tests Performed for Both Dose Escalation and Cohort 
Expansion Patients ................................................................................. 104 
10.2.1.1 
Tests Performed for Cohort Expansion Patients Only ................. 105 
11 
ASSESSMENT OF EFFICACY ............................................................................... 106 
11.1 
Efficacy Assessments ....................................................................................... 106 
11.1.1 
Disease Response Assessments .............................................................. 106 
11.1.2 
Survival Assessments ............................................................................. 107 
11.2 
Immunogenicity Assessments .......................................................................... 107 
12 
ADVERSE EVENT REPORTING AND ASSESSMENT OF SAFETY ................. 108 
12.1 
Definitions........................................................................................................ 108 
12.1.1 
Adverse Event ........................................................................................ 108 
12.1.2 
Adverse Drug Reaction .......................................................................... 109 
12.1.3 
Adverse Event of Special Interest .......................................................... 109 
12.1.4 
Attribution/Assessment of Causality ..................................................... 109 
12.1.5 
Serious Adverse Event ............................................................................110 
12.1.6 
Severity Criteria ......................................................................................110 
12.2 
Adverse Event Collection and Documentation ................................................. 111 
12.2.1 
All Adverse Events ................................................................................. 111 
12.2.2 
Immediately Reportable Events ..............................................................112 
12.2.3 
Serious Adverse Events ...........................................................................113 
12.2.4 
Protocol-specific Adverse Events of Special Interest .............................114 
12.2.5 
Pregnancy ................................................................................................115 
12.2.6 
Reporting of Adverse Events to the Sponsor ..........................................115 
13 
PRODUCT QUALITY COMPLAINT HANDLING ................................................118 
13.1 
Procedures .........................................................................................................118 
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Clinical Trial Protocol: CP-MGD007-02 
Protocol Amendment 1, 22 October 2018 
 
 
13.2 
Contacting Sponsor Regarding Product Quality ...............................................118 
14 
STATISTICAL ANALYSIS .......................................................................................119 
14.1 
Determination of Sample Size ..........................................................................119 
14.2 
Analysis Populations ........................................................................................ 120 
14.3 
Demographics and Baseline Characteristics .................................................... 120 
14.4 
Study Drug Exposures and Concomitant Medications .................................... 120 
14.5 
PK/PD Analysis ............................................................................................... 121 
14.5.1 
Pharmacokinetic Analysis ...................................................................... 121 
14.5.2 
Immunogenicity Analysis ...................................................................... 121 
14.5.3 
Pharmacodynamic Analysis ................................................................... 121 
14.6 
Efficacy and Endpoint Analyses ...................................................................... 121 
14.6.1 
Response Endpoints and Analyses ......................................................... 121 
14.6.2 
Analysis of Tumor Size Change Over Time .......................................... 122 
14.6.3 
Time-to-event Endpoints and Analyses ................................................. 122 
14.7 
Safety Endpoints and Analyses ........................................................................ 123 
14.7.1 
Adverse Events ...................................................................................... 123 
14.7.2 
Laboratory Values .................................................................................. 124 
14.7.3 
Other Safety Endpoints .......................................................................... 124 
14.8 
Other Assessments or Analyses ....................................................................... 124 
15 
QUALITY CONTROL AND ASSURANCE ........................................................... 125 
15.1 
Monitoring, Auditing and Inspections ............................................................. 125 
15.2 
Data Collection and Management .................................................................... 126 
16 
ADMINISTRATIVE CONSIDERATIONS.............................................................. 127 
16.1 
Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) Approval................................................................................................. 127 
16.2 
Ethical Conduct of the Study ........................................................................... 128 
16.3 
Patient Information and Consent ..................................................................... 128 
16.4 
Patient Confidentiality ..................................................................................... 128 
16.5 
Case Report Forms and Study Records ........................................................... 129 
16.6 
Access to Source Documentation .................................................................... 129 
16.7 
Retention of Data ............................................................................................. 129 
16.8 
Sample Retention and Further Testing ............................................................. 129 
16.9 
Financial Disclosure......................................................................................... 130 
16.10 
Publication and Disclosure Policy ................................................................... 130 
16.11 
Discontinuation of the Study or Study Sites .................................................... 130 
16.11.1 
Discontinuation of Study Sites ............................................................... 130 
16.11.2 
Discontinuation of the Study ................................................................. 131 
16.12 
Identification of the Coordinating Principal Investigator ................................ 131 
17 
REFERENCE LIST .................................................................................................. 132 
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Clinical Trial Protocol: CP-MGD007-02 
Protocol Amendment 1, 22 October 2018 
 
 
Figure 8 
MGA012-mediated PD-1/PD-L1 Inhibitory Signaling as 
Measured by Luciferase Gene Expression within a Co-culture 
Reporter Assay System ................................................................................. 42 
Figure 9 
Evaluation of MGA012 to Enhance IFN-γ Signaling Following 
SEB Stimulation of Human PBMCs ............................................................ 43 
Figure 10 
Frequency of PD-1+/CD4+ and PD-1+/CD8+ Cells Bound by 
MGA012 and MGA012 Serum Concentrations in Cynomolgus 
Monkeys ....................................................................................................... 48 
Figure 11 
Overall Study Treatment Schema ................................................................. 59 
 
LIST OF APPENDICES 
APPENDIX 1 
TIME AND EVENTS SCHEDULES: QW COHORT 
APPENDIX 2 
CLINICAL LABORATORY TESTS 
APPENDIX 3 
PHARMACOKINETICS, IMMUNOGENICITY, AND 
PHARMACODYNAMIC BIOMARKERS BLOOD SAMPLING 
SCHEDULE FOR MGD007 & MGA012 
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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Clinical Trial Protocol: CP-MGD007-02 
Protocol Amendment 1, 22 October 2018 
 
 
SPONSOR SIGNATURES 
Study Title: 
A Phase 1b/2, Open Label, Dose Escalation Study of MGD007, a 
Humanized gpA33 × CD3 DART® Protein in Combination with 
MGA012, an Anti-PD-1 Antibody, in Patients with Relapsed or 
Refractory Metastatic Colorectal Carcinoma 
Study Number: 
CP-MGD007-02 
 
This clinical study protocol has been approved by the Sponsor: 
Signed: 
See Appended Electronic Signature Page 
Date: 
 
 
 
Director, Clinical Research 
MacroGenics, Inc. 
 
 
 
 
Signed: 
See Appended Electronic Signature Page 
Date: 
 
 
 
Associate Director, Biostatistics 
MacroGenics, Inc. 
 
 
 
 
 
 
 
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MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGD007-02 
Protocol Amendment 1, 22 October 2018 
 
 
RATIONALE FOR PROTOCOL AMENDMENT 1 
The substantive changes in Amendment 1 are the removal of the Q2W cohort (every 2-week 
MGD007 scheduled dosing) and minor adjustment to the composition of the MGD007 drug 
product formulation buffer while maintaining the same buffer strength. The Q2W cohort was 
removed from the study to focus resources on testing of the combination using the weekly 
regimen of MGD007. This change impacted Sections 2, 4, 7, 9, 14, and appendices in which 
Q2W was included. 
The table below outlines the substantive modifications to the body of the protocol. 
Corresponding changes were made to the Synopsis for consistency; those changes are not 
included below. 
A redline version showing detailed changes to the protocol will be provided upon request. 
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MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGD007-02 
Protocol Amendment 1, 22 October 2018 
 
 
Summary of Changes in CP-MGD007-02 Original Protocol 
Section 
Summary of Main Changes and Rationale 
Sponsor Signatures 
 as Medical Monitor for this program. 
Sections 2, 4, 7, 9, 
and 14 
Language with regards to the Q2W cohort was removed. 
Section 4.1.1 
The amount of treatment a patient must receive to be considered evaluable for the 
DLT evaluation period has been modified to 75% of both the required MGD007 
doses and the required MGA012 doses. 
Section 5.1 
Inclusion criterion 7 was modified to include patients previously treated with 
MGD007 in Study Protocol CP-MGD007-01; stipulations were included. 
Section 5.2 
History of prior allogeneic bone marrow, stem-cell, or solid organ transplantation 
was added, as new Exclusion Criterion 3 and subsequent exclusion criteria were 
renumbered.  
Section 5.5 
Death had been inadvertently omitted in original protocol and has been added as this 
event should be included as a reason for patient discontinuation from a clinical study. 
Section 6 
Minor formulation adjustment in MGD007 drug product composition due to the 
addition of PS80 to the drug substance (DS) formulation. To maintain the same 
buffer strength, it required an adjustment to the sodium phosphate ratio and PS80 
concentration in the DP formulation to account for the addition of PS80 in the DS 
buffer. In addition, there is clarification that allowable colors of MGA012 drug 
product solution may have a pale-yellow color. Edits were made within the 
subsections of this section: Sections 6.4.1, 6.4.3 and 6.4.6. 
Section 7.1 
Guidelines for duration of prophylactic use of budesonide was amended to include a 
continuation of 5 days after MGD007 infusion, to better mitigate MGD007 adverse 
effects on the gastrointestinal tract and limit the use of dexamethasone. 
Section 8.1.1 
Text was included from a protocol change memo, CP-MGD007-02 Original 
Protocol, Change Memo 1 (dated 19 April 2018), regarding avoidance of the 
concomitant use of CYP450 substrates with a narrow therapeutic index during study 
treatment was added, given the potential for CYP enzyme suppression due to 
cytokine elevation. 
Section 12.2.2 
AESIs requiring reporting to the Sponsor within 24 hours were specifically listed for 
clarity, as provided in Section 12.2.4. 
Section 12.2.4 
Infusion-related reactions or CRS events language was modified to include all events 
reported as adverse events of special interest (AESI), similar modification made in 
Section 7.2.   
Section 14.1 
Sample size was decreased from a potential total of 104 to 52 patients due to removal 
of the Q2W cohort. 
Appendix 1 
Vital signs footnote for Cycle 1 footnote was amended for clarity and accuracy. 
Appendix 2 
Appendices renumbered starting at Appendix 2 because of the removal of the Q2W 
cohort (previously Appendix 2). 
 
 
 
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Protocol Amendment 1, 22 October 2018 
 
 
LIST OF ABBREVIATIONS 
%CV 
unknown description 
µg 
microgram 
ADA 
anti-drug antibody 
ADCC 
antibody-dependent cellular cytotoxicity 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
APTT 
activated partial thromboplastin time 
AST 
aspartate transaminase 
AUC 
area under the curve 
BiTE 
bispecific T cell engager 
BiW 
twice a week 
BOR 
best overall response 
BUN 
blood urine nitrogen 
cCR 
confirmed complete response 
CDC 
complement-dependent cytotoxicity 
CEA 
carcinoembryonic antigen 
CFR 
Code of Federal Regulations (U.S.) 
CHO 
Chinese hamster ovary 
CI 
confidence interval 
CL 
clearance 
Cmax 
maximum observed serum concentration 
CNS 
central nervous system 
cPR 
confirmed partial response 
CR 
complete response 
CRC 
colorectal cancer 
CRF 
case report form 
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-associated protein 4 
Ctrough 
trough concentration 
CV 
coefficient of variation 
DART 
Dual Affinity Re-Targeting (protein) 
dL 
deciliter 
DLT 
dose-limiting toxicity 
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Protocol Amendment 1, 22 October 2018 
 
 
DoR 
Duration of Response 
E:T 
effector to target (cell ratio) 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
Electronic Data Capture 
EGFR 
epidermal growth factor receptor 
ELISA 
Enzyme-linked immunosorbent assay 
EOI 
end of infusion 
Fc 
fragment crystallizable 
FcγR 
Fc gamma receptor 
FcRn 
neonatal Fc receptor 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GLP 
Good Laboratory Practice 
gpA33 
glycoprotein A33 
hCG 
urine human chronic gonadotropin 
Hgb 
hemoglobin 
hr 
hour(s) 
IB 
Investigational Brochure 
ICFs 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IFN-γ 
interferon gamma 
IgG 
immunoglobulin G 
IHC 
immunohistochemistry 
IL 
interleukin 
IND 
Investigational New Drug application 
irAE 
immune-related adverse event 
IRB 
Institutional Review Board 
irCR 
immune-related Complete Response 
IRE 
immediately reportable event 
irPD 
immune-related disease progression 
irPR 
immune-related Partial Response 
irRECIST 
immune-related response criteria 
irSD 
immune-related Stable Disease 
IV 
intravenous(ly) 
KD 
equilibrium dissociation constant 
kDa 
kilodalton 
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Protocol Amendment 1, 22 October 2018 
 
 
kg 
kilogram 
LID 
Lead-in dose 
LTFU 
lost to follow up 
μg 
micrograms 
mAb 
monoclonal antibody 
MAD 
maximum administered dose 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean cell volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligrams 
min 
minute 
mL 
milliliter 
mm 
millimeter 
MMR 
mismatch repair 
MRI 
magnetic resonance imaging 
MRT 
mean residence time 
MSI 
microsatellite instability 
MSS 
microsatellite-stable 
MTD 
maximum tolerated dose 
n 
number 
NCA 
noncompartmental analysis 
NCI 
National Cancer Institute 
ng 
nanogram 
NK 
natural killer 
nM 
nanomolar 
NOAEL 
no-observed-adverse-effect level 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PD 
pharmacodynamics 
PFS 
progression-free survival 
PK 
pharmacokinetics 
PQC 
product quality complaint 
PR 
Partial Response 
PT 
prothrombin time 
Q2W 
every 2 weeks 
Q3W 
every 3 weeks 
Q4W 
every 4 weeks 
QW 
once weekly 
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Protocol Amendment 1, 22 October 2018 
 
 
RBC 
red blood cells 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RLU 
relative light unit 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous(ly) 
SD 
standard deviation 
SEB 
Staphylococcal Enterotoxin B 
SOC 
System Organ Class 
SPR 
surface plasmon resonance 
t1/2 
terminal half-life 
TCR 
T cell receptor 
TILs 
tumor infiltrating lymphocytes 
TNF-α 
tumor necrosis factor alpha 
ULN 
upper limit of normal 
US 
United States 
Vss 
unknown description 
WBC 
white blood cells 
 
 
 
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Protocol Amendment 1, 22 October 2018 
 
 
1 
SYNOPSIS 
Sponsor: MacroGenics, Inc. 
IND Number: 119748 
Name of Product: MGD007, MGA012 (also known as INCMGA00012) 
Study Title: A Phase 1b/2, Open Label, Dose Escalation Study of MGD007, a Humanized gpA33 × CD3 
DART® Protein in Combination with MGA012, an Anti-PD-1 Antibody, in Patients with Relapsed or 
Refractory Metastatic Colorectal Carcinoma 
Study Number: CP-MGD007-02 
Study Phase: 1b/2 
Investigator(s)/Centers: This study will be conducted at approximately 10 sites in the United States (US). 
Dose Escalation Phase: 
Primary Objective: 
To characterize the safety, tolerability, dose-limiting toxicities (DLTs), and maximum tolerated dose (MTD) 
of MGD007 when combined with MGA012 in patients with relapsed/refractory metastatic colorectal 
carcinoma after at least 2 and up to 5 prior standard regimens of therapy in metastatic setting; or who did not 
tolerate fluoropyrimidines, oxaliplatin or irinotecan; or who are not good candidates for standard of care. 
Secondary Objective: 
 
To characterize the pharmacokinetics (PK), pharmacodynamic activity, and immunogenicity of 
MGD007 and MGA012 in combination. 
 
To investigate the preliminary antitumor activity of MGD007 combined with MGA012 as measured 
by objective response rate, disease control rate, and progression-free survival (PFS) rate at 16 weeks 
in patients with relapsed/refractory metastatic colorectal carcinoma using both conventional 
Response Evaluation Criteria in Solid Tumors (RECIST 1.1), Appendix 5, and immune-related 
response criteria (irRECIST), Appendix 6. 
Cohort Expansion Phase: 
Primary Objective: 
 
To investigate antitumor activity of MGD007 combined with MGA012 when dosed at the MTD (or 
maximum administered dose [MAD] if no MTD is defined) as measured by objective response rate, 
disease control rate, and PFS rate at 16 weeks in patients with relapsed/refractory metastatic 
colorectal carcinoma using both conventional Response Evaluation Criteria in Solid Tumors 
(RECIST 1.1), Appendix 5, and immune-related response criteria (irRECIST), Appendix 6. 
Secondary Objective: 
 
To further characterize the safety and tolerability, of MGD007 when combined with MGA012 in 
patients with relapsed/refractory metastatic colorectal carcinoma after at least 2 lines of therapy in a 
metastatic setting. 
 
To characterize the PK, pharmacodynamic activity, and immunogenicity of MGD007 and MGA012 
in combination. 
 
To explore the impact of this combination on PFS, immune-related PFS (irPFS), and overall survival 
(OS) in patients with relapsed/refractory metastatic colorectal carcinoma. 
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MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGD007-02 
Protocol Amendment 1, 22 October 2018 
 
 
Study Design: 
Overview: 
This study is an open-label, Phase 1b/2, dose escalation and cohort expansion study designed to characterize 
the safety, tolerability, PK, pharmacodynamics, immunogenicity, and preliminary antitumor activity of 
MGD007 and MGA012, administered in combination by IV infusion, in patients with histologically proven, 
relapsed/refractory metastatic colorectal carcinoma, irrespective of the KRAS and MMR status of their 
tumors. This study will enroll patients as described below. 
The study will proceed in 2 distinct phases as follows: Dose Escalation Phase to determine the MTD or MAD 
(if no MTD is defined) of the combination, followed by a Cohort Expansion Phase to further define the safety 
and initial antitumor activity of the combination with the doses established in the Dose Escalation Phase. 
Patients will be treated with MGD007 and MGA012 as shown in the figure below. MGD007 will be 
administered at the target dose for each assigned cohort as an IV infusion over 120 minutes, once weekly 
(QW), in 8-week treatment cycles. MGA012 will be administered at 3 mg/kg as an IV infusion over 60 
minutes, once every 2 weeks (Q2W) beginning on Cycle 1 Day 15, and every 2 weeks thereafter. For each 
patient, administration of the first dose of MGA012 will occur 2 weeks after the first dosing of MGD007. The 
DLT evaluation period will last until Cycle 1 Day 42. Disease status will be evaluated on Cycle 1 Day 
56 (± 3 days) using CT and/or MRI as appropriate for the sites of disease, accompanied by physical 
examination, and then will be evaluated every 8 weeks while on study treatment. Although response 
assessment will be performed according to both conventional (RECIST 1.1 [Appendix 5]) and irRECIST 
(Appendix 6), patients will be managed according to irRECIST principles. This approach allows for limited 
treatment of patients beyond the initial radiographic documentation of disease progression, assuming the 
Investigator feels that the 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. 
Patients who achieve response status of immune-related complete response (irCR), immune-related partial 
response (irPR), immune-related stable disease (irSD), or unconfirmed immune-related progressive disease 
(irPD), per the immune-related response criteria (Appendix 6) at the end of the Cycle 1 radiographic disease 
assessment, may be eligible to receive subsequent administrations of MGD007 and MGA012 for up to 
12 cycles (~ 2 years), assuming that the patients remain clinically stable and have not experienced DLTs that 
necessitated permanent discontinuation of study drug.  
Overall Study Treatment Schema  
  
The dose levels are shown below: 
Dose Level 
MGD007 Dose (QW) 
MGA012 Dose (Q2W) 
Dose Level 1 
0.4 µg/kg 
3 mg/kg 
Dose Level 2 
0.6 µg/kg 
3 mg/kg 
Dose Level 3 
0.8 µg/kg 
3 mg/kg 
 
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Patients who experience progressive disease, as evidenced by ≥ 20% increase in the dimensions of target 
lesions or the occurrence of new lesions, may continue therapy at the discretion of the Investigator, pending 
confirmation of progressive disease at the next planned tumor assessment and satisfaction of criteria for irPD. 
Subsequent cycles of therapy after an initial documentation of progressive disease should be administered 
only to patients who have demonstrated acceptable tolerance to treatment with study drug, who remain 
otherwise clinically stable, and who in the assessment of the Investigator, may derive clinical benefit from the 
continuation of treatment with study drug. 
No dose reductions of MGA012 or MGD007 are allowed during the study, except for patients being treated at 
doses that are subsequently found to exceed the MTDs for this schedule. 
Data regarding the KRAS and MMR mutational status (MSI or MSS) will be collected for all patients; 
statuses for both must be formally documented for patients in the Cohort Expansion Phase. Patients will be 
required to have at least 1 site of measurable disease as defined by RECIST 1.1 criteria (Appendix 5). In 
addition, patients must have had an identified tumor tissue block (preferred) and/or tumor specimens sufficient 
for 20 slides that can be utilized for assay of gpA33, CD3, PD-1, and PD-L1 expression via 
immunohistochemical staining. 
Following the last dose of study drug, all patients will be followed every 3 months for survival during a 2-year 
Survival Follow-up Period. 
Number of Patients Enrolled: 
The number of patients enrolled in the Dose Escalation Phase cannot be precisely determined in advance. 
There may be up to 27 patients enrolled, depending on results in the course of the trial and the number of 
MGD007 and MGA012 doses explored. This patient number does not take into account replacement of non-
evaluable patients or enrollment to a dose cohort that is expanded in Dose Escalation Phase. 
The Cohort Expansion Phase of the study will enroll approximately 25 patients. This number may be higher 
because at the end of the Cohort Expansion Phase, 15 tumor paired biopsies will be required, if metastases are 
accessible and obtained with acceptable clinical risk (see Section 5.1, # 9). If this number is not reached, 
additional patients will be enrolled in the study to ensure that the 15 paired biopsies are obtained (see 
Section 4.1.2).  
The number of patients does not take into account patients who may be replaced for clinical reasons. For 
initial planning, the maximum number of patients to be enrolled in this trial is anticipated to be approximately 
52 patients. 
Study Population: 
The patient population to be enrolled in this study will consist of adult patients with histologically proven, 
relapsed/refractory metastatic colorectal carcinoma irrespective of the KRAS and MMR status of their tumors, 
although data regarding the KRAS and MMR mutational status will be collected for all patients. 
Key Entry Criteria: 
The patient population to be enrolled in this study, will consist of adult patients with histologically proven, 
relapsed/refractory metastatic colorectal carcinoma. In the Dose Escalation Phase, patients must have had 
recurrence, progression, or intolerance to standard therapy consisting after at least 2 prior standard regimens 
(containing a fluoropyrimidine plus a platinum analogue and/or irinotecan) for metastatic disease. During the 
Cohort Expansion portion of the study, patients will be allowed to participate in the study after 1 prior 
standard regimen. Patients who are inappropriate candidates for or have refused treatment with these regimens 
are also eligible. Patients should have received no more than 5 prior therapies. 
Patients in the Dose Escalation Phase must have ECOG performance status of 0 or 1, radiographic evidence of 
measurable disease suitable for response monitoring, and no serious concurrent illnesses that would increase 
the risk to the patient or confound the study data. 
See Section 5 for a complete list of eligibility criteria. 
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Clinical Trial Protocol: CP-MGD007-02 
Protocol Amendment 1, 22 October 2018 
 
 
Study Drugs: 
 
MGA012 (also known as INCMGA00012) is an anti-PD-1 monoclonal antibody (mAb) protein 
produced in Chinese hamster ovary (CHO) cells. 
 
MGD007 is a gpA33 × CD3 DART protein produced in CHO cells. 
Duration of Treatment and Study Duration: 
Patients will be treated with MGD007 and MGA012 administered in 8-week treatment cycles until disease 
progression, intolerable toxicity, or patient and investigator’s decision. 
The maximum amount of time an individual patient may be on study is 12 treatment cycles, or approximately 
2 years. 
Enrollment of the study should last approximately 18 months. 
The total time for conduct of the trial is expected to be approximately 66 months (which includes 2 years of 
survival follow-up). These estimates of the timing for study conduct may vary from that observed in the actual 
conduct of the trial. 
Criteria for Evaluation: 
Safety Assessments: 
The safety assessment will be based on the evaluation of AEs that occur from the time of initiation of 
administration of study drug through the End of Treatment Visit or 30 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. 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. 
Response Assessments: 
Tumor assessments will be obtained using CT and/or MRI scans. Target and non-target lesions will be 
designated at screening and then evaluated at Cycle 1 Day 56 (±3 days), and subsequently every 8 weeks 
while on study treatment. At each tumor assessment time point, the overall response status will be determined 
based on assessment of target and non-target lesions as well as appearance of any new lesions. For RECIST 
v1.1 (Appendix 5), the overall responses will be categorized as CR, PR, SD, PD, or NE. For irRECIST 
(Appendix 6), the overall responses will be categorized as irCR, irPR, irSD, irPD, or irNE. For patient 
management, the response determination according to irRECIST will prevail. For patients who demonstrate 
acceptable tolerability of treatment with MGD007 and MGA012, and an objective response assessment of 
irCR, irPR, or irSD, or unconfirmed clinically stable irPD, therapy may be continued. For patients in whom 
progression is confirmed at the next scheduled tumor assessment, the criteria for irPD will have been met, and 
treatment with MGD007 and MGA012 should be discontinued. However, for individual patients who meet 
these criteria, but who are otherwise considered to be experiencing clinical benefit in the judgment of the 
Investigator, consideration may be given to continue treatment with the MGD007 and MGA012 combination, 
on a case-by-case basis, in consultation with the Sponsor. 
Pharmacokinetic Assessments: 
Serum concentrations of MGD007 and MGA012 will be measured using ELISAs. Single and multiple dose 
PK parameters, Cmax, Tmax, AUC(0-T), AUC(TAU), AUC(INF), Ctrough, CL, Vss, and t1/2 will be derived from 
MGD007 and MGA012 serum concentration versus time data. 
Pharmacodynamics/Biomarkers: 
Samples collected for serum biomarkers are collected in the Dose Escalation Phase and the Cohort Expansion 
Phase. 
Immunogenicity Assessments: 
The generation of anti-drug antibodies (ADA) directed against MGD007 and MGA012 will be assayed using 
ELISAs. 
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Clinical Trial Protocol: CP-MGD007-02 
Protocol Amendment 1, 22 October 2018 
 
 
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 any study drug. This population will be used for analyses of 
safety, pharmacodynamics, and immunogenicity. It will also be used for summary of baseline data and 
analyses of PFS and OS. 
Response Evaluable Population: 
All patients who received at least one dose of any study drug, had baseline measurable disease, and had at 
least one post-baseline radiographic tumor assessment or discontinued from treatment due to clearly 
documented, clinically progressive disease or death. This population will be used for summary of tumor 
assessment data and analyses of response rates. 
Statistical Methods: 
A separate statistical analysis plan (SAP) and statistical programming plan (SPP) will further describe the 
details regarding statistical methods and will govern the analysis. 
Sample Size: The study plans to treat approximately 52 patients: up to 27 in Dose Escalation Phase and 
approximately 25 in the Cohort Expansion Phase. At the end of the Cohort Expansion Phase, 15 paired tumor 
biopsies will be required; paired tumor biopsies will be mandatory if tumor lesions are accessible for biopsy 
with acceptable clinical risk in the judgment of the investigator and after discussion with the Sponsor. If 15 
paired biopsies have not been collected in the initial 25 patients, additional patients with paired tumor biopsies 
will be enrolled, to ensure that the 15 paired biopsies are obtained. It is estimated that approximately 90% of 
the 25 patients will be MSS patients. 
Safety: Treatment-emergent AEs will be summarized by SOC and PT, by relationship to study drugs, and by 
highest severity. For laboratory tests, number and percent of patients shifted from baseline to post-baseline 
maximum severity in CTCAE grade will be summarized. 
Efficacy: Number and percent of patients with their best overall response will be summarized. Objective 
response rate will be calculated as proportion of patients in response evaluable population achieving a best 
response of CR or PR. Disease control rate is calculated as the proportion of patients who achieve a CR, PR, 
or SD. PFS rate at 16 weeks will be calculated as the probability that patients are free of disease progression 
and alive at 16 weeks after the first dose of MGD007 by Kaplan-Meier method, based on response evaluable 
population and safety population, respectively. The response rates will be determined using both RECIST 1.1 
and irRECIST. Two-sided exact 95% confidence intervals will be constructed around the response rates. 
Kaplan-Meier methods will be used to estimate duration of response, PFS, and OS. 
Pharmacokinetic Analysis: Summary statistics will be tabulated separately for serum PK parameters by 
MGD007 and MGA012 dose. Geometric means and percent coefficients of variation will be reported for Cmax, 
AUC(0-T), AUC(TAU), AUC(INF), and Ctrough; arithmetic means and standard deviations will be reported for t1/2, 
CL, and Vss; and medians, minimum, and maximum will be reported for Tmax. Separate scatter plots of Cmax 
and AUC will be provided versus dose to assess dose dependency. Dose proportionality may be assessed 
using a power model. 
Immunogenicity Analysis: The proportion of patients who are negative for ADA at baseline and become 
positive in this assay, the proportion of patients who are negative at baseline and remain negative, and those 
who have positive ADA at baseline that increase or decrease in titer over the course of treatment will be 
summarized. Analysis will be conducted separately for MGD007 and MGA012. 
 
 
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Clinical Trial Protocol: CP-MGD007-02 
Protocol Amendment 1, 22 October 2018 
 
 
2 
BACKGROUND INFORMATION 
2.1 
Rationale for Study 
Bispecific antibodies are powerful tools for the immunologic treatment of cancer. In 
particular, they can be leveraged to enhance tumor killing in a non-MHC-restricted manner by 
redirecting effector cells (e.g., T cells, NK cells, macrophages, and monocytes) to the tumor 
cells. The interaction of T cells and tumor cells initiates the killing process by T cells, 
including activation of CD3, formation of immunologic synapses, activation and proliferation 
of T cells, secretion of cytokines and cytotoxic granules, and lysis of tumor cells. The 
activated CD8+ and CD4+ T cells lyse cancer cells predominantly through perforin and 
granzyme B. The activated T cells secrete various cytokines such as IFN-γ, TNF, IL-2, IL-6, 
and IL-10. 
The bispecific antibodies include notably DART proteins and bispecific T cell engagers 
(BiTE). Blinatumomab, as a BiTE antibody against CD19/CD3, has been approved for the 
treatment of relapsed/refractory B-precursor acute lymphoblastic leukemia by the U.S. Food 
and Drug Administration (FDA) in December 2014 (51). Bispecific antibodies have had more 
success in hematological malignancies than in solid tumors, but there are numerous ongoing 
studies. 
MGD007 is a glycoprotein A33 (gpA33) × CD3 DART® protein that binds 2 distinct antigens 
(human gpA33 and CD3) simultaneously. The gpA33 antigen is a transmembrane 
glycoprotein expressed almost exclusively in the intestinal epithelium and is present in > 95% 
of primary and metastatic human colorectal cancers (CRCs) (14, 48). CD3 plays an important 
role in T cell receptor (TCR) signaling. Thus, MGD007 was designed to redirect the killing 
function of CD3-expressing effector T cells to target cells expressing gpA33. 
CD3 bispecific molecules that can bring T cells to tumors could potentially introduce T cell 
infiltration in tumors that do not naturally possess this characteristic. In order to have an 
antitumor effect, these T cells should sustain cytolytic and proliferative function in the 
presence of inhibitory signals in the tumor microenvironment. T cells naturally undergo 
activation-induced upregulation of co-inhibitory pathways, which may limit the antitumor 
immune response. PD-1, CTLA-4, and other co-inhibitory receptors are upregulated in T cells 
following exposure to antigens. Additionally, tumor cells increase the expression of 
coinhibitory ligands such as PD-L1 following exposure to T cell secreted T helper 1 
cytokines, including IFN-γ (28, 29, 42). 
MGA012 is an anti-PD-1 antibody that was designed to function as an immune checkpoint 
inhibitor and disrupt a major negative immune signaling axis in exhausted/ dysfunctional 
T cells which express the PD-1 receptor, and to cancer cells or APCs, which express their 
corresponding ligands: PD-L1 and PD-L2. MGA012 is believed to break this inhibitory axis 
and to overcome the suppressive mechanisms that cancer cells and some APCs (i.e., MDSCs, 
macrophages) employ. Indeed, in vitro studies have demonstrated MGA012 blocks 
PD-1/PD-L1 and PD-1/PD-L2 interactions, inhibits PD-1 signaling, and enhances T-cell 
responses to antigenic stimulation (see Section 2.5). 
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Protocol Amendment 1, 22 October 2018 
 
 
MGD007 redirects T-cell killing of gpA33-expressing target cells, predominantly through 
CD8 T cells, and activates CD4 T cells that support cell lysis; MGA012 inhibits the 
PD-1/PD-L1 axis. Based on the 2 molecules’ mechanisms of action, the combination of 
MGD007 with MGA012 is hypothesized to have several antitumor advantages over current 
treatments by disruption of the following mechanisms: 1) Take off the breaks induced by the 
negative signal and functional impairment delivered to T cells by PD-1 with its ligands, 
PD-L1 and PD-L2 interaction and 2) blocking the frequent pre-existing PD-L1 expression in 
the tumor microenvironment, which inhibits CD8+ CTL proliferation and survival and 
promotes differentiation of CD4+ T cells into Treg cells (52). Figure 1 shows a classification 
of tumors based on the location and intensity of CD8+ T cell expression. 
Figure 1 
The Tumor Immunity Continuum: Images of Tumor CD8 
Immunohistochemistry and Patterns of T Cells associated with 
Tumor Cells 
 
Source: Hegde, 2016 (17) 
Tumors with pre-existing immunity are represented by abundance of tumor-infiltrating 
lymphocytes (TILs); dense functional CD8+ T cell infiltration reflected by increased IFNγ 
signaling; expression of checkpoint markers, including PD-L1; and high mutational burden. 
Colorectal cancer can be ranked in the 2 other patterns representative of non-inflamed tumors, 
i.e., either immunologically ignorant and poorly infiltrated by lymphocytes, or with an 
immunosuppressive microenvironment created to evade immune surveillance, by recruiting 
myeloid-derived suppressor cells or secreting factors including TGFβ, which plays a dual role 
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of inducing the expression of extracellular matrix genes and suppressing the expression of 
chemokines and cytokines required to facilitate T-cell infiltration into tumors (17). 
Immunologically ignorant tumors that contain very low infiltration of T cells are genomically 
stable with highly proliferating tumor cells (17). These characteristics do not apply to a 
specific subset of CRCs that display a defect in the mismatch repair (MMR) pathway, 
resulting in microsatellite instability (MSI). MSI-high (MSI-H) CRCs represent 
approximately 10% to 15% of all CRCs. Germline and sporadic MSI-H tumors are similar and 
are often hyper- or ultra-mutated. The 85 percent of CRCs that are not MSI-high are 
considered microsatellite stable (MSS) (7). 
Several studies showed clinical benefit of immunotherapy, mainly PD-1 inhibition for 
immunogenic MSI-H CRCs, whereas there is no evidence to date to suggest the same in MSS 
CRCs (45). As an example, in a Phase 2 study assessing the efficacy of pembrolizumab in 
MSI-H tumors, immune-related objective response rate and immune-related progression-free 
survival (PFS) rate at 20 weeks were 40% (4 of 10 patients) and 78% (7 of 9 patients), 
respectively, for MMR deficient CRCs and 0% (0 of 18 patients) and 11% (2 of 18 patients) 
for MMR proficient CRCs (22). Likewise, nivolumab provided durable responses and disease 
control in pre-treated patients with MSI-H metastatic CRC (31). 
In the most frequent subtype of CRC, i.e. MSS, the reactive stroma and dense extracellular 
matrix create a barrier to the infiltration of immune cells into the tumor, which manifests as an 
excluded infiltrate phenotype with peritumoral or stromal T-cell localization. Tumors that 
exhibit high expression of gene signatures of reactive stroma or TGFβ signaling are often 
associated with lower expression of immune markers (13, 32, 39). Clinical evidence suggests 
that checkpoint inhibitors largely act by reinvigorating pre-existing antitumor T-cell responses 
and are most effective in tumors as characterized by tumor PD-L1 positivity. Inhibition of the 
PD-1/PD-L1 axis with MGA012 could therefore enhance the antitumor activity of MGD007 
in patients by triggering CD8 T cell immune reactivity and tumor infiltration and by 
preventing T cell exhaustion. 
In studies that performed comparisons of local primary tumors vs metastatic deposits in the 
same patient, positive expression of PD-L1 was found in about 80% of metastatic colorectal 
carcinomas, and PD-L1 expression has been reported to be significantly more prevalent in 
metastatic colorectal carcinomas than in primary tumors. PD-L1 expression appears to 
increase during evolution of the metastatic process (16, 47, 37). 
In a study of 49 patients with metastatic CRC, PD-1+ expression was markedly upregulated 
on CD8+ T cells in tumors compared with that in peripheral blood and PD-L1 was highly 
expressed in tumors rather than tumor-free lymph nodes, which was closely correlated with 
the impairment of IFN-γ production of tumor-infiltrating PD-1+ CD8+ T cells. The authors 
suggested a suppressive effect of PD-1+ on CD8+ T-cell function in tumors (52). 
Different authors have assessed the use of Immunoscore (IS), an index based on the density of 
CD3+ and CD8+ TILs in the tumor center and invasive margin of tumors, as a prognostic 
marker for CRC. Tumor-associated macrophages (TAMs) have also been reported to have 
prognostic value. The density of CD3+, CD4+, CD8+, FOXP3+, CD68+, and CD163+ 
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immune cells within CRC tissue was determined using immunohistochemistry (IHC) and 
digital image analyzer (n  196). The IS was obtained by quantifying the densities of CD3+ 
and CD8+ TILs. Higher IS values were significantly correlated with better prognosis 
(p  0.020). Multivariate analysis revealed that IS was an independent prognostic marker 
(p  0.012) (4, 21). 
The clinical relevance of PD-L1 expression by tumor cells and TILs in CRC has been 
investigated in 186 MSI-H and 153 MSS tumors. PD-L1 expression was evaluated in tumor 
cells at the center and periphery, and immune cells at the center (IC) and periphery (IP) of 
CRC tumors. IHC slides were stained for CD3 and CD8. Notably, in both MSI-H and MSS 
CRC, PD-L1 expression in the center and in the periphery were independently associated with 
improved prognosis (P < 0.05) (23). 
Another study, in The Cancer Genome Atlas (TCGA) cohort of 276 patients with CRC, 
assessed the prognostic value of PD-L1 in tumor cells and of PD-1 in TILs. Multivariate Cox 
regression analysis indicated that higher expressions of PD-1 and PD-L1 correlated with 
better prognosis of CRC patients. TILs-PD-1 was an independent prognostic factor for overall 
survival (OS) and disease-free survival (DFS) of CRC patients, especially for the MMR-
proficient subgroup (25). 
In addition to the constitutive expression of PD-1/PD-L1 in the CRC microenvironment, it is 
anticipated that both PD-1 and PD-L1 may be inducibly up-regulated as a consequence of the 
mechanism of action of MGD007, resulting in a possible further layer of checkpoint inhibition 
that theoretically could limit therapeutic responses to MGD007 monotherapy. Concomitant 
with gpA33 expressing Colo205 CRC cell lysis mediated by MGD007 (Figure 2A) is a 
parallel up-regulation of PD-L1 (Figure 2C) on residual target cells. Furthermore, both PD-1 
(Figure 2B) and PD-L1 (Figure 2D) are also up-regulated on the effector T-cell population. 
Overcoming the PD-1/PD-L1 pathway axis with MGA012 could therefore enhance the 
antitumor activity of MGD007 in patients, a hypothesis supported by in vitro evidence of 
enhanced MGD007-mediated gpA33 tumor cell killing at select concentrations of MGD007 
and MGA012 (representative experiment shown in Figure 3). Furthermore, in the presence of 
pre-activated T-cells (expressing PD-1 and PD-L1) and gpA33 expressing cancer cells, 
MGD007-mediated increases in IFN and TNF can be further enhanced in the presence of 
MGA012 (Figure 4). 
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Protocol Amendment 1, 22 October 2018 
 
 
Figure 2 
MGD007 Mediated Up-regulation of PD-1 and PD-L1 
 
A-D: MGD007-mediated cytolysis of gpA33-expressing cells is associated with up-regulation of PD-1 and 
PD-L1. Colo205 colorectal cancer cells were mixed with freshly isolated human T-cells at E:T ratio = 5:1 in 
the presence of increasing concentrations of MGD007 or control CD3 DART. (A) The level of Colo205 
target cell cytotoxicity mediated by MGD007 determined by evaluation of LDH release at 24 hrs. (B) The 
surface expression level of PD-1 on the effector T-cell population and the surface expression level of PD-L1 
on the tumor target cells (C) and the effector T-cell population (D) were determined at 24 hrs by flow 
cytometry. 
 
 
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Protocol Amendment 1, 22 October 2018 
 
 
In those patients with limited resectable metastatic tumors, surgical resection may be 
employed and may be curative in some instances, but most of them have unresectable disease 
at diagnosis. Neoadjuvant chemotherapy may be used in an attempt to achieve reduction in 
the tumor and render it resectable. Neoadjuvant chemotherapy may commonly consist 
of FOLFOX (folinic acid/5-FU, oxaliplatin) or FOLFIRINOX (folinic 
acid/5-FU/irinotecan/oxaliplatin)-based regimens administered +/- anti-EGFR antibody 
(e.g., cetuximab or bevacizumab) (10, 30, 35, 54). 
For patients with unresectable metastatic disease, therapy most commonly consists of 
combination regimens with one or more of the following agents: 5-FU/leucovorin, irinotecan, 
capecitabine, oxaliplatin with or without anti-VEGF agents (bevacizumab, aflibercept) or 
anti-EGFR antibodies (cetuximab, panitumumab), or multi-specific tyrosine-kinase inhibitors 
(TKI) (regorafenib). Common chemotherapy regimens include FOLFOX, FOLFIRI, 
FOLFIRINOX, or CapeOx administered with or without bevacizumab, panitumumab, or 
cetuximab, depending on KRAS status (1, 5, 19, 26, 34, 50). Agents such as aflibercept are 
generally utilized in patients who have progressed after front-line chemotherapy. 
In third-line therapy, there are a few treatments that have received U.S. FDA approval, such as 
Lonsurf® (trifluridine and tipiracil [TAS 102]) (27) and Stivarga® (regorafenib) (15). The FDA 
approved TAS-102 in 2015. The efficacy and safety were evaluated in a randomized, double-
blind, placebo-controlled study involving 800 patients with previously treated metastatic 
colorectal carcinoma. The median OS was 7.1 months (95% confidence interval [CI], 6.5 to 
7.8) in the TAS-102 group and 5.3 months (95% CI, 4.6 to 6.0) in the placebo group. The 
hazard ratio (HR) for death (TAS-102 vs. placebo) was 0.68 (95% CI, 0.58 to 0.81; P < 
0.001). The 1-year OS rates were 27% and 18%, respectively. The median PFS was 2.0 
months (95% CI, 1.9 to 2.1) in the TAS-102 group and 1.7 months (95% CI, 1.7 to 1.8) in the 
placebo group. The HR for progression (TAS-102 vs. placebo) was 0.48 (95% CI, 0.41 to 
0.57; P < 0.001) (27). Regorafenib received FDA approval in 2012 for the treatment of 
patients who have been previously treated with fluoropyrimidine-, oxaliplatin-, and 
irinotecan-based chemotherapy, with an anti-VEGF therapy, and, if KRAS wild type, with an 
anti-EGFR therapy. In an international, randomized, placebo-controlled trial that enrolled 760 
patients, a significant prolongation in OS was observed in patients who received regorafenib 
(HR 0.77 [95% CI: 0.64, 0.94]; p  0.0102). The median survival time was 6.4 months (95% 
CI: 5.8, 7.3) in the regorafenib group and 5.0 months (95% CI: 4.4, 5.8) in the placebo group. 
Median PFS was 2.0 months (95% CI: 1.9, 2.3) in the regorafenib group and 1.7 months (95% 
CI: 1.7, 1.8) in the placebo group (15). 
Even though several existing agents and combination regimens using these agents have 
demonstrated the ability to induce objective responses and to extend both progression-free 
survival and overall survival in patients with colorectal carcinoma, the prognosis of patients 
with metastatic colorectal carcinoma remains extremely poor overall, with 5-year survival 
rates estimated to be as low as 6-8%. There remains an urgent need for new approaches for the 
treatment of patients with colorectal carcinoma, and this has fueled intense effort to test 
various new approaches in this setting, including the use of immunotherapeutic agents. 
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The observation that local infiltration of T cells, including CD8+ T cells, and local expression 
of genes associated with the cytotoxic phenotype (i.e., IFN-γ, granulolysin, and granzyme B) 
and markers of T cell migration may associate with more favorable clinical prognosis in 
patients with colorectal carcinoma, suggests that immune therapeutic approaches that enable 
T cell mediated reactivity against colorectal carcinoma tumors could offer the prospect of 
clinically meaningful antitumor activity. 
2.3 
Background on MGD007 
2.3.1 
Background on MGD007 
MGD007 is a gpA33 × CD3 DART protein produced in Chinese hamster ovary (CHO) cells. 
DART proteins are bispecific, antibody-based molecules that can bind 2 distinct antigens 
simultaneously. MGD007 is designed to target gpA33-positive cells for recognition and 
elimination by CD3-expressing T lymphocytes as effector cells. To prolong half-life, 
MGD007 also contains a human IgG1 Fc region that has been mutated to eliminate undesired 
binding to FcγR and complement, but that retains neonatal FcR (FcRn) binding to take 
advantage of the IgG salvage pathway mediated by this receptor. 
The gpA33 antigen is a transmembrane protein expressed on nearly all primary and metastatic 
colorectal tumors. Expression of gpA33 on normal tissues is restricted to the small and large 
intestines. The anti-gpA33 component of MGD007 is based on a humanized version of the 
MacroGenics proprietary mAb, RECA47. CD3 is an invariant complex of proteins 
(comprising cell surface gamma, delta, epsilon, and zeta chains) that is required for expression 
of and signaling through the antigen-specific TCR on T cells. The anti-CD3 component of 
MGD007 is based on the MacroGenics proprietary mAb, hXR32. MGD007 is under 
development as a therapeutic candidate for the treatment of colorectal carcinoma. 
A schematic of MGD007 is shown in Figure 5. 
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Clinical Trial Protocol: CP-MGD007-02 
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Figure 5 
DART Protein Schematic and Assembly 
 
MGD007 is composed of 3 chains that are covalently linked by disulfide bonds. Chains 1 and 2 form a 
heterodimer by a disulfide bond at the C-terminus of the chains and by virtue of oppositely charged 
coiled-coiled sequences (E-coil and K-coil). Chains 1 and 3 are covalently linked by 2 disulfide bonds in the 
Fc hinge region. To prevent homodimerization of Chains 1 and 3, the knob (T366W) and hole 
(T366S/L368A/Y407V) mutations have been incorporated in the respective CH3 region of each Fc. To 
further assure removal of any remaining homodimers of Chain 3 during purification, the H435R mutation 
also has been incorporated in the CH3 region of the Fc (this mutation ablates binding to Protein A). A 
double mutation (L234A/L235A) has been incorporated in the CH2 region of the Fc to eliminate binding to 
FcγR and C1q. 
For additional detailed description of nonclinical data regarding MGD007, please also refer to 
the MGD007 Investigator’s Brochure. 
2.3.2 
MGD007 Pharmacology 
Bispecific binding of MGD007 to its target antigens gpA33 and CD3 has been characterized 
by both surface plasmon resonance (SPR) analysis and flow cytometry. SPR analysis using 
recombinant soluble human antigens revealed MGD007 binding affinities (KD) of 
approximately 2 nM to gpA33 and 23 nM to CD3. Similar binding affinities for MGD007 
were observed with cynomolgus monkey gpA33 (11 nM) and CD3 (26 nM). The approximate 
10-fold greater affinity of MGD007 for gpA33 is desirable in order to favor initial binding to 
the gpA33-positive target cell and minimize CD3 engagement in the absence of target cells. 
Flow cytometry analyses confirmed the ability of MGD007 to bind natively expressed cell 
surface CD3 on human and cynomolgus monkey T cells and to gpA33 expressed across a 
panel of human CRC cell lines or to CHO cells engineered to express either human or 
cynomolgus monkey gpA33. 
Consistent with its bispecific binding properties and designed mechanism of action, MGD007 
supports potent redirected T-cell killing of multiple gpA33-expressing CRC cells in vitro in 
assays employing either purified human peripheral blood mononuclear cells (PBMC) or 
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been mutated to eliminate FcR binding and silence any unwanted Fc-mediated effector 
functions as demonstrated by negligible antibody-dependent cellular cytotoxicity (ADCC) or 
complement-dependent cytotoxicity (CDC) activity in vitro. 
Antitumor activity of MGD007 has been demonstrated in murine xenograft models in which 
gpA33-expressing Colo205 or LS174T human CRC cells were co-implanted subcutaneously 
(SC) with activated human T cells at a ratio of 1:1 followed by treatment with MGD007 
administered IV for 4 consecutive days (Figure 6). At doses of 4 µg/kg or greater, MGD007 
significantly inhibited tumor growth. Such dose levels are considerably lower than MGD007 
doses and exposure levels that are well tolerated in cynomolgus monkeys (Section 2.3.3). 
The in vivo profile of MGD007 binding to peripheral T cells has been evaluated in 
cynomolgus monkeys following treatment with 4 doses of MGD007 (300 µg/kg) administered 
IV over 2 hours either once weekly or once every other week. Four hours following the start 
of infusion of the 1st MGD007 dose, bound MGD007 was detected on both CD4 and CD8 
T cells at approximately 20-40% of the level of maximal MGD007 occupancy. By 48 hours 
after infusion, the level of detectable MGD007 was reduced to 4-17% of maximal binding 
while by Day 7, no bound MGD007 was detected on either CD4 or CD8 T cells. A similar 
profile of binding was observed in cynomolgus monkeys following subsequent MGD007 
doses (except where anti-drug antibodies [ADA] apparently interfered with MGD007 binding) 
with no discernible difference between dosing on a weekly or every other week schedule. 
Taken together, these data indicate that MGD007 is not retained on circulating T cells for 
prolonged periods. Furthermore, evaluation of ex vivo cytotoxic T-lymphocyte (CTL) activity 
by PBMCs isolated from cynomolgus monkeys following treatment with 4 doses of MGD007 
(300 µg/kg) revealed potent specific lysis of gpA33 target cells by MGD007 demonstrating in 
vivo administration of multiple MGD007 doses does not impact the ability of T cells to 
support CTL activity. 
2.3.3 
MGD007 Pharmacokinetics and Toxicology 
The nonclinical toxicology program for MGD007 was performed exclusively in the 
cynomolgus monkey. The cynomolgus monkey was selected as a relevant species for 
toxicological evaluation because MGD007 binds human and cynomolgus monkey gpA33 and 
CD3 with similar affinities (Section 2.3.2). The similar affinities indicate that the epitopes 
bound by the antigen-binding regions of MGD007 are conserved between humans and 
cynomolgus monkeys. This is not surprising given the 87% identity between human and 
cynomolgus gpA33. Though the percent identity between human and cynomolgus monkey 
CD3 is lower (79%), the antigen binding region of the CD3 (i.e., hXR32)-component of 
MGD007, binds in the first 14 amino acids of the CD3ε chain where there is only 1 amino 
acid difference between the 2 species. Additional in vitro cell-based experiments supporting 
the relevance of the cynomolgus monkey include demonstration of comparable redirected 
T cell mediated lysis of gpA33-expressing CRC tumor cells by MGD007 with either human 
or cynomolgus monkey PBMCs and demonstration of comparable binding of MGD007 to cell 
surface expressed human gpA33 or cynomolgus monkey gpA33. 
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Moreover, a non-GLP tissue cross-reactivity study evaluating MGD007-staining of a panel of 
5 tissues from both human and cynomolgus monkey (colon, liver, lung, pancreas, and small 
intestine) demonstrated the staining profile was the same across both species. As expected, 
strong, frequent staining of the epithelium in colon and small intestine was observed in both 
species. In addition, consistent with CD3 expression, lymphocyte staining was observed 
across all organs examined except pancreas. Some weak to moderate, cytoplasmic and 
membrane staining of lung macrophages was also observed in both species; specific staining 
of lung macrophages, however, was not observed in the GLP tissue cross-reactivity study of 
MGD007 in human tissues. Additionally, MGD007 does not bind with both CD3 and gpA33 
in species such as rat and mouse (data on file), which supports the use of cynomolgus 
monkeys as the single relevant toxicological species. 
In repeated-dose non-GLP and GLP toxicology studies, MGD007 has been administered to a 
total of 52 monkeys at doses ranging from 0.3 to 300 µg/kg. In 2 initial, non-GLP, exploratory 
studies, 4 animals received escalating doses of MGD007 starting at 0.3 or 100 µg/kg and 
increasing to a maximum dose of 300 µg/kg. In the remaining studies (2 non-GLP studies and 
1 GLP study) a total of 48 animals received 4 repeated administrations of MGD007 at weekly 
intervals at doses of 30 (n  12), 100 (n  12), and 200 (n  8) µg/kg or at doses of 300 µg/kg 
(n  16) at weekly or every-other-week intervals. MGD007 administered as 2 to 3-hour IV 
infusions on a weekly schedule for up to 4 weeks was well tolerated in all animals treated with 
doses up to 100 µg/kg and in 7/8 animals with 200 µg/kg. In these animals, the only notable 
toxicological finding was emesis following the first dose of MGD007 (considered only 
possibly related) that occurred in up to 10/24 animals treated with doses of 30, 100, or 
200 µg/kg in the GLP toxicology study. The exact frequency of emesis was uncertain because 
evidence of vomiting sometimes was attributed to 2 animals that were pair-housed in a cage 
per testing facility SOP, even though only 1 animal may have experienced the event. 
The primary toxicity associated with MGD007 was on-target toxicity of the small and large 
intestines, primary sites of gpA33 expression, observed at doses of 300 µg/kg, the highest 
dose studied, and possibly in 1 animal treated at 200 µg/kg. As a result of the 1 animal treated 
at 200 µg/kg experiencing adverse effects that were similar, but less severe, to animals 
experiencing definitive on-target toxicity at the higher dose of 300 µg/kg, the 
no-observed-adverse-effect level (NOAEL) was conservatively set at 100 µg/kg. On-target 
toxicity was associated with clinical observations of emesis and/or abnormal feces 
(e.g., watery feces or feces with mucoid material) occurring in almost all animals after the 
1st and 2nd doses primarily. In some cases, and only in animals receiving an initial dose of 
300 µg/kg, these clinical observations led to moribundity and euthanasia following the first 
administration of MGD007 in 5/16 animals. Two animals treated at the 300 µg/kg level also 
had evidence of blood in fecal material. Histopathological correlates in the animals with the 
most severe clinical signs that had to be euthanized included moderate to severe, focal and 
widespread areas of epithelium necrosis throughout the small and large intestines with 
concurrent ulceration in some animals. Two animals also had evidence of epithelium necrosis 
in the stomach, but with lower severity. 
Mild to moderate decreases in red-cell parameters (~ 20-30%) with intact erythrocyte 
response were also attributed to MGD007 at doses of 300 µg/kg. Additionally, there was 
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1 animal treated with 4 doses of 300 µg/kg MGD007 that was observed to have a brown, red 
fluid adhered to the mucosal surfaces of the stomach at gross necropsy (which occurred 
5 weeks post-last dose); however, there were no associated microscopic findings in the 
stomach of this animal. It is noted that this animal had the most severe drops in red cell 
parameters, exhibited an increased mean cell volume and red cell distribution width, and a 
decreased mean corpuscular hemoglobin concentration in association with a more pronounced 
reticulocyte response. These data, together with the observations of blood in the fecal material 
of 2 animals, indicate that at the highest dose studied (300 µg/kg), MGD007 may be 
associated with some extent of gastrointestinal bleeding. 
An important safety concern associated with CD3-targeting therapies, like MGD007, is the 
potential for cytokine release. Cytokines monitored in the MGD007 toxicology studies 
(supporting IND filing) included TNF-α, IFN-γ, IL-2, IL-4, IL-5, and IL-6 measured 4 hours 
and 24 hours post administration of MGD007. Across all studies and doses tested there were 
no MGD007-related changes in circulating TNF-α, IFN-γ, IL-4, or IL-5 levels, with levels of 
these cytokines remaining below 10 pg/mL, and generally were much lower or undetectable. 
IL-6 and IL-2 levels fluctuated following both vehicle and MGD007 dosing, only exceeding 
100 pg/mL in a few instances. In the high dose non-GLP toxicity study, IL-6 levels were 
tending to be among the highest (peak measured IL-6 levels of 984 pg/mL) in the animals that 
were euthanized due to severe toxicity compared with IL-6 levels in animals that were not 
euthanized. Fluctuation in IL-2 was observed in only one study and was less pronounced than 
the observed changes in IL-6. Overall, observed fluctuations in cytokine levels were greatest 
after the 1st dose of MGD007 but frequently were not higher than fluctuations observed after 
vehicle infusions. These elevations in IL-6 were further confirmed in another recent pre-
clinical non-GLP toxicity study that had been completed in which high dose MGD007 was 
administered with steroids to cynomolgus monkeys (MGD007 Investigator’s Brochure). In 
this study, cytokine levels were evaluated at 2 hours, 6 hours, and 22 hours 
post-administration of MGD007  following both first dose and second dose. Evaluation of 
cytokines revealed increases at 6 hours for IL-6 and IL-10, modest increases in IFN-γ and 
IL-2, and little to no increase in IL-4, IL-5, and TNF-α. Elevations were observed following 
first dose of MGD007, which were much more modest or absent following the second dose, 
similar to earlier GLP toxicity studies. In general, animals that received steroids had lower 
levels of observed cytokines, which is consistent with expected mode of action for steroids. 
Across all studies, transient elevations in circulating cytokine levels, most notably IL-6 and 
IL-10, are observed in cynomolgus monkeys following an initial high dose of MGD007. 
Anti-drug antibodies against MGD007 were detected in approximately half of the monkeys 
treated with MGD007 (24/47 monkeys evaluable for ADA). ADA was generally first detected 
after the 2nd or 3rd weekly infusion of MGD007. The frequency of ADA appeared to increase, 
and the emergence of first detectable ADA tended to occur earlier, with increasing dose level 
over the dose range evaluated (30 to 300 µg/kg). In the GLP toxicology study for which ADA 
titers were also evaluated, higher maximum titers (up to 1:20480) were achieved for the 
highest dose group (200 µg/kg) compared with the lower dose groups (maximum titers of 
1:16 and 1:5120 in the 30 and 100 µg/kg dose groups, respectively). It is important to note 
that ADA in cynomolgus monkeys is not considered predictive of ADA in humans. Of the 
24 animals that developed ADA, only 9 animals also had decreased exposure subsequent to 
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the emergence of the ADA. Nonclinical PK parameter estimates, however, were not affected 
by ADA because the PK evaluations were based primarily on serum concentrations of 
MGD007 measured in monkeys prior to the emergence of ADA. 
MGD007 PK evaluation performed by 2-compartmental modeling using pooled data across 3 
of the toxicology studies conducted in cynomolgus monkeys (n  41 evaluable animals) 
indicated that MGD007 PK appear linear across the 30 to 300 µg/kg dose range evaluated. 
Overall, dose proportional increases in maximum serum concentration (Cmax) were also 
observed across the dose range evaluated in these studies. MGD007 PK was also independent 
of gender. The mean clearance (CL) of MGD007 was 1.0 mL/h/kg, much lower than the 
glomerular filtration rate (GFR) in cynomolgus monkeys (~ 125 mL/h/kg), indicating that 
MGD007 is not cleared renally, as would be expected for a large molecular weight protein 
(~ 109 kDa). The mean volume of distribution for the central compartment (V1; 53 mL/kg) is 
consistent with initial distribution of MGD007 into the plasma space in cynomolgus monkeys 
(~ 45 mL/kg). The mean volume of distribution at steady state (Vss; 134 mL/kg) indicates 
MGD007 distribution into a space smaller than the extracellular space in cynomolgus 
monkeys (~ 200 mL/kg). The mean elimination half-life for the beta phase (t1/2,β) of MGD007 
ranged from 86 to 162 hours (3.6 to 6.8 days) across all groups. Thus, MGD007 demonstrated 
the expected prolonged t1/2 given the human IgG Fc domain in this DART protein. 
Based on these findings, the safety and PK profile of MGD007 appears acceptable to permit 
testing in human patients with advanced colorectal carcinoma. 
The nonclinical safety data generated to date for MGD007 are described in further detail in 
the MGD007 Investigator’s Brochure. 
2.3.4 
CP-MGD007-01 Clinical Study Update 
As of a data cut-off date of 10 January 2018, 75 patients have been treated in the 
CP-MGD007-01 study and have received at least 1 dose of MGD007 administered by 2-hour 
infusion either once a week (QW), twice a week (BiW), every 3 weeks (Q3W), or every other 
week preceded by a Lead-in Dose (LID). The MTD of MGD007 was defined as 1.0 µg/kg in 
either of the QW or Q3W schedules of administration, respectively. Among all patients treated 
to date with MGD007, across all dose levels and schedules of administration, including 
patients treated at doses subsequently determined to exceed the MTD, drug-related adverse 
events (AEs) (any grade), were observed in 96% of patients, and Grade 3 or greater AEs were 
observed in 65% of patients. The most common drug-related AEs occurring in >10% of 
treated patients in decreasing order were as follows: diarrhea, nausea, vomiting, fatigue, 
pyrexia, abdominal pain, chills, lymphocyte count decreased, decreased appetite, tachycardia, 
asymptomatic lipase increased, dehydration, hypophosphatemia, hypocalcemia, hypokalemia, 
and anemia. Side effects have been manageable and readily reversible using protocol 
supportive care measures.  
Notably, based on the mechanism of action of MGD007 with engagement of redirected T-cell 
mediated killing of target cells that express gpA33, and the recognized distribution of gpA33 
in the normal gastrointestinal epithelium, it was anticipated that gastrointestinal (GI) AEs 
could be the most clinically significant toxicity observed in patients treated with MGD007. 
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As anticipated, the most clinically significant AEs observed in patients treated with MGD007 
include nausea, vomiting and diarrhea, and in particular, diarrhea. As of the data cutoff, across 
all doses and schedules tested, including patients treated at doses subsequent found to exceed 
the MTD, drug-related GI AEs, irrespective of grade, were seen in 70 patients (93%), with 
Grade 3 or greater AEs observed in 37 patients (49%). Drug-related diarrhea of any grade was 
observed in 63 patients (84%), with Grade 3 or greater diarrhea in 23 patients (31%). Drug-
related nausea of any grade was observed in 54 patients (72 %) with Grade 3 or greater nausea 
in 10 patients (13 %). Drug-related vomiting of any grade was observed in 55 patients (73 %) 
with Grade 3 or greater vomiting in 21 patients (28 %). Gastrointestinal side effects have been 
manageable and readily reversible using protocol supportive care measures. More details 
regarding the clinical experience with MGD007 monotherapy are described in the MGD007 
Investigator Brochure. 
The breakdown for data regarding the occurrence of diarrhea across the respective schedules 
tested to date is summarized in Table 1. Several distinct doses and schedules have been tested 
to date to optimize the potential therapeutic window for MGD007, including more recent 
investigation of schedules using more frequent, lower dose schedules of administration 
(0.8 µg/kg QW and 0.5 µg/kg BIW) or step-wise intrapatient lead-in dose escalation (LID, 
0.5 µg/kg to 1.0 µg/kg). In addition to conventional, supportive care measures including 
anti-diarrheals, IV fluids, systemic corticosteroids, the approach to supportive care for the 
program has evolved to include prophylactic budesonide, an oral, non absorbable steroid, and 
early intervention with tocilizumab, an anti-IL-6R antibody in patients who develop Grade 2 
or greater GI side effects despite conventional supportive care and prophylactic budesonide. 
Prophylactic budesonide has been incorporated to provide local immune suppression in the GI 
tract, and is intended to help limit the need for use of systemic corticosteroids and the 
accompanying potential for systemic immune suppression. Similarly, tocilizumab has been 
incorporated to enable more selective inhibition of cytokine-mediated side effects in patients 
treated with MGD007, with less potential need for use of systemic corticosteroids. 
Notably, as shown in Table 1, the incidence of diarrhea was noticeably reduced in the 0.8 
µg/kg (QW) cohort and the 0.5 µg/kg (BiW) cohort, while modest reductions in the incidences 
of diarrhea are noted in the LID cohort. Treatment-related SAEs and treatment-related AEs ≥ 
Grade 3 are substantially reduced in the 0.8 µg/kg (QW) cohort (1 patient [10%]) (Table 1). 
Guided by these additional improvements in the tolerability of MGD007, the QW as well as 
the LID dose schedule will be utilized for investigation of the combination of MGD007 and 
MGA012 in this study. The initial starting dose for MGD007 on the QW cohort will be 
0.4 µg/kg, with subsequent planned dose levels utilizing MGD007 doses of 0.6 µg/kg and 
0.8 µg/kg. On the LID cohort, the initial starting dose will be 0.5 µg/kg, followed by a step-up 
to target doses of 0.5, 0.8, and 1.0 µg/kg on successive dose levels. In both cohorts, the 
starting doses of MGD007 for the respective combination cohorts are below those that have 
demonstrated acceptable tolerability for MGD007 monotherapy. 
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Table 1 
Overall Summary of Number of Patients with Adverse Events by 
Preferred Term of Diarrhea 
Patients Reporting at Least One 
event of Diarrhea (PT) 
QW- 0.8 
µg/kg 
(N=10) 
QW 
Other 
(0.6, 1 
µg /kg) 
(N=11) 
Q3W- 1 
µg/kg 
(N=28) 
Q3W 
Other 
(0.6, 1.5, 
3 µg 
/kg) 
(N=14) 
BiW 
(0.5 µg 
/kg) 
(N=6) 
LID 
(0.5/1 µg 
/kg) 
(N=6) 
All 
(N=75) 
Diarrhea 
7 
(70.0%) 
10 
(90.9%) 
27 
(96.4%) 
13 
(92.9%) 
2 
(33.3%) 
5 
(83.3%) 
64 
(85.3%) 
Treatment-Related Diarrhea a 
7 
(70.0%) 
10 
(90.9%) 
26 
(92.9%) 
13 
(92.9%) 
2 
(33.3%) 
5 
(83.3%) 
63 
(84.0%) 
Diarrhea ≥ Grade 3 a 
1 
(10.0%) 
2 
(18.2%) 
10 
(35.7%) 
7 
(50.0%) 
1 
(16.7%) 
2 
(33.3%) 
23 
(30.7%) 
Treatment-Related Diarrhea ≥ Grade 
3 a 
1 
(10.0%) 
2 
(18.2%) 
10 
(35.7%) 
7 
(50.0%) 
1 
(16.7%) 
2 
(33.3%) 
23 
(30.7%) 
Serious Diarrhea 
1 
(10.0%) 
2 
(18.2%) 
10 
(35.7%) 
5 
(35.7%) 
1 
(16.7%) 
3 
(50.0%) 
22 
(29.3%) 
Treatment-Related Diarrhea 
1 
(10.0%) 
2 
(18.2%) 
10 
(35.7%) 
5 
(35.7%) 
1 
(16.7%) 
3 
(50.0%) 
22 
(29.3%) 
Diarrhea that Resulted in Study 
Discontinuation 
0 
0 
0 
3 
(21.4%) 
0 
0 
3 (4.0%) 
Diarrhea that Resulted in Drug 
Withdrawal 
0 
0 
0 
3 
(21.4%) 
0 
0 
3 (4.0%) 
Diarrhea Adverse Events of Special 
Interest 
0 
2 
(18.2%) 
9 
(32.1%) 
6 
(42.9%) 
0 
2 
(33.3%) 
19 
(25.3%) 
a 
 Includes events with causality assessments of 'Possible', 'Probable' or 'Definite'. 
b 
Based on CTCAE criteria version 4.0 
Data cut on 10 January 2018 
Abbreviations: BiW = twice a week; QW = once a week; Q3W = every three weeks; LID= Lead-in Dose. 
 
Finally, among 59 response-evaluable patients, as of the cut-off date of 10 January 2018, 
19 patients had stable disease (SD), 4 patients on the QW schedules, 14 patients on the Q3W 
schedule, and 1 patient on the LID schedule (see Table 2). Among these patients, 7 patients 
had SD for at least 12 weeks from first dose of MGD007. One patient who is now off study, 
who was treated at the 1.5 µg/kg dose of MGD007, a dose level that exceeds the MTD, 
sustained a confirmed partial response and remained on treatment for 8 months since initiation 
of therapy. Additionally, a patient treated at the 1.0 µg/kg dose of MGD007 sustained an 
unconfirmed partial response and had been on treatment for more than 4 months. In addition 
to the clinical evidence of antitumor activity, IHC analyses of fresh tumor biopsy samples 
obtained from patients following treatment at 1.0 µg/kg in the Tumor Biopsy Cohort revealed 
on-target binding of MGD007 to gpA33 on cancer cells. 
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Table 2 
Summary of RECIST Response - Evaluable Population 
Best Overall Response 
QW- 0.8 
µg/kg 
(N=5) 
QW Other 
(0.6, 1 µg 
/kg) 
(N=11) 
Q3W- 1 
µg/kg 
(N=26) 
Q3W 
Other 
(0.6, 1.5, 3 
µg /kg) 
(N=11) 
BiW (0.5 
µg /kg) 
(N=2) 
LID (0.5/1 
µg /kg) 
(N=4) 
All 
(N=59) 
Partial Response a 
0 
0 
1 (3.8) 
1 (9.1) 
0 
0 
2 (3.4) 
Stable Disease 
1 (20.0) 
3 (27.3) 
14 (53.8) 
0 
0 
1 (25.0) 
19 (32.2) 
Progressive Disease 
2 (40.0) 
7 (63.6) 
10 (38.5) 
7 (63.6) 
2 (100) 
2 (50.0) 
30 (50.8) 
Not Evaluable 
2 (40.0) 
1 (9.1) 
1 (3.8) 
3 (27.3) 
0 
1 (25.0) 
8 (13.6) 
a 
Includes 1 confirmed partial response and 1 unconfirmed partial response. 
The SD is based on a minimum of 6 weeks from first dose of MGD007. 
Data cut-off date:10 January 2018 
Note: Evaluable patients are defined as follows: all patients who received at least one dose of MGD007 and had 
at least one post-infusion radiographic tumor assessment or in the absence of this assessment, clear clinical 
evidence of disease progression. 
 
2.4 
Background on PD-1 
Better understanding of the role of the immune system in tumor control has paved the way for 
strategies to enhance the immune response against cancer. Monoclonal antibodies against the 
immune checkpoints such as CTLA-4 and PD-1 and its ligand (PD-L1) have demonstrated 
high activity in lung, melanoma, renal and other tumors. The PD-1 receptor is an inhibitory 
receptor expressed by T-cells, which is engaged by ligands including PD-L1 and PD-L2, 
expressed by antigen-presenting cells. Interaction of PD-1 with its ligands leads to the 
delivery of a negative signal to the T-cell expressing PD-1 and inhibits T-cell function. This 
pathway helps the body maintain self-tolerance. Many tumor cells, however, have co-opted 
this pathway and express high levels of PD-L1 and thereby evade T cell attack. Within the 
tumor microenvironment, PD-1/PD-L1 interactions limit inflammation and inhibit cytotoxic T 
lymphocyte (CTL) activity. PD-1 activation inhibits CD8+ CTL proliferation, survival and 
their effector function and can also induce apoptosis of TILs and promote differentiation of 
CD4+ T cells into Treg cells. 
Immune checkpoint blockade utilizing anti-PD-1 or anti-PD-L1 antibodies has now proven to 
have clinical benefit among numerous clinical indications, including both hematologic 
malignancies and solid tumors. Furthermore, anti-PD-1/PD-L1 directed therapeutics are now 
being investigated in a wide range of combination studies across various indications, 
including studies with other CD3-based bispecifics (44). 
2.5 
Background on MGA012 
MGA012 (also known as INCMGA00012) is a humanized, hinge-stabilized, IgG4κ mAb that 
recognizes human PD-1. MGA012 is derived from the murine mAb clone, MG13.78, which 
was generated using standard hybridoma technology from mice immunized with a His-tagged, 
human PD-1 extracellular domain molecule. MGA012 contains a hinge-stabilized human 
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IgG4 Fc domain to limit effector function, while retaining neonatal FcR (FcRn) binding to 
extend circulating half-life. MGA012 is produced in CHO cells. The molecular weight of the 
intact, glycosylated molecule is approximately 148 kDa. MGA012 is cross-reactive with 
human and cynomolgus monkey PD-1 proteins. 
MGA012 is designed to bind to PD-1, which is expressed on T (CD4+ and CD8+), B cells, 
NK cells and myeloid-derived cells, and to inhibit its interactions with the ligands PD-L1 and 
PD-L2, and thereby disrupt the PD-1  PD-L1/L2 negative signaling pathway, particularly for 
T cells directed against tumors (6, 12, 33). 
2.5.1 
MGA012 Pharmacology 
In vitro pharmacology studies with MGA012 were conducted to demonstrate its biological 
properties, including its ability to bind to PD-1 protein and to cell surface PD-1, to inhibit 
ligand (PD-L1 and PD-L2) binding to cell surface PD-1, to directly inhibit the PD-1/PD-L1 
inhibitory pathway, and to exhibit functional activity with human PBMCs by enhancing IFN-γ 
secretion following stimulation with Staphylococcal Enterotoxin B (SEB). Moreover, these 
biological activities of MGA012 were comparable to those observed with other anti-PD-1 
mAbs, which were evaluated as reference molecules; these included replicas of 
pembrolizumab and nivolumab, which were generated by MacroGenics based on their 
published sequences. Secondary PD studies were conducted to confirm that MGA012 does 
not mediate ADCC or CDC activity, mitogenic activity, hemolytic activity, nor cytokine 
release. MGA012 cross reacts with nonhuman primate PD-1 and in vivo studies with 
MGA012 were conducted in cynomolgus monkeys to evaluate toxicology, PK, and the 
binding of MGA012 to circulating PD-1+ T cells. The combined data from these nonclinical 
studies with MGA012 provide support for the development of MGA012 as a therapeutic 
candidate for the treatment of solid tumors. Please reference the MGA012 Investigator’s 
Brochure for more detailed descriptions. 
Specific binding of MGA012 to human PD-1 has been characterized in vitro by SPR analysis 
and flow cytometry. SPR analysis using recombinant soluble human antigens revealed that 
MGA012 binds to PD-1 with a KD value of 0.6 nM. Flow cytometry analyses confirmed the 
ability of MGA012 to bind to cells expressing PD-1, including human PBMCs, human T cells 
(both CD4+ and CD8+), NS0/PDCD1 cells (cell line stably transfected to express the human 
PD-1 gene) and nonhuman primate (cynomolgus and rhesus monkey) PBMCs. Experiments 
with the PD-1 expressing cell line demonstrated that MGA012 binding to cell surface PD-1 
occurred with a comparable binding curve as that obtained with the pembrolizumab and 
nivolumab replica molecules (MGA012 Investigator’s Brochure). MGA012 also demonstrated 
dose-dependent binding to human PBMCs and CD4+ and CD8+ T cells, which express PD-1 
at basal levels and at enhanced levels upon stimulation. MGA012 binding to human PBMCs 
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and T cells was comparable to that observed with the nivolumab replica (pembrolizumab 
replica was not tested in this experiment). 
Table 3 
Comparison of in Vitro Potencies of MGA012 and Nivolumab and 
Pembrolizumab Replicas 
Property 
EC50 (or IC50) Values (µg/mL) a 
Mean ± SEM 
MGA012 
Nivolumab 
replica 
Pembrolizumab 
replica 
Binding to PD-1-expressing NS0/PDCD1 cells 
0.138 ± 0.046 
0.158 ± 0.058 
0.140 ± 0.048 
Inhibition of sPD-L1 binding to PD-1 
expressing NS0/PDCD1 cells 
0.010 ± 0.001 
0.016 ± 0.005 
0.014 ± 0.001 
Inhibition of sPD-L2 binding to PD-1 
expressing NS0/PDCD1 cells 
0.021 ± 0.001 
0.028 ± 0.004 
0.028 ± 0.003 
Inhibition of PD-1/PD-L1 Signaling in 
luciferase reporter assay 
0.090 ± 0.008 
0.171 ± 0.017 
0.103 ± 0.016 
a 
EC50, effective concentration at 50% of maximal activity; IC50, effective concentration at 50% inhibition of 
activity. 
 
To support the cynomolgus monkey as a relevant species for nonclinical toxicology evaluation 
of MGA012, several in vitro pharmacology studies were performed to evaluate MGA012 
binding to cynomolgus monkey target antigens and cells as well as its biological activity in 
this model system. MGA012 was shown to bind cynomolgus PD-1 though at an 
approximately 6-fold lower binding affinity than human PD-1 (KD values of 3.6 and 0.6 nM 
for monkey and human PD-1, respectively). MGA012 also bound to both cynomolgus and 
rhesus monkey PBMCs induced by SEB stimulation. MGA012 did not bind to PD-1 protein 
from non-primate species (mouse, rat or dog). 
Consistent with its specific binding properties and designed mechanism of action, MGA012 
blocked the binding of the ligands PD-L1 and PD-L2 to cell surface-expressed PD-1 in a 
dose-dependent manner (Figure 7). MGA012 blocked the PD-1/PD-L1 and PD-1/PD-L2 
interactions with mean IC50 values of 0.010 µg/mL and 0.021 µg/mL, respectively. These IC50 
values were comparable to those observed with the replicas of nivolumab and pembrolizumab, 
demonstrating that the in vitro potency of MGA012 is similar to those of the nivolumab and 
pembrolizumab replicas. 
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observed following treatment of either purified red blood cells (RBCs) or whole blood from 
healthy human donors with MGA012 in vitro. 
MGA012-mediated cytokine production was evaluated in vitro with freshly isolated, non-
stimulated PBMCs from normal human donors incubated for 24 hours with soluble MGA012 
or plate-immobilized MGA012 by wet- or dry-coating. Upon exposure of PBMCs to 
MGA012 concentrations of 10 µg/mL and 100 µg/mL (i.e., 10-200 times higher than the 
positive control antibody OKT3), no cytokine production (IFN-, TNF-IL-2, IL-4, IL-6, 
and IL-10) was observed with all three conditions of MGA012 presentation. 
2.5.2 
MGA012 Pharmacokinetics and Toxicology 
A summary of the nonclinical PK and toxicology data with MGA012 are provided below. 
Please reference the MGA012 Investigator’s Brochure for more detailed descriptions. 
The nonclinical toxicology program for MGA012 was performed exclusively in the 
cynomolgus monkey. The cynomolgus monkey was selected as the most appropriate animal 
model for nonclinical safety evaluation of MGA012 given the high degree of homology (96%) 
of the cynomolgus monkey and human PD-1 protein sequences, the ability of MGA012 to 
bind human and monkey PD-1 protein with similar affinity (within 6-fold), and to bind to 
human and monkey PBMCs following stimulation of PD-1 expression with SEB. In addition, 
PD-1 expression detected by the antigen binding regions in MGA012 appears to be similar in 
monkeys and humans as indicated by the fact that the murine mAb precursor to MGA012, 
which shares the same antigen specificity as MGA012, demonstrated a similar 
immunohistochemistry staining profile on lymphocytes in lymphoid organs from monkeys as 
the staining profile observed with MGA012 in lymphoid organs from humans. Non-primate 
species (mouse, rat, dog) were not relevant for toxicology studies due to reduced PD-1 protein 
sequence conservation and lack of detectable MGA012 binding to the PD-1 proteins from 
these species. 
In a GLP tissue cross reactivity study performed on a panel of normal human tissues, 
MGA012 staining was observed in the membrane and cytoplasm of lymphocytes in germinal 
centers of lymphoid organs (lymph node, spleen, and tonsil); in medulla of thymus; in 
submucosal lymphoid aggregates in several human tissues including colon, esophagus, small 
intestine, kidney, ureter, cervix, uterus and lung; and in tissues where lymphocytes were 
present including kidney and prostate. This staining was expected based on literature reports 
of PD-1 expression on T cells in lymphocytes (2, 20, 38, 53). No unexpected tissue staining 
was observed with MGA012. 
A repeat-dose GLP toxicology study of MGA012 was conducted in which MGA012 was 
administered at dose levels of 0 (saline control), 10, 40 or 150 mg/kg to cynomolgus monkeys 
(n  5/sex/group) by 1-hour IV infusions on a once weekly schedule for a total of 4 weeks, 
which was followed by a 10-week recovery period. 
All of the infusions were well tolerated. There were no preterm deaths nor treatment-related 
toxicities. There were no MGA012-related observations for the following parameters: clinical 
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signs, body weights, food consumption, physical examinations, ophthalmology, body 
temperature, blood pressure, heart rate, respiration rate, neurological examinations, 
electrocardiograms (ECGs), clinical chemistry, coagulation, gross pathology and organ 
weights. 
The only findings related to MGA012 were modest decreases in lymphocytes after the first 
infusion and microscopic changes at the IV administration site. 
Compared to pre-study values, mean absolute lymphocyte counts were moderately decreased 
(by 40-55%) at 23 hours after the 1st infusion in males and females treated at doses 
≥ 10 mg/kg (statistically significant for males at 10 and 40 mg/kg and females at 40 and 
150 mg/kg compared to controls). Lymphocyte counts returned to near pre-study levels prior 
to the second infusion but were mildly decreased (by 32-53%) for some individual males and 
females at all dose levels at 23 hours after the 2nd infusion. Lymphocyte counts increased prior 
to the 3rd and 4th infusions but decreased (by 45-74%) for some individual males and females 
at 23 hours post infusion. These modest changes in lymphocyte counts in MGA012-treated 
animals were mirrored by comparable fluctuations in total circulating leukocytes, T cells (both 
CD4+ and CD8+), B cells and NK cells, as measured by flow cytometry of peripheral blood. 
However, there were no changes in circulating monocytes. 
Microscopic changes at the IV administration site, observed at 3 days after the last dose, 
consisted of minimal multifocal perivascular mononuclear cell infiltrates within the 
superficial dermis (males at ≥ 40 mg/kg; females at ≥ 10 mg/kg). This finding is an expected 
reaction to repeated injection of an exogenous protein (monoclonal antibody). No MGA012-
related microscopic changes at the IV administration site were noted at 10 weeks post dosing 
in recovery animals. 
Other microscopic changes were of uncertain relationship to MGA012 because of sporadic 
(non-dose-related) incidence, or because they were also noted in control animals but were 
noted at a higher incidence and/or severity in MGA012-treated animals. These findings 
included: minimal to mild perivascular mononuclear cell infiltrates present in the brain 
(meninges and/or choroid plexus; control and MGA012-treated), spinal cord 
(MGA012-treated), and urinary bladder (control and MGA012-treated); minimal mixed-cell 
infiltrates in adipose associated with thyroid gland (MGA012-treated), heart (control and 
MGA012-treated), and trachea (MGA012-treated); and minimal to mild mononuclear cell 
inflammation in the wall of the rectum (MGA012-treated). These diffuse patterns of immune 
cell infiltration were similar to those observed in the repeat-dose toxicology studies with the 
approved anti-PD1 antibodies, pembrolizumab at 6, 40 or 200 mg/kg and nivolumab at 1, 10, 
or 50 mg/kg, in cynomolgus monkeys (FDA BLA 125514 pembrolizumab; FDA BLA 
125554 nivolumab 2014). 
Serum cytokine levels were not evaluated in the GLP toxicology study based on the lack of 
MGA012-related cytokine responses in two prior non-GLP studies, with the single exception 
of one animal at one time point. No cytokines (IFN-γ, IL-2, IL-4, IL-5, IL-6, IL-10, and 
TNF-α) were induced in serum samples of cynomolgus monkeys treated with MGA012 
following a single dose IV infusion of 10 mg/kg MGA012. Similarly, no cytokines were 
induced in serum samples of monkeys treated once weekly for 3 weeks with MGA012 
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administered at 1 or 100 mg/kg, except that one monkey treated at 100 mg/kg had a single 
significant observed elevation in IL-6 (1946 pg/mL) at 3 hours following the first infusion that 
resolved by 6 hours (returned to 8 pg/mL) without corresponding clinical effect. It is noted 
that an elevation in IL-6 of similar magnitude had been observed in a control treated animal in 
another monkey study. 
As can be expected with a humanized protein administered to non-human primates, ADA 
against MGA012 were detected in several animals after repeat dosing. Evidence of decreased 
MGA012 serum concentrations following repeated doses of MGA012 were observed in 7/10, 
4/10, and 3/10 animals in the 10, 40, and 150 mg/kg dose groups, respectively and the 
presence of ADA against MGA012 was confirmed in 4, 2, and 1 of the animals in these dose 
groups, respectively. All the animals in which ADA was not confirmed were in the terminal 
necropsy group during which MGA012 serum concentrations likely interfered with the ability 
to detect ADA. Accordingly, data from animals in which ADA appeared to affect MGA012 
serum concentrations were excluded from toxicokinetic (TK) evaluations. It is noted that 
immunogenic responses to humanized therapeutic proteins in cynomolgus monkeys are not 
generally predictive of immunogenicity in humans; therefore, immunogenicity is expected to 
be less prevalent in humans. 
PK parameters of clearance (CL), volume of distribution at steady state (Vss) and mean 
residence time (MRT) did not vary significantly with dose, hence the PK of MGA012 are 
linear across the dose range evaluated (10-150 mg/kg). Mean CL by noncompartmental 
analysis (NCA) ranged from 0.19-0.23 mL/h/kg across the 3 dose groups. CL by two-
compartment analysis of data across all 4 cycles, after excluding data after the development of 
ADA, ranged from 0.21 to 0.24 mL/h/kg. Overall, CL was substantially lower than the 
glomerular filtration rate in cynomolgus monkeys (~ 125 mL/h/kg), indicating minimal renal 
clearance as would be expected for a large molecular weight protein (~ 148 kDa). Mean Vss 
was 68 mL/kg by NCA analysis of the first dose and 72 mL/kg by two-compartment modeling 
of data across all cycles for the 3 dose groups. This indicates distribution into a space about 
50-60% larger than the plasma space (~ 45 mL/kg), but less than the extracellular space 
(~ 200 mL/kg) of cynomolgus monkeys, which suggests that MGA012 extravasates from the 
vascular compartment into tissue extracellular space and/or binding of MGA012 to cells or 
tissues. For all groups combined, the mean MRT by NCA analysis of the first dose or two-
compartment analysis of all cycles was 335 hours or 329 hours, respectively, or approximately 
14 days. Based on the two-compartmental modeling, steady-state was predicted to be 
achieved in the monkeys after 5 weekly doses of MGA012 and the accumulation index was 
2.4. 
MGA012 binds to PD-1 on the surface of CD4+ and CD8+ T cells in cynomolgus monkeys 
treated with MGA012 and saturation of the binding of MGA012 to PD-1 on T cells was 
observed at all dose levels during the dosing phase. In animals administered MGA012 at 10, 
40 or 150 mg/kg that did not develop ADA responses, serum MGA012 concentrations 
remained above 29 μg/mL and maximal MGA012 binding to PD-1+/CD4+ T cells and 
PD-1+/CD8+ T cells was maintained during the entire 10-week recovery period (Figure 10). 
In animals that developed ADA responses, the frequency of MGA012-bound PD-1+ T cells 
declined to baseline levels and the declines appeared to initiate when the serum MGA012 
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concentrations dropped below approximately 25 μg/mL. However, it is not known if this 
apparent threshold relationship applies to ADA-negative animals, since the presence of ADA 
in ADA-positive animals may contribute to blocking the binding of MGA012 to PD-1. 
In summary, administration of MGA012 via 1-hour IV once weekly for 4 weeks was clinically 
well tolerated in cynomolgus monkeys at levels of 10, 40, or 150 mg/kg. Observed MGA012-
related effects were limited to transient decreases in circulating lymphocyte counts and 
minimal injection-site changes related to injection of a foreign protein. Based on these results, 
the NOAEL was considered to be 150 mg/kg (gender combined mean Cmax of 3.94 mg/mL 
and AUC of 746 h•mg/mL). The PK parameters for MGA012 were linear across the dose 
range tested and the mean residence time was approximately 14 days. MGA012, at all dose 
levels, exhibited durable binding to PD-1-expressing T cells, which persisted for at least 
10 weeks post-dosing in the monkeys that did not develop ADA responses. 
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and potential anti-tumor activity of MGA012 in patients with relapsed, refractory advanced or 
metastatic solid tumors. The study consists of a Dose Escalation Phase and a Cohort 
Expansion Phase. During the Dose Escalation Phase, two schedules of administration are 
evaluated, once every two weeks (Q2W) and once every four weeks (Q4W), using a standard 
3 + 3 design. Cohort expansion to assess further activity in specific solid tumors (endometrial 
carcinoma, cervical carcinoma, non-small cell lung carcinoma, and sarcoma) is ongoing. 
The study completed enrollment in the Dose Escalation Phase, and the DLT evaluation period 
for the final patient in the top dosing cohorts (Cohorts 3a and 3b) was completed on 22 August 
2017. A total of 37 patients have been treated in Dose Escalation including 3 patients in 
Cohort 1 (1 mg/kg Q2W), 10 patients in Cohort 2a (3 mg/kg Q2W), 10 patients in Cohort 2b 
(3 mg/kg Q4W), 8 patients in Cohort 3a (10 mg/kg Q2W), and 6 patients in Cohort 3b (10 
mg/kg Q4W). These numbers include patients enrolled as replacements for non-evaluable 
patients as well as patients enrolled to gain further experience at respective dose levels. 
The most common treatment-related AEs reported in 2 or more patients in the Dose Escalation 
Phase were: fatigue (n  9, 24.3%), nausea (n  5, 13.5%); tumor flare, pruritus (n  4 each, 
10.8%); hyperthyroidism, influenza-like illness, lipase increased, rash maculo-papular (n  3 
each, 8.1%); lymphopenia, diarrhea, and tumor pain (n  2 each, 5.4%). Most of the adverse 
events experienced by patients have been mild or moderate in severity. Four patients 
experienced treatment-related AEs ≥ Grade 3. Three of these were asymptomatic elevation of 
lipase without clinical or radiographic evidence of pancreatitis and one was a female with 
uterine carcinoma with recurrent Grade 3 vulvovaginal inflammation, ulceration, proctitis and 
oral mucositis. The mucosal inflammation was managed with steroids and the patient remains 
on study with an objective response to MGA012 therapy. 
Only 1 SAE of 7 reported was considered related to MGA012. This was a Grade 2 expressive 
aphasia in a patient with melanoma with brain metastases. Inflammation of existing brain 
metastasis and development of new brain metastasis were considered to have caused the 
aphasia. This patient had experienced similar symptoms secondary to new brain metastases 
four months prior to initiating therapy with MGA012. 
No dose-limiting toxicity has occurred in the CP-MGA012-01 study to date, and the MTD 
was not exceeded at any dose and schedule evaluated. Early evidence of antitumor activity has 
been demonstrated, as 4 patients have experienced a partial response (2 confirmed, 
2 unconfirmed). 
Overall, review of the cumulative safety data demonstrates an acceptable safety profile, 
warranting continued clinical investigation of MGA012. The dose of 3 mg/kg administered 
Q2W has been selected for treatment of patients in the ongoing Cohort Expansion Phase of 
the study. 
Preliminary clinical pharmacokinetic results from this study are described in Section 2.6.2.1. 
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2.6 
MGD007/MGA012 Combination Dose Selection 
In this study, only the dose for MGD007 will be escalated; the dose for MGA012 will be kept 
constant at the dose of 3 mg/kg. The initial dose proposed for MGD007 in this study is 0.4 
µg/kg QW (QW Cohort). The rationale for selection of the respective doses of MGD007 and 
MGA012 is described below. 
MGD007 will be given QW as 120-minute infusion, with planned escalations from 0.4 to 
0.8 µg/kg combined with a 3 mg/kg dose of MGA012 IV (60-minute infusion) given on a 
Q2W schedule. In the event that a given dose level is found to exceed the MTD, subsequent 
patients will be dosed at the next lowest dose level, or an intermediate dose level designated 
based on review of the existing data, and consultation between the study investigators and the 
Sponsor. 
On days when both MGD007 and MGA012 will be administered, MGA012 will be 
administered first. 
2.6.1 
Dose Selection: MGD007 
Based on the observed safety profile during dose escalation, from the 0.6 to 1.0 µg/kg QW 
and 0.6 to 3.0 µg/kg Q3W dosing cohorts, the MTD for MGD007 was determined to be 
1.0 µg/kg. With CP-MGD007-01 Amendment 3, additional cohorts were implemented, 
specifically, QW (0.8 µg/kg) and BiW (0.5 µg/kg), as well as a step-wise LID cohort 
(0.5 µg/kg initially followed by 1.0 µg/kg Q2W) to further optimize the tolerability and 
combinability of MGD007. Based on the safety, tolerability and preliminary antitumor activity 
described in Section 2.3.4, the starting dose will be 0.4 µg/kg administered QW. The starting 
dose of MGD007 for the combination arm is below the dose that has demonstrated acceptable 
tolerability in the MGD007 monotherapy study. 
2.6.1.1 
MGD007 Pharmacokinetics 
In the ongoing Study CP-MGD007-01, MGD007 was evaluated in the dose range of 0.6 to 1.0 
µg/kg QW and 0.6 to 3.0 µg/kg Q3W IV. A preliminary PK modeling approach was used to 
analyze the data using the WinNonlin PK analysis program (Phoenix® 64 WinNonlin®, 
Version 7.0, Certara, Princeton, New Jersey). The model used was either an open 
1-compartment or 2-compartment, where applicable, and a weighting factor that was uniform, 
reciprocal of predicted concentration or reciprocal of predicted concentration2. The model 
was fitted to the Cycle 1, Day 1 (C1D1) first dose data with WinNonlin generated initial 
estimates. 
Serum PK data for the 16 patients treated prior to Amendment 2 of Protocol CP-MGD007-01 
are summarized in Table 4. Both Cmax and AUC increased with increasing dose. Modeling 
also suggested that the clearance, half-life, and volume of distribution (Vss) appear to be 
independent of dose. Lastly, modeling demonstrated that there was minimal accumulation of 
MGD007 with each dose for either a QW or Q3W schedule of administration. 
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Table 4 
Summary Statistics of First Dose (C1D1) Pharmacokinetic 
Parameters for MGD007 in Study CP-MGD007-01 
MGD007 Dose 
(µg/kg) 
PK Parameters 
Cmax 
(ng/mL) 
AUC(INF) 
(ng•h/mL) 
CL 
(mL/h/kg) 
Vss 
(mL/kg) 
t1/2 
(h) 
GeoMean 
(%CV) 
GeoMean 
(%CV) 
Mean (SD) 
Mean (SD) 
Mean (SD) 
0.6 QW (N = 4) 
14.36 (44) 
574.24 (47) 
1.12 (0.48) 
69.93 (42.11) 
54.50 (42.65) 
0.6 Q3W (N = 3) 
13.96 (26) 
871.74 (23) 
0.70 (0.15) 
79.55 (22.01) 
89.40 (35.15) 
1 QW (N = 3) 
29.38 (47) 
813.89 (10) 
1.23 (0.12) 
63.32 (9.10) 
37.61 (8.04) 
1 Q3W (N 4) 
26.43 (83) 
769.28 (21) 
1.32 (0.26) 
68.49 (9.95) 
39.02 (7.67) 
3 Q3W (N = 2) 
66.30 (24) 
3335.31 (13) 
0.90 (0.11) 
74.66 (52.54) 
65.84 (48.41) 
Overall (N = 16) 
NR 
NR 
1.09 (0.34) 
70.72 (21.98) 
55.42 (32.95) 
Abbreviations: AUC(INF) = area under the serum concentration time curve from time zero extrapolated to infinite 
time; C1D1 = Cycle 1 Day 1; Cmax = maximum observed serum concentration; CL = total body clearance; 
CV = coefficient of variation; GeoMean = geometric mean; N = number of patients; NR = not reported; QW = 
once every week; Q3W = once every 3 weeks; SD = standard deviation; t1/2 = serum terminal elimination half-
life; Vss = volume of distribution at steady-state 
First dose exposure parameters for 0.5 mg/kg Q2W (Q2W Cohort) are marginally higher than steady state values, 
because of contribution from the LID. 
 
Modeling and simulations of the PK data of MGD007 were performed, using model 
parameters from the 0.6 to 3.0 µg/kg QW or Q3W (N  16) and the predicted first dose and 
steady state exposure parameters (Cmax, AUC(TAU), and Ctrough) for the 0.4 µg/kg starting dose 
for QW dosing were derived and compared to the exposure parameters for the MTD of 
1.0 µg/kg QW in Study CP-MGD007-01. The first dose and steady-state exposure parameters 
(Cmax, AUC(TAU), and Ctrough) for the 0.4 µg/kg QW starting dose were approximately 2.5-fold 
lower than the MTD dose (1.0 µg/kg QW) in Study CP-MGD007-01 (Table 5). 
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Table 5 
Predicted Exposure Parameters and Exposure Multiples for 
MGD007 0.4 µg/kg for QW Dosing 
Interval 
Exposure 
Parameter 
Study 
CP-MGD007-01 
Study 
CP-MGD007-02 
Multiples of 
Exposure Based 
on Mean Values 
1 µg/kg QW 
(N = 16) 
GeoMean 
(%CV) 
0.4 µg/kg QW 
(N = 16) 
GeoMean 
(%CV) 
0.4 µg/kg 
QW 
First Dose 
Cmax 
(ng/mL) 
25.09 (54) 
10.04 (54) 
2.5 
AUC(TAU) 
(ng•h/mL) 
862.27 (29) 
344.91 (29) 
2.5 
Ctrough 
(ng/mL) 
0.88 (80) 
0.36 (80) 
2.5 
Steady State 
Cmax 
(ng/mL) 
26.66 (50) 
10.66 (50) 
2.5 
AUC(TAU) 
(ng•h/mL) 
970.53 (36) 
388.21 (36) 
2.5 
Ctrough 
(ng/mL) 
1.02 (100) 
0.41 (100) 
2.5 
Abbreviations: AUC(TAU) = area under the serum concentration time curve in a dosing interval; Cmax = maximum 
observed serum concentration; Ctrough = trough serum concentration (concentration at the end of a dosing 
interval); CV = coefficient of variation; GeoMean = geometric mean; N = number of patients; QW = once every 
week. 
NOTE: MTD was established at 1.0 µg/kg QW or Q3W in Study CP-MGD007-01 
 
Evaluation of serum samples obtained from a data set of 23 patients (dose escalation) for 
cytokine levels following the initial dose of MGD007, revealed temporal increases of varying 
magnitude of IL-6, IL-10 and IL-2 in a subset of patients (data not shown). Elevated cytokine 
levels are consistent with MGD007 coengagement of gpA33 and CD3 T-cells and 
consequential T cell activation providing evidence of MGD007-mediated pharmacodynamics 
activity. 
In Study CP-MGD007-01, the starting dose of 0.6 µg/kg was determined using a conservative 
approach to dose selection relying both on the NOAEL from the non-human primate GLP 
toxicology study as well as MABEL principles (per Protocol CP-MGD007-01). The Cmax and 
AUC achieved in monkeys at the NOAEL dose of 100 µg/kg were 114- and 92-fold higher 
than, respectively, the corresponding values predicted in humans treated with the selected 
starting dose of 0.6 µg/kg, thus providing a large safety margin for first human exposure. 
Indeed, observed PK data for the 0.6 µg/kg dose from Study CP-MGD007-01, confirmed the 
large safety margins (112- and 190-fold higher for the QW schedule, respectively; and 
121- and 135-fold higher for the Q3W schedule, respectively). The 0.4 µg/kg starting dose for 
QW dosing in the present study is lower than the NOAEL/MABEL estimated starting dose in 
Study CP-MGD007-01 (0.6 µg/kg) and is expected to provide at least 130-fold safety factor 
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based on the NOAEL of MGD007 in the GLP toxicology study performed in cynomolgus 
monkeys of 100 µg/kg MGD007. 
2.6.2 
Dose Selection: MGA012 
The initial dose proposed for MGA012 in this study is based on the PK and safety profile 
from the ongoing Phase 1, FIH dose escalation and expansion Study CP-MGA012-01, in 
which dose escalation was carried out from 1 mg/kg Q2W to 10 mg/kg Q2W or Q4W. The 
safety profile of MGA012 based on a total of 37 patients exposed to MGA012 in 
Study CP-MGA012-01 demonstrated that the majority of AEs were mild or moderate 
(CTCAE Grade 1 or 2), with toxicities manageable by standard medical therapy. See 
Section 2.5.3 for a more detailed description of the safety profile from Study 
CP-MGA012-01. 
2.6.2.1 
MGA012 Pharmacokinetics 
In the ongoing Study CP-MGA012-01, MGA012 in the dose range of 1 to 10 mg/kg Q2W or 
Q4W IV was evaluated. A preliminary 2-stage PK modeling approach was used to analyze the 
data using the WinNonlin PK analysis program (Phoenix® 64 WinNonlin®, Version 7.0, 
Certara, Princeton, New Jersey). The model used was either an open 1-compartment or 
2-compartment, where applicable, and a weighting factor of reciprocal of predicted 
concentration or predicted concentration2. In the first stage, the model was fitted to the Cycle 
1, Day 1 (C1D1) first dose data with WinNonlin generated initial estimates. In the second 
stage, the model was fitted to the first and multiple dose data together with the initial 
estimates from stage 1. The final modeled PK parameter values after the first dose reported 
were from stage 2. MGA012 PK parameters are summarized by treatment and study day in 
Table 6. 
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Table 6 
Summary Statistics of First Dose (C1D1) Pharmacokinetic 
Parameters for MGA012 in Study CP-MGA012-01 
MGA012 
Dose 
(mg/kg) 
PK Parameters 
Cmax 
(ng/mL) 
AUC(INF)  
(ng•h/mL) 
CL 
(mL/h/kg) 
Vss 
(mL/kg) 
t1/2 
(h) 
GeoMean (%CV) 
GeoMean (%CV) 
Mean (SD) 
Mean (SD) 
Mean (SD) 
1 (N = 3) 
14.9 (37) 
3359 (27) 
0.304 (0.077) 
87.2 (12.1) 
216.8 (45.9) 
3 (N = 18) 
73.1 (36) 
15352 (37) 
0.200 (0.070) 
84.4 (37.8) 
401.5 (346.0) 
10 (N = 10) 
227.7 (22) 
59515 (30) 
0.169 (0.050) 
86.4 (21.0) 
422.3 (167.9) 
Overall 
(N = 28 a) 
NR 
NR 
0.189 (0.072) 
85.1 (30.9) 
408.9 (282.6) 
a 
For Overall, N = 28 because CL, Vss, and t1/2 appear to be comparable between the 3 and 10 mg/kg. 
Abbreviations: AUC(INF) = area under the serum concentration time curve from time zero extrapolated to infinite 
time; C1D1 = Cycle 1 Day 1; Cmax = maximum observed serum concentration; CL = total body clearance; 
CV = coefficient of variation; GeoMean = geometric mean; N = number of patients; NR = not reported; Q2W = 
once every 2 weeks; SD = standard deviation; t1/2 = serum terminal elimination half-life; Vss = volume of 
distribution at steady-state 
NOTE: For the 3 and 10 mg/kg dose groups, data from Q2W and Q4W treated patients were combined into a 
single group because the PK assessment was after the first dose. 
 
Preliminary PK data from 31 patients, including 3 patients in Cohort 1 (1 mg/kg Q2W), 
10 patients in Cohort 2a (3 mg/kg Q2W), 8 patients in Cohort 2b (3 mg/kg Q4W), 6 patients 
in Cohort 3a (10 mg/kg Q2W), and 4 patients in Cohort 3b (10 mg/kg Q4W), suggested that 
first dose MGA012 Cmax was dose proportional and AUC(INF) increased in a greater than dose 
proportional manner over the dose range of 1 to 10 mg/kg IV. Mean (SD) parameter values for 
CL, Vss, and t1/2 appear to be comparable between the 3 and 10 mg/kg doses. Excluding the 
1 mg/kg dose, the overall (N  28) mean CL, Vss, and t1/2 values of MGA012 were 0.189 
mL/h/kg, 85.1 mL/kg, and 408.9 h (~ 17 days), respectively. The half-life of MGA012 
suggests that the drug is expected to attain steady-state conditions within 85 days and 
predicted accumulation for the Q2W and Q4W regimens is expected to be ~ 2 and ~ 1.5, 
respectively. The volume of distribution indicates that MGA012 distribution is > than blood 
volume, but < than extracellular fluid volume. 
Modeling and simulations of the PK data of MGA012 were performed, using model 
parameters from the 3 mg/kg Q2W (N  5) and 10 mg/kg Q2W (N  3) and the predicted first 
dose and steady-state exposure parameters (Cmax, AUC(TAU), and Ctrough) for the 3 mg/kg Q2W 
starting dose were derived and compared to the exposure parameters for the 10 mg/kg Q2W 
dose in Study CP-MGA012-01. The starting dose in this study (3 mg/kg Q2W) is 
approximately 3-fold lower than the top dose demonstrated to be safe in Study 
CP-MGA012-01 (10 mg/kg Q2W). Furthermore, first dose and steady-state exposure 
parameters (Cmax, AUC(TAU), and Ctrough) for the 3 mg/kg Q2W starting dose were 
approximately 3-fold lower than for the top dose investigated in Study CP-MGA012-01 
(10 mg/kg Q2W) (Table 7). 
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Table 7 
Predicted Exposure Parameters and Exposure Multiples for 
MGA012 3 mg/kg Q2W 
Interval 
Exposure 
Parameter 
Study 
CP-MGA012-01 
Study 
CP-MGA012-01 
Multiples of 
Exposure Based 
on Mean Values 
10 mg/kg Q2W 
(N = 3) 
GeoMean (%CV) 
3 mg/kg Q2W 
(N = 5) 
GeoMean (%CV) 
First 
Dose 
Cmax (µg/mL) 
202.7 (21) 
60.9 (15) 
3.3 
AUC(TAU) (µg•h/mL) 
26192 (10) 
8037 (19) 
3.3 
Ctrough (µg/mL) 
41.1 (13) 
11.6 (9) 
3.5 
Steady 
State 
Cmax (µg/mL) 
270.4 (17) 
86.6 (22) 
3.1 
AUC(TAU) (µg•h/mL) 
40816 (8) 
14341 (36) 
2.8 
Ctrough (µg/mL) 
66.9 (16) 
23.6 (67) 
2.8 
Abbreviations: AUC(TAU) = area under the serum concentration time curve in a dosing interval; Cmax = maximum 
observed serum concentration; Ctrough = trough serum concentration (concentration at the end of a dosing 
interval); CV = coefficient of variation; GeoMean = geometric mean; N = number of patients; Q2W = once every 
2 weeks. 
 
 
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3 
STUDY PURPOSE AND OBJECTIVES 
3.1 
Dose Escalation Phase 
3.1.1 
Primary Objectives 
To characterize the safety, tolerability, dose-limiting toxicities (DLTs), and maximum tolerated 
dose (MTD) of MGD007 when combined with MGA012 in patients with relapsed/refractory 
metastatic colorectal carcinoma after at least 2 and up to 5 prior standard regimens of therapy 
in metastatic setting; or who did not tolerate fluoropyrimidines, oxaliplatin or irinotecan; or 
who are not good candidates for standard of care. 
3.1.2 
Secondary Objectives 
 To characterize the pharmacokinetics (PK), pharmacodynamic activity, and 
immunogenicity of MGD007 and MGA012 in combination. 
 To investigate the preliminary antitumor activity of MGD007 combined with 
MGA012 as measured by objective response rate, disease control rate, and 
progression-free survival (PFS) rate at 16 weeks in patients with relapsed/refractory 
metastatic colorectal carcinoma using both conventional Response Evaluation 
Criteria in Solid Tumors (RECIST 1.1), Appendix 5, and immune-related response 
criteria (irRECIST), Appendix 6. 
3.1.3 
Exploratory Objectives 
 To explore the relationships between PK, pharmacodynamics of 
MGD007/MGA012, and antitumor activity. 
 To explore the impact of this combination on PFS, immune-related PFS (irPFS), 
and overall survival (OS) in patients with relapsed/refractory metastatic colorectal 
carcinoma. 
 To investigate the immunoregulatory activity of MGD007 combined with MGA012 
in vivo, including various measures of T cell function in peripheral blood and/or 
tumor biopsy specimens. 
 To assess potential biomarkers predictive of efficacy including but not limited to 
glycoprotein A33 (gpA33), CD3, TILs, PD-1, PD-L1, and immunosuppressive 
myeloid/lymphoid cells via immunohistochemistry and gene expression in archival 
tissue. 
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3.2 
Cohort Expansion Phase 
3.2.1 
Primary Objective 
To investigate antitumor activity of MGD007 combined with MGA012 when dosed at the 
MTD (or maximum administered dose [MAD] if no MTD is defined) as measured by 
objective response rate, disease control rate and PFS rate at 16 weeks in patients with 
relapsed/refractory metastatic colorectal carcinoma using both conventional Response 
Evaluation Criteria in Solid Tumors (RECIST 1.1), Appendix 5, and immune-related response 
criteria (irRECIST), Appendix 6. 
3.2.2 
Secondary Objectives 
 To further characterize the safety and tolerability of MGD007 when combined with 
MGA012 in patients with relapsed/refractory metastatic colorectal carcinoma after 
at least 2 lines of therapy in a metastatic setting. 
 To characterize the PK, pharmacodynamic activity, and immunogenicity of 
MGD007 and MGA012 in combination. 
 To explore the impact of this combination on PFS, immune-related PFS (irPFS), 
and overall survival (OS) in patients with relapsed/refractory metastatic colorectal 
carcinoma. 
 
3.2.3 
Exploratory Objectives 
 To explore the relationships between PK and pharmacodynamics of 
MGD007/MGA012 and antitumor activity. 
 To investigate the immunoregulatory activity of MGD007 combined with MGA012 
in vivo, including various measures of T cell function in peripheral blood and/or 
tumor biopsy specimens. 
 To assess potential biomarkers predictive of efficacy including but not limited to 
glycoprotein A33 (gpA33), CD3, TILs, PD-1, PD-L1, and immunosuppressive 
myeloid/lymphoid cells via immunohistochemistry and gene expression in archival 
tissue and assess the effect of the combination on tumor biomarkers, comparing 
initial and on treatment paired tumor biopsies. 
 
 
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4 
STUDY DESIGN 
4.1 
Overall Study Design and Plan 
This study is an open-label, Phase 1b/2 dose escalation and cohort expansion study designed 
to characterize the safety, tolerability, PK, pharmacodynamics, immunogenicity, and 
preliminary antitumor activity of MGD007 and MGA012, administered in combination by IV 
infusion, in patients with histologically proven, relapsed/refractory metastatic colorectal 
carcinoma, irrespective of the KRAS and MMR status of their tumors. This study will enroll 
patients as described below. 
The study will proceed in 2 distinct phases as follows: Dose Escalation Phase to determine the 
MTD or MAD (if no MTD is defined) of the combination, followed by a Cohort Expansion 
Phase to further define the safety and initial antitumor activity of the combination with the 
doses established in the Dose Escalation Phase. 
Patients will be treated with MGD007 and MGA012 as shown in Figure 11. MGD007 will be 
administered at the target dose for each assigned cohort as an IV infusion over 120 minutes, 
once weekly (QW), in 8-week treatment cycles. MGA012 will be administered at 3 mg/kg as 
an IV infusion over 60 minutes, once every 2 weeks (Q2W) beginning on Cycle 1 Day 15, and 
every 2 weeks thereafter. For each patient, administration of the first dose of MGA012 will 
occur 2 weeks after the first dosing of MGD007. The DLT evaluation period will last until 
Cycle 1 Day 42. Disease status will be evaluated on Cycle 1 Day 56 (± 3 days) using CT 
and/or MRI as appropriate for the sites of disease, accompanied by physical examination, and 
will then be evaluated every 8 weeks while on study treatment. Although response assessment 
will be performed according to both conventional (RECIST 1.1 [Appendix 5]) and irRECIST 
(Appendix 6), patients will be managed according to irRECIST principles. This approach 
allows for limited treatment of patients beyond the initial radiographic documentation of 
disease progression, assuming that the Investigator feels that the 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. 
Patients who achieve response status of immune-related complete response (irCR), 
immune-related partial response (irPR), immune-related stable disease (irSD), or unconfirmed 
immune-related progressive disease (irPD), per the immune-related response criteria 
(Appendix 6) at the end of Cycle 1 radiographic disease assessment may be eligible to receive 
subsequent administrations of MGD007 and MGA012 for up to 12 cycles (~ 2 years), 
assuming that the patients remain clinically stable and have not experienced DLTs that 
necessitated permanent discontinuation of study drug. 
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Figure 11 
Overall Study Treatment Schema  
 
Patients who experience progressive disease, as evidenced by ≥ 20% increase in the 
dimensions of target lesions or the occurrence of new lesions, may continue therapy at the 
discretion of the Investigator, pending confirmation of progressive disease at the next planned 
tumor assessment and satisfaction of criteria for irPD. Subsequent cycles of therapy after an 
initial documentation of progressive disease should be administered only to patients who have 
demonstrated acceptable tolerance to treatment with study drug, who remain otherwise 
clinically stable, and who in the assessment of the Investigator, may derive clinical benefit 
from the continuation of treatment with study drug. 
No dose reductions of MGA012 or MGD007 are allowed during the study, except for patients 
being treated at doses that are subsequently found to exceed the MTDs for either schedule. 
Data regarding the KRAS and MMR mutational status (MSI or MSS) will be collected; 
statuses for both must be formally documented for patients in the Cohort Expansion Phase. 
Patients will be required to have at least 1 site of measurable disease as defined by 
RECIST 1.1 criteria (Appendix 5). In addition, patients must have had an identified tumor 
tissue block (preferred) and/or tumor specimens sufficient for 20 slides that can be utilized for 
assay of gpA33, CD3, PD-1, and PD-L1 expression via immunohistochemical staining. 
Following the last dose of study drug, all patients will be followed every 3 months for survival 
during a 2-year Survival Follow-up Period. 
4.1.1 
Dose Escalation Phase 
The goal of the Dose Escalation Phase is to initially characterize the safety and tolerability of 
MGD007 combined with MGA012, and to define the DLTs and MTD (or MAD if no MTD is 
defined) of the combination. The MTD is defined as the dose level at which < 33% of patients 
experience a DLT. 
For the purpose of guiding decisions regarding dose escalation, the definition of DLT will be 
based on the occurrence of drug-related AEs that occur up to Cycle 1 Day 42 of MGD007 
combined with MGA012 administration. 
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Dose escalation will follow a conventional 3+3+3 design: MGD007 and MGA012 will be 
evaluated in sequential escalating doses in cohorts of 3 to 9 patients each. Dose levels of 
MGD007 to be evaluated are displayed in Table 8. 
MGA012 will be administered at an unchanged dose of 3 mg/kg Q2W, i.e., the recommended 
dose in combination, beginning on Cycle 1 Day 15. On days when both MGD007 and 
MGA012 will be administered, MGA012 should be administered first. 
During the 42-day DLT evaluation period, patients who receive less than 75% of the planned 
doses of either MGD007 or MGA012 secondary to AEs considered unrelated to study 
treatment or any other cause unrelated to study treatment are considered unevaluable for 
safety and toxicity during the DLT evaluation period and will be replaced. 
Continued dose escalation will proceed using a conventional 3+3+3 design according to the 
dose escalation rules outlined below. Dose escalation cohorts are presented in Table 8. 
Table 8 
MGD007 QW: Dose Escalation Cohorts 
Dose Level 
MGD007 Dose 
(QW) 
MGA012 Dose 
(Q2W) 
Dose Level 1:  
0.4 µg/kg 
3 mg/kg 
Dose Level 2:  
0.6 µg/kg 
3 mg/kg 
Dose Level 3:  
0.8 µg/kg 
3 mg/kg 
The MGA012 dose remains unchanged during the escalation. 
In the event of a drug-related DLT occurring in a patient, the number of patients will be 
expanded according to the 3+3+3 design (see Section 4.3). 
No intra-patient dose reduction will be performed. 
If the MTD is exceeded at any dose level, a dose de-escalation to an intermediate dose level 
will be discussed, based on review of the available safety, efficacy, and/or PK data, and will 
be implemented upon agreement between the Investigators and the Sponsor. Any escalation 
cohort, not exceeding the MTD, can be expanded to a maximum of 15 patients for further 
evaluation of safety and efficacy. 
4.1.2 
Cohort Expansion Phase 
The Cohort Expansion Phase will include 25 patients; approximately 90% of these will be 
MSS patients and 10% MSI-H. 
Paired tumor biopsies will be mandatory if tumor lesions are accessible for biopsy with 
acceptable clinical risk in the judgment of the investigator and after discussion with the 
Sponsor. Fifteen paired biopsies will be required at the end of the Cohort Expansion Phase 
(see Section 5.1, # 9). If 15 paired biopsies have not been collected in the initial 25 patients, 
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additional patients with paired tumor biopsies will be enrolled, to ensure that the 15 paired 
biopsies are obtained (see Section 4.5.1). 
Patients who withdraw before completing the first tumor assessment for a reason other than 
progression of disease or death 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. 
4.2 
Dose Limiting Toxicity 
For the purpose of guiding dose escalation decisions, dose-limiting toxicities (DLTs) are 
defined by drug-related AEs that occur up to Cycle 1 Day 42. 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 will be defined separately for 
hematologic, non-hematologic, and hepatic non-hematologic events. 
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 drug. Criteria for subsequent continuation of 
therapy are outlined in are outlined below. 
Dose limiting toxicities are defined separately for hematologic and non-hematologic events as 
described below. 
4.2.1 
Hematologic Dose Limiting Toxicity 
Hematologic DLT is 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 
 ≥ Grade 3 anemia associated with other clinically significant complications. 
 
The following event will be specifically excluded from the definition of hematologic DLT: 
 ≥ Grade 3 lymphopenia 
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4.2.2 
Non-hematologic Dose-Limiting Toxicity 
Non-hematologic DLT is 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 or 4 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 7 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 anti-tumor 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 MGA012 due to 
patient intolerance. 
 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. 
 
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4.2.3 
Hepatic Non-hematologic Dose Limiting Toxicity 
Hepatic non-hematologic DLT will be defined as follows: 
 Any elevation of one or more transaminases > 8 × the institutional upper limit of 
normal (ULN) irrespective of duration. 
 Any Grade 3 elevation of one or more transaminases > 5.0  8.0 × the ULN that 
does not resolve to Grade 2 (i.e., > 3.0  5.0 × ULN) within 7 days and Grade 1 
(i.e., > ULN  3.0 × ULN) within 14 days. In addition, steroids must be tapered to 
≤ 10 mg of prednisone or equivalent per day, by Day 14. 
 A Grade 3 elevation of total bilirubin that is > 5 × the ULN, irrespective of 
duration. 
 Any Grade 3 elevation of total bilirubin >3.0  5.0 × ULN that does not resolve to 
Grade 2 (i.e., >1.5  3.0 × ULN) within 7 days and Grade 1 (i.e., >ULN  
1.5 × ULN) within 14 days. In addition, steroids must be tapered to ≤ 10 mg of 
prednisone or equivalent per day, by Day 14. 
 Any event meeting the criteria for Hy’s law as follows (all 3 features): 
o Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
> 3 × ULN 
o Concurrent elevation of total bilirubin > 2 × ULN without initial evidence 
of cholestasis 
o No alternative etiology can be identified 
 
4.3 
Dose Escalation Rules 
The Dose Escalation Phase of this trial will proceed using a conventional 3 + 3 + 3 approach. 
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). 
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 MGD007 and MGA012. 
 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 MGD007. 
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 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 first 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 MGD007 has been exceeded at 
that dose level, and an additional 3 patients will be added and treated at the next lower dose 
level. 
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%. Depending on the nature of the DLT, the dose reduction can concern both drugs or 
only one. 
Dose escalation to the next dose level is permitted only after the patients enrolled in the 
current dose cohort have completed the DLT evaluation period and safety data have been 
reviewed by the Sponsor’s Medical Monitor and Pharmacovigilance Physician as well as the 
Investigators participating in the study. 
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 available PK, PD, safety, and 
response data. An MTD does not have to be reached to initiate the Cohort Expansion Phase of 
the study if the available data demonstrate that a lower dose level may provide antitumor 
activity while minimizing potential risk. In addition, if an MTD is established, the Sponsor 
may decide to open the Cohort Expansion Phase at a dose lower than the MTD, based on the 
totality of the PK, PD, biomarker, safety, and response data. 
At the discretion of the Sponsor, any escalation cohort at a dose level not exceeding the MTD 
may be expanded to a maximum of 15 patients for further evaluation of safety, PK, and 
antitumor activity. 
When an MTD or MAD is established, any patient remaining on treatment at a lower dose 
level will be given the option to escalate to the MTD/MAD dose. 
4.4 
Guidelines for Dose Modification 
No dose modifications will be allowed with exception of 1) reduction of infusion rate during 
re-challenge for patients experiencing an infusion reaction (Section 7.2) or 2) reduction of 
dose in patients receiving MGD007 or MGA012 at a dose that is subsequently determined to 
exceed the MTD (Section 4.1.1). 
4.4.1 
Dose Delays in Escalation and Expansion Cohorts 
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 
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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 as per guidelines outlined 
in Section 7. Dose interruptions of up to 28 days are allowed. Reinstitution of therapy shall be 
conducted as follows: 
 The procedures at the originally 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 should receive the planned 
dose and have assessments performed as outlined in the Time and Events Schedule 
(Appendix 1). 
4.5 
Study Duration 
Enrollment of the study should last approximately 18 months. 
The maximum amount of time an individual patient may be on study is 12 treatment cycles, or 
approximately 2 years. The total time for conduct of the trial is expected to be approximately 
66 months (which includes 2 years of survival follow-up). These estimates of the timing for 
study conduct may vary from that observed in the actual conduct of the trial. 
4.5.1 
Patient Accrual 
The number of patients enrolled in the Dose Escalation Phase cannot be precisely determined 
in advance. There may be up to 27 patients enrolled depending on results in the course of the 
trial and the number of MGD007 and MGA012 doses explored. This patient number does not 
take into account replacement of non-evaluable patients or enrollment to a dose cohort that is 
expanded in Dose Escalation Phase. 
The Cohort Expansion Phase of the study will enroll approximately 25 patients. This number 
may be higher because at the end of the Cohort Expansion Phase, 15 tumor paired biopsies 
will be required, if metastases are accessible and obtained with acceptable clinical risk 
(see Section 5.1, # 9). If this number is not reached, additional patients will be enrolled in the 
study to ensure that the 15 paired biopsies are obtained (see Section 4.1.2).  
The number of patients does not take into account patients who may be replaced for clinical 
reasons. For initial planning, the number of patients to be enrolled in this trial is anticipated to 
be approximately 52 patients. 
4.5.2 
Definition of End of Study 
The end of study will occur after the last patient has met off-study criteria and the data 
collection process is completed (time of study database lock). 
End of study for each patient is defined as follows: Patient is lost to follow-up (LTFU) 
(Section 5.3) or discontinues from the study due to any reason listed in Section 5.5. Each 
patient’s end of study status will be recorded in the End of Study CRF page. 
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4.6 
Appropriateness of Measurements 
Routine laboratory evaluations including hematology, 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. 
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5 
SELECTION AND WITHDRAWAL OF PATIENTS 
To be eligible for study participation, patients must meet all the inclusion criteria. Patients will 
be excluded from the study if they meet any exclusion criteria. No exceptions to these criteria 
will be granted by the Sponsor. 
The patient population to be enrolled in this study will consist of adult patients with 
histologically proven, relapsed or refractory metastatic colorectal carcinoma. 
5.1 
Inclusion Criteria 
1. Ability to provide informed consent and documentation of informed consent prior to 
initiation of any study-related tests or procedures that are not part of standard-of-care for 
the patient’s disease. 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. Histologically proven, relapsed/refractory metastatic colorectal carcinoma. 
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Appendix 4). 
5. Life expectancy ≥ 12 weeks. 
6. Measurable disease as per RECIST 1.1 criteria (Appendix 5) and documented by 
computed tomography and/or magnetic resonance imaging. Patients with evaluable 
disease only will not 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, or b) have 
demonstrated clear evidence of radiographic progression since the completion of prior 
radiotherapy and prior to study enrollment. 
7. During the dose escalation portion of the study, patients must have had recurrence, 
progression or intolerance to standard therapy consisting of at least 2 prior standard 
regimens (containing a fluoropyrimidine plus a platinum analogue and/or irinotecan) for 
metastatic disease. During the Cohort Expansion portion of the study, patients will be 
allowed to participate in the study after 1 prior standard regimen. Patients who are 
inappropriate candidates for or have refused treatment with these regimens are also 
eligible. Patients should have received no more than 5 prior therapies. Patients previously 
treated with MGD007 on Study Protocol CP-MGD007-01 and who did not develop 
antibodies to MGD007 while on the CP-MGD007-01 study, may be enrolled. Patients that 
were previously treated on CP-MGD007-01 will only be treated on this study once 
MTD/MAD has been defined. 
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8. In addition, patients to be enrolled in the study must have an identified formalin-fixed, 
paraffin embedded tumor specimen and/or tumor specimens sufficient for 20 slides to 
enable determination of the expression of gpA33, CD3, PD-1, and PD-L1 within tumor 
specimens using immunohistochemical staining. The expression of gpA33 in tumor 
specimens will be analyzed retrospectively and will not be used to prospectively 
determine protocol eligibility. 
9. For the 15 patients who will have paired tumor biopsies, tumor lesions must be accessible 
for biopsy with acceptable clinical risk in the judgment of the investigator. Paired tumor 
biopsies will be mandatory if tumor lesions are accessible for biopsy with acceptable 
clinical risk in the judgment of the investigator and after discussion with the Sponsor. 
Fifteen paired biopsies will be required in each cohort at the end of the Cohort Expansion 
Phase. For each patient, the identified lesion to be biopsied should not have been 
previously irradiated and should not be the only lesion being utilized as measurable 
disease target lesion for objective response assessment. The lesion to be biopsied should 
be of sufficient size to enable acquisition of at least 2 tumor biopsy cores using a biopsy 
needle. 
10. Acceptable laboratory parameters as follows: 
a. Platelet count  100 × 103/microliter without transfusion within 4 weeks prior 
to the initiation of study drug. 
b. Hemoglobin  8.0 g/dL without transfusion within 1 week prior to the initiation 
of study drug. 
c. White blood cell count (WBC) ≥ 2.0 × 103/microliter in the absence of any 
growth factor support within 4 weeks prior to the initiation of study drug. 
d. Absolute neutrophil count  1.5 × 103/microliter in the absence of any growth 
factor support within 4 weeks prior to the initiation of study drug. 
e. ALT/AST  3.0 times the ULN, up to 5.0 times the ULN for patients with liver 
metastases. 
f. Total bilirubin  1.5 times ULN, except patients with Gilbert’s syndrome, who 
may enroll if the conjugated bilirubin is within normal limits. 
g. Creatinine < 1.5 mg/dL, or a calculated or measured creatinine clearance 
> 50 mL/min. 
h. Negative urine or serum pregnancy test for women of child-bearing potential. 
11. Female patients of childbearing potential (not surgically sterilized and between menarche 
and 1-year post menopause) must have a negative urine or serum pregnancy test 
performed within 72 hours prior to the initiation of study drug administration. If a patient 
is sexually abstinent but capable of becoming pregnant, she must agree to remain abstinent 
from the time of consent through 120 days after discontinuation of study drug 
administration. Should sexual activity commence, the patient must agree to use highly 
effective contraceptive measures from the time of consent through 120 days after 
discontinuation of study drug administration. 
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a. Highly effective methods of contraception include hormonal contraceptives, 
intrauterine device or system, vasectomy, or tubal ligation. If a highly effective 
method is not achievable, then a “double barrier” method is an effective 
alternative in which the male partner must use a condom with spermicide and 
the female partner must use a diaphragm or cervical cap concurrently. 
12. Male patients with partners of childbearing potential must use barrier contraception (i.e., 
condom). 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. Patients who are not pregnant or breastfeeding or expecting to conceive or father children 
within the projected duration of the study, starting with the prescreening or screening visit 
through 120 days after the last dose of study drug. 
 
5.2 
Exclusion Criteria 
1. Patients with symptomatic central nervous system (CNS) metastases. Patients with history 
of prior CNS metastasis must have been treated, must be asymptomatic, and must not have 
any of 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. Criterion for excluded prior therapies: 
a. Treatment with any major surgical procedure, systemic anti-neoplastic therapy, 
or investigational therapy within the 4 weeks prior to the initiation of study 
drug administration. 
b. Treatment with radiation therapy within 2 weeks prior to the initiation of study 
drug administration. 
c. Treatment with systemic corticosteroids (≥ 10 mg per day prednisone or 
equivalent) or other immune suppressive drugs within the 14 days prior to the 
initiation of study drug administration. 
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d. Prior history of Grade 3 or greater drug-related diarrhea/colitis during 
treatment with checkpoint inhibitors including anti-LAG-3, anti-PD-1, 
anti-PD-L1, or anti-CTLA-4 antibodies. 
5. Clinically significant cardiovascular disease including but not limited to: 
a. Myocardial infarction or unstable angina within the 6 months prior to the 
initiation of study drug. 
b. Stroke or transient ischemic attack within 6 months prior to the initiation of 
study drug. 
c. Clinically significant cardiac arrhythmias. 
d. Uncontrolled hypertension: systolic blood pressure (SBP) > 180 mmHg, 
diastolic blood pressure (DBP) > 100 mmHg. 
e. Congestive heart failure (New York Heart Association class III-IV). 
f. Pericarditis or clinically significant pericardial effusion. 
g. Myocarditis. 
6. Clinically significant gastrointestinal disorders including but not limited to: 
a. Any history of gastrointestinal perforation unless the affected area has been 
surgically resected no less than 3 months prior to the initiation of study drug and 
is deemed to no longer be at risk of perforation by the investigator. 
b. History of clinically significant gastrointestinal bleeding within 6 months prior 
to the initiation of study drug. 
c. Chronic malabsorption syndromes. 
d. Current acute or chronic diarrhea > Grade 2 in severity. 
e. Chronic gastrointestinal infection in the 3 months prior to the initiation of study 
drug administration. 
f. History of Clostridium difficile colitis within 3 months prior to the initiation of 
study drug administration. 
g. History of acute pancreatitis within 3 months prior to the initiation of study drug 
administration or any history of chronic pancreatitis. 
h. 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 3 months prior to the initiation of 
study drug administration. 
7. Clinically significant pulmonary compromise, including but not limited to pneumonia, 
presence of active pneumonitis or history of non-infectious pneumonitis, or a requirement 
for supplemental oxygen use to maintain adequate oxygenation. 
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8. 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. 
9. Known history of positive testing for human immunodeficiency virus or history of 
acquired immune deficiency syndrome. 
10. 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. 
11. Second primary invasive malignancy that has not been in remission for greater than 
2 years; except non-melanoma skin cancer; cervical carcinoma in situ on biopsy; or 
squamous intraepithelial lesion on Pap smear; localized prostate cancer (Gleason score < 
6); or resected melanoma in situ. 
12. History of trauma or major surgery within 4 weeks prior to the initiation of study drug 
administration. 
13. Any serious underlying medical or psychiatric condition that would impair the ability of 
the patient to receive or tolerate the planned treatment at the study site. 
14. Known hypersensitivity to recombinant proteins, polysorbate 80, or any excipient 
contained in the drug formulation or custom vehicle (Section 6.4). 
15. Vaccination with any live virus vaccine within 4 weeks prior to the initiation of study drug 
administration. Inactivated annual influenza vaccination is allowed. 
16. Dementia or altered mental status that would preclude understanding and rendering of 
informed consent. 
17. Prisoners or other individuals who are involuntarily detained. 
18. Any investigative site personnel directly affiliated with this study. 
19. 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 Study 
Patients who withdraw before Cycle 1 Day 42 during the Dose Escalation Phase for a reason 
unrelated to drug toxicity or efficacy may be considered to have inadequate data to support 
efficacy assessment (see Section 4.1.1). In this case, replacement patients may be enrolled but 
the patients will be considered in intention to treat. These patients will be followed for safety 
assessments (see Section 12.2). 
See Section 4.5.1 for replacement criteria for those patients who were planned to have paired 
tumor biopsies. 
Procedures for handling patients who fail to appear for study visits and criteria regarding 
when to consider patients lost-to-follow-up (LTFU) will be defined in the Study Procedures 
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Manual. A patient may be determined to be LTFU after there have been 3 documented phone 
contact attempts. If this fails, a certified letter should be sent to the patient. Only after these 
attempts have failed can a patient be determined to be LTFU. 
5.4 
Rules for Study Treatment Discontinuation 
Patients who tolerate treatment may continue to receive treatment with the study drug(s) as 
specified in the protocol until any one of the following conditions are met: 
 Patient meets any criteria for immune-related disease progression (irPD) 
 Withdrawal of patient due to an AE or SAE 
 Withdrawal of patient consent 
 Completion of protocol-defined therapy 
 Investigator discretion 
 Pregnancy 
 Occurrence of drug-related DLT 
 Dose delay > 28 days due to drug-related AE 
 Repeated administration of prohibited concomitant medications 
 The Sponsor, Investigator, or Regulatory Agency terminates the study 
 Death 
 
For individual patients who meet these criteria, but who are otherwise considered to be 
experiencing compelling clinical benefit in the judgment of the Investigator, consideration 
may be given to continue treatment with the MGD007 and MGA012 combination, for up to 
maximum of total of 12 cycles, on a case-by-case basis, in consultation with the Sponsor. 
For patients who experience drug-related DLTs that occurs prior to the initiation of MGA012, 
or for selected immune-related adverse events clearly related to the mechanism of action of 
MGA012, continued treatment of patients with either MGA012 or MGD007 monotherapy, 
respectively, may be considered selectively on a case-by-case basis, in consultation with the 
Sponsor. 
If the Investigator decides that the patient should be withdrawn from the study or from dosing 
for any reason other than disease progression, the site must enter the information in the eCRFs 
within 24 hours (Section 12.2.2). 
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5.5 
Guidelines for Discontinuation of Patient from Study 
Patients who are no longer on treatment but are still followed on the study can be terminated 
from the study for the following reasons: 
 Completion of protocol-defined follow-up period. 
 Uncontrolled intercurrent illness unrelated to cancer that prevents continuing study 
follow-up. 
 Noncompliance with protocol-required evaluations. 
 The patient requests to be discontinued from the study, i.e., withdrawal of consent. 
 The Sponsor, investigator, or regulatory agency terminates the study. 
 Death 
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7 
POTENTIAL ADVERSE EVENTS AND SUPPORTIVE CARE 
MEASURES 
7.1 
Premedication and Prophylaxis 
Clinically significant AEs that may be anticipated based on the mechanisms of action and/or 
clinical experience to date with MGD007 and/or MGA012 include, but are not limited to 
gastrointestinal AEs (nausea, vomiting, diarrhea, etc.), infusion related reactions (including 
CRS), and immune-related AEs. Guidelines for management of these events are provided 
below in Sections 7.2 to 7.5. In addition, premedication and prophylactic measures described 
here should be implemented to ameliorate the occurrence and/or severity of gastrointestinal 
adverse events and infusion-related reaction/CRS. 
The supportive care regimen should generally be utilized for all patients being treated with 
MGD007/MGA012, and will include: 
 Dexamethasone (20-mg IV) should be given prior to first dose of MGD007 on 
Cycle 1.  
 Budesonide (9 mg PO daily) starting at 48 hours prior to MGD007 infusion and 
continuing for 5 days after the MGD007 infusion must be given for at least the 
first 2 and up to 6 doses of MGD007. Further use of budesonide may be used 
selectively as indicated in the judgment of the investigator. 
 Nonsteroidal supportive care medications will be given prior to first dose of 
MGD007 on Cycle 1 Day 1 and as clinically indicated post infusion. Use of these 
medications must be given for the first 6 doses of MGD007 infusion; further use 
may be given selectively as indicated in the judgment of the investigator. These 
medications include: 
o Acetaminophen 650 mg PO 
o Diphenhydramine 50 mg IV 
o Ranitidine 50 mg IV or equivalent H2-antagonist 
o Ondansetron 16 mg IV or equivalent antiemetic 
 
Post-infusion: 
 IV hydration  500 to 1000cc normal saline administered over 1 to 2 hours post 
infusion of MGD007 should be considered. 
 Monitor for at least 6 hours after each of the following infusions: Cycle 1 Days 1 
and 15. 
 Inpatient observation for up to 24 hours after initial dose of MGD007 is 
recommended and may be implemented with subsequent doses of MGD007 at the 
discretion of the investigator. 
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7.1.1 
Rationale for Premedication and Prophylaxis 
In addition to 20 mg dexamethasone intravenously (IV) prior to the first dose of MGD007 
only, all new patients will receive prophylactic budesonide, an oral non-absorbable 
corticosteroid, in an attempt to limit the GI toxicities of MGD007 with less systemic immune 
suppression. This measure focuses on providing budesonide as local steroidal supportive 
medication within the intestinal tract, to mitigate and control the adverse effects of MGD007 
on the GI tract and limit the use of systemic dexamethasone. Limiting systemic corticosteroid 
use is desirable, in that the immunosuppressive effects of high doses of systemic steroids 
could interfere with the mechanism of action of MGD007 and MGA012. 
Based on preclinical data and the clinical experience noted to date, early management of 
toxicity will include tocilizumab. Specifically, if Grade 2 or greater vomiting or diarrhea 
occurs, early management will include tocilizumab (anti-IL6 receptor) at a dose of 8 mg/kg 
given intravenously. This approach is being deployed to intervene earlier and limit the 
progression of GI toxicity in patients treated with MGD007 with a less steroid-intensive 
approach. Repeat dosing of tocilizumab may occur after each MGD007 dosing if required in 
the judgment of the investigator. Nonetheless, if toxicities are not well controlled with 
prophylactic oral budesonide and early use of tocilizumab, systemic steroids and/or other 
measures may be employed as clinically indicated to treat toxicity. Rehydration with oral 
and/or IV supplemental fluids is also encouraged. 
7.2 
Infusion-Related Reactions Including Cytokine Release 
Syndrome 
The predicted mechanism of action of MGD007 is the creation of an immunological synapse 
between the tumor target cells bearing gpA33 and immune effectors bearing the T cell 
specific-CD3 complex, leading to T cell activation and killing of the tumor cell. Activation of 
T cells can be associated with the production of various cytokines. 
Infusion-related reactions including 
hypersensitivity/anaphylactic/anaphylactoid reactions 
or Cytokine Release Syndrome (CRS) may occur. 
Precautions for the management of these reactions should be observed  
during MGD007 administration. 
Infusion reactions have also been observed with monoclonal antibodies, including antibodies 
directed against PD-1 or PD-L1. Infusion reactions (including cytokine release syndrome 
[CRS]) associated with administration of either MGD007 or MGA012 should be managed 
according to the standard practice of medicine. General guidelines for the management of 
such reactions are provided in this section. However, severe reactions may require more 
intensive interventions (e.g., steroids, anti-TNF antibodies, and/or IL-6 inhibitors). 
Patients should be monitored closely for the development of infusion-related reactions during 
infusions. Patients must remain in the infusion center for monitoring for at least 6 hours after 
the infusions on Cycle 1 Days 1 and 15. Medications and supportive measures for the 
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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 25- to 100-mg IV 
push or equivalent), IV fluids, vasopressors, oxygen, bronchodilators, and antipyretics. 
Resuscitation equipment and other supplies for the emergency management of an 
allergic/toxic reaction must be available. The patient should be treated according to the best 
available local practices and procedures. All supportive measures consistent with optimal 
patient care will be provided throughout the study according to institutional standards. 
Should symptoms of fever or chills develop, it may be difficult to distinguish among potential 
causes 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 7.2.2 for detailed guidance regarding the management of 
infusion reactions. 
7.2.1 
Grading and Management of Infusion Reactions 
Infusion reactions will be categorized as follows: 
 Grade 1: mild reaction; infusion interruption not indicated, intervention not 
indicated; Note: Although interruption in infusion is not indicated, temporary rate 
reduction is indicated before resuming original rate, as the patient tolerates 
(see Section 7.2.2) 
 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 v4.03 grading scale for CRS, which is nearly identical 
to the CTCAE v4.03 grading scale for infusion reaction and allergic reaction and is therefore 
considered appropriate for grading all infusion reactions in this study, irrespective of the 
underlying mechanism of the reaction. The Sponsor’s Medical Monitor or designee should be 
contacted immediately if questions arise concerning the grade of the reaction. 
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7.2.2 
Management of Observed Infusion Reactions 
All infusion-related reactions should be reported as AESIs and/or SAEs, as applicable. 
The following are treatment guidelines (which may be modified as needed by the Investigator 
according to the best practices of medicine) for infusion reactions. If symptoms of IRR 
develop follow the guidelines provided in Table 11. 
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Table 11 
Management of Infusion-Related Reactions  
IRR/CRS (NCI CTCAE v4.03) 
Management 
Follow-up 
Grade 1 
Mild transient reaction, infusion 
interruption not indicated, 
intervention not indicated 
 
Decrease rate of infusion by 
50%. 
 
Monitor for worsening. 
 
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. 
 
Monitor closely for worsening 
symptoms. Educate patient to 
report worsening 
immediately. 
 
If worsens: Treat as Grade 
2 or 3/4, as appropriate. 
 
Consideration can be given to 
beginning all subsequent 
infusions at 50% rate and 
increasing as tolerated. 
 
Premedication for subsequent 
dose as recommended 
(Section 7.1) 
Grade 2 
Therapy or infusion interruption 
indicated but responds promptly to 
symptomatic treatment 
 
Stop the infusion if ongoing. 
 
Administer: 
o 
Diphenhydramine 50 mg 
IV 
o 
Ibuprofen 400 mg PO for 
fever 
o 
Oxygen/bronchodilators/I
V fluids 
 
Resume the infusion at 50% 
of the prior rate once the 
infusion reaction has resolved 
or decreased to Grade 1. 
 
Tocilizumab 8 mg/kg IV may 
be considered selectively in 
patients where the event is 
clearly associated with the 
administration of MGD007 or 
occurs prior to the initiation 
of therapy with MGA012 
 
Consult Medical Monitor. 
 
Monitor for worsening of 
symptoms 
 
If worsens or persists after 
medical intervention: Treat as 
Grade 3/4 as appropriate 
 
Consideration can be given to 
beginning all subsequent 
infusions at 50% rate and 
increasing as tolerated. 
 
Premedication for subsequent 
dose as recommended 
(Section 7.1). 
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Table 11 
Management of Infusion-Related Reactions  
IRR/CRS (NCI CTCAE v4.03) 
Management 
Follow-up 
Grade 3 
Prolonged (not responsive to 
symptomatic treatment) or 
recurrence after initial 
improvement, hospitalization 
indicated for clinical sequelae. 
 
Stop the infusion if ongoing. 
 
Disconnect tubing. 
 
DO NOT FLUSH the tubing. 
 
Administer: 
o 
Diphenhydramine 50 mg 
IV 
o 
Dexamethasone 20 mg 
IV or methylprednisolone 
2-4 mg/kg 
o 
Ibuprofen 400mg PO for 
fever 
o 
Oxygen/bronchodilators/I
V fluids 
 
Tocilizumab 8 mg/kg IV may 
be considered selectively in 
patients where the event is 
clearly associated with the 
administration of MGD007 or 
occurs prior to the initiation 
of therapy with MGA012 
 
Consult Medical Monitor. 
 
Report as IRE  
 
Report as SAE (if 
appropriate) 
 
Monitor for worsening of 
symptoms 
 
If worsens: Treat as Grade 4 
 
If reaction resolves within 
12 hours, then MGA012 can 
be administered on next 
scheduled dose. 
 No further doses of study drugs 
(MGD007 and MGA012) if a 
Grade 3 infusion reaction does 
not resolve within 12 hours 
despite medical management 
 Premedication for subsequent 
dose as recommended 
(Section 7.1). 
 Permanently discontinue study 
drugs (MGD007 and MGA012) 
if there is a recurrence of Grade 
3 reaction at rechallenge. 
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Table 11 
Management of Infusion-Related Reactions  
IRR/CRS (NCI CTCAE v4.03) 
Management 
Follow-up 
Grade 4 
Life threatening consequences, 
urgent intervention indicated 
 Stop the infusion if ongoing. 
 Disconnect tubing.  
 DO NOT FLUSH the tubing. 
 Administer: 
o Diphenhydramine 50 mg IV 
o Dexamethasone 20 mg IV  
OR methylprednisolone 
2 mg/kg. 
o Tocilizumab 8 mg/kg as for 
Grade 3 events 
o Ibuprofen 400 mg PO for 
fever 
o Oxygen/bronchodilators/IV 
fluids. 
o Pressors/Ventilatory support  
 Consult Medical Monitor 
 Report as IRE & SAE 
 No further doses of study drugs 
(MGD007 and MGA012). 
Permanently discontinue study 
drugs (MGD007 and MGA012). 
Grade 5 
Death 
 Report as IRE & SAE 
 
 
7.3 
Management of Diarrhea or Colitis 
Based on the respective mechanisms of action, both MGD007 and MGA012 may cause GI 
side effects that may include diarrhea and/or colitis. 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. Clinical observations have shown that MGD007 may cause very early 
(within 72 hours of drug administration) GI side effects that may include diarrhea, nausea and 
vomiting. These events can be managed successfully with careful supportive care, as well as 
prompt recognition and intervention with immune suppression where indicated, including 
anti-cytokine antibody (tocilizumab) and corticosteroids. Colitis related to checkpoint 
inhibition with anti PD-1 antibodies is much less common than diarrhea associated with 
treatment with MGD007, typically doses not arise acutely after drug treatment, and is 
generally treated initially with corticosteroids followed by anti-cytokine therapy (anti-TNF) in 
patients who fail to respond to corticosteroids. Patients on the present study should be 
monitored closely for evidence of diarrhea or other change in bowel habits, and patients who 
develop signs or symptoms including abdominal pain, bloating, nausea, vomiting, and 
diarrhea with blood in the stools should also be evaluated carefully for potential colitis. 
For patients who develop acute GI symptoms prior to the initiation of MGA012 or within 72 
hours of treatment with the combination of MGD007 and MGA012 should be treated initially 
according to MGD007 supportive care principles as outlined below in Section 7.3.1. For 
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patients who fail to respond to early anti-cytokine therapy within 48 to 72 hours, 
corticosteroids should be initiated promptly as outlined below. For patients in whom the onset 
of GI symptoms are over 72 hours after administration of the MGD007/MGA012 combination 
or in whom signs and symptoms are suggestive of colitis, supportive care should be initiated 
according to Section 7.3.2, with initial treatment with corticosteroids as outlined below. 
7.3.1 
Diarrhea Occurring Before Addition of MGA012 to MGD007 
or Early (within 72 Hours) After Administration of the 
MGD007/MGA012 Combination 
 Grade 1 diarrhea - Closely monitor the diarrhea until resolution 
 Grade 2 diarrhea: 
o Bowel rest 
o Supplemental IV fluids when necessary with close monitoring of fluid and 
electrolyte status 
o Tocilizumab (anti IL6 receptor) administered as a single 8 mg/kg IV dose. 
Repeat dosing of tocilizumab may occur after each MGD007 dosing.  
o Monitoring of frequency of bowel movements and stool guaiac 
o For patients unresponsive to tocilizumab (which should be given first), 
implementation of additional immune suppression consisting of IV 
corticosteroids using solumedrol 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 and guided by the patients’ clinical status.  
 Grade 3 diarrhea (or Grade 2 diarrhea with blood) 
o Hold both MGD007 and MGA012 
o Hospitalize promptly for further evaluation and management 
o Bowel rest 
o Supplemental IV fluids with close monitoring of fluid and electrolyte status 
o Tocilizumab 8 mg/kg IV 
o Monitoring of frequency of bowel movements and stool guaiac 
o For patients unresponsive to tocilizumab (which should be given first), 
implementation of additional immune suppression consisting of IV 
corticosteroids using solumedrol 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. 
o Stool characterization tests should be performed 
o Imaging to rule out bowel obstruction or perforation 
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o Consideration of colonoscopy as appropriate 
o For patients with severe colitis, or those who do not respond to tocilizumab 
or corticosteroids, additional immune suppression with anti TNF-alpha 
antibodies (i.e., infliximab) should be considered early in the course 
o For patients with Grade 3 diarrhea that lasts less than 48 hours and 
responds to medical intervention, treatment may be resumed after 
resolution of the diarrhea to Grade 1 or less in severity within 14 days.  
 Grade 4 diarrhea: discontinue MGD007 and MGA012 and treat as for Grade 3 
diarrhea. MGD007 and MGA012 should be permanently discontinued. 
 
7.3.2 
Diarrhea with Onset > than 72 Hours After Administration of 
the Combination of MGD007/MGA012 or Clinical 
Manifestations Suggestive of Colitis 
 Grade 1 diarrhea - Closely monitor the diarrhea until resolution. 
 Grade 2 diarrhea - Increase frequency of monitoring until resolution. For 
management of symptoms: 
o loperamide/diphenoxylate 
o low-dose steroids if clinically indicated. 
o Consider management as per Grade 3 diarrhea with prolonged Grade 2 
event lasting more than 5 to 7 days or relapsed diarrhea. 
 Grade 3 diarrhea - Hold both MGD007 and MGA012. Hospitalize patient promptly 
for further evaluation and management including: 
o Bowel rest 
o Supplemental IV fluids with close monitoring of fluid and electrolyte 
status. 
o Monitor frequency of bowel movements 
o Consider imaging to rule out bowel obstruction or perforation 
o Consideration of colonoscopy as appropriate 
o Implementation of initial empiric immune suppression consisting of IV 
corticosteroids using methylprednisolone at a dosage of 2 mg/kg/day (or 
equivalent) divided twice daily. As tolerated, patients may be converted to 
oral corticosteroids (i.e., prednisone 2 mg/kg/day divided twice daily) and 
tapered as appropriate and guided by the patients' clinical status. 
o Taper corticosteroids as clinically indicated 
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o For patients with severe colitis, or those who do not respond to 
corticosteroids, additional immune suppression with anti TNF-alpha 
antibodies (i.e., infliximab) should be considered early in the course. 
o May consider restarting MGD007 and MGA012 if it is determined that 
there is no colitis, or an alternative cause of diarrhea is found, and diarrhea 
resolves to ≤ Grade 1 within 14 days 
 Grade 4 diarrhea-discontinue MGD007 and MGA012 and treat as for Grade 3. 
MGD007 and MGA012 should be permanently discontinued. 
 
If the etiology of the diarrhea is uncertain, tocilizumab administration also can be considered, 
in the case of Grade 2 or greater diarrhea at the discretion of the Investigator, in consultation 
with the Sponsor. 
7.4 
Nausea/Emesis 
Based on observations from nonclinical and the clinical experience to date, there is some risk 
that patients may experience nausea and/or vomiting in conjunction with MGD007 treatment. 
It is recommended that patients be treated prophylactically with antiemetics in conjunction 
with the first and subsequent doses of MGD007 (Section 7.1). For those patients who do 
experience nausea and/or vomiting after initial dosing, antiemetics should be given as 
clinically appropriate and consistent with institutional practice. Acceptable antiemetics 
include but are not limited to serotonin 5-HT3 receptor antagonists, neurokinin 1 receptor 
antagonists, prochlorperazine, and diphenhydramine. Patients with Grade 2 vomiting despite 
the specified pre-medication regimen should be promptly managed with a one-time dose of 
tocilizumab (anti-IL6 receptor) 8 mg/kg IV. Repeat dosing of tocilizumab may occur after 
each MGD007 dosing. If toxicities are not controlled with tocilizumab, systemic steroids 
and/or other measures as clinically indicated are recommended. Rehydration with oral or IV 
supplemental fluids should also be considered. 
7.5 
Immune-Related Adverse Events 
Blockade of immune checkpoints (PD-1, PD-L1 and CTLA-4) has been associated with 
several immune mediated adverse events that develop as a result of disruption of immune 
tolerance in normal tissues (18, 36, 43). These include but are not limited to pneumonitis, 
autoimmune hepatitis, glomerulonephritis, central neurotoxicity (encephalitis), peripheral 
neuromuscular toxicity, diarrhea or colitis (discussed in Section 7.3), hypophysitis, thyroiditis, 
or other autoimmune endocrinopathies (e.g., pancreatitis and diabetes), myocarditis, and 
Stevens Johnson Syndrome/Toxic Epidermal Necrolysis. These IrAEs can occur lately and 
require a prolonged follow up. The occurrence of any of these may dictate interruption and 
potentially discontinuation of study drug administration pending further evaluation and 
reporting them to the Sponsor as AESIs. Most low-grade immune-related AEs (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 
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mycophenolate or infliximab. High-grade immune-related toxicities will, in almost all cases, 
require treatment with high-dose corticosteroids. 
Temporary interruptions of the study drugs may be required in the event of treatment-related, 
immune-related toxicity. General guidelines for specific toxicity regarding dosing and 
treatment are provided below. All toxicities will be graded according to NCI CTCAE v4.03. 
Patients who receive corticosteroid therapy for ≥ 4 weeks at a dose equivalent to ≥ 20 mg of 
prednisone per day, consideration should be given to implementation of antibiotic prophylaxis 
for opportunistic infections. 
7.5.1 
Hepatic Toxicity 
7.5.1.1 
Elevations in Transaminases 
Treatment management algorithm for patients experiencing hepatic toxicity are as follows: 
 Grade 1 elevations - No specific therapy required. 
 Grade 2 elevations - For elevations in transaminases 3 to 5 × ULN, rule out viral 
and other etiologies, and consider immediate oral steroids such as prednisone 
60 mg/day divided twice daily, and hold MGD007 and MGA012. 
o If improvement to ≤ Grade 1 does not occur within 48 hours consider IV 
steroids such as methylprednisolone at 2 mg/kg/day divided twice daily or 
oral steroids such as prednisone 60 to 120 mg per day, divided twice daily. 
o Resume MGD007 and MGA012 at the next scheduled dose if no more than 
2 doses of the combination were missed. 
o If improvement to ≤ Grade 1 does not occur within 14 days, discontinue 
MGD007 and MGA012. 
 Grade 3 elevations - Hold MGD007 and MGA012. 
o For elevations in transaminases > 8 × ULN, permanently discontinue 
MGD007 and MGA012. 
 Begin immediate IV steroids, and 
 If no response to corticosteroid therapy within 3 to 5 days is 
observed, consider adding immune suppression therapy with 
mycophenolate. 
 Monitor liver function tests at least twice weekly (or more 
frequently as clinically appropriate in the judgment of the 
Investigator) until transaminases have returned to Grade 1 or 
baseline. 
o For elevations in transaminases > 5 but ≤ 8 × ULN: 
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 Begin immediate IV steroids; suggest methylprednisolone at a 
dosage of 2 mg/kg/day divided twice daily. 
 Consider additional immune suppression as above for patients who 
do not respond to corticosteroid therapy within 3 to 5 days. 
 Monitor liver function tests at least twice weekly (or more 
frequently as clinically appropriate in the judgment of the 
Investigator) until transaminases have returned to Grade 1 or 
baseline. 
 If the elevation does not improve to Grade 2 within 7 days and to 
Grade 1 within 14 days, discontinue MGD007 and MGA012. 
o Resume MGD007 and MGA012 administration if following conditions are 
met: 
 Laboratory elevations downgrade to ≤ Grade 2 within 7 days and 
improve to ≤ Grade 1 or baseline within 14 days. 
 Steroids have been tapered to ≤ 10 mg per day of prednisone or 
equivalent. 
 On resuming MGD007 and MGA012, AST, ALT, and total and 
direct bilirubin laboratory test values will be evaluated at least once 
per week for 3 consecutive weeks. 
o Permanently discontinue MGD007 and MGA012 treatment in the case of a 
second increase of AST or ALT to ≥ Grade 3. 
 Grade 4 elevations - Discontinue MGD007 and MGA012 and treat as for 
Grade 3 elevation. MGD007 and MGA012 should be permanently 
discontinued. 
 
7.5.2 
Elevations in Total Bilirubin 
Management guidelines for patients experiencing elevations in total bilirubin are as follows: 
 Grade 1 elevations - No specific therapy required. 
 Grade 2 elevations - Hold MGD007 and MGA012 until improvement to ≤ Grade 1. 
o Consider oral steroids. 
o If improvement to ≤ Grade 1 does not occur within 14 days, discontinue 
MGD007 and MGA012 and begin oral steroids. 
 Grade 3 elevations - Hold MGD007 and MGA012  
o For elevations in total bilirubin > 5 × ULN, permanently discontinue 
MGD007 and MGA012 and initiate IV steroids, suggest 
methylprednisolone at a dosage of 2 mg/kg/day divided twice daily, and, 
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 If no response to corticosteroid therapy within 3 to 5 days is 
observed, consider adding immune suppression therapy with 
mycophenolate. 
 Monitor liver function testing at least twice weekly (or more 
frequently as clinically appropriate in the judgment of the 
Investigator) until total bilirubin has returned to Grade 1 or 
baseline. 
o For elevations in total bilirubin > 3.0 but ≤ 5 × ULN: 
 Begin immediate IV steroids, suggest methylprednisolone at a 
dosage of 2 mg/kg/day divided twice daily. Consider additional 
immune suppression as above for patients who do not respond to 
corticosteroid therapy within 3 to 5 days. 
 Monitor liver function including total bilirubin testing at least twice 
weekly (or more frequently as clinically appropriate in the judgment 
of the Investigator) until total bilirubin has returned to Grade 1 or 
baseline. 
 If the elevation does not improve to Grade 2 within 7 days and to 
Grade 1 within 14 days, discontinue MGD007 and MGA012. 
o Resume MGD007 and MGA012 administration if: 
 Laboratory elevations downgrade to ≤ Grade 2 within 7 days and 
improve to ≤ Grade 1 or baseline within 14 days. 
 Steroids have been tapered to ≤ 10 mg per day of prednisone or 
equivalent. 
 On resuming MGD007 and MGA012, AST, ALT, and total bilirubin 
laboratory test values will be evaluated at least once per week for 
3 consecutive weeks. 
o Permanently discontinue MGD007 and MGA012 in the case of a second 
increase of total bilirubin to ≥ Grade 3. 
 Grade 4 elevations - Discontinue MGD007 and MGA012 and treat as for 
Grade 3 elevation. MGD007 and MGA012 should be permanently discontinued. 
 
7.5.3 
Pneumonitis 
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 MGD007 and MGA012 
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o Consider corticosteroids: 1 to 2 mg/kg of oral prednisone or equivalent, per 
day divided twice daily. 
o Taper over 4 weeks as clinically indicated. 
o Resume MGD007 and MGA012 administration at the next scheduled dose 
if pneumonitis resolves to ≤ Grade 1 within 3 days with or without 
treatment. 
 Grade 3 and 4 pneumonitis - discontinue MGD007 and MGA012. 
o Hospitalize the patient. 
o Initiate maximal supportive care including IV corticosteroids, suggest 
methylprednisolone at 2 to 4 mg/kg/day divided twice daily. Higher doses 
may be used in consultation with the Sponsor’s Medical Monitor. 
o If no response to corticosteroid therapy is observed within 3 to 5 days, 
consider adding immune suppression therapy (i.e., infliximab, etc.). 
o MGA012 should be permanently discontinued 
o Upon resolution of the pneumonitis to Grade 1 or less in severity, 
resumption of MGD007 monotherapy may be considered on a case-by-case 
basis in consultation with the Sponsor. 
 
7.5.4 
Dermatologic Toxicity 
Management guidelines for patients experiencing dermatologic toxicity are as follows: 
 Grade 1 or 2 skin reactions 
o Symptomatic treatment with low-dose topical corticosteroids 
(betamethasone 0.1% or hydrocortisone 1%) or antihistamines 
(diphenhydramine). 
o Persistent Grade 1 or 2 rash should be managed with higher dose topical 
corticosteroids and/or oral prednisone (1 to 2 mg/kg/day) if there is not 
improvement with topical therapies or the rash is associated with other 
dermal toxicities such as pruritus. 
 Grade 3 skin reactions  Hold MGD007 and MGA012  
o Initiate oral corticosteroids (oral prednisone 1 to 2 mg/kg/day). 
o MGD007 and MGA012 may be restarted at the next scheduled dosing if 
symptoms resolve to ≤ Grade 2 within 14 days. 
o Grade 3 skin toxicity that does not resolve to ≤ Grade 2 within 14 days of 
initiation of oral corticosteroids requires permanent discontinuation of 
study drugs (MGD007 and MGA012). 
 Grade 4 skin reactions - Discontinue MGA012 and MGD007 
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o Initiate oral corticosteroids (oral prednisone 1 to 2 mg/kg/day). 
o Consideration should be given to start IV corticosteroids 
(methylprednisolone 1 to 2 mg/kg/day) for Grade 4 dermatologic toxicities 
with tapering on resolution to < Grade 2 over 30 days. 
o MGD007 and MGA012 should be permanently discontinued. 
 
7.5.5 
Nephritis 
Management guidelines for patients experiencing nephritis are as follows: 
 Grade 1 nephritis - No specific therapy required; close monitoring of renal function. 
 Grade 2 nephritis - Hold MGD007 and MGA012. 
o Consider nephrology consultation and renal biopsy to confirm interstitial 
nephritis. 
o Begin corticosteroids: 1 to 2 mg/kg of oral prednisone or equivalent, per 
day divided twice daily. Taper over 4 weeks as clinically indicated. 
o Resume MGD007 and MGA012 administration at next scheduled dose if: 
 Nephritis resolves to ≤ Grade 1 within 14 days with or without 
treatment. 
 Grade 3 and 4 nephritis - Permanently discontinue MGD007 and MGA012. 
o Consider hospitalization, nephrology consultation, and renal biopsy to 
confirm interstitial nephritis. 
o Begin corticosteroids: 2 to 4 mg/kg of oral or IV prednisolone or equivalent 
per day divided twice daily. Taper over 4 weeks as clinically indicated. 
 
7.5.6 
Immune-mediated Hypophysitis 
Management guidelines for patients experiencing hypophysitis are as follows:  
 Grade 1 hypophysitis - No specific therapy required. 
 Grade ≥ 2 hypophysitis - Hold MGD007 and MGA012 
o Consult endocrinologist. 
o Consider hospitalization.  
o Consider short course of high dose IV 
corticosteroids: e.g., methylprednisolone 2-4 mg/kg IV (or 
equivalent) divided twice daily. 
o Initiate hormonal replacement as indicated. 
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o MGD007 and MGA012 treatment may be resumed as allowed by protocol 
when: 
 Endocrinopathy is controlled with appropriate replacement therapy. 
 Corticosteroid dose reduced to ≤ 10 mg prednisone or equivalent 
per day. 
o Brain MRI recommended. 
 Grade 4 hypophysitis - MGD007 and MGA012 should be permanently 
discontinued. 
 
7.5.7 
Thyroid Toxicity 
Thyroid disorders may occur at any time during treatment. Monitor patients for changes in 
thyroid function per protocol and as indicated based on clinical evaluation and for clinical 
signs and symptoms of thyroid disorders. Isolated hypothyroidism may generally be managed 
with replacement therapy without treatment interruption and without corticosteroids; 
treatment management algorithms for patients experiencing endocrinopathy, and a suggested 
treatment guideline for hyperthyroidism is described below: 
 Grade 1 hyperthyroidism - No specific therapy required. 
 Grade 2 hyperthyroidism - Hold MGD007 and MGA012. 
o Consider starting oral corticosteroid therapy. 
o Short course of corticosteroid such as methylprednisolone 1 to 2 mg/kg IV 
(or equivalent) divided twice daily. 
o Resume MGD007 and MGA012 if corticosteroid dose is reduced to ≤ 
10 mg prednisone or equivalent per day and stable on hormone replacement 
therapy (if necessary). 
 Grade 3 or 4 hyperthyroidism - Hold MGD007 and MGA012. 
o Consider hospitalization and consulting endocrinologist. 
o Begin IV corticosteroids such as methylprednisolone 2 to 4 mg/kg IV (or 
equivalent) divided twice daily. 
o Initiate hormonal replacement as necessary. 
o Consider restarting MGD007 and MGA012 with complete resolution or 
stable on hormone replacement therapy within 14 days and if corticosteroid 
dose is reduced to ≤ 10 mg prednisone or equivalent per day. 
 
PLEASE NOTE FOR EVENTS DESCRIBED IN SECTIONS 7.2 - 7.5: For patients who 
experience drug-related DLT that occurs prior to the initiation of MGA012, or for selected 
immune-related AEs clearly related to the mechanism of action of MGA012, continued 
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treatment of patients with either MGA012 or MGD007 monotherapy, respectively, may be 
considered selectively, on a case-by-case basis, in consultation with the Sponsor. 
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8 
CONCOMITANT THERAPY AND RESTRICTIONS 
8.1 
Concomitant Therapy 
All concomitant medications, including prophylactic pre-infusion medications, and blood 
products administered during the patient’s participation in the study until the end of treatment 
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. 
8.1.1 
Prohibited Therapy 
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. 
o For patients who require palliative radiotherapy (i.e., cumulative dose less 
than 30 Gy, limited field of distribution) for reasons other than disease 
progression, therapy may be interrupted for up to 4 weeks. Palliative 
radiotherapy may not be given concurrently with the study drug. Treatment 
with palliative therapy should be initiated at least 24 hours after receiving 
study drug, and reinitiation can begin 2 weeks after the completion of 
palliative radiotherapy. If palliative radiotherapy fields overlap tumor 
lesions that are designated target lesions, 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. 
 The use of other immunosuppressive agents is prohibited unless they are being used 
to treat an AE. 
 Prophylactic use of granulocyte colony stimulating factor, granulocyte-macrophage 
colony stimulating factor, or other growth factors is prohibited. 
 Patients should not receive vaccination with any live virus vaccine during the study 
and for 120 days following a patient’s last dose of MGA012 or of MGD007. 
Inactivated annual influenza vaccination is allowed. 
 Because both MGD007 and MGA012 employs 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 MGD007- and MGA012-associated autoimmune AEs in consultation 
with the Sponsor. Specifically, use of budesonide is required with MGD007 dosing 
per schedule outlined in Section 7.1. 
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 Use of biphosphonates or RANK-L inhibitors is prohibited. 
 Concomitant use of CYP450 substrates with a narrow therapeutic index should be 
avoided. 
 
8.1.2 
Permitted Therapies 
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. 
8.2 
Restrictions 
8.2.1 
Fluid and Food Intake 
There are no requirements for fasting and no restrictions for fluid and food intake by the 
patients during the study, although it is recommended that, to the extent possible, patients 
have a fluid intake of  2 liters on days associated with PK sampling, and that 
electrocardiograms be obtained pre-meal. 
8.2.2 
Patient Activity Restrictions 
There are no restrictions on patient activities and no requirement for patient confinement 
during the study. 
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9 
STUDY PROCEDURES 
This section provides a general description of the procedures and assessments associated with 
this study. The timing of the study procedures is presented in Appendix 1. 
9.1 
Informed Consent 
The Investigator is responsible for ensuring that the patient or his/her legal representative 
provides informed consent prior to performing any study-related assessments, evaluations, or 
procedures that are not part of standard-of-care for the patient’s disease. Informed consent for 
this study must be provided by signing an Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC)-approved informed consent document (Consent for Study 
Participation). A copy of the relevant signed informed consent document must be provided to 
the patient and the original maintained according to institutional procedures. The patient’s 
medical records will include documentation of the informed consent process. 
9.2 
Screening Period 
Patients may receive the first dose up to 28 days from signing the informed consent. This 
period is defined as the screening period. At the screening visit, patients will enter the study 
upon signing the informed consent document. No screening activities outside of usual 
standard-of-care should be performed prior to obtaining informed consent from the patient. 
Only those patients who meet all inclusion/exclusion criteria specified in Section 5 will be 
entered into this study. 
9.3 
Registration 
Only those patients who meet all inclusion/exclusion criteria specified in Section 5 will be 
entered into this study. 
Once the patient has been determined to be eligible for enrollment into the study, the patient 
must be registered with MacroGenics. The following information should be provided during 
registration: 
 Date of signed informed consent 
 Planned date of first administration 
 
Instructions for the registration process are provided in the Study Procedures Manual. 
9.4 
Medical History 
A complete medical history should be obtained during the screening visit. All 
concurrent medical conditions in the last 60 days and any significant past medical conditions 
(e.g., hospitalizations, surgeries, chronic conditions, prior cancer history, etc.) should be 
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collected. Any untoward event that occurs prior to the first dose of study drug should be 
recorded as medical history and not as an AE unless it is due to a protocol-related procedure.
9.5 
Prior and Concomitant Medications
All concomitant medications and blood products administered during screening and 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.
9.6 
Physical Examination
The Investigator will perform physical examination of all patients; the examination will be 
conducted as specified in Appendix 1. Full physical examination will be performed at 
screening and at the End of treatment visit, and it will include height (screening only), weight, 
and examination of skin, HEENT (head, eyes, ears, nose, and throat), lymph nodes, heart, 
chest, lungs, abdomen, extremities, and neurologic system. All other physical examinations 
will be directed physical examinations based on patient symptoms, tumor location, and as 
clinically indicated.
9.6.1 
Vital Signs
Vital signs include temperature, pulse, blood pressure, and respiratory rate and are obtained 
as specified in Appendix 1. It is recommended vital signs are obtained in a seated, 
semi-recumbent, or supine position after an appropriate rest.
9.7 
ECOG Performance Status
ECOG performance status should be measured as specified in Appendix 1 and Appendix 4.
9.8 
Clinical Laboratory Tests
Blood and urine samples will be collected at the times specified in Appendix 1. Hematology, 
chemistry, pregnancy, urinalysis, coagulation time, and endocrine evaluation tests will be 
performed locally. Safety laboratory tests should be performed and reviewed before study 
drug administration.
9.8.1 
Central Laboratory Assays
Clinical laboratory tests to be performed are presented in Appendix 2. There are no 
clinical laboratory tests (see Appendix 2) being analyzed at a central laboratory for this 
study. 
Other laboratory tests (e.g., PK, anti-drug antibody [ADA] assays [Appendix 3]) will be 
analyzed at Sponsor-specified central laboratories. Additional details on collection, 
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processing, storage, and shipping of central laboratory samples will be provided in the 
Laboratory Manual. 
9.8.2 
Pharmacokinetics 
Blood samples for MGD007 and MGA012 PK will be collected at the time points shown in 
Appendix 3. Blood samples will be collected from the arm contralateral to the site of IV 
infusion. If an indwelling catheter is used, the fluid in the catheter will be removed and 
discarded prior to the collection of blood sample for PK assessment. 
Actual date and time of the start and end of infusions and PK sample collection will be 
recorded on the eCRFs. 
9.8.3 
Pharmacodynamics/Biomarkers 
Procedures for the acquisition, handling, and processing of pharmacodynamic biomarker 
specimens will be provided in the Laboratory Manual. These tests will be collected according 
to Appendix 3. Samples are to be obtained at the time points specified in the Time and Events 
Schedule and the PK, immunogenicity, and pharmacodynamic biomarkers blood sample 
schedule for MGD007 and MGA012 (Appendix 1 and Appendix 3, respectively). 
9.8.4 
Sample Collection, Storage, and Shipping 
Details on laboratory specimen processing, storage, and shipping will be provided in the 
Laboratory Manual. 
9.9 
Radiographic, CT, or MRI Assessments 
Baseline tumor imaging consists of a CT/MRI scan for all patients. The subsequent tumor 
assessments on treatment should use the same imaging modality as that for the baseline 
assessment; for subsequent imaging timepoints see Appendix 1. 
A CT or MRI scan of the brain will be performed in cases in which it is clinically indicated 
(e.g., suspicion of brain metastases) and repeat brain scans will be performed only if the 
screening brain scan was positive, or as clinically indicated. 
9.10 
Electrocardiography 
Twelve-lead electrocardiograms will be obtained according to the Time and Events Schedules 
(Appendix 1) in order to evaluate the potential cardiac effect, including QTc interval 
prolongation. 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. 
To account for intrinsic variability, all ECGs should be obtained in triplicate (3 ECGs per time 
point at approximately 1-minute intervals). Central interpretation of ECGs will be used for 
data analysis purposes. 
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Actual times of the ECG assessments will be recorded on the eCRFs. 
9.11 
End of Treatment Visit 
A list of evaluations to be performed for the EOTV is provided in Appendix 1; a CT or MRI 
Scan should be performed during the EOTV, unless a previous scan was performed < 28 days 
of the EOTV. Criteria for triggering the End of Treatment visit are specified in Section 5.4. 
The End of Treatment Visit should be performed after the patient has met off-study criteria. 
This visit should occur no later than 30 days since the last study dose and before any 
subsequent anti-cancer treatment. If EOTV < 30 days since the last study dose, the site should 
contact the patient for safety follow-up no later than 30 days after the last study dose (see 
Section 12). It is recognized that certain patients (such as those experiencing progression of 
disease) may be cared for in facilities other than the participating study site, may proceed to 
receive other cancer therapy, and/or may elect not to return to the study site. Therefore, this 
visit is considered optional, but should be carried out whenever possible. All required 
procedures and tests should be performed if a visit is performed. 
9.12 
Post-treatment Follow-Up Visits 
The post-treatment follow-up period includes the following: 
 Survival follow-up: approximately a 2-year period for each patient following the 
last dose of any study drug. 
 During this time, patients will be followed via telephone or other electronic contact 
at 3-month intervals for follow-up of OS. 
 Response status: will be collected every 3 months on all patients who discontinued 
from study treatment due to reasons other than PD, if they have not initiated any 
other cancer-directed therapy. 
 
Post-treatment follow-up is performed until the end of study for each patient. 
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10 
ASSESSMENT OF PHARMACOKINETICS AND 
PHARMACODYNAMICS 
10.1 
Pharmacokinetics Assessments 
Serum concentrations of study drug will be monitored using a quantitative sandwich 
enzyme-linked immunosorbent assay (ELISA) method in the Sponsor’s designated central 
laboratory. Single and multiple dose PK parameters, maximal concentration (Cmax), time to 
maximal concentration (Tmax), area under the concentration-time curve from time zero to time 
T (AUC(0 T)), area under the concentration-time curve in a dosing interval (AUCtau), area 
under the concentration-time curve from time zero to infinite time (AUC(INF)), trough 
concentration (Ctrough), clearance (CL), volume of distribution at steady state (Vss), and 
terminal half-life (t1/2), will be derived from serum concentration versus time data. Population 
PK analyses may be conducted using data from this study alone or combined with data from 
other studies. 
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. Samples will be collected for evaluation of ADA. 
10.2 
Pharmacodynamic/Biomarker Assessments 
10.2.1 
Tests Performed for Both Dose Escalation and Cohort 
Expansion Patients 
Tests to be performed for PD/Biomarker assessments include, but are not limited to, the 
following: 
 Characterization of alterations in serum cytokine levels to include, but not limited 
to, IFN-γ, IL-2, IL-6, IL-10, and TNF-α. 
 MGD007 and MGA012 occupancy on PBMCs using multiparameter flow 
cytometry 
 Characterization and comparison of the immune phenotype including PBMCs, 
B cells, T cells, NK cells, myeloid, and monocytes in peripheral blood and 
enumeration of T-cell subsets and expression of markers of T-cell activation and/or 
exhaustion (including, but not limited to, PD-1, CTLA-4, LAG-3, TIM-3, CD25, 
and markers of cytolytic activity) on PBMCs using multiparameter flow cytometry. 
 Determination of immune cell infiltration (including T‑cell infiltrate and 
immunosuppressive myeloid/lymphoid subsets), PD‑1, PD‑L1, FoxP-3, and gpA-
33 and other potential checkpoint/TAMs/regulatory expression levels in archival 
tumor tissue as it relates to MGD007 and MGA012 antitumor activity will be 
explored via immunohistochemistry (IHC) staining of archival or contemporaneous 
tumor biopsy specimens based on specimen availability and applicability. 
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10.2.1.1 
Tests Performed for Cohort Expansion Patients Only 
Tests to be performed for PD/Biomarker assessments include, but are not limited to, the 
following: 
 Determination of T-cell infiltration (including but not limited to CD4+ and CD8+ 
T cells) into the tumor bed of paired pretreatment and on-treatment tumor biopsy 
specimens. Mandatory pretreatment and on-treatment tumor biopsies will be carried 
out only during the Cohort Expansion Phase. 
 Characterization of T-cell repertoire using T-cell spectratyping on PBMCs and on 
immune-cellular infiltrate in the tumors done on both pre- and on-treatment tumor 
biopsy samples depending on tumor response and tissue availability. 
 Characterization of transcript profiles in peripheral blood and/or pre- and on-
treatment tumor biopsies and archival tumor specimens. Additional genomic 
profiling approaches and analyses, including, but not limited to, i.e.: NanoString, 
ctDNA, and mutational load, may be undertaken depending on tumor response and 
tissue availability. 
 Characterization serum biomarkers may be carried out depending on observed 
antitumor activity. 
 To evaluate MGD007 binding to gpA33 and MGA012 binding to PD-1 within 
tumor tissue from on-treatment biopsy specimens. 
 
 
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11 
ASSESSMENT OF EFFICACY 
11.1 
Efficacy Assessments 
11.1.1 
Disease Response Assessments 
Tumor assessments will be obtained using CT and/or MRI scans. Target and non-target lesions 
will be designated at screening and then evaluated at Cycle 1 Day 56 (±3 days), and then 
every 8 weeks while on study treatment. At each tumor assessment time point, the overall 
response status will be determined based on assessment of target and non-target lesions as 
well as appearance of any new lesions. For patients who discontinued from study treatment 
due to reasons other than documented, confirmed progressive disease, their treating physicians 
will be contacted every 3 months during post-treatment follow up period about the response 
status and survival of these patients. 
For RECIST v1.1 (Appendix 5), the overall responses will be categorized as Complete 
Response (CR), Partial Response (PR), Stable Disease (SD), Progressive Disease (PD), or Not 
Evaluable (NE). For patients who experience an objective response of CR or PR, responses 
will be considered unconfirmed until the response has been documented by a subsequent 
confirmatory scan obtained no less than 4 weeks after the initial scan demonstrating an 
objective response. 
For irRECIST (Appendix 6), the overall responses will be categorized as immune-related 
Complete Response (irCR), immune-related Partial Response (irPR), immune-related Stable 
Disease (irSD), immune-related Progressive Disease (irPD), or immune-related Not Evaluable 
(irNE). For patients who experience an objective response of irCR or 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. 
For the purpose of patient management, the response determination according to irRECIST 
will prevail. 
For patients who demonstrate acceptable tolerability of treatment with MGD007 and 
MGA012, and an objective response assessment of irCR, irPR, or irSD, or unconfirmed 
clinically stable irPD, therapy may be continued. 
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 irRECIST principles is supported by well-documented evidence that 
in some patients treated with T-cell directed, immune-modulatory agents, tumors can evolve 
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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. 
For patients in whom progression is confirmed at the next scheduled tumor assessment, the 
criteria for irPD will have been met, and treatment with MGD007 and MGA012 should be 
discontinued. The patient should be removed from study participation after completion of the 
Post-treatment Follow-up period (see Section 9.12). However, for individual patients who 
meet these criteria, but who are otherwise considered to be experiencing clinical benefit in the 
judgment of the Investigator, consideration may be given to continue treatment with the 
MGD007 and MGA012 combination, on a case-by-case basis, in consultation with the 
Sponsor; see Section 5.4. 
11.1.2 
Survival Assessments 
Patients who are discontinued from study treatment will be followed for survival status every 
3 months for a 2-year survival follow up period following the final dose of study drug, or until 
they expire, withdraw consent, or are lost to follow up (see Section 9.12). 
11.2 
Immunogenicity Assessments 
The generation of ADA directed against MGD007 and MGA012 will be assayed using ELISA 
method. Blood samples for the immunogenicity assessments will be collected at the time 
points shown in Appendix 3. 
 
 
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12 
ADVERSE EVENT REPORTING AND ASSESSMENT OF 
SAFETY 
The safety assessment will be based on the evaluation of AEs that occur from the time of 
initiation of administration of study drug through the End of Treatment Visit or 30 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. 
Protocol-related AEs and SAEs will be collected from the time the patient has consented to 
study participation. AEs and SAEs reported between the time the patient signs the informed 
consent form and the administration of the first dose of study drug will be captured as medical 
history unless the events are attributed to protocol-specified procedures that are not part of 
standard of care that occur during this time period, in which case the events will be collected 
on the SAE Form (as appropriate) and the Adverse Event CRFs. 
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. 
 A laboratory abnormality should be reported as an AE if it is associated with an 
intervention. An intervention includes, but is not limited to, discontinuation of 
treatment, dose reduction/delay, or concomitant therapy. In addition, any medical 
important laboratory abnormality may be reported as an AE at the discretion of the 
investigator. This includes laboratory abnormalities for which there are no 
interventions but the abnormal value(s) suggests a disease or organ toxicity. If 
clinical sequelae are associated with a laboratory abnormality, the diagnosis or 
medical condition should be reported (e.g., renal failure, hematuria) not the 
laboratory abnormality (e.g., elevated creatinine, Urine RBC increased). 
 
12.1 
Definitions 
12.1.1 
Adverse Event 
Adverse event means any untoward medical occurrence in a patient or clinical trial patient 
associated with the use of a drug in humans, whether or not considered drug related. An 
adverse event can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
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This includes any occurrence that is new in onset or aggravated in severity or frequency from 
the baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities. 
12.1.2 
Adverse Drug Reaction 
Adverse drug reaction (ADR) is a noxious and unintended response to the medicinal product 
related to any dose. As used herein, the phrase “response to a medicinal product” means that a 
causal relationship between a medicinal product and an AE is at least a reasonable possibility. 
12.1.3 
Adverse Event of Special Interest 
An adverse event of special interest (AESI) is an event of scientific and medical interest or 
concern to the Sponsor’s product or program, for which ongoing monitoring and rapid 
communication to the Sponsor could be appropriate. It may be a serious or non-serious AE, 
which may require further investigation in order to characterize and understand it. 
12.1.4 
Attribution/Assessment of Causality 
Attribution/Assessment of Causality is a determination that describes the relationship or 
association of the study product with an adverse event.  
This assessment of causality or relationship of AEs to the study drug is provided by the 
investigator and is determined by 1) temporal relationship of the event to the administration of 
study drug; 2) whether an alternative etiology has been identified, and 3) biological 
plausibility. Causality must be assessed separately for each study drug. 
The causality assessment categories that will be used for this study are described below. 
Causality assessments that are considered not related to study drug: 
None: The event is related to an etiology other than the study drug (the alternative etiology 
should be documented in the patient’s medical record). 
Unlikely: The event is unlikely to be related to the study drug and likely to be related to 
factors other than study drug. An alternative explanation is more likely (e.g., concomitant 
drugs, concomitant disease), or the relationship in time suggests that a causal relationship is 
unlikely. 
If an SAE is considered “unlikely” or “unrelated” to study drug, the Investigator should offer 
his/her clinical opinion as to what factor(s), agent(s), or process(es) were the likely causative 
mechanism for the event. 
Causality assessments that are considered related to study drug: 
Possible: There is an association between the event and the administration of the study drug 
and there is a plausible mechanism for the event to be related to study drug; but there may 
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also be alternative etiology, such as characteristics of the patient’s clinical status or underlying 
disease. 
Probable: There is an association between the event and the administration of study drug; 
there is a plausible mechanism for the event to be related to the study drug and the event could 
not be reasonably explained by known characteristics of the patient’s clinical status or an 
alternative etiology is not apparent. 
Definite: There is an association between the event and the administration of study drug; there 
is a plausible mechanism for the event to be related to the study drug, causes other than the 
study drug is ruled out, and/or the event re-appeared on re-exposure to the study drug. 
12.1.5 
Serious Adverse Event 
A SAE is any adverse event that results in any of the following outcomes: 
 Death 
 Life-threatening (immediate risk of death) 
 Inpatient hospitalization for longer than 24 hours or prolongation of existing 
hospitalization (even if the event is Grade 1) 
 Persistent or significant disability or incapacity  
 Congenital anomaly/birth defect  
 Important medical events 
 
12.1.6 
Severity Criteria 
An assessment of severity grade will be made using the National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) (Version 4.03). The CTCAE are 
published standardized definitions for AEs to describe the severity of laboratory and organ 
toxicity for patients receiving cancer therapy. The investigator should use clinical judgment in 
assessing the severity of events not directly experienced by the patient (e.g. laboratory 
abnormalities). 
For events not contained in CTCAE, the Investigator may assign intensity according to the 
following generic CTCAE grading scale: 
 Grade 1  Mild; asymptomatic or mild symptoms, clinical, or diagnostic 
observations only; intervention not indicated. 
 Grade 2  Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL). 
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 Grade 3  Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL. 
 Grade 4  Life-threatening consequences; urgent intervention indicated. 
 Grade 5  Death related to AE. 
 
12.2 
Adverse Event Collection and Documentation 
12.2.1 
All Adverse Events 
All patients who receive at least one dose of study drug will be considered evaluable for 
safety. AEs will be determined based on signs, symptoms, physical examination findings, 
and/or laboratory test results from enrolled patients as appropriate. 
All adverse events whether serious or non-serious, will be reported from the time a signed and 
dated ICF is obtained until 30 days following the last dose of study drug or until the start of a 
subsequent systemic anti-cancer therapy, if earlier. 
Both protocol-related AEs and SAEs will be collected from the time the patient has consented 
to study participation. AEs and SAEs reported between the time the patient signs the informed 
consent form and the administration of the first dose of study drug will be captured as 
concurrent medical history unless the events are attributed to protocol-specified procedures. 
Events attributed to protocol-specified procedures will be collected on the Adverse Event 
eCRFs and Serious Adverse Event form as appropriate. 
All adverse events, regardless of seriousness, severity, or presumed relationship to study drug, 
must be recorded using medical terminology in the source document and the eCRF. All 
records will need to capture: 
 The details of the duration, severity, and seriousness of each adverse event, 
 the action taken with respect to the study drug(s), 
 the investigator’s attribution/causality assessment concerning the relationship of the 
adverse event to study therapy, 
 the outcome of the event. 
 
Whenever possible, diagnoses should be given when signs and symptoms are due to a 
common etiology (e.g. cough, runny nose, sneezing, sore throat, and head congestion should 
be reported as "upper respiratory infection"). All treatment measures that are required for 
adverse event management must be recorded in the source document. The intensity (severity) 
of adverse events will be assessed using NCI CTCAE (Version 4.03) and serious events will 
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be determined by the definition provided in Section 12.1.5 above. Generally, all non-serious 
AEs should be entered into the eCRFs within 5 business days of the sites awareness. 
The sponsor assumes responsibility for appropriate reporting of adverse events to the 
regulatory authorities. The Sponsor will also report to the investigator all suspected 
unexpected serious adverse reactions. The investigator must report suspected unexpected 
serious adverse reactions to the appropriate Independent Ethics Committee/Institutional 
Review Board (IEC/IRB) that approved the protocol, unless otherwise required and 
documented by the IEC/IRB. 
For this study, the patient must be provided with a “wallet (study) card” and instructed to 
carry this card with them for the duration of the study. 
12.2.2 
Immediately Reportable Events 
Immediately Reportable Events (IREs) are events that must be reported immediately to 
MacroGenics within 24 hours of the study site’s awareness of the event. 
 SAEs 
 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.] Upon confirmation of serum pregnancy 
testing, the patient will be followed for the outcome of pregnancy. All live 
newborns will be followed 6 months after the birth, and all necessary information 
will be collected to assess the effects of study drug on the newborn. If necessary, 
the follow-up period will be extended for the newborn. 
 The following AESIs (Section 12.2.4): 
o ≥ Grade 3 IRRs or CRS  
o Grade 2 or greater immune-related AEs of the following: events of colitis, 
pneumonitis, hepatitis, Stevens-Johnson syndrome (SJS), and toxic 
epidermal necrolysis (TEN), myocarditis, nephritis, hypophysitis, and 
hypo/hyper-thyroidism which are considered immune-mediated events 
o Abnormal liver enzymes that meet the criteria for potential Hy’s law, which 
is defined as AST and/or ALT that is greater than 3 × ULN and total 
bilirubin that is greater than 2 × ULN and without any alternate etiology 
o Grade 2 or greater diarrhea associated with visible blood in the stool or 
melena 
o Any Grade 3 or greater diarrhea irrespective of evidence of GI bleeding  
 Administration of a dose significantly greater (specifically, + 20% or higher) than 
the planned dose, and results in an event of clinical consequence. 
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 AEs leading to permanent discontinuation of study drug in an individual patient. 
 Withdrawal of the patient from study drug administration for any reason other than 
disease progression. 
 
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 or withdrew the consent). 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 Product Safety. 
12.2.3 
Serious Adverse Events 
All SAEs occurring during the study must be reported to the Sponsor. 
After 30 days following the last dose of study drug administration, only SAEs the Investigator 
believes considered related to study drug or a protocol procedure, should be reported to the 
Sponsor. 
Information regarding SAEs will be transmitted to the Sponsor using the Serious Adverse 
Event Form, which must be completed and signed by a physician from the study site and 
transmitted to the Sponsor within 24 hours of the site becoming aware of the serious adverse 
event. The initial and follow-up serious adverse reports should be scanned and emailed or 
transmitted by facsimile (fax) to the Sponsor. 
All Grade 3 or Grade 4 SAEs considered related to study drug must be followed until 
recovery to baseline or Grade 1. 
The Investigator must follow all SAEs until resolution and record the date of resolution. 
Resolution of an event is defined as the return to pre-treatment status or stabilization of the 
condition with the expectation that it will remain chronic. 
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the patient 's participation in the study, must be followed until any of the 
following occurs: 
 The event resolves. 
 The event stabilizes. 
 The event returns to baseline, if a baseline value/status is available. 
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 The event can be attributed to etiology other than the study drug or to factors 
unrelated to study conduct. 
 It becomes unlikely that any additional information can be obtained (patient or 
health care practitioner refusal to provide additional information, lost to follow-up 
after demonstration of due diligence with follow-up efforts). 
 
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the 
course of a patient's participation in a study must be reported as a SAE, except 
hospitalizations for the following: 
 A standard hospitalization for administration of study drug therapy will not be 
reported as a serious adverse event. 
 A procedure for protocol/disease-related investigations (e.g., surgery, scans, 
endoscopy, sampling for laboratory tests, bone marrow sampling, pharmacokinetic 
or biomarker blood sampling). 
 Hospitalizations not intended to treat an acute illness or adverse event (e.g., social 
reasons such as pending placement in long-term care or hospice facility). 
 Surgery or procedure planned before entry into the study (must be documented in 
the eCRF). 
 
Disease progression should not be recorded as an AE or SAE term; 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. 
12.2.4 
Protocol-specific Adverse Events of Special Interest 
Specific adverse events or groups of adverse events will be followed as part of standard safety 
monitoring activities by the Sponsor. The Sponsor will be notified of these events in a timely 
manner, regardless of seriousness (i.e., serious and non-serious adverse events). 
 All infusion-related reactions or CRS events (Note: ≥ Grade 3 IRRs or CRS events 
are additionally considered immediately reportable events) (see Section 7.2) 
 Grade 2 or greater Immune related AEs of the following: events of colitis, 
pneumonitis, hepatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal 
necrolysis (TEN), myocarditis, nephritis, hypophysitis, and hypo/hyper-thyroidism 
which are considered immune-mediated events (see Section 7.5) 
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 Abnormal liver enzymes that meet the criteria for potential Hy’s law, which is 
defined as AST and/or ALT that is greater than 3 × ULN and total bilirubin that is 
greater than 2 × ULN and without any alternate etiology 
 Grade 2 or greater diarrhea associated with visible blood in the stool or melena 
 Any Grade 3 or greater diarrhea irrespective of evidence of GI bleeding 
 
12.2.5 
Pregnancy 
All initial reports of pregnancy in female patients or partners of male patient s must be 
reported to the Sponsor by the study-site personnel within 24 hours of their knowledge of the 
event using the MacroGenics Pregnancy Exposure Form. Abnormal pregnancy outcomes 
(e.g., spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) 
are considered SAEs and must be reported using the Serious Adverse Event Form. Any patient 
who becomes pregnant during the study must discontinue further study drug administration. 
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male 
patient is included in the study will be reported by the study-site personnel within 24 hours of 
their knowledge of the event. If the female partner of a male 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. 
Upon confirmation of serum pregnancy testing, the patient will be followed for the outcome 
of pregnancy. All live newborns will be followed at birth and 6 months after birth, and all 
necessary information will be collected to assess the effects of study drug on the newborn. If 
necessary, the follow-up period will be extended for the newborn. 
12.2.6 
Reporting of Adverse Events to the Sponsor 
Throughout the study, the Investigator must document all AEs on the eCRF in a timely 
manner. IREs, as defined in Section 12.2.2 are events that must be reported immediately to 
MacroGenics within 24 hours of being identified. These IREs must be transmitted via an SAE 
form (if the event meets serious criteria) or be entered into the eCRFs within 24 hours of 
awareness; see Table 9. 
The Investigator must immediately complete and transmit the Serious Adverse Event (SAE) 
Report Form, within 24 hours of identifying the serious adverse event, to MacroGenics 
Product Safety or designee. The SAE Report Form and Completion Guidelines, and Contact 
Information for Reporting SAEs, are found in the Study Procedures Manual. 
For reports of pregnancy, the MacroGenics Pregnancy Exposure Form must be completed and 
transmitted to MacroGenics Product Safety within 24 hours of becoming aware of the 
pregnancy. The Investigator must attempt to follow the pregnancy to term or termination in 
order to report the outcome and health status of the mother and child. The Pregnancy 
Exposure Form is found in the Study Procedures Manual. 
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Please refer to the Table 12 for reporting timeframes to MacroGenics by event type. 
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Table 12 
CP-MGD007-02 Safety Reporting  
Type of Event: 
Hard Copy Form/Timeline for 
reporting/Where to Report 
eCRF 
Timeline for Data 
Entry 
Serious Adverse Event (SAE) *a 
Serious Adverse Event Form within 24 
hours of awareness 
Report mail to 
SAEReports@macrogenics.com 
Or fax to (301) 354-3800 
Within 5 calendar 
days of awareness 
Pregnancy a 
Pregnancy Exposure Form/ 
Within 24 hours of awareness/ 
Email to SAEReports@macrogenics.com 
Or fax to (301) 354-3800 
Within 5 calendar 
days of awareness 
≥ Grade 3 IRRs or CRS b 
Not Applicable*  
Within 24 hours of 
awareness 
Hy’s law b (AST and/or ALT that is greater 
than 3 × ULN and total bilirubin that is 
greater than 2 × ULN, without any alternate 
etiology) 
Not Applicable* 
Within 24 hours of 
awareness 
≥ Grade 2 immune-related AEs b 
Not Applicable* 
Within 24 hours of 
awareness 
≥ Grade 2 diarrhea associated with visible 
blood in the stool or melena b 
Not Applicable* 
Within 24 hours of 
awareness 
≥ Grade 3 diarrhea irrespective of evidence 
of gastrointestinal bleeding b 
Not Applicable* 
Within 24 hours of 
awareness 
AEs leading to permanent discontinuation 
of study drug in a patient b 
Not Applicable* 
Within 24 hours of 
awareness 
Withdrawal of patient from study drug 
administration due to toxicity (e.g. AE, 
SAE, AESI) or pregnancy b 
Not Applicable* 
Within 24 hours of 
awareness 
Administration of a dose significantly 
greater (specifically, + 20% or higher) than 
the planned dose, and results in an event of 
clinical consequence b 
Not Applicable* 
Within 24 hours of 
awareness 
Product quality issues with an associated 
clinical consequence b 
Not Applicable* 
Within 24 hours of 
awareness 
Non-Serious Adverse Events (except for 
Pregnancy) c 
Not Applicable 
Within 5 calendar 
days of awareness 
Abbreviations: AE = adverse event; AESI = adverse event of special interest; CRS = Cytokine Release 
Syndrome; eCRF=electronic case report form; IRR = infusion-related reaction; SAE = serious adverse event.  
*If it meets SAE criteria – refer to SAE reporting instructions 
a 
Hard Copy Form within 24 hours of awareness and eCRF data entry within 5 calendar days. 
b 
E-CRF data entry within 24 hour of awareness. 
c 
E-CRF data entry within 5 calendar days of awareness. 
 
 
 
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13 
PRODUCT QUALITY COMPLAINT HANDLING 
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, i.e., any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may 
have an impact on the safety and efficacy of the product. Timely, accurate, and complete 
reporting and analysis of PQC information from studies are crucial for the protection of 
patient s, investigators, and the Sponsor, and are mandated by regulatory agencies worldwide. 
The sponsor has established procedures in conformity with regulatory requirements 
worldwide to ensure appropriate reporting of PQC information; all studies conducted by the 
Sponsor or its affiliates will be conducted in accordance with those procedures. 
13.1 
Procedures 
All initial clinical PQCs must be reported to the Sponsor by the study-site personnel within 24 
hours after being made aware of the event. 
If the defect is combined with a SAE, the study-site personnel must report the PQC to the 
Sponsor according to the SAE reporting timelines (refer to Section 12.2.3, Serious Adverse 
Events). A sample of the suspected product should be maintained for further investigation if 
requested by the Sponsor. 
13.2 
Contacting Sponsor Regarding Product Quality 
Report any product quality issue via e-mail to the following: 
Quality.complaints@macrogenics.com. 
 
 
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14 
STATISTICAL ANALYSIS 
This section outlines the statistical methodology and principles which will be used for data 
analysis in this study. A separate statistical analysis plan (SAP) and statistical programming 
plan (SPP) will further describe the details regarding statistical methods and will govern the 
analysis. 
14.1 
Determination of Sample Size 
The study plans to treat approximately 52 patients: up to 27 in Dose Escalation Phase and 
approximately 25 in the Cohort Expansion Phase. 
The sample size of up to 27 patients for each cohort in the Dose Escalation Phase is based on 
3+3+3 design with planned 3 dose cohorts. Additional patients may be enrolled for 
nonevaluable patients or if the enrollment to a dose cohort is expanded (up to 15 patients) or 
intermediate dose levels are evaluated in Dose Escalation Phase. 
The Cohort Expansion Phase plans to treat approximately 25 patients in relapsed/refractory 
metastatic colorectal carcinoma, approximately 90% of them are MSS patients, e.g., 22 MSS 
and 3 MSI-H patients. At the end of the Cohort Expansion Phase, 15 paired tumor biopsies 
will be required, if tumor lesions are accessible with acceptable clinical risk (see Section 5.1, 
# 9). If 15 paired biopsies have not been collected in the initial 25 patients, additional patients 
with paired tumor biopsies will be enrolled, to ensure that the 15 paired biopsies are obtained. 
The sample size in the Cohort Expansion Phase is primarily based on providing preliminary 
estimation of objective response rate and disease control rate. Table 13 provides the 2-sided 
95% confidence interval (CI) for a number of potential responses among the 25 patients. 
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During the Cohort Expansion Phase, patients who withdraw before completing the first tumor 
assessment for a reason other than clinically confirmed progressive disease or death may be 
considered unevaluable for response. In these cases, replacement patients may be enrolled in 
the same dose level. 
14.2 
Analysis Populations 
The study analyses will be performed on the following populations: 
 Safety Population: All patients who received at least one dose of any study drug. 
This population will be used for analyses of safety, PD, and immunogenicity. It will 
also be used for summary of baseline data and analyses of PFS and OS. 
 Response Evaluable Population: All patients who received at least one dose of any 
study drug, had baseline measurable disease, and had at least one post-baseline 
radiographic tumor assessment or discontinued treatment due to clearly 
documented, clinically progressive disease or death. This population will be used 
for summary of tumor assessment data and analyses of response rates. 
 
14.3 
Demographics and Baseline Characteristics 
Patient disposition, demographics, baseline characteristics, disease history, medical history, 
and prior cancer treatment will be summarized using descriptive statistics. 
14.4 
Study Drug Exposures and Concomitant Medications 
Study drug exposures and concomitant medications will be summarized by descriptive 
statistics. The summary of study drug exposure will include descriptive statistics as well as 
frequency counts for the number of doses or cycles received, the total dose actually 
administrated as well as the total dose intended, and the dose intensity which is calculated as 
percentage of total dose actually administrated divided by total dose intended during whole 
treatment period. Dose intensity by cycle will be summarized. 
Table 13 
Response Rates and 95% Confidence Intervals 
Sample Size 
Number of Responses 
Response Rate (%) 
95% Confidence Interval 
(%) 
25 
2 
8 
1.0, 26.0 
25 
3 
12 
2.5, 31.2 
25 
4 
16 
4.5, 36.1 
25 
5 
20 
6.8, 40.7 
25 
6 
24 
9.4, 45.1 
25 
7 
28 
12.1, 49.4 
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14.5 
PK/PD Analysis 
14.5.1 
Pharmacokinetic Analysis 
Summary statistics will be tabulated separately for serum PK parameters by MGD007 and 
MGA012 dose. Geometric means and percent coefficients of variation will be reported for 
Cmax, AUC(0 T), AUC(TAU), AUC(INF), and Ctrough; arithmetic means and standard deviations will 
be reported for t1/2, CL, and Vss; and medians, minimum, and maximum will be reported for 
Tmax. Separate scatter plots of Cmax and AUC will be provided versus dose to assess 
dose dependency. Dose proportionality may be assessed using a power model. Population 
PK analyses may be conducted using data from this study alone or combined with data from 
other studies. 
14.5.2 
Immunogenicity Analysis 
The proportion of patients who are negative for ADA at baseline and become positive in this 
assay, the proportion of patients who are negative at baseline and remain negative, and those 
who have positive ADA at baseline that increases or decreases in titer over the course of 
treatment will be summarized. Analysis will be conducted separately for MGD007 and 
MGA012. 
14.5.3 
Pharmacodynamic Analysis 
Summary statistics for pharmacodynamic parameters, such as, but not limited to, those listed 
under in Section 10.2 and corresponding changes from baseline, will be summarized and/or 
may also be presented graphically as will possible associations between changes in 
pharmacodynamic measures of interest and MGD007 in combination with MGA012 dose and 
exposure may be explored. 
14.6 
Efficacy and Endpoint Analyses 
14.6.1 
Response Endpoints and Analyses 
For RECIST v1.1, the best overall response (BOR) will be categorized as CR, PR, SD, PD, or 
NE. To be qualified as BOR, CR and PR require confirmation at least 4 weeks after initial 
observation of such response, and SD requires to be observed at least once after 8 weeks 
(minus 3 days) from the start of MGD007 treatment. 
For irRECIST, the best overall response (BOR) will be categorized as irCR, irPR, irSD, irPD, 
or irNE. To be qualified as BOR, irCR, irPR, and irPD require confirmation at least 4 weeks 
after initial observation of such response, and irSD requires to be observed at least once after 
8 weeks (minus 3 days) from the start of MGD007 treatment. 
The objective response rate (ORR) per RECIST v1.1 is estimated as the proportion of patients 
in response evaluable population who achieve BOR of CR or PR. Disease control rate is 
calculated as the proportion of patients who achieve a CR, PR, or SD. Progression-free 
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survival rate at 16 weeks will be calculated as the probability that patients are free of disease 
progression and alive at 16 weeks after the first dose of MGD007 by Kaplan-Meier method 
described below, based on response evaluable population and safety population, respectively. 
The 2-sided 95% exact binomial CI of the response rates will be calculated. The response 
rates per irRECIST will be estimated similarly. Subgroup analyses of these response rates by 
KRAS gene type (wild and mutant) and by MMR status (MSS and MSI-H) will be performed. 
14.6.2 
Analysis of Tumor Size Change Over Time 
The tumor size is defined as the sum of diameters of the target lesions. The tumor size change 
from baseline over time will be summarized and may be presented by spider plot. The best 
tumor size percent change from baseline will be presented by waterfall plot. 
14.6.3 
Time-to-event Endpoints and Analyses 
Progression-free survival will be defined as the time from the first dose date of MGD007 to 
the date of first documented progression or death from any cause, whichever occurs first. The 
documented progression is determined by objective assessment of disease per RECIST v1.1 
and irRECIST, respectively. For patients who are not known to be dead or progressed at the 
time of data cut-off for PFS analysis, the PFS will be censored at the date of the last tumor 
assessment. Specifically, the following censoring rules will be applied as primary analysis of 
PFS. Sensitivity analyses may be performed to assess the robustness of the primary PFS 
analysis and will be described in the SAP. 
Table 14 
Censoring Rules for Primary Analysis of PFS 
Situation 
Date 
Outcome 
No baseline tumor assessments  
First dose date 
Censored 
Death prior to first scheduled 
tumor assessment 
Date of death 
Progressed 
No post-baseline tumor 
assessments in absence of death 
prior to first scheduled tumor 
assessment 
First dose date 
Censored 
Documented progression 
Date of progression 
Progressed 
Initiation of alternative anti-
cancer treatments in absence of 
documented progression 
Date of last tumor assessment prior 
to initiation of such treatment 
Censored 
Death or documented progression 
immediately after missing two or 
more consecutive scheduled 
tumor assessments 
Date of last tumor assessment prior 
to missed assessments 
Censored 
 
Duration of Response (DoR) is defined as the time from the date of initial response (CR or 
PR) to the date of first documented progression or death from any cause, whichever occurs 
first. The DoR is calculated only for the responders. For responders who are not known to be 
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dead or progressed at the time of data cut-off for DoR analysis, the DoR will be censored at 
the date of the last tumor assessment. Specifically, the last three situations described in 
Table 14 will be applied. The DoR analyses will be performed only if there are enough 
responders to render the analyses meaningful. 
Overall survival (OS) is defined as the time from the first dose date of MGD007 to the date of 
death from any cause. For patients who are not known to be dead at the time of data cut-off 
for OS analysis, the OS will be censored at the time they are last known to be alive. 
The Kaplan-Meier method will be applied to estimate PFS, DoR, and OS curves; their median 
times; PFS rates at 4 (corresponding to 16 weeks), 6, and 12 months; and OS rates at 6, 12, 
and 24 months, respectively. The method of Brookmeyer and Crowley (3) will be used to 
construct 95% CI for median time of each time-to-event endpoint. The 95% CIs for PFS and 
OS rates at each time point of interests will be calculated by normal approximation after 
log(-log) transformation. PFS and OS will be analyzed by MMR status and by KRAS gene 
type when sample size warrants. 
The above PFS and DoR analyses will be performed with the documented progression 
determined by RECIST v1.1 and irRECIST, respectively. 
14.7 
Safety Endpoints and Analyses 
14.7.1 
Adverse Events 
Only treatment-emergent AEs will be summarized in tables. The following AEs will be 
provided in summary tables as well as displayed in listings: 
 All AEs 
 AEs with CTCAE severity grade ≥ 3 
 Study drug related AEs 
 Study drug related AEs with CTCAE severity grade ≥ 3 
 SAEs  
 Study drug related SAEs 
 AEs that result in discontinuation of study treatment 
 AEs that led to interruption or withdrawal of individual study drug 
 Fatal AEs 
 Immediately reportable AEs (if applicable) 
 AEs of special interest (if applicable) 
 
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All of these tables will display the number and percent of patients that experience the given 
event and will display events by MedDRA System Organ Class (SOC) and Preferred Term 
(PT). Events will be displayed alphabetically for SOC and in descending order of overall PT 
incidence. An overall summary of AEs will display the number and percent of patients who 
experience at least one event of each of the above types. 
14.7.2 
Laboratory Values 
Summaries of laboratory values will display descriptive statistics for numerically quantified 
labs. Summaries will be grouped by laboratory panel (hematology, blood chemistry, and 
urinalysis) and will be displayed by visit for each laboratory parameter. Number and percent 
of patients shifted from baseline to post-baseline maximum severity in CTCAE grade will be 
summarized. 
14.7.3 
Other Safety Endpoints 
ECGs will be collected and analyzed for evidence of cardiac toxicity, especially prolongation 
of QT interval. Vital signs will be summarized with descriptive statistics at each visit and time 
point where they are collected. Shift tables may be performed. 
14.8 
Other Assessments or Analyses 
Additional analyses, if any, will be described in the statistical analysis plan. 
 
 
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15 
QUALITY CONTROL AND ASSURANCE 
Quality review activities will be undertaken to ensure accurate, complete, and reliable data. 
MacroGenics and/or its representatives will do the following: 
 Provide instructional material to the study sites, as appropriate. 
 Sponsor a start-up training session (Investigator Meeting or Study Initiation Visit) 
to instruct the Investigators and study coordinators. This session will give 
instruction on the protocol, the completion of the eCRFs, and study procedures. 
 Make periodic visits to the study site to monitor protocol compliance and general 
Good Clinical Practice GCP compliance. 
 Be available for consultation and stay in contact with the study site personnel by 
mail, e-mail, telephone, and/or fax. 
 Review and evaluate eCRF data and use standard computer checks to detect and 
query errors in data collection. 
 Conduct a quality review of the database. 
 
15.1 
Monitoring, Auditing and Inspections 
To ensure the safety of patients in the study, compliance with applicable regulations, and 
ensure accurate, complete, and reliable data, the Investigator will keep records of laboratory 
tests, clinical notes, and patient medical records in the patient files as source documents for 
the study. 
MacroGenics or its designee will monitor the study on a regular basis throughout the study 
period according to the study Monitoring Plan. The Investigator will allocate adequate time 
for such monitoring activities. The study monitor periodically will conduct a cross-check of 
the patient data recorded on eCRFs against source documents at the study site. The 
Investigator will also ensure that the monitor is given access to all the above noted study-
related documents, source documents (regardless of media) and study-related facilities (e.g., 
investigational pharmacy, etc.), and has adequate space to conduct the monitoring visit. 
Queries may be raised if any datum is unclear or contradictory. The Investigator and study site 
personnel must address all queries in a timely manner. 
Participation as an Investigator in this study implies acceptance of the potential for inspection 
by the study Sponsor/Representatives, US or non-US government regulatory authorities, 
IRB/IEC and applicable compliance and quality assurance offices. The Investigator will 
permit study-related audits and inspections and will provide access to all study-related 
documents (e.g., source documents, regulatory documents, data collection instruments, 
study data etc.). The Investigator will ensure the capability for inspections of applicable 
study-related facilities (e.g., pharmacy, diagnostic laboratory, etc.). 
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15.2 
Data Collection and Management 
The Investigator is responsible for maintaining accurate, complete, and up-to-date records for 
each patient. The Investigator is also responsible for maintaining any source documentation 
related to the study, including any films, tracings, or other media containing data pertaining to 
this protocol. 
The anonymity of participating patients must be maintained. For data collection, and 
management purposes, patients are to be identified by a patient number only. Documents that 
identify the patient beyond patient number (e.g., patient initials) will not be submitted to the 
Sponsor (e.g., the signed informed consent document) and must be maintained in strict 
confidence by the Investigator, except to the extent to allow auditing by the regulatory 
authorities, study monitor, or Sponsor representatives. 
Site personnel record all data for each patient through electronic case report forms (eCRFs) 
using the Medidata RAVE™ an Electronic Data Capture (EDC) system provided and 
approved by the Sponsor. Refer to the Study Procedures Manual for additional information 
regarding eCRFs, if any that will be used as source documentation. Study sites must complete 
eCRFs for each patient in a timely manner shortly after each patient visit. As the person 
ultimately responsible for the accuracy of all eCRF data, the Investigator must sign the 
Investigator’s Statement in each patients eCRF. 
The EDC system automatically generates queries resulting from the computer checks 
embedded into the system to ensure data accuracy, quality, consistency, and completeness. 
Manual queries resulting from review by monitors, medical coders, and Data Management 
staff are also generated from within the EDC system, where they are tracked. Study sites 
resolve the queries and correct the entered data accordingly. Every change to data is captured 
in the EDC system audit trail. Adverse events are coded using MedDRA, whereas 
concomitant medications are coded using the WHO Drug Dictionary. Upon completion of the 
study, or after reaching a pre-specified point in the study, Data Management will lock the 
database and generate the SAS datasets necessary for analysis and reporting. Upon completion 
of the study, each study site will be provided with the eCRFs for each of their patients. 
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16 
ADMINISTRATIVE CONSIDERATIONS 
16.1 
Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) Approval 
The Investigator should provide the Sponsor with a statement of compliance from the 
IRB/IEC indicating compliance with the applicable regulations in the region and ICH. Any 
documents that the IRB/IEC may need to fulfill its responsibilities, such as the protocol and 
any amendments, IB, and information concerning patient recruitment, payment or 
compensation procedures, or information from the Sponsor will be submitted to the IRB/IEC. 
The IRB/IEC’s written approval of the study protocol and the 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 approval statement to 
the Sponsor. This approval must include the date of review and refer to the study by protocol 
title and/or study number and version number and refer to the ICFs by version number or date. 
If the IRB/IEC or institution uses its own unique number for the protocol instead of the 
Sponsor’s number, that unique number should be noted on the approval statement. If approval 
of the ICFs is stamped on the forms (instead of documented in the IRB/IEC approval 
statement) the date of approval and/or expiration must be included. 
Protocol modifications or changes may not be initiated without approval from the Sponsor and 
prior written IRB/IEC approval (when required), except when necessary to eliminate 
immediate hazards to the patients. Such modifications will be submitted to the IRB/IEC; and 
written verification that the modification was submitted should be obtained. 
The Investigator must, where required by local regulations, submit to the IRB/IEC: 
 The 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 deviations. 
 Notification when the study has been completed. 
 Proof of indemnity/liability insurance. 
 Other documents required by the IRB/IEC. 
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16.2 
Ethical Conduct of the Study 
The investigational study will be conducted according to the Protection of Human Patients 
(21 CFR [Code of Federal Regulations] 50), Institutional Review Boards (21 CFR 56), 
Obligations of Clinical Investigators (21 CFR 312.60  312.69), the current ICH Guideline for 
Good Clinical Practice (ICH E6), and all other applicable regulations. 
16.3 
Patient Information and Consent 
It is the responsibility of the Investigator to obtain and document written informed consent 
from the patient. Informed consent in compliance with the principles of informed consent in 
ICH E6 and all applicable local regulations should be obtained before any protocol-specified 
procedures or interventions are conducted. The Sponsor reserves the right to delay initiation of 
the study at a site where ICFs do not meet the standards of applicable local regulations or 
ICH E6. 
Information should be given to the patient in both oral and written form, and patients must be 
given ample opportunity to inquire about details of the study. 
The consent form generated by the Investigator must be approved by the IRB/IEC. The 
Investigator will provide the Sponsor with a copy of the IRB/IEC-approved consent forms and 
a copy of the IRB/IEC’s written approval before the start of the study. 
Consent forms must be written (and appropriately translated in the patient’s native language 
or language in which the patient has fluency) so as to be understood by the prospective 
patient. Informed consent will be documented by the use of a written consent form approved 
by the IRB/IEC. The form must be signed and dated by the patient, and by the person who 
conducted the discussion of the informed consent. 
All versions of each patient’s signed ICF must be kept on file by the Investigator for possible 
inspection by regulatory authorities and/or authorized MacroGenics monitoring and regulatory 
compliance persons. The patient should receive a copy of the signed and dated written ICF 
and any other written information provided to the patients. 
16.4 
Patient Confidentiality 
To maintain confidentiality of patients, all laboratory specimens, evaluation forms, reports, 
and other records will be identified by a coded number. Clinical information will not be 
released without written permission of the patient, or an individual with legal decision making 
authority for the patient or the patient’s interests, except as necessary for monitoring by the 
relevant regulatory authorities, the Sponsor of the clinical study, or the Sponsor’s 
representative. The Investigator must also comply with all local applicable privacy regulations 
[e.g., US Health Insurance Portability and Accountability Act of 1996 (HIPAA)], on 
protection of individuals with regard to personal data. 
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16.5 
Case Report Forms and Study Records 
Source data in a clinical study are the original records or certified copies where clinical 
observations are first recorded, which may include, but are not limited to, the patient’s 
medical file, original laboratory reports, histology, and pathology reports (as applicable). The 
Investigator is responsible for maintaining adequate and accurate medical records from which 
accurate information will be entered into the eCRFs designed to capture data pertinent to the 
clinical investigation. Data should be recorded on paper source documents or electronic in an 
electronic medical records system. Electronic CRFs should be completely in their entirety by 
the Investigator or his/her designee. Prior to eCRF database lock, the Investigator will verify 
the completeness and accuracy of the data and indicate that he/she has done so by providing 
an electronic signature on the appropriate eCRF. The Investigator will retain a copy of all 
source documents. 
16.6 
Access to Source Documentation 
The Investigator and study center will permit the Sponsor, its representatives, IRB/IEC, and 
all relevant regulatory agencies access to all original source data and documents regardless of 
media, for study monitoring audits and inspections. 
16.7 
Retention of Data 
Per ICH guidelines, all essential documents, including eCRFs, source documents (regardless 
of media), signed ICFs, and laboratory test results, should be retained by the Investigator for 
at least 2 years after last approval of a marketing application in an ICH region and until there 
are no pending or contemplated marketing applications in an ICH region or until at least 
2 years have elapsed since formal discontinuation of clinical development of the 
investigational product. There may be other circumstances for which MacroGenics is required 
to maintain study records for longer periods; therefore, MacroGenics should be contacted 
before study records are removed from the control of the study site for any reason. The 
Investigator must obtain written permission from MacroGenics prior to destruction of study 
documents. 
16.8 
Sample Retention and Further Testing 
Samples acquired for protocol-specified assays will be retained for at least 1 year following 
the end of the study and may be retained up to 2 years after last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since formal 
discontinuation of clinical development of the investigational product. If patients consent, or 
an individual with legal decision making authority for the patient or the patient’s interests 
consent, to the use of their study samples for non-study research purposes, these samples may 
also be used for exploratory testing (including assay development/ optimization) and may be 
retained up to 15 years from the end of study. 
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16.9 
Financial Disclosure 
The Investigator and Sub-Investigators will be required to disclose any applicable financial 
arrangement as defined in US regulation (i.e., 21 CFR 54).  
The following information will be collected about the investigators, their spouse and each 
dependent child: any significant payments of other sorts from MacroGenics, Inc., or any 
alliance partner, such as a grant to fund ongoing research, compensation in the form of 
equipment, retainer for ongoing consultation or honoraria; any proprietary interest in the study 
drug; and any significant equity interest in MacroGenics, Inc., as defined in 21 CFR 54. 
Investigators are obliged to update the Sponsor with any changes in reported information up 
to 1 year following the end of the study. 
In addition, Investigators and Sub-Investigators will be required to disclose if they are an 
employee of MacroGenics, or an immediate family member of a MacroGenics employee, 
officer, or director. This is in order to assist MacroGenics with its compliance with Securities 
and Exchange Commission rules requiring disclosure of certain transactions with related 
persons as defined in 17 CFR 229.404. “Immediate family member of a MacroGenics 
employee” means a child, stepchild, parent, stepparent, spouse, sibling, mother-in-law, 
father-in-law, son-in-law, brother-in-law, or sister-in-law of any MacroGenics employee, 
officer, or director or any person sharing the household of such MacroGenics employee, 
officer, or director. 
In consideration of participation in the study, MacroGenics, will pay the Investigator or 
nominated payee the sums set out in the payment schedule attached to the Investigator 
agreement. 
Financial disclosure information will be documented in writing and signed and dated by the 
Investigator. This information will be collected prior to that investigator taking part in the 
research. 
16.10 
Publication and Disclosure Policy 
Data collected in this clinical study belong to the study Sponsor. The publication terms 
regarding use of the study data will be noted in the Clinical Trial Agreement. This includes 
authorship: scheduling and prioritizing analyses for reports, publications, and presentations; 
and developing a review and approval process. 
16.11 
Discontinuation of the Study or Study Sites 
16.11.1 
Discontinuation of Study Sites 
Site participation may be discontinued if MacroGenics, the Investigator, a regulatory 
authority, or the IRB/IEC of the study sites deems it necessary for any reason. 
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16.11.2 
Discontinuation of the Study 
The study may be discontinued by a regulatory authority or at the discretion of the Sponsor. 
The Investigator maintains the right to discontinue his/her participation in the study should 
his/her clinical judgment so dictate. The Investigator will notify the IRB/IEC of any study 
discontinuation. Study records must be retained as noted above. 
16.12 
Identification of the Coordinating Principal Investigator 
A Coordinating Principal Investigator will be appointed by the Sponsor Medical Monitor prior 
to the end of the study. 
As part of his or her responsibilities, the Coordinating Principal Investigator will review the 
final clinical study report (CSR). Agreement with the final CSR will be documented by the 
dated signature of the Coordinating Principal Investigator. 
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17 
REFERENCE LIST 
1. Andre T, Louvet C, Maindrault-Goebel F, Couteau C, Mabro M, Lotz JP, et al. CPT-
11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-
infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer. GERCOR. 
Eur J Cancer. 1999;35(9):1343-7. 
2. Breitfeld D, Ohl L, Kremmer E, Ellwart J, Sallusto F, Lipp M, et al. Follicular B 
helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support 
immunoglobulin production. J Exp Med. 2000;192(11):1545-52. 
3. Brookmeyer R, Crowley J. A Confidence Interval for the Median Survival Time. 
Biometrics. 1982;38:29-41. 
4. Bupathi M, Wu C. Biomarkers for immune therapy in colorectal cancer: mismatch-repair 
deficiency and others. J Gastrointest Oncol. 2016;7(5):713-20. 
5. Cassidy J, Tabernero J, Twelves C, Brunet R, Butts C, Conroy T, et al. XELOX 
(capecitabine plus oxaliplatin): active first-line therapy for patients with metastatic 
colorectal cancer. J Clin Oncol. 2004;22(11):2084-91. 
6. Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat 
Rev Immunol. 2013;13(4):227-42. 
7. Chen W, Swanson BJ, Frankel WL. Molecular genetics of microsatellite-unstable 
colorectal cancer for pathologists. Diagn Pathol. 2017;12(1):24. 
8. Cheng L, Eng C, Nieman LZ, Kapadia AS, Du XL. Trends in colorectal cancer 
incidence by anatomic site and disease stage in the United States from 1976 to 2005. Am J 
Clin Oncol. 2011;34(6):573-80. 
9. Cong M, Cheng A, Karassina N, Grailer J, Hartnett J, Cosby N, et al. Advertorial: 
Novel Bioassay to Assess PD-1/PD-L1 Therapeutic Antibodies in Development for 
Immunotherapy. Bioluminescent Reporter-Based PD-1/PD-L1 Blockade Bioassay. GEN. 
2015;35(10): 1-3. 
10. Delaunoit T, Alberts SR, Sargent DJ, Green E, Goldberg RM, Krook J, et al. 
Chemotherapy permits resection of metastatic colorectal cancer: experience from 
Intergroup N9741. Ann Oncol. 2005;16(3):425-9. 
11. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur 
J Cancer. 2009; 45:228-47. 
12. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. 
Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads 
to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027-34. 
Confidential
Page
132
of
168
                    and Proprietary

MGD007/MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGD007-02 
Protocol Amendment 1, 22 October 2018 
 
 
13. Gajewski TF. The Next Hurdle in Cancer Immunotherapy: Overcoming the Non-T-Cell-
Inflamed Tumor Microenvironment. Semin Oncol. 2015;42(4):663-71. 
14. Garinchesa P, Sakamoto J, Welt S, Real F, Rettig W, Old L. Organ-specific expression 
of the colon cancer antigen A33, a cell surface target for antibody-based therapy. Int J 
Oncol. 1996;9(3):465-71. 
15. Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, et al. 
Regorafenib monotherapy for previously treated metastatic colorectal cancer 
(CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. 
Lancet. 2013;381(9863):303-12. 
16. Halama N, Spille A, Lerchl T, Brand K, Herpel E, Welte S, et al. Hepatic metastases of 
colorectal cancer are rather homogeneous but differ from primary lesions in terms of 
immune cell infiltration. Oncoimmunology. 2013;2(4):e24116. 
17. Hegde PS, Karanikas V, Evers S. The Where, the When, and the How of Immune 
Monitoring for Cancer Immunotherapies in the Era of Checkpoint Inhibition. Clin Cancer 
Res. 2016;22(8):1865-74. 
18. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. 
Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 
2010;363(8):711-23. 
19. Jager E, Heike M, Bernhard H, Klein O, Bernhard G, Lautz D, et al. Weekly high-
dose leucovorin versus low-dose leucovorin combined with fluorouracil in advanced 
colorectal cancer: results of a randomized multicenter trial. Study Group for Palliative 
Treatment of Metastatic Colorectal Cancer Study Protocol 1. J Clin Oncol. 
1996;14(8):2274-9. 
20. Kim CH, Rott LS, Clark-Lewis I, Campbell DJ, Wu L, Butcher EC. Subspecialization 
of CXCR5+ T cells: B helper activity is focused in a germinal center-localized subset of 
CXCR5+ T cells. J Exp Med. 2001;193(12):1373-81. 
21. Kwak Y, Koh J, Kim DW, Kang SB, Kim WH, Lee HS. Immunoscore encompassing 
CD3+ and CD8+ T cell densities in distant metastasis is a robust prognostic marker for 
advanced colorectal cancer. Oncotarget. 2016;7(49):81778-90. 
22. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 
Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015. 
23. Lee KS, Kwak Y, Ahn S, Shin E, Oh HK, Kim DW, et al. Prognostic implication of 
CD274 (PD-L1) protein expression in tumor-infiltrating immune cells for microsatellite 
unstable and stable colorectal cancer. Cancer Immunol Immunother. 2017;66(7):927-39. 
Confidential
Page
133
of
168
                    and Proprietary

MGD007/MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGD007-02 
Protocol Amendment 1, 22 October 2018 
 
 
24. Lee WS, Yun SH, Chun HK, Lee WY, Yun HR, Kim J, et al. Pulmonary resection for 
metastases from colorectal cancer: prognostic factors and survival. Int J Colorectal Dis. 
2007;22(6):699-704. 
25. Li Y, Liang L, Dai W, Cai G, Xu Y, Li X, et al. Prognostic impact of programed cell 
death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor infiltrating 
lymphocytes in colorectal cancer. Mol Cancer. 2016;15(1):55. 
26. Maindrault-Goebel F, Louvet C, Andre T, Carola E, Lotz JP, Molitor JL, et al. 
Oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as 
second-line therapy for metastatic colorectal cancer (FOLFOX6). GERCOR. Eur J 
Cancer. 1999;35(9):1338-42. 
27. Mayer RJ, Van CE, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, et al. 
Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 
2015;372(20):1909-19. 
28. McGray AJ, Hallett R, Bernard D, Swift SL, Zhu Z, Teoderascu F, et al. 
Immunotherapy-induced CD8+ T cells instigate immune suppression in the tumor. Mol 
Ther. 2014;22(1):206-18. 
29. Moon EK, Wang LC, Dolfi DV, Wilson CB, Ranganathan R, Sun J, et al. 
Multifactorial T-cell hypofunction that is reversible can limit the efficacy of chimeric 
antigen receptor-transduced human T cells in solid tumors. Clin Cancer Res. 
2014;20(16):4262-73. 
30. Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, et al. 
Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable 
liver metastases from colorectal cancer (EORTC 40983): long-term results of a 
randomised, controlled, phase 3 trial. Lancet Oncol. 2013;14(12):1208-15. 
31. Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz HJ, Morse MA, et al. 
Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite 
instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 
study. Lancet Oncol. 2017;18(9):1182-91. 
32. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev 
Cancer. 2012;12(4):252-64. 
33. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi 
SV, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. 
Mol Cell Biol. 2005;25(21):9543-53. 
34. Petrelli N, Herrera L, Rustum Y, Burke P, Creaven P, Stulc J, et al. A prospective 
randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 
5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal 
carcinoma. J Clin Oncol. 1987;5(10):1559-65. 
Confidential
Page
134
of
168
                    and Proprietary

MGD007/MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGD007-02 
Protocol Amendment 1, 22 October 2018 
 
 
35. Pozzo C, Basso M, Cassano A, Quirino M, Schinzari G, Trigila N, et al. Neoadjuvant 
treatment of unresectable liver disease with irinotecan and 5-fluorouracil plus folinic acid 
in colorectal cancer patients. Ann Oncol. 2004;15(6):933-9. 
36. Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, et al. Ipilimumab 
plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 
2011;364(26):2517-26. 
37. Rosenbaum MW, Bledsoe JR, Morales-Oyarvide V, Huynh TG, Mino-Kenudson M. 
PD-L1 expression in colorectal cancer is associated with microsatellite instability, BRAF 
mutation, medullary morphology and cytotoxic tumor-infiltrating lymphocytes. Mod 
Pathol. 2016;29(9):1104-12. 
38. Schaerli P, Willimann K, Lang AB, Lipp M, Loetscher P, Moser B. CXC chemokine 
receptor 5 expression defines follicular homing T cells with B cell helper function. J Exp 
Med. 2000;192(11):1553-62. 
39. Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 
2015;348(6230):56-61. 
40. Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of 
eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J 
Clin. 2011;61(4):212-36. 
41. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7-
30. 
42. Spranger S, Spaapen RM, Zha Y, Williams J, Meng Y, Ha TT, et al. Up-regulation of 
PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) 
T cells. Sci Transl Med. 2013;5(200):200ra116. 
43. Sun Y, Wang Y, Zhao J, Gu M, Giscombe R, Lefvert AK, et al. B7-H3 and B7-H4 
expression in non-small-cell lung cancer. Lung Cancer. 2006;53(2):143-51. 
44. Tabernero J MI, Ros W. Phase Ia and Ib studies of the novel carcinoembryonic antigen 
(CEA) T-cell bispecific (CEA CD3 TCB) antibody as a single agent and in combination 
with atezolizumab: preliminary efficacy and safety in patients with metastatic colorectal 
cancer (mCRC). J Clin Oncol. 2017;35. 
45. Toh JW, de Souza P, Lim SH, Singh P, Chua W, Ng W, et al. The Potential Value of 
Immunotherapy in Colorectal Cancers: Review of the Evidence for Programmed Death-1 
Inhibitor Therapy. Clin Colorectal Cancer. 2016;15(4):285-91. 
46. Van Cutsem E, Nordlinger B, Adam R, Kohne CH, Pozzo C, Poston G, et al. Towards 
a pan-European consensus on the treatment of patients with colorectal liver metastases. 
Eur J Cancer. 2006;42(14):2212-21. 
Confidential
Page
135
of
168
                    and Proprietary

MGD007/MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGD007-02 
Protocol Amendment 1, 22 October 2018 
 
 
47. Wang H, Yao H, Li C, Liang L, Zhang Y, Chen Y, et al. Rise of PD-L1 expression 
during metastasis of colorectal cancer: implications for immunotherapy. J Dig Dis. 2017. 
48. Welt S, Divgi CR, Real FX, Yeh SD, Garin-Chesa P, Finstad CL, et al. Quantitative 
analysis of antibody localization in human metastatic colon cancer: a phase I study of 
monoclonal antibody A33. J Clin Oncol. 1990;8(11):1894-906. 
49. 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;15(23):7412-20. 
50. Wolmark N, Rockette H, Fisher B, Wickerham DL, Redmond C, Fisher ER, et al. 
The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for 
primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project 
protocol C-03. J Clin Oncol. 1993;11(10):1879-87. 
51. Wu J, Fu J, Zhang M, Liu D. Blinatumomab: a bispecific T cell engager (BiTE) 
antibody against CD19/CD3 for refractory acute lymphoid leukemia. J Hematol Oncol. 
2015;8:104. 
52. Wu X, Zhang H, Xing Q, Cui J, Li J, Li Y, et al. PD-1(+) CD8(+) T cells are exhausted 
in tumours and functional in draining lymph nodes of colorectal cancer patients. Br J 
Cancer. 2014;111(7):1391-9. 
53. Yang ZZ, Grote DM, Ziesmer SC, Xiu B, Novak AJ, Ansell SM. PD-1 expression 
defines two distinct T-cell sub-populations in follicular lymphoma that differentially 
impact patient survival. Blood Cancer J. 2015;5:e281. 
54. Ye LC, Liu TS, Ren L, Wei Y, Zhu DX, Zai SY, et al. Randomized controlled trial of 
cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal 
liver-limited metastases. J Clin Oncol. 2013;31(16):1931-8. 
55. Yoo PS, Lopez-Soler RI, Longo WE, Cha CH. Liver resection for metastatic colorectal 
cancer in the age of neoadjuvant chemotherapy and bevacizumab. Clin Colorectal Cancer. 
2006;6(3):202-7. 
 
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Appendix 1 
Time and Events Schedules: QW Cohort 
QW Cohort 
EVALUATION/ 
PROCEDURE 
Screening 1 
Cycle 1 
Cycle 2 and Subsequent Cycles 
EOTV 2 
Post-
treatment 
Follow up 3 
Day 1 
Day 2 4 
Day 8 
(± 
1day) 
Day 
15, 29, 
43 (± 
1day) 
Day 
16,17,
19 4 
Day 
22, 36, 
50 (± 
1day) 
Day 
42 (± 
5 
days) 
Day 56 
(± 3 
days) 
Day 1 
(± 
1day) 
Day 2 4 
Day 8 
(± 
1day) 
Day 
15, 29, 
43 (± 
1day)  
Day 
22, 36, 
50 (± 
1day) 
Day 56 
(± 3 days) 
STUDY DRUG ADMINISTRATION (patients may switch to MGA012 monotherapy after receiving 2 full cycles of MGD007 and MGA012 treatment) 
Administer MGA012 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
Administer MGD007 
 
X 
 
X 
X 
 
X 
 
 
X 
 
X 
X 
X 
 
 
 
ELIGIBILITY 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline Tumor 
Imaging 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Designate Target/ 
Non-Target Lesions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Appendix 5. 
Medical 
History/Cancer 
Disease History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history/Cancer Disease History: History will be collected during Screening, up through the first dose of study drug. 
 
Weight 
X 
X 
 
X 
X 
 
X 
 
 
X 
 
X 
X 
X 
 
X 
 
Physical Exam  
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Physical Exam: Height (screening only) and examination of skin, head, eyes, ears, nose, throat, lymph nodes, heart, chest, lungs, abdomen, extremities, and neurologic systems. 
Directed 
History/Physical 
 
 
 
X 
X 
 
X 
 
 
 
 
X 
X 
X 
 
 
 
Directed Physical Exam: To be guided based on review of systems and patient history 
Archival Tumor 
Specimen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All patients to be enrolled in the study must have an identified formalin-fixed, paraffin embedded tumor specimen and/or tumor specimens sufficient for 20 slides. The specimens will be analyzed 
retrospectively and will not be used to determine patient eligibility. 
Premedication and 
prophylaxis 
Required pre-meds and prophylaxis include: Oral budesonide, IV dexamethasone and nonsteroidal supportive care medications. All pre-med and prophylaxis 
requirements are detailed in Section 7.1. 
 
Concomitant 
Medications 
---Continuous--- 
 
ECOG PS 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
ECG 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
Electrocardiogram: To be performed in triplicate (approximately 1 minute apart). 
Screening: ECG will be taken at one timepoint. Cycle 1 Day 1: pre-infusion (before the start of infusion on visit day), end of infusion (± 10 min of the EOI). 
Cycle 1 Day 15 and subsequent doses of MGD007 and MGA012 combined: pre-infusion of MGA012 (before the start of infusion on visit day), end of infusion of MGD007 (± 10 min of the EOI);  
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QW Cohort
EVALUATION/
PROCEDURE
Screening 1
Cycle 1
Cycle 2 and Subsequent Cycles
EOTV 2
Post-
treatment 
Follow up 3 
Day 1 
Day 2 4 
Day 8 
(± 
1day) 
Day 
15, 29, 
43 (± 
1day) 
Day 
16,17,
19 4
Day 
22, 36, 
50 (± 
1day) 
Day 
42 (± 
5 
days) 
Day 56 
(± 3 
days) 
Day 1 
(± 
1day) 
Day 2 4 
Day 8 
(± 
1day) 
Day 
15, 29, 
43 (± 
1day)  
Day 
22, 36, 
50 (± 
1day) 
Day 56 
(± 3 days) 
at End of Treatment Visit ECG will be taken at one timepoint. 
Pregnancy Test 
X 
X 
X 
X 
Pregnancy test: Serum or urine human chorionic gonadotropin (hCG) for women of childbearing potential should be performed at Screening visit and on Day 1 pre-infusion. Test results must be 
reviewed before the study drug infusion on Day 1 of Cycle 1 and all subsequent cycles. Testing should also be performed at the End of Treatment visit. If screening test is performed within 72 hours of 
1st infusion, repeat of the test on Day 1 may be deferred. 
Eligibility Checklist 
& Register Patient 
X 
SAFETY/PK/MECHANISTIC STUDIES 
Assess for Protocol 
Procedure Related 
AEs/SAEs 
X 
Assess for 
Adverse Events 
-----Continuous---- 
The safety assessment will be based on the evaluation of AEs that occur from the time of initiation of administration of study drug through the End of Treatment Visit or 30 days after the last dose of 
study drug (whichever is later). 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs: Temperature, heart rate, blood pressure, and respiratory rate. 
Screening: Vital signs will be taken once. 
Cycle 1 Days 1, 8, 22, 36, and 50 (MGD007 alone): Vital signs will be taken immediately before the infusion (up to 10 minutes before the infusion); at 15 (± 5 min), 30 (± 5 min), and 60 minutes 
(± 10 min) after the start of the infusion; at the end of infusion (± 10 min); and at 1- and 4-hours after completion of the infusion (±10 min). The 4-hour post infusion vital signs may be deferred based on 
the judgment of the investigator for all days except Cycle 1 Day 1 
Cycle 1 Days 15, 29, 43 (MGA012 and MGD007 combined): Vital signs will be taken immediately before MGA012 infusion (up to 10 minutes before the infusion) and at the end of MGA012 
infusion (±10 min );  at 15 (± 5 min), 30 (± 5 min), and 60 minutes (± 10 min) after the start of MGD007 infusion; at the end of MGD007 infusion (± 10 min); and at 1- and 4-hours after completion of 
MGD007 infusion (±10 min). The 4-hour post infusion vital signs may be deferred based on the judgment of the investigator for all days except Cycle 1 Day 15. 
Cycle 2 and Beyond (MGA012 and MGD007 combined): Vital signs will be taken immediately before MGA012 infusion (up to 10 minutes before the infusion) and at end of MGA012 infusion (±10 
min); at the end of the MGD007 infusion (± 10 min); and at 1 hour after completion of the infusion (±10 min). 
Cycle 2 and Beyond (MGD007 alone): Vital signs will be taken immediately before MGD007 infusion (up to 10 minutes before the infusion); at the end of the MGD007 infusion (± 10 min); and at 1 
hour after completion of the infusion (±10 min). 
At End of Treatment: Visit vital signs will be taken once. 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See Appendix 2 for list of hematology assessments; To be taken pre-infusion. Labs can be taken up to 3 days before infusion. 
Serum Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See Appendix 2 for list of chemistries; To be taken pre-infusion. Labs can be taken up to 3 days before infusion. 
Coagulation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See Appendix 2 for list of coagulation assessments; To be taken pre-infusion. Labs can be taken up to 3 days before infusion. 
Endocrine tests 
X 
X 
X 
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QW Cohort
EVALUATION/
PROCEDURE
Screening 1
Cycle 1
Cycle 2 and Subsequent Cycles
EOTV 2
Post-
treatment 
Follow up 3 
Day 1 
Day 2 4 
Day 8 
(± 
1day) 
Day 
15, 29, 
43 (± 
1day) 
Day 
16,17,
19 4
Day 
22, 36, 
50 (± 
1day) 
Day 
42 (± 
5 
days) 
Day 56 
(± 3 
days) 
Day 1 
(± 
1day) 
Day 2 4 
Day 8 
(± 
1day) 
Day 
15, 29, 
43 (± 
1day)  
Day 
22, 36, 
50 (± 
1day) 
Day 56 
(± 3 days) 
See Appendix 2 for list of endocrine tests; To be taken pre-infusion. Labs can be taken up to 3 days before infusion. 
CEA 
X 
X 
X 
CEA: At screening; Cycle 2, Day 1 pre-dose; Day 1 of every other cycle thereafter - predose 
Urinalysis 
X 
X 
X 
X 
See Appendix 2 for list of urinalysis test; To be taken pre-infusion. Labs can be taken up to 3 days before infusion. 
Pharmacokinetic, 
Immunogenicity, and 
Pharmacodynamic 
Biomarkers 
Sampling to be performed according to Appendix 3. 
Tumor biopsies on 
study (Cohort 
Expansion subjects 
only) 
X 
X 
On treatment tumor biopsy: Fresh tumor biopsy pre-treatment (after enrollment and prior to the Cycle 1 Day 1 dose) and at Cycle 1 Day 42 ± 5 days.  
Paired tumor biopsies will be mandatory if tumor lesions are accessible for biopsy with acceptable clinical risk in the judgment of the investigator and after discussion with the sponsor. 
Tumor Assessment 
(CT/MRI)  
X 
X 
X 
Tumor Assessment (CT/MRI): Radiographic disease assessments will occur on Cycle 1 Day 56 (±3 days) and then every 8 weeks. Assessment will also be done at End of Treatment Visit. 
KRAS and MMR 
X 
Formal documentation required for all patients in the Cohort Expansion Phase. Should be captured as part of cancer disease history. If unavailable during screening, this can be collected while on study. 
Follow-up by phone 
or electronic contact 
Overall Survival Follow-up: Documentation of overall survival follow-up described in protocol Section 9.12. 
X 
1 
The Screening visit should occur within 28 days prior to Day 1. 
2 
The End of Treatment Visit should be performed after the patient has met off-treatment criteria and occur no later than 30 days since the last study dose and 
before any subsequent anti-cancer treatment; see Section 9.11. 
3 
Post-treatment follow-up collected every 3 months by phone or other electronic contact; response status, if available, will be collected every 3 months in 
patients who discontinued from study treatment due to reasons other than progressive disease, if they have not initiated any other cancer-directed therapy. See 
Section 9.12. 
4 
See Appendix 3 for samples to be collected at visit. 
Abbreviations: CEA = carcinoembryonic antigen; D = day; ECG = Electrocardiogram; EOI = end of infusion; EOTV = end of treatment visit;
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Appendix 2  
Clinical Laboratory Tests 
Pregnancy test: 
Blood or Urine Human chorionic gonadotropin (hCG) 
 
Hematology: 
Hemoglobin  
Platelet count 
White blood cell count 
Absolute neutrophils, lymphocytes, and eosinophils 
 
Serum chemistry: 
Albumin  
Alkaline phosphatase 
Alanine aminotransferase  
Amylase 
Aspartate aminotransferase 
Bicarbonate 
Bilirubin (Total and Direct) 
Blood urea nitrogen 
Calcium 
Chloride  
Creatinine 
Glucose  
Lipase 
Magnesium 
Phosphate 
Potassium 
Sodium 
Urate 
Coagulation: 
Prothrombin time (PT) 
Activated Partial Thromboplastin Time (aPTT) 
INR 
Fibrinogen 
 
Endocrine tests: 
Free thyroxine  
Thyroid-stimulating hormone  
 
Urinalysis: 
Protein 
Occult blood 
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Appendix 3 
Pharmacokinetics, Immunogenicity, and Pharmacodynamic 
Biomarkers Blood Sampling Schedule for MGD007 & 
MGA012 
Blood samples for MGD007 and MGA012 PK, ADA, and PD biomarkers will be collected per 
Table 15. 
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Table 15 
Pharmacokinetic, Immunogenicity, and Pharmacodynamic Biomarkers Blood Sampling Schedule for 
MGD007 & MGA012 1 
Cycle 
Day 
MGD007 
& 
MGA012 
PK 
Sampling 
Time 2 
MGD007 
& 
MGA012 
ADA 
Sampling 
Time 
Cytokines 2 
Flow 
Cytometry 
Occupancy 
Flow 
Cytometry 
Subsets 
Serum 
Bio-
markers 3 
T-cell 
repertoire 3 
ctDNA 
analysis 3 
Transcript 
profile 3 
1 
1 
Pre 
MGD007 
infusion 
Pre 
MGD007 
infusion 
Pre 
MGD007 
infusion 
Pre 
MGD007 
infusion 
Pre 
MGD007 
infusion 
Pre 
MGD007 
infusion 
Pre 
MGD007 
infusion 
Pre 
MGD007 
infusion 
Pre 
MGD007 
infusion 
 
1 
End of 
MGD007 
infusion  
 
 
 
 
 
 
 
 
 
1 
2 hours 
after end of 
MGD007 
infusion  
 
2 hours 
after end of 
MGD007 
infusion 
2 hours 
after end of 
MGD007 
infusion 
2 hours 
after end of 
MGD007 
infusion 
 
 
 
 
 
1 
6 hours 
after end of 
MGD007 
infusion 
 
6 hours 
after end of 
MGD007 
infusion 
 
 
 
 
 
 
1 
2 
 
 
Day 2 
Day 2 
Day 2 
 
 
 
 
1 
8 
Pre 
MGD007 
infusion 
 
 
Pre 
MGD007 
infusion 
Pre 
MGD007 
infusion 
Pre 
MGD007 
infusion 
 
 
 
 
8 
End of 
MGD007 
infusion 
 
 
 
 
 
 
 
 
 
8 
 
 
 
2 hours 
after end of 
MGD007 
infusion 
2 hours 
after end of 
MGD007 
infusion 
 
 
 
 
1 
15 
Pre 
MGA012 
infusion 
Pre 
MGA012 
infusion 
Pre 
MGA012 
infusion 
Pre 
MGA012 
infusion 
Pre 
MGA012 
infusion 
Pre 
MGA012 
infusion 
 
 
 
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Table 15 
Pharmacokinetic, Immunogenicity, and Pharmacodynamic Biomarkers Blood Sampling Schedule for 
MGD007 & MGA012 1 
Cycle 
Day 
MGD007 
& 
MGA012 
PK 
Sampling 
Time 2 
MGD007 
& 
MGA012 
ADA 
Sampling 
Time 
Cytokines 2 
Flow 
Cytometry 
Occupancy 
Flow 
Cytometry 
Subsets 
Serum 
Bio-
markers 3 
T-cell 
repertoire 3 
ctDNA 
analysis 3 
Transcript 
profile 3 
1 
15 
End of 
MGA012 
infusion 
 
 
 
 
 
 
 
 
 
15 
End of 
MGD007 
infusion 
 
 
 
 
 
 
 
 
 
15 
 
 
 
2 hours 
after end of 
MGD007 
infusion 
2 hours 
after end of 
MGD007 
infusion 
 
 
 
 
 
15 
1 hour after 
end of 
MGD007 
infusion 
 
 
 
 
 
 
 
 
 
15 
2 hours 
after end of 
MGD007 
infusion 
 
 
 
 
 
 
 
 
 
15 
4 hours 
after end of 
MGD007 
infusion 
 
 
 
 
 
 
 
 
 
15 
 
 
6 hours 
after end of 
MGD007 
infusion 
 
 
 
 
 
 
1 
16 
Day 16 
 
Day 16 
Day 16 
Day 16 
 
 
 
 
1 
17 
Day 17 
 
 
 
 
 
 
 
 
1 
19 
Day 19 
 
 
 
 
 
 
 
 
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Table 15 
Pharmacokinetic, Immunogenicity, and Pharmacodynamic Biomarkers Blood Sampling Schedule for 
MGD007 & MGA012 1 
Cycle 
Day 
MGD007 
& 
MGA012 
PK 
Sampling 
Time 2 
MGD007 
& 
MGA012 
ADA 
Sampling 
Time 
Cytokines 2 
Flow 
Cytometry 
Occupancy 
Flow 
Cytometry 
Subsets 
Serum 
Bio-
markers 3 
T-cell 
repertoire 3 
ctDNA 
analysis 3 
Transcript 
profile 3 
1 
22 
Pre 
MGD007 
infusion 
 
 
 
Pre 
MGD007 
infusion 
 
 
 
 
 
22 
End of 
MGD007 
infusion 
 
 
 
End of 
MGD007 
infusion 
 
 
 
 
1 
29 
Pre 
MGA012 
infusion 
Pre 
MGA012 
infusion 
Pre 
MGA012 
infusion 
Pre 
MGA012 
infusion 
Pre 
MGA012 
infusion 
Pre 
MGA012 
infusion 
 
 
 
 
29 
End of 
MGA012 
infusion 
 
 
 
 
 
 
 
 
 
29 
End of 
MGD007 
infusion 
 
 
End of 
MGD007 
infusion 
End of 
MGD007 
infusion 
 
 
 
 
 
29 
 
 
2 hours 
after end of 
MGD007 
infusion 
 
 
 
 
 
 
1 
42 
 
 
 
 
 
 
Pre Biopsy 
Pre Biopsy 
Pre Biopsy 
1 
43 
Pre 
MGA012 
infusion 
 
 
 
 
 
 
 
 
 
43 
End of 
MGA012 
infusion 
 
 
 
 
 
 
 
 
 
43 
End of 
MGD007 
infusion 
 
 
 
 
 
 
 
 
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Table 15 
Pharmacokinetic, Immunogenicity, and Pharmacodynamic Biomarkers Blood Sampling Schedule for 
MGD007 & MGA012 1 
Cycle 
Day 
MGD007 
& 
MGA012 
PK 
Sampling 
Time 2 
MGD007 
& 
MGA012 
ADA 
Sampling 
Time 
Cytokines 2 
Flow 
Cytometry 
Occupancy 
Flow 
Cytometry 
Subsets 
Serum 
Bio-
markers 3 
T-cell 
repertoire 3 
ctDNA 
analysis 3 
Transcript 
profile 3 
2 
1 
Pre 
MGA012 
infusion 
Pre 
MGA012 
infusion 
Pre 
MGA012 
infusion 
Pre 
MGA012 
infusion 
Pre 
MGA012 
infusion 
Pre 
MGA012 
infusion 
Pre 
MGA012 
infusion 
Pre 
MGA012 
infusion 
 
 
1 
End of 
MGA012 
infusion 
 
 
 
 
 
 
 
 
 
1 
End of 
MGD007 
infusion 
 
 
End of 
MGD007 
infusion 
 
 
 
 
 
 
1 
 
 
2 hours 
after end of 
MGD007 
infusion 
 
 
 
 
 
 
2 
2 
 
 
Day 2 
 
 
 
 
 
 
2 
15 
Pre 
MGA012 
infusion 
 
 
 
 
 
 
 
 
 
15 
End of 
MGA012 
infusion 
 
 
 
 
 
 
 
 
 
15 
End of 
MGD007 
infusion 
 
 
 
 
 
 
 
 
2 
29 
 
 
 
Pre 
MGA012 
infusion 
Pre 
MGA012 
infusion 
 
 
 
 
 
29 
 
 
 
End of 
MGD007 
infusion 
 
 
 
 
 
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Table 15 
Pharmacokinetic, Immunogenicity, and Pharmacodynamic Biomarkers Blood Sampling Schedule for 
MGD007 & MGA012 1 
Cycle 
Day 
MGD007 
& 
MGA012 
PK 
Sampling 
Time 2 
MGD007 
& 
MGA012 
ADA 
Sampling 
Time 
Cytokines 2 
Flow 
Cytometry 
Occupancy 
Flow 
Cytometry 
Subsets 
Serum 
Bio-
markers 3 
T-cell 
repertoire 3 
ctDNA 
analysis 3 
Transcript 
profile 3 
3 
1 
Pre 
MGA012 
infusion 
Pre 
MGA012 
infusion 
 
 
Pre 
MGA012 
infusion 
Pre 
MGA012 
infusion 
Pre 
MGA012 
infusion 
Pre 
MGA012 
infusion 
 
 
1 
End of 
MGA012 
infusion 
 
 
 
 
 
 
 
 
 
1 
End of 
MGD007 
infusion 
 
 
 
 
 
 
 
 
3 
29 
 
 
 
 
Pre 
MGA012 
infusion 
 
 
 
 
4 
1 
Pre 
MGA012 
infusion 
Pre 
MGA012 
infusion 
 
 
Pre 
MGA012 
infusion 
Pre 
MGA012 
infusion 
 
 
 
 
1 
End of 
MGA012 
infusion 
 
 
 
 
 
 
 
 
 
1 
End of 
MGD007 
infusion 
 
 
 
 
 
 
 
 
4 
29 
 
 
 
 
Pre 
MGA012 
infusion 
 
 
 
 
5 and 
Subsequent 
Cycles 
1 
Pre 
MGA012 
infusion 
Pre 
MGA012 
infusion 
 
 
 
 
 
 
 
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Table 15 
Pharmacokinetic, Immunogenicity, and Pharmacodynamic Biomarkers Blood Sampling Schedule for 
MGD007 & MGA012 1 
Cycle 
Day 
MGD007 
& 
MGA012 
PK 
Sampling 
Time 2 
MGD007 
& 
MGA012 
ADA 
Sampling 
Time 
Cytokines 2 
Flow 
Cytometry 
Occupancy 
Flow 
Cytometry 
Subsets 
Serum 
Bio-
markers 3 
T-cell 
repertoire 3 
ctDNA 
analysis 3 
Transcript 
profile 3 
5 and 
Subsequent 
Cycles 
1 
End of 
MGA012 
infusion 
 
 
 
 
 
 
 
 
 
1 
End of 
MGD007 
infusion 
 
 
 
 
 
 
 
 
EOT Visit 
EOT 
EOT 
 
EOT 
EOT 
 
 
 
 
 
 
IRR/CRS 
 
IRR/CRS 
 
 
 
 
 
 
Note: Do not collect PK samples from infusion port; samples will be collected from the contralateral arm. When collecting multiple samples, collect the PK 
sample first. Actual start and end of infusion times and all sample collection times will be recorded on the CRFs. All sample time points are hours (h) after EOI, 
unless otherwise specified.  
Note: Duration of infusion for MGA012 = 60 minutes and for MGD007 = 120 minutes 
1 
Window times for samples required at EOI or after EOI are as follows: up to -10 minutes before the infusion is complete; ± 10 min for samples to be collected 
at 1, 2, 4, 6 hours after EOI. 
2 
Additional samples may be obtained selectively at additional time points in patients who experience signs and symptoms of cytokine release. 
3 
Cohort Expansion Subjects only. Samples on Cycle 1 Day 42 are for subjects having biopsies only. 
Abbreviations: ADA = Anti-drug antibody; EOI = End of infusion; EOT = End of treatment; PK = Pharmacokinetic; QW = Once a week; Trt = Treatment 
 
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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 (11). 
All patients with be required to have at least 1 measurable lesion to be considered as having 
measureable disease at baseline for the determination of eligibility for this study. Measurable 
lesions are defined below. 
1 
Measurability of Tumor at Baseline 
1.1 
Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
1.1.1 
Measurable 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
 10 mm by CT scan (CT scan slice thickness no greater than 5 mm). 
 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as nonmeasurable). 
 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 nontarget lesions’ 
for information on lymph node measurement. 
1.1.2 
Nonmeasurable 
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 nonmeasureable 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. 
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1.1.3 
Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
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 nonmeasurable. 
Cystic lesions: 
 Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor nonmeasurable) 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 noncystic 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 
locoregional therapy, are not considered measurable unless there has been 
demonstrated progression in the lesion prior to study enrollment. 
 
1.2 
Specifications by methods of measurements 
1.2.1 
Measurement of lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
1.2.2 
Method of assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
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always be done rather than clinical examination unless the lesions(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
and ≥ 10 mm diameter as assessed using calipers (e.g. skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken since it is more objective and may also be reviewed at 
the end of the study. 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. 
MRI is also acceptable in certain situations (e.g., for body scans). 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of 
CT in selected instances. 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised. 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. 
2 
Tumor Response Evaluation 
2.1 
Assessment of Overall Tumor Burden and Measurable Disease 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. Only patients with 
measurable disease at baseline should be included. Measurable disease is defined by the presence 
of at least one measurable lesion (as detailed above). 
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2.1.1 
Baseline Documentation of ‘Target’ and ‘non-target’ Lesions 
Where more than one measurable lesion is present at baseline all lesions up to a maximum of 
five lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. For 
example, in instances where patients have only one or two organ sites involved, a maximum of 
two and four lesions respectively will be recorded). Target lesions should be selected on the basis 
of their size (lesions with the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated measurements. It may be 
the case that, on occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesions which can be measured reproducibly should be 
selected. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. As noted above, pathological nodes which are 
defined as measurable and may be identified as target lesions must meet criterion of a short axis 
of ≥ 15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. 
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as two dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal or coronal). The smaller of these measures is the short axis. For 
example, an abdominal node which is reported as being 20 mm x30 mm has a short axis of 20 
mm and qualifies as a malignant, measurable node. In this example, 20 mm should be recorded 
as the node measurement. All other pathological nodes (those with short axis ≥ 10 mm but 
< 15 mm) should be considered non-target lesions. Nodes that have a short axis < 10 mm are 
considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression. 
In addition, it is possible to record multiple non-target lesions involving the same organ as a 
single item on the case record form (e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple 
liver metastases’). 
2.2 
Response Criteria 
This section provides the definitions of the criteria used to determine objective tumor response 
for target lesions. 
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2.2.1 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm. 
Partial Response (PR): at least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters. 
Progressive Disease (PD): at least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
2.2.2 
Special Notes on the Assessment of Target Lesions 
Lymph nodes. Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to below 10 mm on study. This means that when lymph nodes are 
included as target lesions, the ‘sum’ of lesions may not be zero even if complete response criteria 
are met, since a normal lymph node is defined as having a short axis of < 10 mm. In order to 
qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD and PD, the actual 
short axis measurement of the nodes is to be included in the sum of target lesions. 
Target lesions that become ‘too small to measure’. While on study, all lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g. 2 mm). However, sometimes lesions or lymph nodes 
which are recorded as target lesions at baseline become so faint on CT scan that the radiologist 
may not feel comfortable assigning an exact measure and may report them as being ‘too small to 
measure’. When this occurs, it is important that a value be recorded on the case report form. If it 
is the opinion of the radiologist that the lesion has likely disappeared, the measurement should be 
recorded as 0 mm. If the lesion is believed to be present and is faintly seen but too small to 
measure, a default value of 5 mm should be assigned (Note: It is less likely that this rule will be 
used for lymph nodes since they usually have a definable size when normal and are frequently 
surrounded by fat such as in the retroperitoneum; however, if a lymph node is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should be assigned 
in this circumstance as well). This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness). The measurement of these lesions is 
potentially non-reproducible, therefore providing this default value will prevent false responses 
or progressions based upon measurement error. However, if the radiologist is able to provide an 
actual measure, that should be recorded, even if it is below 5 mm. 
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Lesions that split or coalesce on treatment. When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesions. If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the ‘coalesced lesion’. 
2.2.3 
Evaluation of Nontarget 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 measureable, 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 nontarget lesions. All lymph nodes must be non-
pathological in size (< 10 mm short axis). 
Non-CR/Non-PD: Persistence of one or more nontarget lesions(s). 
Progressive Disease (PD): Unequivocal progression (see comments below) of existing non-
target lesions. (Note: the appearance of one or more new lesions is also considered progression). 
2.2.4 
Special Notes on Assessment of Progression of Nontarget Disease 
The concept of progression of nontarget 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 
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overall PD at that point. While it would be ideal to have objective criteria to apply to non-
measurable disease, the very nature of that disease makes it impossible to do so; therefore, the 
increase must be substantial. 
2.2.5 
New Lesions 
The appearance of new malignant lesions denotes disease progression. There are no specific 
criteria for the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal: i.e. not attributable to differences in scanning technique, change in 
imaging modality or findings thought to represent something other than tumor (for example, 
some ‘new’ bone lesions may be simply healing or flare of pre-existing lesions). This is 
particularly important when the patient’s baseline lesions show partial or complete response. For 
example, necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, 
which it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this is 
the patient who has visceral disease at baseline and while on study has a CT or MRI brain 
ordered which reveals metastases. The patient’s brain metastases are considered to be evidence 
of PD even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-
up evaluation will clarify if it represents truly new disease. If repeat scans confirm there is 
definitely a new lesion, then progression should be declared using the date of the initial scan. 
2.3 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study treatment until 
the end of treatment taking into account any requirement for confirmation. The patient’s best 
overall response assignment will depend on the findings of both target and non-target disease and 
will also take into consideration the appearance of new lesions. 
2.3.1 
Time Point Response 
It is assumed that at each protocol specified time point, a response assessment occurs. Table A-1 
on the next page provides a summary of the overall response status calculation at each time point 
for patients who have measureable disease at baseline. 
2.3.2 
Missing Assessments and Inevaluable Designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. If only a subset of lesion measurements is made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not change 
the assigned time point response. This would be most likely to happen in the case of PD. For 
example, if a patient had a baseline sum of 50 mm with three measured lesions and at follow-up 
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only two lesions were assessed, but those gave a sum of 80 mm, the patient will have achieved 
PD status, regardless of the contribution of the missing lesion. 
2.3.3 
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. 
 
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. 
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For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at 
the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 
2.4 
Confirmation/Duration of response 
2.4.1 
Confirmation 
Objective responses should be confirmed by CT and/or MRI scans obtained no less than 4 weeks 
after the original scan. 
2.4.2 
Duration of overall response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded on study). The duration of overall complete response is measured from the time 
measurement criteria are first met for CR until the first date that recurrent disease is objectively 
documented. 
2.4.3 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest sum on study (if the baseline sum is the smallest, this is the 
reference for calculation of PD). 
 
 
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Appendix 6  
Immune-Related RECIST Guidelines 
The immune-related RECIST (irRECIST) are adapted from Wolchok 2009 (49). 
All patients will be required to have at least 1 measurable lesion to be considered as having 
measureable disease at baseline for the determination of eligibility for this study. Measurable 
lesions are defined below. 
1 
Measurability of Tumor at Baseline 
1.1 
DEFINITIONS 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
1.1.1 
Measurable 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
 10 mm by CT scan (CT scan slice thickness no greater than 5 mm). 
 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measureable). 
 20 mm by chest X-ray. 
Malignant lymph nodes: To be considered pathologically enlarged and measureable, 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. 
1.1.2 
Non-measurable 
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with ≥ 10 to < 15 mm short axis) as well as truly non-measurable lesions. Lesions 
considered truly non-measureable 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 measureable by 
reproducible imaging techniques. 
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1.1.3 
Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
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 measureable 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 noncystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
 
Lesions with prior local treatment: 
 Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are not considered measurable unless there has been 
demonstrated progression in the lesion prior to study enrollment. 
 
1.2 
Specifications by Methods of Measurements 
1.2.1 
Measurement of Lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
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1.2.2 
Method of Assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesions(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
and ≥ 10 mm diameter as assessed using calipers (e.g., skin nodules). For the case of skin 
lesions, documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken since it is more objective and may also be reviewed at 
the end of the study. 
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. 
2 
Tumor Response Evaluation 
2.1 
Assessment of Overall Tumor Burden and Measurable Disease 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. Only patients with 
measurable disease at baseline should be included. Measurable disease is defined by the presence 
of at least one measurable lesion (as detailed above). 
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2.2 
Baseline Documentation of ‘Target’ And ‘Non-Target’ Lesions 
Where more than one measurable lesion is present at baseline all lesions up to a maximum of 
five lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. For 
example, in instances where patients have only one or two organ sites involved, a maximum of 
two and four lesions respectively will be recorded). Target lesions should be selected on the basis 
of their size (lesions with the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated measurements. It may be 
the case that, on occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesions which can be measured reproducibly should be 
selected. 
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’). 
2.3 
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). 
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2.3.1 
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. 
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. 
2.3.2 
Special Notes on the Assessment of Target Lesions 
Lymph nodes. Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to below 10 mm on study. This means that when lymph nodes are 
included as target lesions, the ‘sum’ of lesions may not be zero even if complete response criteria 
are met, since a normal lymph node is defined as having a short axis of < 10 mm. In order to 
qualify for 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 
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present and is faintly seen but too small to measure, a default value of 5 mm should be assigned 
in this circumstance as well). This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness). The measurement of these lesions is 
potentially non-reproducible, therefore providing this default value will prevent false responses 
or progressions based upon measurement error. However, if the radiologist is able to provide an 
actual measure, that should be recorded, even if it is below 5 mm. 
Lesions that split or coalesce on treatment. When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesions. If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the ‘coalesced lesion’. 
2.3.3 
Evaluation of Non-target Lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measureable, 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 (< 10 mm 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. 
2.3.4 
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. 
2.4 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study treatment until 
the end of treatment taking into account any requirement for confirmation. The patient’s best 
overall response assignment will depend on the findings of both target and non-target disease. 
2.4.1 
Time Point Response 
It is assumed that at each protocol specified time point, a response assessment occurs. For 
patients experiencing irCR or irPR, a confirmatory scan obtained no less than 4 weeks after the 
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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. 
 
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 
measureable lesions has increased by ≥ 20% from the nadir sum of diameters. 
2.4.2 
Missing Assessments and Inevaluable Designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. If only a subset of lesion measurements is made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not change 
the assigned time point response. 
2.4.3 
Best Overall Response: All Time Points 
The best overall response is determined once all the data for the patient is known. 
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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. 
2.4.4 
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. 
2.5 
Confirmation/Duration of Response 
2.5.1 
Confirmation 
Objective responses should be confirmed by CT and/or MRI scans obtained no less than 4 weeks 
after the original scan. 
2.5.2 
Duration of Overall Response 
The duration of overall response is 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. 
2.5.3 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest sum on study (if the baseline sum is the smallest, this is the 
reference for calculation of irPD). 
 
 
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MGD007/MGA012 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGD007-02 
Protocol Amendment 1, 22 October 2018 
 
 
Appendix 7 
Principal Investigator’s Agreement 
Study Title: 
A Phase 1b/2, Open Label, Dose Escalation Study of MGD007, a 
Humanized gpA33 × CD3 DART® Protein in Combination with 
MGA012, an Anti-PD-1 Antibody, in Patients with Relapsed or 
Refractory Metastatic Colorectal Carcinoma 
Study Number: 
CP-MGD007-02 
 
I have read the protocol described above. 
I have fully discussed the objectives of this study and the contents of this protocol with the 
Sponsor’s representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution of the ethical review of the study, without 
written authorization from MacroGenics, Inc. It is, however, permissible to provide information 
to a patient in order to obtain consent. 
I agree to conduct this trial according to this protocol and to comply with its requirements, 
patient to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with ICH guidelines on GCP and with the applicable regulatory requirements. 
I understand that the Sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study, I will communicate my intention 
immediately in writing to the Sponsor. 
Signed: 
 
Date: 
 
Name (printed): 
 
Title: 
 
Affiliation: 
 
Address: 
 
Phone Number: 
 
 
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CP-MGD007-02 Protocol Amendment 1 (22-Oct-2018)
This is the electronic signature page for the above referenced document.
User Task: eSignatories Approval
Data Management/Statistics Approval
(Intended or Designee)
23-Oct-2018 20:06:10 GMT+0000
User Task: eSignatories Approval
search Approval (Intended or Designee)
23-Oct-2018 20:40:42 GMT+0000
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